Sarcoidosis with esophageal involvement: an uncommon clinical enigma.

We present the case of a 46-year-old male, a former smoker, with a medical history significant for morbid obesity grade III, hypothyroidism, hyperuricemia, and dyslipidemia. Four months ago, he was diagnosed with sarcoidosis involving mediastinal lymph nodes and is currently undergoing treatment with corticosteroids. The patient presented to the emergency department with persistent epigastric and thoracic pain lasting one week, accompanied by dysphagia and odynophagia intermittently. Laboratory tests showed elevated acute-phase reactants, with no other notable abnormalities. Chest X-ray revealed pre-existing mediastinal adenopathy. Despite an abdominal CT scan with contrast showing no significant findings, esophagogastroduodenoscopy revealed marked extrinsic compression of the esophagus between 25 and 32 cm from the dental arch, with less intensity distally. Although passage of the endoscope through this area caused significant pain, it did not hinder its advancement. A chest CT scan with oral contrast demonstrated filamentous narrowing of the esophagus in the middle third, along with concentric thickening of its walls and multiple paratracheal, parahilar, and periesophageal lymphadenopathies. Following a tapering regimen of corticosteroids, the patient was discharged with a clinical diagnosis of sarcoidosis with mediastinal and esophageal involvement secondary to extrinsic compression. Due to clinical improvement with the prescribed treatment, endoscopic ultrasound and biopsies to assess esophageal wall involvement were deemed unnecessary.

Intraductal papillary neoplasms of the bile ducts: a comparative study of a rare disease in Europe and Nagoya, Japan.

BACKGROUND: Intraductal papillary neoplasm of the bile ducts (IPNB) is a rare disease in Western countries. The aim of this study was to compare tumor characteristics, management strategies, and outcomes between Western and Eastern patients who underwent surgical resection for IPNB. METHODS: A multi-institutional retrospective series of patients with IPNB undergoing surgery between January 2010 and December 2020 was gathered under the auspices of the European-African Hepato-Pancreato-Biliary Association (E-AHPBA), and at Nagoya University Hospital, Japan. RESULTS: A total of 85 patients (51% male; median age 66 years) from 28 E-AHPBA centers were compared to 91 patients (64% male; median age 71 years) from Nagoya. Patients in Europe had more multiple lesions (23% vs 2%, P < .001), less invasive carcinoma (42% vs 85%, P < .001), and more intrahepatic tumors (52% vs 24%, P < .001) than in Nagoya. Patients in Europe experienced less 90-day grade >3 Clavien-Dindo complications (33% vs 68%, P < .001), but higher 90-day mortality rate (7.0% vs 0%, P = .03). R0 resections (81% vs 82%) were similar. Overall survival, excluding 90-day postoperative deaths, was similar in both regions. DISCUSSION: Despite performing more extensive resections, the low perioperative mortality rate observed in Nagoya was probably influenced by a combination of patient-, tumor-, and surgery-related factors.

Lateral wedge insoles and their use in ankle instability.

The aim of the present study is to assess the immediate effects of applying lateral wedge insoles of different heights (0.00, 0.3, 0.4, and 0.6 cm) in patients with chronic ankle instability (CAI) in normal and supinated feet during a Star Excursion Balance Test (SEBT) and in the reflex response of Peroneus Longus (PL), Peroneus Brevis (PB), and Tibialis Anterior (TA) over a 30° inversion of the feet. The effects of the height of the wedges were assessed using a double-blind, crossover design. In total, 25 participants were allocated into two groups, depending on the foot posture (Normal = 12, Supinated = 13) and performed the tests in a random fashion. Reaction time (RT) of stabilizing muscles of the ankle was measured using superficial electromyography (EMG) and postural balance with the SEBT. Foot posture did not show any significant effects on the analyzed variables. Nonetheless, the use of a 0.3 cm external rearfoot wedge (PB p = 0.002; PL p = 0.066 and TA p = 0.006) and 0.6 cm (PB p = 0.043; PL p = 0.058 and TA p = 0.071) reduces RT in stabilizing muscles of the ankle and improves results in SEBT, except for the anterolateral direction, in subjects with CAI. Therefore, our results suggest that the use of lateral wedge insoles could reduce RT and improve dynamic balance in chronic ankle instability.

Type 2 Diabetes in Obesity: A Systems Biology Study on Serum and Adipose Tissue Proteomic Profiles.

Obesity is associated with metabolic disorders such as insulin resistance and type 2 diabetes mellitus (T2DM), further increasing an already heightened cardiovascular risk. Here, amongst obese class III bariatric surgery patients, we have investigated the effect of T2DM in serum and in two, same patient, adipose tissue (AT) depots through proteomic profile expression analyses. Serum and AT samples from subcutaneous (SAT) and visceral (VAT) fat were collected during bariatric surgery. Bead-based targeted multiplex assay systems were used to simultaneously detect and quantify multiple targets in serum samples (targeted proteomics) and analyze changes in adipokine serum composition. AT samples were assessed through an untargeted proteomics approach. Through a systems biology analysis of the proteomic data, information on the affected biological pathways was acquired. In obese class III individuals, the presence of T2DM induced a significantly higher systemic release of ghrelin, GLP-1, glucagon, MMP3, BAFF, chitinase 3-like 1, TNF-R1 and TNF-R2, and a lower systemic release of IL-8. SAT and VAT proteomes belonging to the same patient showed significant differences in local protein content. While the proteins upregulated in VAT were indicative of metabolic dysregulation, SAT protein upregulation suggested adequate endocrine regulation. The presence of T2DM significantly affected VAT protein composition through the upregulation of dysregulating metabolic pathways, but SAT protein composition was not significantly modified. Our results show that T2DM induces metabolic dysregulation in obese individuals with changes in systemic marker levels and impairment of proteostasis in VAT but not in SAT.

Changing perspectives: unveiling the risks of ashwagandha-induced hepatotoxicity.

Ashwagandha, an herb popular in Ayurvedic medicine, is renowned for its health-enhancing properties. However, its association with liver damage in recent years has raised significant concerns, necessitating careful assessment and management. This case underscores the dangers of Ashwagandha, particularly for individuals with preexisting liver conditions, where it can lead to life-threatening acute-on-chronic liver failure. The lack of solid clinical evidence supporting Ashwagandha's health claims emphasizes the need for an evidence-based approach. Public education is essential to raise awareness of the risks associated with herbal supplements and prevent liver diseases.

Design and validation of recombinant protein standards for quantitative Western blot analysis of cannabinoid CB1 receptor density in cell membranes: an alternative to radioligand binding methods.

BACKGROUND: Replacement of radioligand binding assays with antibody-antigen interaction-based approaches for quantitative analysis of G protein-coupled receptor (GPCR) levels requires the use of purified protein standards containing the antigen. GPCRs in general and cannabinoid CB1 receptor in particular show a progressive tendency to aggregate and precipitate in aqueous solution outside of their biological context due to the low solubility that the hydrophobic nature imprinted by their seven transmembrane domains. This renders full-length recombinant GPCRs useless for analytical purposes, a problem that can be overcome by engineering soluble recombinant fragments of the receptor containing the antigen. RESULTS: Here we generated highly soluble and stable recombinant protein constructs GST-CB1414-472 and GST-CB1414-442 containing much of the human CB1 receptor C-terminal tail for use as standard and negative control, respectively, in quantitative Western blot analysis of CB1 receptor expression on crude synaptosomes of the adult rat brain cortex. To this end we used three different antibodies, all raised against a peptide comprising the C-terminal residues 443-473 of the mouse CB1 receptor that corresponds to residues 442-472 in the human homolog. Estimated values of CB1 receptor density obtained by quantitative Western blot were of the same order of magnitude but slightly higher than values obtained by the radioligand saturation binding assay. CONCLUSIONS: Collectively, here we provide a suitable Western blot-based design as a simple, cost-effective and radioactivity-free alternative for the quantitative analysis of CB1 receptor expression, and potentially of any GPCR, in a variety of biological samples. The discrepancies between the results obtained by quantitative Western blot and radioligand saturation binding techniques are discussed in the context of their particular theoretical bases and methodological constraints.

Curcumin and curcumoids: hepatoprotection or hepatotoxicity?

Curcumin (Curcuma longa) and curcumin analogues are plant-based drugs used because of their possible antioxidant and anti-inflammatory. Clinical data on the efficacy of curcumin as a hepatoprotectant are limited, with growing concern for formulations that may potentially increase curcumin hepatotoxicity.

Solid-phase synthesis of imprinted nanoparticles as artificial antibodies against the C-terminus of the cannabinoid CB1 receptor: exploring a viable alternative for bioanalysis.

The production of artificial anti-CB1 antibodies in nanoparticle format is described using the solid-phase imprinting approach. Instead of whole protein imprinting, a linear C-terminus sequence of the receptor comprising 15 amino acids (458-KVTMSVSTDTSAEAL-472) has been used as template, in accordance with the epitope imprinting approach. This sequence is located intracellularly, and it is involved in coupling to Gi/o proteins, being responsible for CB1 receptor desensitisation and internalisation. Developed molecularly imprinted materials were found to be in the nanometre scale, with a particle size of 126.4 ± 10.5 nm at pH 3 (25 ºC) and spherical shape. It was also observed that the size was sensible to temperature changes being reduced to 106.3 ± 15.2 nm at 35 °C. Lower critical solution temperature of this polymer was found to be ≈ 33.4 °C. The affinity and selectivity of the artificial antibody were assessed through dot blot and Western blot experiments. For the latter, recombinant fusion proteins GST-CB1414-472 and GST-CB1414-442 were produced to work respectively as target and negative control proteins. The control protein did not carry the target epitope for being devoid of last 30 amino acids at the C-terminus. The results demonstrated that the anti-CB1 material recognised selectively the target protein, thanks to the presence of the 15-amino acid sequence selected as epitope, which revealed that binding occurred at the C-terminus of the receptor itself. The methodology presented may pave the way for the development of novel imprinted nanomaterials for other proteins included in the superfamily of the G-protein-coupled receptors (GPCR).

A methodological framework for selecting an optimal sediment source within a littoral cell.

One of the most used measures to counteract coastal erosion is beach nourishment. It has advantages with respect to the use of rigid structures that sometimes entail non desired impacts on the surrounding areas. However, beach nourishments are often unsuccessful, requiring frequent refills due to the use of sediments that are not suitable. In this paper, a methodological framework for increasing the probability of success of beach nourishment projects is presented. First, this framework consists of detecting potential borrowing areas, by analysing shoreline evolution and selecting the stretch that shows a more accretive character. Once the borrowing area has been identified, several sand extraction options are defined. The beach response (in terms of erosion and flooding) to each sand extraction alternative is analysed by using two numerical models, which simulate the hydro-morphodynamic patterns in the studied area. The numerical model results allow to find the best extraction alternative, which is that producing the least impact in the borrow area. As an example, the methodology is applied to a stretch of the Catalan coast (NW Mediterranean) to illustrate its potential. The proposed methodology shows to be a useful tool for helping coastal managers to optimize their available resources.

Minimally Invasive Surgical Approach for the Treatment of Superior Mesenteric Artery Syndrome: Long-Term Outcomes.

BACKGROUND: Latero-lateral duodenojejunostomy is the treatment of choice for superior mesenteric artery syndrome (SMAS). The present study analyzes the long-term outcomes in 13 patients undergoing laparoscopic surgery for SMAS. MATERIALS AND METHODS: A retrospective study of 10 females and three males undergoing surgery between 2001 and 2013 was performed. Demographic, clinical and radiologic data and long-term surgical outcomes were recorded. In 12 patients latero-lateral duodenojejunostomy and in one patient distal laparoscopic gastrectomy with Roux-en-Y reconstruction were performed. The median age was 24 years (20-28), and the median duration of symptoms was 24 months (5-24). The most frequent symptoms were abdominal pain (n = 11; 92.3%), nausea and vomiting (n = 10; 77%) and weight loss (n = 9; 69.2%). The median operating time was 98 min (86-138) and hospital stay was 3 days (1-14). RESULTS: No reconversions occurred, and one patient experienced gastric emptying delay in the immediate postoperative period with spontaneous resolution. In four patients, SMAS was associated with severe stenosis of the celiac trunk which was treated in the same operation, and four patients presented stenosis of the left renal vein (the "nutcracker" phenomenon). With a median follow-up of 94 months (SD 65.3), eight patients (61.5%) had excellent results. One patient had a relapse of symptoms 4 years after surgery requiring distal gastrectomy, two patients presented delay in gastric emptying following temporary improvement and one patient experienced no improvement. CONCLUSIONS: Latero-lateral duodenojejunostomy yields good results in SMAS although it requires other gastric motility disorders to be ruled out for appropriate treatment to be established.

Determination of mercury(ii) in water at sub-nanomolar levels by laser ablation-ICPMS analysis of screen printed electrodes used as a portable voltammetric preconcentration system.

Environmental pollution by mercury in ambient water samples is a recognized problem worldwide. Sample preservation and transport to the laboratory lead to uncertain analytical results. This study outlines the development of a procedure for on-site electrodeposition of mercury from water samples on a screen-printed gold electrode (SPGE) using portable voltammetric techniques. Once in the laboratory, Hg is analyzed by laser ablation inductively coupled plasma-mass spectrometry (LA-ICPMS) in order to ensure that the required sensitivity and precision levels for environmental sample analysis are reached. A new ablation chamber was intentionally designed for the analysis of SPGE's gold electrode. This cell has a small internal volume of 15 cm3 and the SPGE device perfectly fits inside. This design assures signal stability, avoids elemental fractionation and reduces wash-out time to a few seconds, reducing the analysis time considerably. The proposed method is capable of measuring dissolved mercury at the ng L-1 level (quantification limit 200 ng L-1) with good precision (RSD < 7.6%). The proposed method was tested with the NCS ZC 76303 (NIM-GBW08603) Mercury in water Certified Reference Material.

Iniferter-mediated grafting of molecularly imprinted polymers on porous silica beads for the enantiomeric resolution of drugs.

A surface-imprinted chiral stationary phase for the enantiomeric resolution of the antidepressant drug, citalopram, is presented in this work. N, N'-diethylaminodithiocarbamoylpropyl(trimethoxy)silane has been used as silane iniferter for the surface functionalization of the solid silica support. A molecularly imprinted polymer thin film, in the nm scale, was then grafted on the silanized silica using itaconic acid as the functional monomer and ethylene glycol dimethacrylate as the cross-linker in the presence of the template S-citalopram. The total monomer amount was calculated to obtain the desired thickness. Non-imprinted stationary phases were prepared similarly in the absence of S-citalopram. Characterization of the materials was carried out by scanning electron microscopy, thermogravimetric analysis, elemental analysis and Fourier transform infrared spectroscopy. Stationary phases have been applied to the chromatographic separation of the target. Conditions for best chromatographic resolution of the enantiomers were optimized, and it was found that a mobile phase consisting of a mixture of formate buffer (40 mM, pH 3) and acetonitrile (30:70 v/v) at 40 °C provided best results. Binding behaviour of the developed material was finally assessed by batch rebinding experiments. The obtained binding isotherm was fitted to different binding models being the Freundlich-Langmuir model, the one that best fitted the experimental data. The developed material has shown high selectivity for the target enantiomer, and the stationary phase could be undoubtedly exploited for chiral separation of the drug.

Value of the biomarker soluble tyrosine kinase 1 type fms (sFLT-1) in the diagnosis and prognosis of sepsis: a systematic review. / Valor del biomarcador tirosina quinasa 1 soluble tipo fms (sFLT-1) en el diagnóstico y pronóstico de la sepsis: una revisión sistemática.

INTRODUCTION: The present systematic review analyses the role of soluble fms-like tyrosine kinase-1 (sFLT-1) as an indirect biomarker of endothelial dysfunction in sepsis or septic shock from articles published in PubMed between 2010 and March 2022. MATERIALS AND METHODS: A systematic review of studies studying sFLT-1 monitoring in intensive care units in adults with sepsis or septic shock vs. controls for sepsis diagnosis and prognosis has been carried out (PROSPERO CRD42023412929 Registry). RESULTS: The endothelial dysfunction of sepsis is one of the keys to the development of the disease. VEGF binds to sFLT-1 acting as a competitive inhibitor of VEGF signalling in endothelial cells and thus neutralizes its pro-inflammatory effects. Endothelial dysfunction is reflected in increased sFLT-1 levels. High values of sFLT-1 were used for the differential diagnosis of sepsis versus other inflammatory pathologies, septic shock versus other types of shock, were elevated over time, estimation of disease prognosis, correlation with sepsis severity, organ dysfunction, and mortality prediction. CONCLUSIONS: It is evident that sepsis is based on endothelial dysfunction. sFLT-1 is one of the main biomarkers of microvascular alteration and is a predictive diagnostic and prognostic biomarker.

High Rate of Change of the Foot in Ecuadorian Children: The Need for Proper Shoe Design.

BACKGROUND: Physiological changes in the foot may be influenced by external factors such as shoe types or demographic parameters, leading to podiatric conditions in adulthood. The aim of this study was to assess the changes in morphological measurements of the feet of boys and girls during childhood and adolescence. METHODS: A total of 1678 Ecuadorian children aged 8 to 17 years participated in the study. The length, width, and height of the foot were analyzed using a 3D scanner to obtain the arch height ratio for the diagnosis of pediatric flat foot. RESULTS: Statistical differences were observed for lengths, widths, and perimeters of the foot in boys aged 5 to 15-16 years and girls aged 5 to 12-13 years. Differences in the height of the navicular bone were found in all age groups, with changes from 2.8 to 4.1% in boys and from 1.3 to 1.5% in girls. The greatest differences between boys and girls of the same age were found at 14 years old onwards. The highest prevalence of flat foot was found in 8-year-old girls (64.9%) and in 12-year-old boys (82.5%). CONCLUSIONS: The feet of Ecuadorian children develop progressively during childhood and adolescence. Boys presented with longer and wider feet than girls of the same age. The highest prevalence of flat foot was found in 12-year-old boys and 8-year-old girls.

Differentiation of Adipose Tissue Mesenchymal Stem Cells into Endothelial Cells Depends on Fat Depot Conditions: Regulation by miRNA.

The development of obesity is associated with substantial modulation of adipose tissue (AT) structure. The plasticity of the AT is reflected by its remarkable ability to expand or reduce in size throughout the adult lifespan, which is linked to the development of its vasculature. This increase in AT vasculature could be mediated by the differentiation of adipose tissue-derived stem cells (ASCs) into endothelial cells (ECs) and form new microvasculature. We have already shown that microRNA (miRNA)-145 regulates the differentiation of ASCs into EC-like (ECL) cells. Here, we investigated whether ASCs-differentiation into ECs is governed by a miRNAs signature that depends on fat depot location and /or the metabolic condition produced by obesity. Human ASCs, which were obtained from white AT by surgical procedures from lean and obese patients, were induced to differentiate into ECL cells. We have identified that miRNA-29b-3p in both subcutaneous (s)ASCs and visceral ASCs and miRNA-424-5p and miRNA-378a-3p in subcutaneous (s)ASCs are involved in differentiation into EC-like cells. These miRNAs modulate their pro-angiogenic effects on ASCs by targeting FGFR1, NRP2, MAPK1, and TGF-ß2, and the MAPK signaling pathway. We show for the first time that miRNA-29b-3p upregulation contributes to ASCs' differentiation into ECL cells by directly targeting TGFB2 in both sASCs and visceral ASCs. Moreover, our results reveal that, independent of sASCs' origin (obese/lean), the upregulation of miRNA-378a-3p and the downregulation of miRNA-424-5p inhibit MAPK1 and overexpress FGFR1 and NRP2, respectively. In summary, both the adipose depot location and obesity affect the differentiation of resident ASCs through the expression of specific miRNAs.

Revealing novel biomarkers for diagnosing chronic kidney disease in pediatric patients.

Pediatric chronic kidney disease (CKD) is a clinical condition characterized by progressive renal function deterioration. CKD diagnosis is based on glomerular filtration rate, but its reliability is limited, especially at the early stages. New potential biomarkers (citrulline (CIT), symmetric dimethylarginine (SDMA), S-adenosylmethionine (SAM), n-butyrylcarnitine (nC4), cis-4-decenoylcarnitine, sphingosine-1-phosphate and bilirubin) in addition to creatinine (CNN) have been proposed for early diagnosis. To verify the clinical value of these biomarkers we performed a comprehensive targeted metabolomics study on a representative cohort of CKD and healthy pediatric patients. Sixty-seven children with CKD and forty-five healthy children have been enrolled in the study. Targeted metabolomics based on liquid chromatography-triple quadrupole mass spectrometry has been used for serum and plasma samples analysis. Univariate data analysis showed statistically significant differences (p < 0.05) in the concentration of CNN, CIT, SDMA, and nC4 among healthy and CKD pediatric patients. The predictive ability of the proposed biomarkers was also confirmed through specificity and sensitivity expressed in Receiver Operating Characteristic curves (AUC = 0.909). In the group of early CKD pediatric patients, AUC of 0.831 was obtained, improving the diagnostic reliability of CNN alone. Moreover, the models built on combined CIT, nC4, SDMA, and CNN allowed to distinguish CKD patients from healthy control regardless of blood matrix type (serum or plasma). Our data demonstrate potential biomarkers in the diagnosis of early CKD stages.

Stem cells isolated from adipose tissue of obese patients show changes in their transcriptomic profile that indicate loss in stemcellness and increased commitment to an adipocyte-like phenotype.

BACKGROUND: The adipose tissue is an endocrine regulator and a risk factor for atherosclerosis and cardiovascular disease when by excessive accumulation induces obesity. Although the adipose tissue is also a reservoir for stem cells (ASC) their function and "stemcellness" has been questioned. Our aim was to investigate the mechanisms by which obesity affects subcutaneous white adipose tissue (WAT) stem cells. RESULTS: Transcriptomics, in silico analysis, real-time polymerase chain reaction (PCR) and western blots were performed on isolated stem cells from subcutaneous abdominal WAT of morbidly obese patients (ASCmo) and of non-obese individuals (ASCn). ASCmo and ASCn gene expression clustered separately from each other. ASCmo showed downregulation of "stemness" genes and upregulation of adipogenic and inflammatory genes with respect to ASCn. Moreover, the application of bioinformatics and Ingenuity Pathway Analysis (IPA) showed that the transcription factor Smad3 was tentatively affected in obese ASCmo. Validation of this target confirmed a significantly reduced Smad3 nuclear translocation in the isolated ASCmo. CONCLUSIONS: The transcriptomic profile of the stem cells reservoir in obese subcutaneous WAT is highly modified with significant changes in genes regulating stemcellness, lineage commitment and inflammation. In addition to body mass index, cardiovascular risk factor clustering further affect the ASC transcriptomic profile inducing loss of multipotency and, hence, capacity for tissue repair. In summary, the stem cells in the subcutaneous WAT niche of obese patients are already committed to adipocyte differentiation and show an upregulated inflammatory gene expression associated to their loss of stemcellness.

The subcutaneous adipose tissue reservoir of functionally active stem cells is reduced in obese patients.

It has been demonstrated that the adipose tissue, a highly functional metabolic tissue, is a reservoir of mesenchymal stem cells. The potential use of adipose-derived stem cells (ADSCs) from white adipose tissue (WAT) for organ repair and regeneration has been considered because of their obvious benefits in terms of accessibility and quantity of available sample. However, the functional capability of ADSCs from subjects with different adiposity has not been investigated. It has been our hypothesis that ADSCs from adipose tissue of patients with metabolic syndrome and high adiposity may be functionally impaired. We report that subcutaneous WAT stromal vascular fraction (SVF) from nonobese individuals had a significantly higher number of CD90+ cells than SVF from obese patients. The isolated ADSCs from WAT of obese patients had reduced differentiation potential and were less proangiogenic. Therefore, ADSCs in adipose tissue of obese patients have lower capacity for spontaneous or therapeutic repair than ADSCs from nonobese metabolically normal individuals.

Recent Advances in Metal Powder-Based Additive Manufacturing.

Over the past two decades, laser additive manufacturing technology has evolved rapidly and has been applied in many industrial sectors [...].