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Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic approach in the management of several pathologies, including central nervous system diseases. Previously, we demonstrated the therapeutic potential of human adipose-derived MSCs for neurological sequelae of oncological radiotherapy using the intranasal route as a non-invasive delivery method. However, a comprehensive investigation of the safety of intranasal MSC treatment should be performed before clinical applications. Here, we cultured human MSCs in compliance with quality control standards and administrated repeated doses of cells into the nostrils of juvenile immunodeficient mice, mimicking the design of a subsequent clinical trial. Short- and long-term effects of cell administration were evaluated by in vivo and ex vivo studies. No serious adverse events were reported on mouse welfare, behavioral performances, and blood plasma analysis. Magnetic resonance study and histological analysis did not reveal tumor formation or other abnormalities in the examined organs of mice receiving MSCs. Biodistribution study reveals a progressive disappearance of transplanted cells that was further supported by an absent expression of human GAPDH gene in the major organs of transplanted mice. Our data indicate that the intranasal application of MSCs is a safe, simple and non-invasive strategy and encourage its use in future clinical trials, This work was funded by grants from the Andalusian Regional Ministry of Health (PI- 0272-2017 to V.C.-G), the Institute of Health Carlos III co-funded by Fondos FEDER (PI20/00341, CP19/00046 to V.C.-G; PI18/01590, CPII19/00023 to A.M.-M.), the Fundación Científica de la Asociación Española Contra el Cáncer (IDEAS20051CAPI to V.C.-G.), the crowdfunding platform PRECIPITA of the Spanish Foundation for Science and Technology (2018-000237 to V.C.-G.), and the Asociación Pablo Ugarte (+ VIDA project to V.C.-G).

Objectives Preoperative breast magnetic resonance imaging (MRI) can inform surgical planning but might cause overtreatment by increasing the mastectomy rate. The Multicenter International Prospective Analysis (MIPA) study investigated this controversial issue. Methods This observational study enrolled women aged 18–80 years with biopsy-proven breast cancer, who underwent MRI in addition to conventional imaging (mammography and/or breast ultrasonography) or conventional imaging alone before surgery as routine practice at 27 centers. Exclusion criteria included planned neoadjuvant therapy, pregnancy, personal history of any cancer, and distant metastases. Results Of 5896 analyzed patients, 2763 (46.9%) had conventional imaging only (noMRI group), and 3133 (53.1%) underwent MRI that was performed for diagnosis, screening, or unknown purposes in 692/3133 women (22.1%), with preoperative intent in 2441/3133 women (77.9%, MRI group). Patients in the MRI group were younger, had denser breasts, more cancers ≥ 20 mm, and a higher rate of invasive lobular histology than patients who underwent conventional imaging alone (p p p p Conclusions Clinicians requested breast MRI for women with a higher a priori probability of receiving mastectomy. MRI was associated with 11.3% more mastectomies, and with 3.2% fewer reoperations in the breast conservation subgroup. Key Points • In 19% of patients of the MIPA study, breast MRI was performed for screening or diagnostic purposes. • The current patient selection to preoperative breast MRI implies an 11% increase in mastectomies, counterbalanced by a 3% reduction of the reoperation rate. • Data from the MIPA study can support discussion in tumor boards when preoperative MRI is under consideration and should be shared with patients to achieve informed decision-making.

Contains fulltext : 225795.pdf (Publisher’s version ) (Closed access) Despite its high diagnostic performance, the use of breast MRI in the preoperative setting is controversial. It has the potential for personalized surgical management in breast cancer patients, but two of three randomized controlled trials did not show results in favor of its introduction for assessing the disease extent before surgery. Meta-analyses showed a higher mastectomy rate in women undergoing preoperative MRI compared to those who do not. Nevertheless, preoperative breast MRI is increasingly used and a survey from the American Society of Breast Surgeons showed that 41% of respondents ask for it in daily practice. In this context, a large-scale observational multicenter international prospective analysis (MIPA study) was proposed under the guidance of the European Network for the Assessment of Imaging in Medicine (EuroAIM). The aims were (1) to prospectively and systematically collect data on consecutive women with a newly diagnosed breast cancer, not candidates for neoadjuvant therapy, who are offered or not offered breast MRI before surgery according to local practice; (2) to compare these two groups in terms of surgical and clinical endpoints, adjusting for covariates. The underlying hypotheses are that MRI does not cause additional mastectomies compared to conventional imaging, while reducing the reoperation rate in all or in subgroups of patients. Ninety-six centers applied to a web-based call; 36 were initially selected based on volume and quality standards; 27 were active for enrollment. On November 2018, the target of 7000 enrolled patients was reached. The MIPA study is presently at the analytic phase. Key Points • Breast MRI has a high diagnostic performance but its utility in the preoperative setting is controversial. • A large-scale observational multicenter prospective study was launched to compare women receiving with those not receiving preoperative MRI. • Twenty-seven centers enrolled more than 7000 patients. The study is presently at the analytic phase.

The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyse brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice. The observational study was registered at Clinicaltrial.gov as NCT02076763.

Introduction: The objective of this study was to evaluate the association between the type of initial fluid therapy used (isotonic or hypotonic solutions) and the development of hyponatremia, the plasma chlorine values and the tolerance of venous access. Patients and Method: Retrospective cohort study in a Pediatric Intensive Care Unit (PICU) of a high complexity hospital. There were included children younger than 15 years old hospitalized during the first semester of 2010 and 2013 who received intravenous maintenance fluid therapy, excluding patients undergoing cardiac surgery, kidney transplant and admissions that lasted less than 24 hours. Epidemiological, comorbidity and admission related data were collected, including type of solution received, sodium and chlorine values in the first 72 hours of hospitalization and the incidence of extravasation of peripheral intravenous lines. Results: 111 children were included; 68 children (61.3%) were treated with hypotonic solutions and 43 (38.7%) with isotonic solutions. There were no differences in pathology and severity, and also in the volume of fluid received. Among the patients who received hypotonic solutions, 28 (41.2%) developed hyponatremia, wich was moderate (Na

Introduction: Total hip and knee arthroplasty (THA/TKA) are surgical procedures with proven benefits. Although the literature reports outcomes of fusion of the lumbar spine comparable to those of THA/TKA in general health-related quality-of-life (HRQoL) questionnaires, functional assessment is nevertheless needed for these results to be of use in clinical practice and management. Aim of our study was to prove that lumbar spinal fusion has similar if not better outcomes than THA/TKA using intervention-specific HRQoL questionnaires and functional assessment questionnaires. Materials and methods: Observational, ambispective, multicentre study of three cohorts undergoing lumbar spinal fusion (n = 115), THA (n = 119) and TKA (n = 253). Patients were evaluated using the Short-Form-12 (SF-12), Harris–Hip-Score, Hospital for Special Surgery Scale (HSS) and Oswestry Low Back Pain Disability questionnaires. A minimum follow-up of two years was conducted. Results: The SF-12 showed significant improvement in all groups. The SF-12 physical component summary score indicated a more severe pre-operative status (p = 0.031) in the THA cohort. The mental component summary score indicated a less severe pre-operative status in the TKA cohort (p = 0.008) and greater post-operative improvement in the TKA and THA cohorts across follow-up (six months p = 0.021; one year p = 0.012; two years p = 0.042). Functional assessment indicated greater pre-operative disability in the THA group. At two years of follow-up, functional improvement according to the Harris, HSS and Oswestry questionnaires were 152.01%, 50.07% and 41.14% respectively. Conclusions: This study demonstrates that lumbar spinal fusion and total knee and hip arthroplasty are comparable in terms of functional improvement when thoroughly studied with health, quality-of-life and functional assessment questionnaires.

Meningoencephalitis of unknown origin (MUO) is a common inflammatory disease of the central nervous system. Several studies investigated finding prognostic factors, but results are contradictory. The aim of this study was to determine the concentrations of blood lactate (Blood-L) and cerebrospinal fluid lactate (CSF-L) in dogs with MUO for prognostic purposes. A total of 45 dogs with MUO (MUO group) and 11 with idiopathic epilepsy (IE group) were included. In the MUO group, 22 dogs were treated with prednisolone + cytosine arabinoside, 17 with prednisolone ± cyclosporine, and six received no treatment. In the MUO group, there was a strong-moderate positive correlation between Blood-L and CSF-L (ρ = 0.63557; P 0.0001), a strong-moderate negative correlation between survival and CSF-L (ρ= -0.50210; P 0.0004), and a weak negative correlation between survival and Blood-L (ρ= -0.35685; P 0.0220). Dogs with a favourable response to treatment at 1 month had lower initial concentrations of Blood-L and CSF-L (P 0.0010; P 0.0037), and those with a worse response had higher values (P 0.0497; P 0.0004). Dogs that remained stable with treatment showed lower CSF-L concentrations (P 0.0013). Dogs with Blood-L4 mmol/L (P 0.03) and/or CSF-L4 mmol/L (P 0.009) had lower survival rates with the latter also showing more severe signs, probably indicating severe neuronal damage. These findings suggest that concentrations of CSF-L and Blood-L in dogs with MUO could be used as prognostic indicators.

Objective To assess the contribution of mammography and ultrasound in men with nipple discharge. Materials and methods All men with nipple discharge who underwent mammography and/or ultrasound between 1993 and 2011 in our hospital were retrospectively evaluated. Radiological findings were classified according to BI-RADS lexicon. The final diagnosis was made based on histopathological results or clinical–radiological follow-up. The diagnostic performance of physical examination, mammography and ultrasound was calculated and compared. Results 26 men with 21 mammograms and 19 ultrasounds were reviewed. The final diagnoses were: 6 carcinomas (23.1%), 10 gynaecomastias, 2 pseudogynaecomastias and 8 normal breast tissues. Mammograms and ultrasounds performed on all five patients with infiltrating carcinoma showed a mass (categories 4 and 5). In all these patients except one, a breast mass was also noted and the physical examination was positive or suspected malignancy. In the patient with carcinoma in situ, the only conspicuous clinical sign was bloody nipple discharge and the mammography showed calcifications (category 4) that were not visible on ultrasound. Radiological findings of all patients without malignancy were classified as categories 1 and 2. The diagnostic performance of physical examination was lower than mammography and ultrasound (P > 0.05). Mammography was more sensitive than ultrasound (100% vs. 83.3%). Both techniques showed the same specificity (100%). Conclusions Men with nipple discharge have a high incidence of breast carcinoma. Nipple discharge may be the only clinical sign of carcinoma in situ. Mammography and ultrasound are useful in the evaluation of men with nipple discharge, diagnosing carcinoma in initial stages, avoiding unnecessary biopsies.

Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks when hepatic heme synthesis is activated by endogenous or environmental factors including fasting. While the molecular mechanisms underlying the nutritional regulation of hepatic heme synthesis have been described, glucose homeostasis during fasting is poorly understood in porphyria. Our study aimed to analyse glucose homeostasis and hepatic carbohydrate metabolism during fasting in PBGD-deficient mice. To determine the contribution of hepatic PBGD deficiency to carbohydrate metabolism, AIP mice injected with a PBGD-liver gene delivery vector were included. After a 14 h fasting period, serum and liver metabolomics analyses showed that wild-type mice stimulated hepatic glycogen degradation to maintain glucose homeostasis while AIP livers activated gluconeogenesis and ketogenesis due to their inability to use stored glycogen. The serum of fasted AIP mice showed increased concentrations of insulin and reduced glucagon levels. Specific over-expression of the PBGD protein in the liver tended to normalize circulating insulin and glucagon levels, stimulated hepatic glycogen catabolism and blocked ketone body production. Reduced glucose uptake was observed in the primary somatosensorial brain cortex of fasted AIP mice, which could be reversed by PBGD-liver gene delivery. In conclusion, AIP mice showed a different response to fasting as measured by altered carbohydrate metabolism in the liver and modified glucose consumption in the brain cortex. Glucose homeostasis in fasted AIP mice was efficiently normalized after restoration of PBGD gene expression in the liver.

A number of metabolites have signaling properties by acting through G-protein–coupled receptors. Succinate, a Krebs cycle intermediate, increases after dysregulated energy metabolism and can bind to its cognate receptor succinate receptor 1 (Sucnr1, or GPR91) to activate downstream signaling pathways. We show that Sucnr1 is highly expressed in the white adipose tissue (WAT) compartment of mice and regulates adipose mass and glucose homeostasis. Sucnr1−/− mice were generated, and weight gain was monitored under basal and nutritional stress (high-fat diet [HFD]) conditions. On chow diet, Sucnr1−/− mice had increased energy expenditure, were lean with a smaller WAT compartment, and had improved glucose buffering. Lipolysis measurements revealed that Sucnr1−/− mice were released from succinate-induced inhibition of lipolysis, demonstrating a function of Sucnr1 in adipose tissue. Sucnr1 deletion also protected mice from obesity on HFD, but only during the initial period; at later stages, body weight of HFD-fed Sucnr1−/− mice was almost comparable with wild-type (WT) mice, but WAT content was greater. Also, these mice became progressively hyperglycemic and failed to secrete insulin, although pancreas architecture was similar to WT mice. These findings suggest that Sucnr1 is a sensor for dietary energy and raise the interesting possibility that protocols to modulate Sucnr1 might have therapeutic utility in the setting of obesity.

16 páginas, 9 figuras, 1 tabla, Adult neurogenesis is restricted to specific brain regions. Although involved in the continuous supply of interneurons for the olfactory function, the role of neural precursors in brain damage-repair remains an open question. Aiming to in vivo identify endogenous neural precursor cells migrating towards a brain damage site, the monoclonal antibody Nilo2 recognizing cell surface antigens on neuroblasts, was coupled to magnetic glyconanoparticles (mGNPs). The Nilo2-mGNP complexes allowed, by magnetic resonance imaging in living animals, the in vivo identification of endogenous neural precursors at their niche, as well as their migration to a lesion site (induced brain tumor), which was fast (within hours) and orderly. Interestingly, the rapid migration of neuroblasts towards a damage site is a characteristic that might be exploited to precisely localize early damage events in neurodegenerative diseases. In addition, it might facilitate the study of regenerative mechanisms through the activation of endogenous neural cell precursors. A similar approach, combining magnetic glyconanoparticles linked to appropriate antibodies could be applied to flag other small cell subpopulations within the organism, track their migration, localize stem cell niches, cancer stem cells or even track metastatic cells, This work was supported by CSIC (PIF200620F0041), MICINN (SAF2009-07974; RD06/0010/1010 from the Instituto de Salud Carlos III, CTQ2008-04638) and the Department of Industry, Innovation and Technology of the Basque Country (grant ETORTEK)

To assess clinical variables that may be useful in differentiating gynaecomastia from carcinoma and to analyse the contribution of mammography and ultrasound to the evaluation of male breast disease.All men who underwent mammography and/or ultrasound between 1993 and 2006 in our hospital were retrospectively evaluated. Clinical characteristics in patients with gynaecomastia and those with carcinoma were compared. Radiological findings were classified according to the BI-RADS (Breast Imaging Reporting and Data System) criteria. The diagnostic performance of physical examination, mammography and ultrasound was determined and compared.A total of 628 patients with 518 mammograms and 423 ultrasounds were reviewed. The final diagnoses were: 19 carcinomas, 526 gynaecomastias, 84 other benign conditions and 25 normal. There were statistically significant differences in age, bilateral involvement, clinical presentation and physical examination between patients with carcinoma and those with gynaecomastia. The diagnostic performance of physical examination was lower than that of mammography and ultrasound (p0.05 for specificity). Mammography was the most sensitive (94.7%) and ultrasound the most specific (95.3%) for detection of malignancy (p0.05). We propose an algorithm for the use of mammography and ultrasound in men.Mammography and ultrasound, with a negative predictive value close to 100%, make it possible to avoid very many unnecessary surgical procedures in men.

Preoperative diagnosis of axillary metastases in breast cancer patients enables treatment planning. We aimed to evaluate the diagnostic accuracy of axillary ultrasonography and percutaneous biopsy, both alone and in combination, in detecting axillary metastases in patients with breast cancer and to assess the impact of these techniques on the patients’ management. Materials and methods Retrospective study of consecutive patients with suspected breast cancer examined between October 2006 and December 2008. The diagnosis of a primary tumor was histologically confirmed in all patients. All patients underwent axillary ultrasonography and percutaneous core biopsy (14G) of suspicious lymph nodes. We evaluated the morphological characteristics of the lymph nodes by ultrasonography. We calculated the diagnostic accuracy of ultrasonography and of core biopsy, and assessed the impact of these techniques on patients’ treatment. Results We evaluated 675 axillary regions and performed 291 core biopsies of axillary lymph nodes in 662 patients. In 650 patients, breast cancer was histologically confirmed and in 12 patients malignant tumors in other locations were confirmed. The sensitivity and specificity of axillary ultrasonography were 63.2% and 88.7%, respectively. The absence of a fatty hilum within the lymph node was the ultrasonographic finding with the highest positive predictive value for malignancy (93.1%). The sensitivity and specificity of axillary core biopsy were 69.1% and 100%, respectively. Sentinel lymph node biopsy was avoided in 33% of initial candidates and immediate breast reconstruction was undertaken in 35.1% of the patients with mastectomy and negative axillary core biopsy. Conclusions Ultrasonography and axillary core biopsy enable adequate pretreatment staging in patients with breast cancer and has a positive impact on their management.