Allelic variants of the estrogen receptor genes and frailty phenotype in postmenopausal women.

OBJECTIVE: The prevalence of frailty has been related to menopause. Our main objective was to investigate whether single nucleotide polymorphisms (SNPs) of the estrogen receptor (ER) ERα and ERß genes were related to the frailty phenotype in a population of community-dwelling postmenopausal women. METHODS: A cross-sectional study was performed in which we selected five SNPs, three in the ERα gene and two in the ERß. Linear regression was used to estimate the percentage of phenotypic variance after adjusting for confounding variables. RESULTS: A total of 470 women (mean ± standard deviation age 63.83 ± 8.16 years) were included, of whom 137 women were frail. The SNP rs3798577 of the ERα gene was the only variant associated with frailty, but this significance faded in the multivariant analysis. Body mass index (p = 0.012), number of comorbidities (0 vs. ≥2, p = 0.002) and two reproductive variables, number of miscarriages (none vs. ≥2, p = 0.036) and of childbirths (one vs. ≥3, p = 0.008), were independently related to frailty. CONCLUSION: The five SNPs of the ERα and ERß genes tested were not correlated with frailty. Other SNPs of the ER warrant analysis to clarify whether variance in the gene response affects frailty status.

Exploring the potential of Physics-Informed Neural Networks to extract vascularization data from DCE-MRI in the presence of diffusion.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is widely used to assess tissue vascularization, particularly in oncological applications. However, the most widely used pharmacokinetic (PK) models do not account for contrast agent (CA) diffusion between neighboring voxels, which can limit the accuracy of the results, especially in cases of heterogeneous tumors. To address this issue, previous works have proposed algorithms that incorporate diffusion phenomena into the formulation. However, these algorithms often face convergence problems due to the ill-posed nature of the problem. In this work, we present a new approach to fitting DCE-MRI data that incorporates CA diffusion by using Physics-Informed Neural Networks (PINNs). PINNs can be trained to fit measured data obtained from DCE-MRI while ensuring the mass conservation equation from the PK model. We compare the performance of PINNs to previous algorithms on different 1D cases inspired by previous works from literature. Results show that PINNs retrieve vascularization parameters more accurately from diffusion-corrected tracer-kinetic models. Furthermore, we demonstrate the robustness of PINNs compared to other traditional algorithms when faced with noisy or incomplete data. Overall, our results suggest that PINNs can be a valuable tool for improving the accuracy of DCE-MRI data analysis, particularly in cases where CA diffusion plays a significant role.

Biomechanical Evaluation of Hemiarthroplasty in the First Proximal Phalanx. A Finite Element Study

ABSTRACT Hallux rigidus produces a decrease in the dorsiflexion of the first metatarsophalangeal joint and is usually associated with the appearance of osteophytes. Hemiarthroplasty in the first proximal phalanx is a recommended surgical procedure in patients with advanced grade of hallux rigidus. Finite element analysis allows us to understand the biomechanical behavior of the foot. The objective of this work is to evaluate the biomechanical effects of an hemi implant placed in first proximal phalanx. Two models of finite elements are going to be compared, one free of pathologies and the other with a hemiarthroplasty in the first ray of the foot. We detected after inserting the prosthesis in the model that passive windlass mechanism is lost, and the lesser toes become overloaded, which leads to a loss of efficiency in gait as well as being able to cause postsurgical medical complications.

Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease. / Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert.

BACKGROUND AND OBJECTIVES: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. MATERIAL AND METHODS: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. RECOMMENDATIONS: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. CONCLUSION: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.

Intraocular pressure fluctuations in patients implanted with an implantable collamer lens (ICL V4c). Three-month follow-up. / Fluctuaciones de presión intraocular en pacientes operados con implante de implantable collamer lens (ICL V4c). Seguimiento a 3 meses.

INTRODUCTION: Fluctuating elevated intraocular pressure (IOP) is one of the complications of an implantable collamer lens (ICL), and its alteration is a predictive factor for the development of glaucoma. MATERIAL AND METHODS: A prospective, cross-sectional analytic study was conducted on patients suitable for ICL implantation. Complete clinical and biometric work-ups were performed, as well as night-time IOP curve, in supine position, with 4 determinations, in order to assess fluctuation, considering abnormal with a value higher than 5 mmHg. Patients underwent surgery with conventional technique and three months after the work-ups were repeated, including a night-time IOP curve to assess any changes in IOP fluctuations. RESULTS: A total of 31 eyes of 16 patients were studied. Mean IOP fluctuation in the preoperative assessment was 3.35 ± 2 mmHg, whereas the postoperative mean was 3.0 ± 2.2 mmHg, with the difference not being statistically significant. Visual acuity and capacity, as well as spheric equivalent did show a statistically significant improvement. There were 6 cases of complications, which were related to a higher vault and a greater ICL size. There was no relationship between these findings and the angle grade, pigment, and the level of training of the surgeon. CONCLUSIONS: The effect of an ICL on IOP fluctuations, has been studied for the first time, which was found to be not statistically significant. As in previous publications, the procedure was safe and reproducible, adding the fact that the level of training of the surgeon is not a determining factor in these findings.

Adhesión y proliferación de las células troncales mesenquimales de médula ósea en andamios fibrilares de poli (ácido L-láctico) (PLA) / Adhesion and proliferation of bone marrow mesenchymal stem cells onto poli-L lactic acid (PLA) fiber scaffolds

Resumen: Los andamios fibrilares han recibido un enorme interés como futuros biomateriales con potencial aplicación en el campo de la biomedicina regenerativa. En este sentido, hemos optimizado los parámetros para la síntesis de diferentes concentraciones (6, 7, y 10 %) de andamios de ácido poli-láctico (PLA) por la técnica de hilado por propulsión de gas (AJS). Dichos andamios fueron caracterizados por Microscopía Electrónica de Barrido (SEM) y por espectrometría Infrarroja con Transformada de Fourier (FTIR). Nuestros resultados mostraron que los andamios son fibrilares con diámetros en escalas nanométricas. Asimismo; se estudió la biocompatibilidad celular in vitro al realizar ensayos de adhesión, proliferación y de interacción célula-material al cultivar células troncales mesenquimales derivadas de médula ósea. Nuestros datos indican que las membranas fibrilares de PLA aumentan la respuesta celular, no son citotóxicas al compararse con las películas delgadas de PLA. Por lo tanto; el método de síntesis propuesto tiene potencial para la fabricación de membranas hiladas con una facilidad de procesamiento y podría ser un prometedor biomaterial económico con futuras aplicaciones en la regeneración de tejidos.

Abstract: Fiber scaffolds have received increasing interest as promising biomaterials for potential application in the field of tissue regeneration. In this sense, we optimized the parameters for the synthesis of different concentrations (6, 7, and 10 %) of poly-lactic acid (PLA) scaffolds by air jet spinning technology (AJS). The PLA scaffolds were characterized by Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FTIR) analysis. Our results by SEM micrographs showed that scaffolds have a fibrilar morphology with nanoscale diameter of fibers. Biocompatibility assay was observed through an in vitro experiment based on cell attachment, MTT and cell-material interaction assay when culturing bone marrow-derived mesenchymal stem cells onto the PLA spun membrane scaffolds. Our data indicate that fiber membrane of PLA scaffold increase the cellular response, are not cytotoxic when compared to thin films of PLA. Thus; the proposed synthesis method has potential for easy processing of spun fibrilar scaffolds with good biocompatibility and could be a promising economical biomaterial with future potential applications in tissue regeneration.

Hoxa-10 and Cyclin D3 Overexpression in the Decidual Reaction in a Superovulation Protocol in Young Adult C57BL/6J Mice.

Following the performance of a superovulation protocol, multiple nodules were observed bilaterally in the uterine horns of 31 of 276 (11.2%) C57BL/6 J female mice aged 8.5 ± 0.6 (mean and standard error of mean) weeks. These lesions prevented embryo collection, and the uterine decidual reaction was suspected. Samples of pathological uteri (n = 20) and the normal genital tracts of donors treated with a similar superovulation protocol (control group, n = 10) were collected. Immunohistochemistry was performed to evaluate pancytokeratin, desmin, vimentin, progesterone receptor (PR), estrogen receptor α (ERα), Ki-67, cyclin D3 and c-Myc expression, as well as quantitative polymerase chain reaction to assess cyclin D3, Hoxa-10 and heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA expression. The uterine decidual reaction presented a high degree of structural organization and specifically affected the antimesometrial region of the endometrium. The abnormal decidual cells were large polygonal cells that were frequently polyploid or binucleated and strongly positive for desmin. Immunohistochemistry showed higher Ki-67 proliferation index and higher expression of PR and cyclin D3 in decidual cells in the antimesometrial aspect of the endometrium, compared to nondecidualized endometrial stromal cells in the mesometrial aspect of affected uteri, and compared to endometrial stromal cells in healthy uteri. High expression of cyclin D3 and Hoxa-10 mRNA was also observed in uteri affected by the decidual reaction. These results suggest that PR overexpression in endometrial stromal cells, likely due to high progesterone levels, triggers cyclin D3 and Hoxa-10 overexpression, which may be involved in the pathological mechanisms of the mouse uterine decidual reaction.

Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation.

In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.

Effects on growth and osteogenic differentiation of mesenchymal stem cells by the strontium-added sol-gel hydroxyapatite gel materials.

In the present study, strontium-modified hydroxyapatite gels (Sr-HA) at different concentrations were prepared using sol-gel approach and their effect on human-bone-marrow-derived mesenchymal stem cells, were evaluated. The effect of Strontium on physico-chemical and morphological properties of hydroxyapatite gel were evaluated. Morphological analyses (SEM and TEM) demonstrate that an increasing in the amount of Sr ions doped into HA made the agglomerated particles smaller. The substitution of large Sr2+ for small Ca2+ lead to denser atomic packing of the system causing retardation of crystals growth. The biological results demonstrated that hydroxyapatite gel containing from 0 to 20 mol% of Sr presented no cytotoxicity and promote the expression of osteogenesis related genes including an early marker for osteogenic differentiation ALP; a non-collagen protein OPN and a late marker for osteogenic differentiation OCN. Finally, the Sr-HA gels could have a great potential application as filler in bone repair and regeneration and used in especially in the osteoporotic disease.

Effect of citric acid crosslinking cellulose-based hydrogels on osteogenic differentiation.

Understanding the relationships between material surface properties and cellular responses is essential to designing optimal material surfaces for implantation and tissue engineering. In this study, cellulose hydrogels were crosslinked using a non-toxic and natural component namely citric acid. The chemical treatment induces COOH functional groups that improve the hydrophilicity, roughness, and materials rheological properties. The physiochemical, morphological, and mechanical analyses were performed to analyze the material surface before and after crosslinking. This approach would help determine if the effect of chemical treatment on cellulose hydrogel improves the hydrophilicity, roughness, and rheological properties of the scaffold. In this study, it was demonstrated that the biological responses of human mesenchymal stem cell with regard to cell adhesion, proliferation, and differentiation were influenced in vitro by changing the surface chemistry and roughness.

Iberian pig early pregnancy: vascular endothelial growth factor receptor system expression in the maternofetal interface in healthy and arresting conceptuses.

In Iberian pigs, a high conceptus loss occurs during the first 30 days of gestation. Although the exact causes for these losses have not been determined to date, the importance of blood vessel development during early pregnancy has been noted. The aim of this study was to analyze the messenger RNA (mRNA) and protein expression of VEGF-rs (vascular endothelial growth factor, the VEGFR1, and the VEGFR2 receptor system) and elucidate a possible relationship with the conceptus status (healthy or arrested) on gestational Days (gd) 22 and 32. Both mRNA and protein expression for VEGF-rs molecules were consistently expressed in conceptuses and endometrium during the pregnancy period analyzed. In endometrium, a significant increase in VEGF mRNA and VEGFR2 mRNA expression in healthy sites was observed as pregnancy advances (P < 0.001 and P < 0.05, respectively), whereas VEGFR1 mRNA expression was maintained at a constant level. Interestingly, a significantly elevated VEGFR2 mRNA expression (P < 0.05) was observed on gd 22 in endometrium from arrested conceptuses. Furthermore, VEGF mRNA and VEGFR1 mRNA expression in trophoblasts from healthy conceptuses decreased as pregnancy proceeded (P < 0.001). Arrested trophoblasts on gd 32 showed higher VEGFR2 mRNA expression than healthy conceptuses (P < 0.05). Although, in endometrium attachment sites, the pattern of VEGF-rs immunostaning was not affected by conceptus status, the immunoexpression of VEGF-rs in healthy attachment sites increased slightly but consistently as gestation proceeded. In arresting trophoblasts, VEGF and VEGFR2 staining decreased from gd 22 to 32. Moreover, the number of VEGF and VEGFR1-positive capillaries in the subepithelial vascular plexus of endometrium was related to the conceptus status, showing a moderate increase in healthy sites as pregnancy advances. In conclusion, it appears that VEGF-rs is expressed and related to vascular development in Iberian pigs between gd 22 and 32. The upregulated expression of VEGF mRNA and VEGFR2 mRNA in healthy uterine sites suggests a significant role for these angiogenic factors in early pregnancy.

Use of the FLUKA Monte Carlo code for 3D patient-specific dosimetry on PET-CT and SPECT-CT images.

Patient-specific absorbed dose calculation for nuclear medicine therapy is a topic of increasing interest. 3D dosimetry at the voxel level is one of the major improvements for the development of more accurate calculation techniques, as compared to the standard dosimetry at the organ level. This study aims to use the FLUKA Monte Carlo code to perform patient-specific 3D dosimetry through direct Monte Carlo simulation on PET-CT and SPECT-CT images. To this aim, dedicated routines were developed in the FLUKA environment. Two sets of simulations were performed on model and phantom images. Firstly, the correct handling of PET and SPECT images was tested under the assumption of homogeneous water medium by comparing FLUKA results with those obtained with the voxel kernel convolution method and with other Monte Carlo-based tools developed to the same purpose (the EGS-based 3D-RD software and the MCNP5-based MCID). Afterwards, the correct integration of the PET/SPECT and CT information was tested, performing direct simulations on PET/CT images for both homogeneous (water) and non-homogeneous (water with air, lung and bone inserts) phantoms. Comparison was performed with the other Monte Carlo tools performing direct simulation as well. The absorbed dose maps were compared at the voxel level. In the case of homogeneous water, by simulating 10(8) primary particles a 2% average difference with respect to the kernel convolution method was achieved; such difference was lower than the statistical uncertainty affecting the FLUKA results. The agreement with the other tools was within 3­4%, partially ascribable to the differences among the simulation algorithms. Including the CT-based density map, the average difference was always within 4% irrespective of the medium (water, air, bone), except for a maximum 6% value when comparing FLUKA and 3D-RD in air. The results confirmed that the routines were properly developed, opening the way for the use of FLUKA for patient-specific, image-based dosimetry in nuclear medicine.

Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (II).

The most relevant data presented at the 28th edition of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) held in October 2012 in France have been summarised in the fifth edition of the Post-ECTRIMS Expert Meeting held in Madrid in October 2012. This review is the result of the meeting, which is being published in three parts. This second part of the Post-ECTRIMS review discusses the biology of recovery and remyelination in multiple sclerosis (MS) as well as the different repair and endogenous and exogenous remyelination strategies currently being evaluated based on the fact that resident microglia and oligodendroglial progenitor cells have been implicated in the remyelination process. This review also discusses the current state and future use of biomarkers in MS and proposes as markers of neurodegeneration the following: T2 lesion volume and brain atrophy using MRI and the loss of the ganglion cell layer as assessed by optical coherence tomography. A greater future utility for double inversion recovery (DIR) sequences is proposed to correlate cognitive impairment with MS impairment, given its higher diagnostic yield in locating and defining cortical lesions. The availability of novel biomarkers in the future requires strict validation. In this context, this paper proposes possible areas of action to improve the current situation and also presents the latest research results in identifying potential candidates with useful diagnostic characteristics, prognostic characteristics, treatment responses, and safety procedures.

TITLE: Revision de las novedades presentadas en el XXVIII Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS) (II).Los datos mas relevantes presentados en la XXVIII edicion del Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS), celebrado en octubre de 2012 en Francia, han sido resumidos en la quinta edicion de la Reunion de Expertos Post-ECTRIMS celebrada en Madrid en octubre de 2012, fruto de la cual nace esta revision que se publica en tres partes. En esta segunda parte de la revision Post-ECTRIMS se analiza la biologia de la recuperacion y remielinizacion en la esclerosis multiple (EM), y se discuten las diferentes estrategias de reparacion y remielinizacion endogena y exogena que actualmente estan siendo evaluadas, sobre la base de que la microglia residente y las celulas precursoras de oligodendrocitos se han visto implicadas en el proceso de remielinizacion. Asimismo, se expone el estado actual y uso futuro de los biomarcadores en EM, y se proponen como marcadores de neurodegeneracion el volumen lesional en T2 y la atrofia cerebral mediante resonancia magnetica, asi como la perdida de capa de celulas ganglionares mediante tomografia de coherencia optica. Se plantea una mayor utilidad futura de las secuencias DIR para correlacionar las alteraciones cognitivas con las alteraciones de la EM, dado su mayor rendimiento diagnostico en localizar y definir lesiones corticales. La disponibilidad de nuevos biomarcadores en un futuro requiere una validacion estricta. En este sentido, se plantean posibles areas de actuacion dirigidas a mejorar la situacion actual, y ademas se presentan los resultados de las investigaciones mas recientes en la identificacion de posibles candidatos con utilidad diagnostica, pronostica, de respuesta al tratamiento y de seguridad.

Allogeneic hematopoietic cell transplantation for neuroblastoma: the CIBMTR experience.

Although the role of autologous hematopoietic cell transplantation (auto-HCT) is well established in neuroblastoma (NBL), the role of allogeneic HCT (allo-HCT) is controversial. The Center for International Blood and Marrow Transplant Research conducted a retrospective review of 143 allo-HCT for NBL reported in 1990-2007. Patients were categorized into two different groups: those who had not (Group 1) and had (Group 2) undergone a prior auto-HCT (n=46 and 97, respectively). One-year and five-year OS were 59% and 29% for Group 1 and 50% and 7% for Group 2, respectively. Among donor types, disease-free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not at 5 years post HCT. Patients in CR or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared with those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared with those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.

[Neurological complications in patients receiving solid organ transplants]. / Complicaciones neurológicas en trasplantados de órgano sólido.

INTRODUCTION: Neurological complications (NC) are a significant cause of morbidity and mortality in paediatric patients receiving solid organ transplants. Our aim was to describe the experience of our hospital with NC in paediatric patients receiving heart, lung and liver transplants. PATIENTS AND METHODS: A retrospective study was conducted on 140 paediatric patients who received a solid organ transplant during the period 2000-2011. RESULTS: A total of 23 paediatric solid organ transplant recipients (16.4% of cases), with a median age of 6 years, had NC. The symptoms were, in order of frequency: acute symptomatic seizures (12 patients); acute encephalopathy (11 patients); neuromuscular weakness (4 children), tremor (4 children), headache (2 children), neuropathic pain (2 children), and visual disturbances (2 children). The aetiologies of NC were: the neurotoxicity of the immunosuppressive drugs (12 patients), post-hypoxic-ischaemic encephalopathy (6 patients), infections (2 cases), mechanical compression of peripheral nerve during surgery (2 cases), and a metabolic complication (1 case). The five patients who met the criteria of posterior reversible encephalopathy syndrome had a favourable outcome. Seven patients died, four of them due to hypoxic-ischaemic encephalopathy. CONCLUSIONS: NC are common in paediatric patients receiving heart, liver, lung, and renal transplants, with acute symptomatic seizures and acute encephalopathy being the most common clinical signs. No differences were found in the NC with the different types of transplants. Neurotoxicity of the immunosuppressive drugs and hypoxic-ischaemic encephalopathy were the main causes of NC, having different management and outcomes. The prognosis was favourable in most of the patients, except for those who had moderate or severe post-hypoxic-ischaemic damage.