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Circulating extracellular vesicles (EVs) can participate in innate repair processes triggered after intracerebral hemorrhage (ICH). We aimed to describe changes in the proteomic profile of circulating EVs between the acute and subacute phases of ICH and to compare the findings depending on outcomes, as an approach to unraveling such repair mechanisms.This was a prospective observational study including patients with non-traumatic supratentorial ICH. Exclusion criteria were previous disability, signs of herniation on baseline computed tomography, or limited life expectancy. EVs were isolated from blood samples at 24 h and 7 days after symptom onset. After 6-months' follow-up, patients were dichotomized into poor and good outcomes, defining good as an improvement of >10 points or > 50 % on the National Institutes of Health Stroke Scale and a modified Rankin Scale of 0–2. The protein cargo was analyzed by quantitative mass spectrometry and compared according to outcomes.Forty-four patients completed follow-up, 16 (35.5 %) having good outcomes. We identified 1321 proteins in EVs, 37 with differential abundance. In patients with good outcomes, proteins related to stress response (DERA, VNN2, TOMM34) and angiogenesis (RHG01) had increased abundance at 7 days. EVs from patients with poor outcomes showed higher levels of acute-phase reactants (CRP, SAA2) at 7 days compared with 24 h.In conclusion, the protein content of circulating EVs in patients with ICH changes over time, the changes varying depending on the clinical outcome, with greater abundance of proteins potentially involved in the repair processes of patients with good outcomes.

Abstract. Background. Malignant ureteral obstruction (MUO) is a common condition that complicates the course of advanced malignancies. The aims of this study are to analyze the causes, management, and survival of patients with obstructive nephropathy due to malignant ureteric obstruction and to determine prognostic factors. Furthermore, we studied the complications and outcomes in patients who underwent urinary diversion. Materials and methods. A retrospective study was conducted on patients with computed tomography–confirmed MUO between January 2016 and November 2020. Demographic, clinical, radiological, laboratory, and management data were collected. Survival curves were estimated using the Kaplan-Meier method, and univariate and multivariate Cox proportional hazards models were used to test the association between parameters and survival. Results. A total of 188 patients were included. The mean age was 69.01 years (SD, 14.95 years), and the majority (54.8%) were male. The most common mechanism leading to MUO was compression by a pelvic mass (36.9%), and the 3 most frequent tumors causing MUO were prostate (17.6%), bladder (16.5%), and rectal cancer (11.7%). Forty-seven patients (25%) underwent urinary diversion: 23 (48.9%) underwent double-J stenting and 21 (44.7%) underwent percutaneous nephrostomy. The most common reason for urinary diversion was acute kidney injury (53.3%). Recovery of renal function was observed in 55.8% of the patients after urinary diversion. The most frequently identified complications after urinary diversion were urinary tract infection (24.4%), hematuria (17.0%), and urinary sepsis (14.9%). The median survival after hydronephrosis diagnosis was 6.43 months (interquartile range, 1.91–14.81 months). In patients who underwent urinary decompression, the median survival after urinary diversion was 8.67 months (interquartile range, 2.99–17.28 months). In the multivariate analysis, a lower grade of hydronephrosis and cancer cachexia negatively impacted survival. Conclusions. Cancer patients with MUO have a poor prognosis; therefore, the risk-benefit ratio of urinary diversion should be carefully considered. Cachexia and hydronephrosis grade can be useful in selecting suitable candidates for urinary diversion.

Circulating extracellular vesicles (EVs) are proposed to participate in enhancing pathways of recovery after stroke through paracrine signaling. To verify this hypothesis in a proof-of-concept study, blood-derived allogenic EVs from rats and xenogenic EVs from humans who experienced spontaneous good recovery after an intracerebral hemorrhage (ICH) were administered intravenously to rats at 24 h after a subcortical ICH. At 28 days, both treatments improved the motor function assessment scales score, showed greater fiber preservation in the perilesional zone (diffusion tensor-fractional anisotropy MRI), increased immunofluorescence markers of myelin (MOG), and decreased astrocyte markers (GFAP) compared with controls. Comparison of the protein cargo of circulating EVs at 28 days from animals with good vs. poor recovery showed down-expression of immune system activation pathways (CO4, KLKB1, PROC, FA9, and C1QA) and of restorative processes such as axon guidance (RAC1), myelination (MBP), and synaptic vesicle trafficking (SYN1), which is in line with better tissue preservation. Up-expression of PCSK9 (neuron differentiation) in xenogenic EVs-treated animals suggests enhancement of repair pathways. In conclusion, the administration of blood-derived EVs improved recovery after ICH. These findings open a new and promising opportunity for further development of restorative therapies to improve the outcomes after an ICH.

Abstract. Background. Primary testicular lymphoma (PTL) is a rare testicular malignancy, despite being considered the most common testicular tumor in patients older than 60 years. Primary testicular lymphoma represents only 1%–9% of testicular neoplasms. Few studies have been published regarding its clinical features and management. This study aimed to analyze the clinical characteristics and outcomes of PTL. Materials and methods. Orchiectomy specimens of 15 patients with PTL diagnosed during 2000–2020 at our institution were retrospectively studied. We collected information on demographic data, clinical features, management aspects, and outcomes of PTL treatment. Kaplan-Meier survival curves and Cox regression analyses were used to study survival. Results. The median patient age was 69 years (interquartile range, 61–72 years). The most prevalent clinical presentation was testicular swelling (80%), and only 13.33% of the patients presented with systemic symptoms. Central nervous system involvement was detected in 6 patients (40%). Of the 15 patients, 5 (33.33%) had stage IE and 10 (66.67%) had stage IVE lymphoma. Diffuse large B-cell lymphoma was the most common histological subtype. Twelve patients (80%) received chemotherapy. During follow-up, 4 patients (26.67%) relapsed. The recurrence rate in the contralateral testicle was 13.33%. The median cancer-specific survival was 21.58 months (95% confidence interval, 0–43.95 months). Univariate Cox regression analysis showed that central nervous system involvement and International Prognostic Index score were significantly associated with shorter cancer-specific survival. Conclusions. Primary testicular lymphoma has a high relapse rate and poor prognosis. Management strategies typically include radical orchiectomy and systemic chemotherapy. Central nervous system involvement and International Prognostic Index scores were associated with lymphoma-specific survival.

IntroductionMultiple sclerosis is an inflammatory and demyelinating disease caused by a pathogenic immune response against the myelin sheath surfaces of oligodendrocytes. The demyelination has been classically associated with pathogenic B cells residing in the central nervous system that release autoreactive antibodies against myelin. The aim of the present study was to investigate whether extracellular vesicles (EVs) mediate delivery of myelin autoreactive antibodies from peripheral B cells against oligodendrocytes in multiple sclerosis (MS) and to analyze whether these EVs could mediate demyelination in vitro. We also studied the role of these EV-derived myelin antibodies as a diagnostic biomarker in MS.MethodsThis is a prospective, observational, and single-center study that includes patients with MS and two control groups: patients with non-immune white matter lesions and healthy controls. We isolated B-cell-derived EVs from the blood and cerebrospinal fluid (CSF) and analyzed their myelin antibody content. We also studied whether antibody-loaded EVs reach oligodendrocytes in patients with MS and the effect on demyelination of B-cell-derived EVs containing antibodies in vitro.ResultsThis study enrolled 136 MS patients, 23 white matter lesions controls, and 39 healthy controls. We found autoreactive myelin antibodies in EVs that were released by peripheral B cells, but not by populations of B cells resident in CSF. We also identified a cut-off of 3.95 ng/mL of myelin basic protein autoantibodies in EVs from peripheral B cells, with 95.2% sensitivity and 88.2% specificity, which allows us to differentiate MS patients from healthy controls. EV-derived myelin antibodies were also detected in the oligodendrocytes of MS patients. Myelin antibody-loaded EVs from B cells induced myelin markers decrease of oligodendrocytes in vitro.DiscussionPeripheral reactive immune cells could contribute remotely to MS pathogenesis by delivering myelin antibodies to oligodendrocytes. EV-derived myelin antibodies could play a role as diagnostic biomarker in MS.

Introduction: Extracellular vesicles (EVs) participate in cell-to-cell paracrine signaling and can be biomarkers of the pathophysiological processes underlying disease. In intracerebral hemorrhage, the study of the number and molecular content of circulating EVs may help elucidate the biological mechanisms involved in damage and repair, contributing valuable information to the identification of new therapeutic targets.Methods: The objective of this study was to describe the number and protein content of blood-derived EVs following an intracerebral hemorrhage (ICH). For this purpose, an experimental ICH was induced in the striatum of Sprague-Dawley rats and EVs were isolated and characterized from blood at baseline, 24 h and 28 days. The protein content in the EVs was analyzed by mass spectrometric data-dependent acquisition; protein quantification was obtained by sequential window acquisition of all theoretical mass spectra data and compared at pre-defined time points.Results: Although no differences were found in the number of EVs, the proteomic study revealed that proteins related to the response to cellular damage such as deubiquitination, regulation of MAP kinase activity (UCHL1) and signal transduction (NDGR3), were up-expressed at 24 h compared to baseline; and that at 28 days, the protein expression profile was characterized by a higher content of the proteins involved in healing and repair processes such as cytoskeleton organization and response to growth factors (COR1B) and the regulation of autophagy (PI42B).Discussion: The protein content of circulating EVs at different time points following an ICH may reflect evolutionary changes in the pathophysiology of the disease.

Multiple sclerosis (MS) remains the leading cause of neurological disability among young adults worldwide, underscoring the urgent need to define the best therapeutic strategy. Recent advances in proteomics have deepened our understanding of treatment mechanisms and revealed promising biomarkers for predicting therapeutic outcomes. This study focuses on the identification of a protein profile of circulating extracellular vesicles (EVs) derived from neurons, oligodendrocytes, and B and T cells able to differentiate treatment responders and non-responders in 80 patients with MS. In the patients who responded to treatment, T cell-derived EVs were enriched in LV151, a protein involved in the promotion of anti-inflammatory cytokines, whereas Bcell-derived EVs showed elevated PSMD6 and PTPRC, related to immunoproteasome function. Oligodendrocyte- and neuron-derived EVs showed upregulated CO6A1 and COEA1, involved in extracellular matrix reorganisation, as well as LAMA5, NonO, SPNT, and NCAM, which are critical for brain repair. In contrast, non-responders showed higher levels of PSMD7 and PRS10 from B cell-derived EVs, associated with DNA damage, and increased levels of PERM and PERL from T cell-derived EVs, linked to nuclear factor kappa B activation and drug-resistant proteins such as HS90A and RASK. These findings highlight a distinct panel of proteins in EVs that could serve as an early indicator of treatment efficacy in MS. [ABSTRACT FROM AUTHOR]

Abstract Background Xanthogranulomatous pyelonephritis (XGP) is an inflammatory condition of the kidney and its treatment most often involves a combination of antibiotics and nephrectomy. This study aimed to define the clinical features and management of XGP, focusing on microbiological aspects and antibiotic therapy. Methods We performed a retrospective study of 27 cases of XGP diagnosed between January 2001 and January 2020 to analyse their clinical and management characteristics. In addition, a literature review was conducted of XGP case series covering the period from 2000–2020. We searched PubMed for case series through April 2020 without language restrictions. Studies reporting case series of XGP (more than ten cases) were included if they were relevant to this study. Results Twenty-seven patients were diagnosed with XGP, and 26 of them were histologically proven to have XGP. A total of 81.5% of the patients were female and the mean age was 59.6 years (SD 19.2). The most frequent symptoms were flank pain (70.4%) and fever (59.3%), while 77.8% of patients had renal stones. Proteus mirabilis was detected in the urine culture in 18.5% of patients, followed by detection of Escherichia coli in 14.8% of patients. The computed tomography (CT) findings included perirenal (29.6%) or pararenal (29.6%) involvement in the majority of patients. Twenty-six patients underwent nephrectomy. Piperacillin/tazobactam and ceftriaxone were the most commonly prescribed antibiotics for treatment. The reported piperacillin/tazobactam and ceftriaxone resistance rates were 14.3% and 16.6%, respectively. Twenty-six case series were included in the literature review, reporting 693 cases in total. Conclusion We found well-established characteristics of XGP patients among series in terms of previous history, clinical, laboratory and imaging findings, and operative and postoperative outcomes. It is important to know the clinical presentation and potential severity of XGP, as well as the most frequently involved microorganisms and their antibiotic resistance profiles, to select the most appropriate antibiotic therapy.

Abstract Introduction Glycemic variability (GV) represents the amplitude of oscillations in glucose levels over time and is associated with higher mortality in critically ill patients. Our aim is to evaluate the impact of GV on acute ischemic stroke (IS) outcomes in humans and explore the impact of two different insulin administration routes on GV in an animal model. Methods This translational study consists of two studies conducted in parallel: The first study is an observational, multicenter, prospective clinical study in which 340 patients with acute IS will be subcutaneously implanted a sensor to continuously monitor blood glucose levels for 96 h. The second study is a basic experimental study using an animal model (rats) with permanent occlusion of the middle cerebral artery and induced hyperglycemia (through an intraperitoneal injection of nicotinamide and streptozotocin). The animal study will include the following 6 groups (10 animals per group): sham; hyperglycemia without IS; IS without hyperglycemia; IS and hyperglycemia without treatment; IS and hyperglycemia and intravenous insulin; and IS and hyperglycemia and subcutaneous insulin. The endpoint for the first study is mortality at 3 months, while the endpoints for the animal model study are GV, functional recovery and biomarkers. Discussion The GLIAS-III study will be the first translational approach analyzing the prognostic influence of GV, evaluated by the use of subcutaneous glucose monitors, in acute stroke. Trial registration https://www.clinicaltrials.gov (NCT04001049)

Inés María Laso-García, Fernando Arias-Fúnez, Gema Duque-Ruiz, David Díaz-Pérez, Javier Lorca-Álvaro, Francisco Javier Burgos-Revilla Urology Department, Ramón y Cajal University Hospital, Alcalá University, IRYCIS, Madrid, SpainCorrespondence: Inés María Laso-GarcíaUrology Department, Ramón y Cajal University Hospital, Alcalá University, IRYCIS, Carretera de Colmenar Km 9.100, Madrid 28029, SpainEmail ines.laso.garcia@gmail.comPurpose: The objective is to present a case of well-leg compartment syndrome in the Galdakao-modified supine Valdivia position.Results: The case of a 32-year-old male, obese (105 Kg) and a former smoker is presented. The patient was positioned in the Galdakao-modified supine Valdivia position, with lower limbs bandaged, to perform a right percutaneous nephrolithotomy. In the immediate postoperative period, significant pain was reported in the left lower limb. The limb appeared oedematous and cyanotic, although pedis pulses were preserved. Doppler ultrasound ruled out venous thrombosis. Suspecting compartment syndrome, the patient underwent a complete decompression fasciotomy of the four left leg compartments. After the surgery, values of creatine phosphokinase reached 80.000 UI/L and serum creatinine levels were 1.53 mg/dL. The patient was taken to the intensive care unit. Six months after the episode, the patient still needs rehabilitation care. The compartment syndrome is a rare complication in lithotomy position, but never described in the Galdakao-modified supine Valdivia position before, with the lower limbs in moderate flexion, and with the ipsilateral lower limb in a slightly inferior position with respect to the other. It may lead to skin necrosis, permanent neuromuscular dysfunction, myoglobinuric renal failure, amputation and even death. Therefore, this complication must be suspected and early decompression of the compartment must be performed. Risk factors include obesity, peripheral vascular disease (advanced age, hypertension, hyperlipidemia and diabetes mellitus), height, hypothermia, acidemia, BMI, male sex, combined general-spinal anesthesia, prolonged surgery time, systemic hypotension, ASA (American Society of Anesthesiologists) class, lack of operative experience, vasoconstricting drugs, important bleeding during the surgery and increased muscle bulk.Conclusion: Compartment syndrome is a potentially life-threatening complication that may occur in the Galdakao-modified supine Valdivia position. It should be suspected in cases with risk factors and compatible clinical symptoms and signs, and treated rapidly to avoid further complications.Keywords: well-leg compartment syndrome, percutaneous nephrolithotomy, Galdakao-modified supine Valdivia position

Acute ischemic stroke is currently a major cause of disability despite improvement in recanalization therapies. Stem cells represent a promising innovative strategy focused on reduction of neurologic sequelae by enhancement of brain plasticity. We performed a phase IIa, randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. Patients aged ≥60 years with moderate to severe stroke (National Institutes of Health Stroke Scale [NIHSS] 8–20) were randomized (1:1) to receive intravenous adipose tissue–derived mesenchymal stem cells (AD-MSCs) or placebo within the first 2 weeks of stroke onset. The primary outcome was safety, evaluating adverse events (AEs), neurologic and systemic complications, and tumor development. The secondary outcome evaluated treatment efficacy by measuring modified Rankin Scale (mRS), NIHSS, infarct size, and blood biomarkers. We report the final trial results after 24 months of follow-up. Recruitment began in December 2014 and stopped in December 2017 after 19 of 20 planned patients were included. Six patients did not receive study treatment: two due to technical issues and four for acquiring exclusion criteria after randomization. The final study sample was composed of 13 patients (4 receiving AD-MSCs and 9 placebo). One patient in the placebo group died within the first week after study treatment delivery due to sepsis. Two non-treatment-related serious AEs occurred in the AD-MSC group and nine in the placebo group. The total number of AEs and systemic or neurologic complications was similar between the study groups. No injection-related AEs were registered, nor tumor development. At 24 months of follow-up, patients in the AD-MSC group showed a nonsignificantly lower median NIHSS score (interquartile range, 3 [3–5.5] vs 7 [0–8]). Neither treatment group had differences in mRS scores throughout follow-up visits up to month 24. Therefore, intravenous treatment with AD-MSCs within the first 2 weeks from ischemic stroke was safe at 24 months of follow-up.

Introduction. Transplantation surgery teams often have to face complex cases. In certain circumstances, such as occlusion of the iliac vessels or prior pelvic surgery, heterotopic kidney transplantation may not be feasible and orthotopic kidney transplantation (OKT) could be a good alternative. Kidney autotransplantation (KAT) has been described as a potential treatment for complex renovascular, ureteral, or neoplastic conditions. There are scarce data regarding the complications and outcomes of these procedures; therefore, we present our experience. Materials and Methods. We retrospectively analysed the medical records of both 21 patients who had received OKT and 19 patients who underwent KAT between 1993 and 2020. We collected demographic features and data regarding surgical technique, complications, and graft outcomes. Kidney graft survival was calculated using Kaplan–Meier survival analysis. Results. Regarding OKT, in 15 (71.43%) cases, it was the first kidney transplantation. The most common indication was the unsuitable iliac region due to vascular abnormalities (57.14%). The early postoperative complication rate was high (66.67%), with 23.81% of Clavien grade 3b complications. During the follow-up period (mean 5.76 -SD 6.15- years), we detected 9 (42.85%) graft losses. At 1 year, the survival rate was 84.9%. Concerning KAT, the most frequent indication was ureteral pathology (52.63%), followed by vascular lesions (42.11%). The overall early complication rate was 42.11%. During the follow-up period (mean of 4.47 years), 4 (15.79%) graft losses were reported. Conclusions. Although OKT and KAT have high complication rates, these techniques can be considered as two valuable approaches for complex cases, in the absence of other therapeutic options.

Background: Magnetic resonance imaging (MRI) is currently used for the study of intracerebral hemorrhage (ICH) in animal models. However, ultrasound is an inexpensive, non-invasive and rapid technique that could facilitate the diagnosis and follow-up of ICH. This study aimed to evaluate the feasibility and reliability of B-mode ultrasound as an alternative tool for in vivo monitoring of ICH volume and brain structure displacement in an animal model.Methods: A total of 31 male and female Sprague-Dawley rats were subjected to an ICH model using collagenase-IV in the striatum following stereotaxic references. The animals were randomly allocated into 3 groups: healthy (n = 10), sham (n = 10) and ICH (n = 11). B-mode ultrasound studies with a 13-MHz probe were performed pre-ICH and at 5 h, 48 h, 4 d and 1 mo post-ICH for the assessment of ICH volume and displacement of brain structures, considering the distance between the subarachnoid cisterns and the dura mater. The same variables were studied by MRI at 48 h and 1 mo post-ICH.Results: Both imaging techniques showed excellent correlation in measuring ICH volume at 48 h (r = 0.905) and good at 1 mo (r = 0.656). An excellent correlation was also observed in the measured distance between the subarachnoid cisterns and the dura mater at 1 mo between B-mode ultrasound and MRI, on both the ipsilateral (r = 0.870) and contralateral (r = 0.906) sides of the lesion.Conclusion: B-mode ultrasound imaging appears to be a reliable tool for in vivo assessment of ICH volume and displacement of brain structures in animal models.

Abstract Background Mesenchymal stem cell-derived extracellular vesicles (EVs) are one of the most promising therapeutics in protective and/or regenerative therapy in animal models of stroke using a dose of 100 μg. However, whether EVs dose is related to outcomes is not known. This study aimed to identify the optimal effective dose of EVs from adipose tissue-derived mesenchymal stem cells that promote functional recovery in subcortical stroke. Materials and methods For this purpose, various doses of EVs were tested in an in vitro oxygen-glucose deprivation (OGD) model of oligodendrocytes and neuronal ischemia. At least 50 μg of EVs were necessary to induce proliferation and differentiation of oligodendrocyte and neurons in OGD conditions. For in vivo study, rats were subjected to subcortical stroke and various doses (50 μg, 100 μg, or 200 μg) of EVs were intravenously administered after 24 h. Results All the animals in the EV groups showed significant improvement in functional tests, with an increase in tract connectivity and brain repair-associated markers, and a decrease in cell death and in astrocyte-marker expression. Cell proliferation was increased in the groups receiving 50 μg and 100 μg doses. Only the 50-μg dose was associated with significant increases in brain-derived neurotrophic factor expression. Conclusion In conclusion, 50 μg of EVs appears to be the minimal effective dose to enhance protection, brain repair, and recovery in subcortical ischemic stroke.

Abstract Background Over 50% of acute stroke patients have hyperglycemia, which is associated with a poorer prognosis and outcome. Our aim was to investigate the impact of hyperglycemia on behavioral recovery and brain repair of delivered human adipose tissue-derived mesenchymal stem cells (hAD-MSCs) in a rat model of permanent middle cerebral artery occlusion (pMCAO). Methods Hyperglycemia was induced in rats by the administration of nicotinamide and streptozotocin. The rats were then subjected to stroke by a pMCAO model. At 48 h post-stroke, 1 × 106 hAD-MSCs or saline were intravenously administered. We evaluated behavioral outcome, infarct size by MRI, and brain plasticity markers by immunohistochemistry (glial fibrillary acidic protein [GFAP], Iba-1, synaptophysin, doublecortin, CD-31, collagen-IV, and α-smooth muscle actin [α-SMA]). Results The hyperglycemic group exhibited more severe neurological deficits; lesion size and diffusion coefficient were larger compared with the non-hyperglycemic rats. GFAP, Iba-1, and α-SMA were increased in the hyperglycemic group. The hyperglycemic rats administered hAD-MSCs at 48 h after pMCAO had improved neurological impairment. Although T2-MRI did not show differences in lesion size between groups, the rADC values were lower in the treated group. Finally, the levels of GFAP, Iba-1, and arterial wall thickness were lower in the treated hyperglycemic group than in the nontreated hyperglycemic group at 6 weeks post-stroke. Conclusions Our data suggest that rats with hyperglycemic ischemic stroke exhibit increased lesion size and impaired brain repair processes, which lead to impairments in behavioral recovery after pMCAO. More importantly, hAD-MSC administration induced better anatomical tissue preservation, associated with a good behavioral outcome.

Intraparenchymal renal artery aneurysms are uncommon and represent less than 10% of all renal artery aneurysms. They are caused by trauma or iatrogenic injury, and their rupture can lead to life-threatening hemorrhage. We report the case of a 48-year-old male with history of left solitary kidney and orthotopic neobladder, who presented with massive hematuria 7 days after nephrostomy tube placement because of obstructive uropathy and acute renal failure due to ureteroileal stricture. An abdominal CT angiography revealed an intraparenchymal renal artery aneurysm, and it was successfully treated with superselective endovascular embolization, achieving maximal parenchymal preservation.