Characterization of Nanoparticles in Mixtures by Taylor Dispersion Analysis Hyphenated to Inductively Coupled Plasma Mass Spectrometry.

A novel methodology for investigating the behavior of nanoparticles in their mixtures in aqueous high-ionic strength conditions is presented in this work. Our approach utilizes Taylor dispersion analysis in capillaries connected to inductively coupled plasma mass spectrometry (ICP-MS) to probe metal-derived nanoparticles. This methodology simultaneously distinguishes between different kinds of nanoparticles and accurately determines their essential parameters, such as hydrodynamic size, diffusion coefficient, and elemental composition. Moreover, the isotope-specific ICP-MS detection allows for unique targeting of the fate of isotopically enriched nanoparticles. The complexity of our methodology opens the way for studying barely explored areas of interparticle interactions or unequivocal characterization of one type of nanoparticle in complex mixtures without any need for calibration as well as labor-consuming sample preparation.

Epstein-Barr virus-positive mucocutaneous ulcer in a patient with ulcerative colitis: a recently described entity to take into account.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a new entity recently included in the classification of B-cell lymphoproliferative disorders associated with Epstein-Barr virus (EBV). It is related to immunosuppression and it usually appears in the oropharynx or the skin, being the colon an uncommon location. We present the case of a 31-year-old man with ulcerative proctitis being treated with azathioprine (AZA) and adalimumab (ADA), who was admitted to the hospital due to suspicion of a moderate-severe flare of ulcerative proctitis. Microbiological stool analyses were negative, with a positive fecal calprotectin test (2700 mg/kg). Rectoscopy showed severe endoscopic activity, taking multiple biopsies. Intravenous steroids were started at a dose of 60 mg/day. He presented a favorable clinical and analytical evolution, being discharged from the hospital. The histological results were received at gastroenterology consultation, being compatible with EBVMCU. AZA and ADA were withdrawn, whereas descending steroid regimen and oral and topical mesalazine were continued, being the clinical response adequate.

The risk of developing dementia in the COVID-19 pandemic; a cohort study.

OBJECTIVES: The effects of the COVID-19 pandemic on cognitive decline are not fully understood. Higher social activity and relationships have been associated with decreased risk of dementia. We hypothesised that risk of transition to dementia would increase after the start of the first national lockdown. METHODS: We obtained data from the Brains for Dementia (BDR) cohort, which has collected roughly annual data on 3726 older adults with and without dementia since 2008. Data continued to be collected during the lockdowns, although by telephone and/or video call instead of in person. Individuals diagnosed with dementia at study entry were excluded from this study as were individuals with only one visit. Cognitive status was classified using the Clinical Dementia Rating (CDR) global score. Poisson regression with cubic splines to account for differences in age was used to compare the incidence of dementia before and after March 1st 2020. RESULTS: Out of 2242 individuals, 208 individuals developed dementia before and 50 developed dementia after 01/03/20. The incidence rate ratio of developing dementia after 01/03/20 was 0.847 (0.538-1.335) p = 0.570. In our secondary analysis we found that the positive association between mild cognitive impairment (MCI) and dementia incidence decreased after 1/3/20 (interaction effect p = 0.031). CONCLUSION: The incidence of dementia as defined using the CDR global score did not change significantly after the first lockdown began, but we found evidence that lockdown decreased the positive association between MCI and dementia incidence. This may reflect that individuals were progressing to dementia more rapidly and thus missing the MCI stage or that assessing patients over the phone made diagnosing MCI more challenging.

Detection of Neuroendocrine Tumours by Enteroscopy: A Case Report.

We present the case of a 62-year-old patient who developed melenas and in whom conventional endoscopic tests could not detect any bleeding lesion. In our case, capsule endoscopy and enteroscopy were the pivotal elements in establishing the diagnosis of a neuroendocrine tumour with an atypical location. As a result, it was possible to surgically remove the lesions at an early stage of the malignancy without metastatic disease and without the need for adjuvant therapy. Our case demonstrates the need for these new techniques in tumours of atypical location and aggressive course. Otherwise, this malignancy may be underdiagnosed until an advanced stage.

Pereskia aculeata Miller as a Novel Food Source: A Review.

Pereskia aculeata Miller is an edible plant species belonging to the Cactaceae family. It has the potential to be used in the food and pharmaceutical industries due to its nutritional characteristics, bioactive compounds, and mucilage content. Pereskia aculeata Miller is native to the Neotropical region, where it is traditionally employed as food in rural communities, being popularly known as 'ora-pro-nobis' (OPN) or the Barbados gooseberry. The leaves of OPN are distinguished by their nontoxicity and nutritional richness, including, on a dry basis, 23% proteins, 31% carbohydrates, 14% minerals, 8% lipids, and 4% soluble dietary fibers, besides vitamins A, C, and E, and phenolic, carotenoid, and flavonoid compounds. The OPN leaves and fruits also contain mucilage composed of arabinogalactan biopolymer that presents technofunctional properties such as thickener, gelling, and emulsifier agent. Moreover, OPN is generally used for pharmacological purposes in Brazilian folk medicine, which has been attributed to its bioactive molecules with metabolic, anti-inflammatory, antioxidant, and antimicrobial properties. Therefore, in the face of the growing research and industrial interests in OPN as a novel food source, the present work reviews its botanical, nutritional, bioactive, and technofunctional properties, which are relevant for the development of healthy and innovative food products and ingredients.

Ureteric stent associated spondylodiscitis.

This case report describes a clinical presentation of spondylodiscitis, following an emergency ureteric stent placement for an infected and obstructed kidney in a woman in her late 70s who presented with right flank pain, raised inflammatory markers and an acute kidney injury. Non-contrast CT kidney, ureters and bladder (KUB) revealed a 9 mm obstructing stone and prompt decompression with a JJ stent was performed. Although the urine culture showed no growth at first, an extended spectrum beta-lactamase Escherichia coli was found in a subsequent urine culture after discharge. Postoperatively, the patient described a novel, worsening lower back pain and had persistently elevated inflammatory markers. An MRI revealed spondylodiscitis of L5/S1, for which she was treated with a 6-week course of antibiotics, and she has made a good but slow recovery. This case shows the unusual finding of spondylodiscitis postureteric stent placement and clinicians should be aware of this rare complication.

Detailed insight into chromium species released from failed CoCrMo implants: Ex vivo periprosthetic tissues study.

This unique study provides information on Cr species and their distribution in periprosthetic tissues of patients with metal-on-polyethylene joint implants. Co-Cr-Mo alloy has been widely used in joint replacement and represents a source of metal derived species. In the case of chromium, previous studies on periprosthetic tissues revealed mainly Cr(III) distribution, whereas the potential release of carcinogenic Cr(VI) species has been still a subject of debate. Here, an analytical approach utilizing speciation and fractionation was developed to analyze periprosthetic tissue samples collected from wide range of patients with failed total hip or knee replacements. The results reveal that Cr(III) is mainly released in the form of insoluble CrPO4 and Cr2 O3 particles. The highest Cr contents were found in periprosthetic tissues of patients suffering from aseptic loosening and having more Cr-based implants in the body. Cr species penetrated tissue layers, but their levels decreased with the distance from an implant. The detailed speciation/fractionation study carried out using the set of consecutive periprosthetic tissues of a patient with extensive metallosis showed the presence of trace amounts of free Cr(III), nanoparticles, and metal-protein complexes, but the majority of Cr still occurred in CrPO4 form. Carcinogenic Cr(VI) species were not detected. Up to date, there is no published human tissue study focused on the detailed speciation of both soluble and insoluble Cr-based species in the context of failing total hip and knee replacements.

Renin Angiotensin System as a Potential Treatment Target for Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Traumatic brain injury (TBI) is a major health concern and leading cause of death and disability in young adults in the United Kingdom and worldwide; however, there is a paucity of disease modifying therapies for the treatment of TBI. This review investigates the potential of the renin-angiotensin system (RAS) as a treatment pathway for TBI in adults. Relevant electronic databases were searched on December 18, 2019, and updated May 16, 2021. All English language articles with adult human or animal populations investigating RAS drugs as an intervention for TBI or reporting genetic evidence relevant to the RAS and TBI were screened. Eighteen pre-clinical randomized controlled trials (RCTs) (n = 2269) and two clinical cohort studies (n = 771) were included. Meta-analyses of six pre-clinical RCTs (n = 99) indicated that candesartan improved neurological function over the short term (< 7 days: standardized mean difference [SMD] 0.61, 95% confidence interval [CI] 0.19-1.03, I2 = 0%) and over the long term (≥ 7 days: SMD 1.06, 95% CI 0.38; 1.73, I2 = 0%) post-TBI. Findings were similar for most secondary outcomes. There was a suggestion of benefit from other RAS-targeting drugs, although evidence was limited because there were few small studies. There was insufficient evidence to enable strong assessment of these drugs on mortality post-TBI. We conclude that angiotensin-receptor blockers, especially candesartan, show positive outcomes post-TBI in pre-clinical studies with moderate quality of evidence (Grading of Recommendations Assessment, Development and Evaluation [GRADE]). More research into the effect of regulatory-RAS targeting drugs is needed. Clinical trials of candesartan following TBI are recommended, because there is strong and consistent evidence of neuroprotection shown by these pre-clinical studies.

Study of interactions between carboxylated core shell magnetic nanoparticles and polymyxin B by capillary electrophoresis with inductively coupled plasma mass spectrometry.

In this work, interactions of carboxylated core shell magnetic nanoparticles with polymyxin B sulfate were studied by connecting capillary electrophoresis with inductively coupled plasma mass spectrometry. The interaction was probed by affinity mode of capillary electrophoresis with 25 mM phosphate buffer at physiological pH. 54Fe, 56Fe, 57Fe, 34S, and 12C isotopes were used to monitor the migration of an electroosmotic flow marker and the interaction of the nanoparticles with polymyxin B. The analysis of interaction data showed two distinct interaction regions, one with low polymyxin B concentration, the second with high polymyxin B concentration. These regions differed in the strength of the interaction, 1.49 × 107 M-1 and 1.60 × 104 M-1, and in the stoichiometry of 0.7 and 3.5, respectively. These differences can be explained by the decrease of electrostatic repulsion between nanoparticles caused by polymyxin B. This is also in agreement with the nanoparticles peak shapes: sharp for low polymyxin B concentrations and broad for high polymyxin B concentrations.

Primitive neuroectodermal tumor of the esophagus with metastasis in the pineal gland.

Primitive neuroectodermal tumors (PNET) are very rare tumors that belong to a family of malignant neoplasms of tiny round cells which are derived from the neural crest. This report discusses a rare case of an adult woman with esophageal PNET, confirmed by immunohistochemistry, that presented with metastasis to the pineal gland. To our knowledge, this is the first case report of a PNET with these features. Despite surgery and chemotherapeutic treatment, our case has shown disease progression.

Determination of oxaliplatin enantiomers at attomolar levels by capillary electrophoresis connected with inductively coupled plasma mass spectrometry.

The aim of this study was to develop a method for the separation of oxaliplatin enantiomers at attomolar concentration levels. A combination of capillary electrophoresis and inductively coupled plasma mass spectrometry was chosen due to their unique characteristics, including fast and easy modification of separation selectivity, and significant limits of detection and linearity. In the first step, we optimized conditions for the separation of oxaliplatin enantiomers including background electrolyte composition and concentration, pH, and type and concentration of the chiral selector. Under optimal conditions, sodium borate buffer pH 9.5, ionic strength 40 mmol L-1, with 60 mg mL-1 sulfated ß-cyclodextrin, separation was obtained with a resolution of 2.0. This electrolyte system was then used in the 'in-house' connection of capillary electrophoresis with inductively coupled plasma mass spectrometer. In this instance, separation lasted for 9.5 min. Calibrations were linear in the range of 0.1-500 µg mL-1 with R2 of 0.9999. LOD and LOQ values were of 64 ng mL-1 and 116 ng mL-1 of oxaliplatin, respectively. This represents detection of 49 fg or 125 attomol of oxaliplatin enantiomers in the capillary electrophoresis injected sample zone. Finally, the method was successfully applied for detection of oxaliplatin enantiomers in spiked urine samples.

Reconciling the Mitscherlich's law of diminishing returns with Liebig's law of the minimum. Some results on crop modeling.

Reliable fertilizer recommendations depend on the correctness of the crop production models fitted to the data, but generally the crop models are built empirically, neglecting important physiological aspects related with response to fertilizers, or they are based in laws of plant mineral nutrition seen by many authors as conflicting theories: the Liebig's Law of the Minimum and Mitscherlich's Law of Diminishing Returns. We developed a new approach to modelling the crop response to fertilizers that reconcile these laws. In this study, the Liebig's Law is applied at the cellular level to explain plant production and, as a result, crop models compatible with the Law of Diminishing Returns are derived. Some classical crop models appear here as special cases of our methodology, and a new interpretation for Mitscherlich's Law is also provided.

True lab-in-a-syringe technology for bioassays.

In our work, we introduced a novel concept of the lab-in-a-syringe tests. We solved the problem of detection in already published LIS tests by putting all the reaction and detection pads directly into the syringe barrel. We also used more layers to make the results visible for users. Two detection layouts: (i) with using rounded pads-based detection, and (ii) with using rectangular detection pads, were studied. As the proof of concept, we studied the determination of Ni(II) using dimethylglyoxime as the reagent and blocking of the interference of Fe(II). The calibrations for Ni(II) at the optimal conditions has excellent R2 of 0.998 with production costs of 0.2 USD per one test.

Online stacking of carboxylated magnetite core-shell nanoparticles in capillary electrophoresis.

The stacking effect on carboxylated magnetite core-shell nanoparticles using sodium borate buffer pH 9.5 as the background electrolyte is presented. The ionic strength of the background electrolyte ranged from 5 to 100 mM, and the ionic strength of a sample zone ranged from 5 to 100 mM. Moreover, water was used as the sample dispersant. Both stacking and de-stacking effects were observed when conductivities of the sample zone and the background electrolyte differed. An explanation of carboxylated magnetic core-shell nanoparticles behavior was suggested based on the Derjaguin-Landau-Verwey-Overbeek theory supposing that the aggregation point is defined by the energetic barrier as the sum of energies given by electrostatic interactions and Van der Waals interactions. Moreover, the stacking conditions were applied for the evaluation of the lowest detectable dilution of magnetic nanoparticles. The carboxylated magnetic nanoparticles were dispersed in 10 mM borate/NaOH pH 9.5 and injected for 60 s to the background electrolyte composed of 100 mM borate/NaOH pH 9.5 that allowed the detection of 100-fold diluted nanoparticles.

Electrokinetic preconcentration of magnetite core - carboxylic shell nanoparticles by capillary electrophoresis.

Online electrokinetic preconcentration of magnetite core/carboxylic shell nanoparticles (MNPs) was studied by capillary electrophoresis using reversed and suppressed electroosmotic flow (EOF). 50mM sodium borate pH 9.5 was used as a background electrolyte. CTAB additive was used to reverse EOF and commercial polyvinylalcohol (PVA)-coated capillaries were used for EOF suppressed studies. Analyses in PVA-coated capillaries were more reproducible and therefore, the setup was further optimized in terms of water plug injection time, sample injection time, and voltage. Within the optimal conditions, the MNPs dispersed in water are electrokinetically loaded into BGE consisting of 50mM sodium borate pH 9.5 using -10kV for 120s. In comparison with the hydrodynamic injection of 5s by 50mbar, the electrokinetic injection allows 860-fold preconcentration of MNPs.

Neuropathologic, phenotypic and functional analyses of Mucosal Associated Invariant T cells in Multiple Sclerosis.

BACKGROUND: The involvement of Mucosal Associated Invariant T (MAIT) cells, which are anti-microbial semi-invariant T cells, remains elusive in Multiple Sclerosis (MS). OBJECTIVE: Deciphering the potential involvement of MAIT cells in the MS inflammatory process. METHODS: By flow cytometry, blood MAIT cells from similar cohorts of MS patients and healthy volunteers (HV) were compared for frequency, phenotype, activation potential after in vitro TCR engagement by bacterial ligands and transmigration abilities through an in vitro model of blood-brain barrier. MS CNS samples were also studied by immunofluorescent staining and quantitative PCR. RESULTS AND CONCLUSION: Blood MAIT cells from relapsing-remitting MS patients and HV presented similar frequency, ex vivo effector phenotype and activation abilities. MAIT cells represented 0.5% of the total infiltrating T cells on 39 MS CNS lesions. This is low as compared to blood frequency (p<0.001), but consistent with their low transmigration rate. Finally, transcriptional over-expression of MR1 - which presents cognate antigens to MAIT cells - and of the activating cytokines IL-18 and IL-23 was evidenced in MS lesions, suggesting that the CNS microenvironment is suited to activate the few infiltrating MAIT cells. Taken together, these data place MAIT cells from MS patients as minor components of the inflammatory pathological process.

Expanded CD8 T-cell sharing between periphery and CNS in multiple sclerosis.

OBJECTIVE: In multiple sclerosis (MS), central nervous system (CNS), cerebrospinal fluid (CSF), and blood display TCR clonal expansions of CD8(+) T cells. These clones have been assumed - but never demonstrated - to be similar in the three compartments. Addressing this key question is essential to infer the implication of peripheral clonally expanded CD8(+) T cells in the disease. METHODS: For the first time, TCR Vß repertoire from paired blood (purified CD8(+) and CD4(+) T cells), CSF and CNS (22 lesions, various inflammatory and demyelination statuses) samples from three MS patients was studied using complementary determining region 3 (CDR3) spectratyping and high-throughput sequencing. In parallel, blood and CNS clonally expanded CD8(+) T cells were characterized by fluorescent staining. RESULTS: TCR Vß repertoire analysis revealed strong sharing of predominant T-cell clones between CNS lesions, CSF, and blood CD8(+) T cells. In parallel, we showed that blood oligoclonal CD8(+) T cells exhibit characteristics of pathogenic cells, as they displayed a bias toward a memory phenotype in MS patients, with increased expression of CCR5, CD11a and Granzyme B (GZM-B) compared to non oligoclonal counterparts. CNS-infiltrating T cells were mainly CD8 expressing CD11a and GZM-B. INTERPRETATION: This study highlights the predominant implication of CD8(+) T cells in MS pathophysiology and demonstrates that potentially aggressive CD8(+) T cells can be easily identified and characterized from blood and CSF samples.

Reconsidering the detection of tolerance to individualize immunosuppression minimization and to improve long-term kidney graft outcomes.

In kidney transplantation, minimizing the side effects of the immunosuppressive regimen and inducing tolerance to allograft are the two main objectives to improve outcome. At present, these objectives are far from being achieved and remain elusive for the majority of transplant recipients. Rejection rate and mortality on the long term are still unacceptable. There is thus a pressing need to improve this situation. Therefore, some spontaneously tolerant kidney recipients are described in clinics, and recent advances in immunological and molecular techniques have led to a resurgence of interest in studying those rare transplanted recipients through coordinated efforts from international consortia. Indeed, they offer, on the one hand, the possibility to develop specific biomarkers indicative of this state that would constitute a major advantage in the care of the patients allowing personalized minimization of drugs, so reducing related costs and side effects. On the other hand, they represent a unique model of study to understand the mechanisms of regulation implicated in this state that may help the development of inducing therapies. Recent efforts, concentrated on noninvasive analyses of peripheral blood, identified a predominance of several B-cell subsets, some of which harbouring regulatory functions, and related marker genes. These findings, validated in independent multicentric cohorts, led credence to an unsuspected role for the B-cell compartment in tolerance to kidney allograft. The identification of patients, harbouring these markers, among immunosuppressed recipients with stable graft function and the existence of drugs with selective effect on B cell pave the way for the possibility to improve long-term graft outcomes. Therefore, before routine application, these findings need to be confirmed in large prospective studies in the context of planned reduced immunosuppression.

Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties.

Whereas a B cell-transcriptional profile has been recorded for operationally tolerant kidney graft patients, the role that B cells have in this tolerance has not been reported. In this study, we analyzed the role of B cells from operationally tolerant patients, healthy volunteers, and kidney transplant recipients with stable graft function on T cell suppression. Proliferation, apoptosis, and type I proinflammatory cytokine production by effector CD4(+)CD25(-) T cells were measured after anti-CD3/anti-CD28 stimulation with or without autologous B cells. We report that B cells inhibit CD4(+)CD25(-) effector T cell response in a dose-dependent manner. This effect required B cells to interact with T-cell targets and was achieved through a granzyme B (GzmB)-dependent pathway. Tolerant recipients harbored a higher number of B cells expressing GzmB and displaying a plasma cell phenotype. Finally, GzmB(+) B-cell number was dependent on IL-21 production, and B cells from tolerant recipients but not from other patients positively regulated both the number of IL-21(+) T cells and IL-21 production, suggesting a feedback loop in tolerant recipients that increases excessive B cell activation and allows regulation to take place. These data provide insights into the characterization of B cell-mediated immunoregulation in clinical tolerance and show a potential regulatory effect of B cells on effector T cells in blood from patients with operationally tolerant kidney grafts.

Central Role of CD45RA- Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance.

The role of Foxp3(+) regulatory T cells (Tregs) in operational tolerance remains elusive, as initial results revealed an increased frequency of this subset in tolerant patients but no functional differences compared with immunosuppressed recipients. In addition, recent studies of regulatory B cells strongly suggest that Tregs may not have a central role in kidney transplantation tolerance. However, recent investigations of the crucial role of Foxp3 demethylation in Treg function and the possibility of identifying distinct Foxp3 T cell subsets prompted us to more thoroughly characterize Tregs in operationally tolerant patients. Thus, we studied the level of demethylation of the Foxp3 Treg-specific demethylated region (TSDR) in circulating CD4(+) T cells and analyzed Treg subset frequency in tolerant patients, healthy volunteers, patients with stable graft function under immunosuppression, and chronically rejecting recipients. We observed a higher proportion of CD4(+) T cells with demethylated Foxp3 and a specific expansion of CD4(+) CD45RA(-) Foxp3(hi) memory Tregs exclusively in tolerant patients. The memory Tregs of tolerant recipients exhibited increased Foxp3 TSDR demethylation, expressed higher levels of CD39 and glucocorticoid-induced TNF-related receptor, and harbored greater suppressive properties than memory Tregs from patients with stable graft function. Taken together, our data demonstrate that operationally tolerant patients mobilize an array of potentially suppressive cells, including not only regulatory B cells but also Tregs. Our results also indicate that tolerant patients have potent CD4(+)CD45RA(-) Foxp3(hi) memory Tregs with a specific Foxp3 TSDR demethylation pattern, which may contribute to the maintenance of graft tolerance.