A Rare Giant Nasofrontal Meningoencephalocele with Nasal and Visual Obstruction.

The encephalocele is a malformation that is manifested by the protrusion of brain tissue through a defect in the skull. The meningoencephalocele contains the meninges and brain tissue. Frontoethmoidal or nasal meningoencephalocele is rare; the frequency is approximately one in 40,000 live births. Three subtypes are currently known: nasoethmoid, nasofrontal, and nasoorbital. The authors report the clinical case of a 2-month-old girl with a very rare giant nasofrontal meningoencephalocele, which affected vision and breathing. The patient underwent surgery at an early age to avoid significant functional sequelae and promote the normal development and growth of the girl.

Subclassification of B-acute lymphoblastic leukemia according to age, immunophenotype and microenvironment, predicts MRD risk in Mexican children from vulnerable regions.

Introduction: The decisive key to disease-free survival in B-cell precursor acute lymphoblastic leukemia in children, is the combination of diagnostic timeliness and treatment efficacy, guided by accurate patient risk stratification. Implementation of standardized and high-precision diagnostic/prognostic systems is particularly important in the most marginalized geographic areas in Mexico, where high numbers of the pediatric population resides and the highest relapse and early death rates due to acute leukemias are recorded even in those cases diagnosed as standard risk. Methods: By using a multidimensional and integrated analysis of the immunophenotype of leukemic cells, the immunological context and the tumor microenvironment, this study aim to capture the snapshot of acute leukemia at disease debut of a cohort of Mexican children from vulnerable regions in Puebla, Oaxaca and Tlaxcala and its potential use in risk stratification. Results and discussion: Our findings highlight the existence of a distinct profile of ProB-ALL in children older than 10 years, which is associated with a six-fold increase in the risk of developing measurable residual disease (MRD). Along with the absence of CD34+ seminal cells for normal hematopoiesis, this ProB-ALL subtype exhibited several characteristics related to poor prognosis, including the high expression level of myeloid lineage markers such as MPO and CD33, as well as upregulation of CD19, CD34, CD24, CD20 and nuTdT. In contrast, it showed a trend towards decreased expression of CD9, CD81, CD123, CD13, CD15 and CD21. Of note, the mesenchymal stromal cell compartment constituting their leukemic niche in the bone marrow, displayed characteristics of potential suppressive microenvironment, such as the expression of Gal9 and IDO1, and the absence of the chemokine CXCL11. Accordingly, adaptive immunity components were poorly represented. Taken together, our results suggest, for the first time, that a biologically distinct subtype of ProB-ALL emerges in vulnerable adolescents, with a high risk of developing MRD. Rigorous research on potential enhancing factors, environmental or lifestyle, is crucial for its detection and prevention. The use of the reported profile for early risk stratification is suggested.

Cauliflower fractal forms arise from perturbations of floral gene networks.

Throughout development, plant meristems regularly produce organs in defined spiral, opposite, or whorl patterns. Cauliflowers present an unusual organ arrangement with a multitude of spirals nested over a wide range of scales. How such a fractal, self-similar organization emerges from developmental mechanisms has remained elusive. Combining experimental analyses in an Arabidopsis thaliana cauliflower-like mutant with modeling, we found that curd self-similarity arises because the meristems fail to form flowers but keep the "memory" of their transient passage in a floral state. Additional mutations affecting meristem growth can induce the production of conical structures reminiscent of the conspicuous fractal Romanesco shape. This study reveals how fractal-like forms may emerge from the combination of key, defined perturbations of floral developmental programs and growth dynamics.

Fracturas de columna posterior de acetábulo tratadas mediante tornillo ilioisquiático retrógrado percutáneo. Serie de casos / Posterior spine acetabulum fractures treated with percutaneous retrograde ilioischial screw. Number of cases

Introducción: Las fracturas de acetábulo suponen un reto para los traumatólogos. Tradicionalmente el tratamiento de estas fracturas ha sido la reducción abierta y fijación interna, sin embargo, recientemente se han popularizado técnicas percutáneas para el tratamiento de fracturas no desplazadas o mínimamente desplazadas. En este estudio exponemos nuestros resultados en pacientes tratados mediante fijación percutánea con un tornillo ilioisquiático retrógrado de fracturas no desplazadas de columna posterior. Material y Métodos: Desde 2016 a 2020, Ocho varones con una edad media de 59,75 años (27-79), fueron intervenidos en nuestro centro de fracturas simples o combinadas de columna posterior no desplazadas mediante tornillo ilioisquiático retrógrado percutáneo. Realizamos una evaluación postoperatoria mediante el WOMAC Score y el Oxford Hip Score. Registramos complicaciones. Resultados: Los resultados postoperatorios del cuestionario WOMAC fueron 81,24 de media (50-100) y los resultados del Oxford Hip Score 36,42 de media (22-45). Un paciente desarrolló una coxartrosis secundaria a infección del material de osteosíntesis que requirió de artroplastia total de cadera. Un paciente falleció por motivos no relacionados con la fractura. Conclusiones: El tratamiento percutáneo constituye una de las herramientas terapéuticas para el manejo de estas fracturas, con bajas tasas de lesiones neurovasculares, calcificaciones heterotópicas, infecciones, y escaso sangrado quirúrgico.(AU)

Introduction: Acetabulum fractures present a challenge for orthopedic surgeons. Traditionally the usual treatment of these fractures has been open reduction and internal fixation. However, percutanous techniques have recently become popular for the treatment of minimally displaced fractures. In the present paper the results in a group of patients treated by percutaneous fixation with a retrograde ilioischial screw are reported. Material and methods: From 2016 to 2020, Eight men with a mean age of 59.75 years (27-79) were operated on in our center for undisplaced simple or combined posterior column fractures using a percutaneous retrograde ilioischial screw. We performed a postoperative evaluation using the WOMAC Score and the Oxford Hip Score. The number and kind of complications are analyzed. Results: The postoperative results of the WOMAC questionnaire were 81.24 on average (50- 100) and the results of the Oxford Hip Score were 36.42 on average (22-45). One patient developed coxarthrosis secondary to infection of the osteosynthesis material that required total hip arthroplasty. One patient died for reasons unrelated to the fracture. Conclusions: Percutaneous treatment constitutes one of the therapeutic tools for the management of these fractures, with low rates of neurovascular injuries, heterotopic calcifications, infections, and little surgical bleeding.(AU)

Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study.

BACKGROUND: Several risk stratification models have been proposed in recent years for systemic mastocytosis but have not been directly compared. Here we designed and validated a risk stratification model for progression-free survival (PFS) and overall survival (OS) in systemic mastocytosis on the basis of all currently available prognostic factors, and compared its predictive capacity for patient outcome with that of other risk scores. METHODS: We did a retrospective prognostic modelling study based on patients diagnosed with systemic mastocytosis between March 1, 1983, and Oct 11, 2019. In a discovery cohort of 422 patients from centres of the Spanish Network on Mastocytosis (REMA), we evaluated previously identified, independent prognostic features for prognostic effect on PFS and OS by multivariable analysis, and designed a global prognostic score for mastocytosis (GPSM) aimed at predicting PFS (GPSM-PFS) and OS (GPSM-OS) by including only those variables that showed independent prognostic value (p<0·05). The GPSM scores were validated in an independent cohort of 853 patients from centres in Europe and the USA, and compared with pre-existing risk models in the total patient series (n=1275), with use of Harrells' concordance index (C-index) as a readout of the ability of each model to risk-stratify patients according to survival outcomes. FINDINGS: Our GPSM-PFS and GPSM-OS models were based on unique combinations of independent prognostic factors for PFS (platelet count ≤100 × 109 cells per L, serum ß2-microglobulin ≥2·5 µg/mL, and serum baseline tryptase ≥125 µg/L) and OS (haemoglobin ≤110 g/L, serum alkaline phosphatase ≥140 IU/L, and at least one mutation in SRSF2, ASXL1, RUNX1, or DNMT3A). The models showed clear discrimination between low-risk and high-risk patients in terms of worse PFS and OS prognoses in the discovery and validation cohorts, and further discrimination of intermediate-risk patients. The GPSM-PFS score was an accurate predictor of PFS in systemic mastocytosis (C-index 0·90 [95% CI 0·87-0·93], vs values ranging from 0·85 to 0·88 for pre-existing models), particularly in non-advanced systemic mastocytosis (C-index 0·85 [0·76-0·92], within the range for pre-existing models of 0·80 to 0·93). Additionally, the GPSM-OS score was able to accurately predict OS in the entire cohort (C-index 0·92 [0·89-0·94], vs 0·67 to 0·90 for pre-existing models), and showed some capacity to predict OS in advanced systemic mastocytosis (C-index 0·72 [0·66-0·78], vs 0·64 to 0·73 for pre-existing models). INTERPRETATION: All evaluated risk classifications predicted survival outcomes in systemic mastocytosis. The REMA-PFS and GPSM-PFS models for PFS, and the International Prognostic Scoring System for advanced systemic mastocytosis and GPSM-OS model for OS emerged as the most accurate models, indicating that robust prognostication might be prospectively achieved on the basis of biomarkers that are accessible in diagnostic laboratories worldwide. FUNDING: Carlos III Health Institute, European Regional Development Fund, Spanish Association of Mastocytosis and Related Diseases, Rare Diseases Strategy of the Spanish National Health System, Junta of Castile and León, Charles and Ann Johnson Foundation, Stanford Cancer Institute Innovation Fund, Austrian Science Fund.

Effect of intramuscular baculovirus encoding mutant hypoxia-inducible factor 1-alpha on neovasculogenesis and ischemic muscle protection in rabbits with peripheral arterial disease.

BACKGROUND AIMS: Peripheral arterial disease (PAD) is a progressive, disabling ailment for which no effective treatment exists. Gene therapy-mediated neovascularization has emerged as a potentially useful strategy. We tested the angiogenic and arteriogenic efficacy and safety of a baculovirus (BV) encoding mutant, oxygen-resistant hypoxia-inducible factor 1-alpha (mHIF-1α), in rabbits with PAD. METHODS: After assessing the transfection efficiency of the BV.mHIF-1α vector and its tubulogenesis potential in vitro, we randomized rabbits with experimental PAD to receive 1 × 109 copies of BV.mHIF-1α or BV.null (n = 6 per group) 7 days after surgery. Two weeks post-treatment, collateralization (digital angiography) and capillary and arteriolar densities (immunohistochemistry) were measured in the posterior limbs. Ischemic damage was evaluated in adductor and gastrocnemius muscle samples. Tracking of viral DNA in injected zones and remote tissues at different time points was performed in additional rabbits using a BV encoding GFP. RESULTS: Angiographically visible collaterals were more numerous in BV.mHIF-1α-treated rabbits (8.12 ± 0.42 vs 6.13 ± 1.15 collaterals/cm2, P < 0.05). The same occurred with arteriolar (27.9 ± 7.0 vs 15.3 ± 4.0 arterioles/mm2) and capillary (341.8 ± 109.9 vs 208.8 ± 87.7 capillaries/mm2, P < 0.05) densities. BV.mHIF-1α-treated rabbits displayed less ischemic muscle damage than BV.null-treated animals. Viral DNA and GFP mRNA were detectable only at 3 and 7 days after injection in hind limbs. Neither the virus nor GFP mRNA was detected in remote tissues. CONCLUSIONS: In rabbits with PAD, BV.mHIF-1α induced neovascularization and reduced ischemic damage, exhibiting a good safety profile at 14 days post-treatment. Complementary studies to evaluate its potential usefulness in the clinic are needed.

Novel insights into cardiac regeneration based on differential fetal and adult ovine heart transcriptomic analysis.

The adult mammalian cardiomyocyte has a very limited capacity to reenter the cell cycle and advance into mitosis. Therefore, diseases characterized by lost contractile tissue usually evolve into myocardial remodeling and heart failure. Analyzing the cardiac transcriptome at different developmental stages in a large mammal closer to the human than laboratory rodents may serve to disclose positive and negative cardiomyocyte cell cycle regulators potentially targetable to induce cardiac regeneration in the clinical setting. Thus we aimed at characterizing the transcriptomic profiles of the early fetal, late fetal, and adult sheep heart by employing RNA-seq technique and bioinformatic analysis to detect protein-encoding genes that in some of the stages were turned off, turned on, or differentially expressed. Genes earlier proposed as positive cell cycle regulators such as cyclin A, cdk2, meis2, meis3, and PCNA showed higher expression in fetal hearts and lower in AH, as expected. In contrast, genes previously proposed as cell cycle inhibitors, such as meis1, p16, and sav1, tended to be higher in fetal than in adult hearts, suggesting that these genes are involved in cell processes other than cell cycle regulation. Additionally, we described Gene Ontology (GO) enrichment of different sets of genes. GO analysis revealed that differentially expressed gene sets were mainly associated with metabolic and cellular processes. The cell cycle-related genes fam64a, cdc20, and cdk1, and the metabolism-related genes pitx and adipoq showed strong differential expression between fetal and adult hearts, thus being potent candidates to be targeted in human cardiac regeneration strategies.NEW & NOTEWORTHY We characterized the transcriptomic profiles of the fetal and adult sheep hearts employing RNAseq technique and bioinformatic analyses to provide sets of transcripts whose variation in expression level may link them to a specific role in cell cycle regulation. It is important to remark that this study was performed in a large mammal closer to humans than laboratory rodents. In consequence, the results can be used for further translational studies in cardiac regeneration.

Factores pronóstico en el tratamiento quirúrgico de las fracturas de acetábulo / Prognostic factors in the surgical treatment of acetabular fractures

Objetivo: Variables pronóstico en las fracturas de acetábulo tratadas de manera quirúrgica. Material y métodos: De la base de datos de nuestro hospital se analizaron 47 pacientes tratados de fractura de acetábulo de manera quirúrgica en los últimos 10 años. El seguimiento mínimo tras la cirugía fue de 2 años mediante valoración clínica, según la escala funcional Harris Hip Score, y radiológica mediante radiografía simple y/o tomografía computarizada. Resultados: Se analizaron las variables edad, sexo, mecanismo de acción, clasificación de la fractura según Letournel, cuerpos libres prequirúrgicos, tiempo hasta la cirugía definitiva, tipo de abordaje, calidad de la reducción y osificación heterotópica. Observamos que el aumento de la edad está íntimamente relacionada con la implantación de artroplastia total de cadera en los 2 primeros años tras la cirugía (p=0.045). Demostramos peores resultados funcionales en pacientes con presencia de osificación heterotópica y pacientes de edad más avanzada (p = 0.016 y p<0.001, respectivamente). Además se observó mejor calidad de la reducción en aquellas fracturas tratadas mediante un único abordaje (p = 0.012) Conclusión: Los pacientes de edad avanzada, la utilización de abordaje combinados y la presencia de osificacion heterotópica influyen negativamente en el pronostico funcional y aumentan la probabilidad de una futura conversión a artroplastia primaria de cadera

Objectives: Prognostic variables in acetabular fractures treated surgically. Material and Methods: Forty-seven patients with acetabulum fractures surgically treated in our center during the last ten years were retrospectively clinically analyzed following the Harris Hip Score Functional Scale and radiologically by means of straight x-rays and ct-scans. The minimum follow-up period was two years. Results: We analyzed the variables age, sex, mechanism of action, classification of the fracture according to Letournel, intra-articular foreign bodies, time to definitive surgery, type of approach, quality of reduction and heterotopic ossification. We observed that the increase in age is closely related to the implantation of total hip arthroplasty in the first 2 years after surgery (p = 0.045). We showed worse functional results in patients with presence of heterotopic ossification and older patients (p = 0.016 and p < 0.001, respectively). In addition, better quality of the reduction was observed in those fractures treated by a single approach (p = 0.012)

Suplementación en osteosístesis de fracturas de humero proximal con aloinjerto de peroné / Fibular strut graft augmentation for open reduction and internal fixation of proximal humerus fractures

Las fracturas de húmero proximal constituyen la tercera fractura osteoporótica en frecuencia. Con una población cada vez más añosa y con la osteoporosis como uno de los principales factores de riesgo de fracaso de la osteosíntesis, se requieren nuevas técnicas de mejora de la fijación que impidan el desplazamiento en varo de la cabeza humeral. En los últimos años no sólo se han mejorado los sistemas de placas al añadir tornillos de bloqueo sino que además se han desarrollado técnicas como la suplementación con tornillo inferomedial, la cementación de los tornillos o el aporte de injerto estructural. En este estudio presentamos dos casos de fracturas de húmero proximal en pacientes con mala calidad ósea que fueron tratados con aloinjerto estructural de peroné intramedular y hacemos una revisión bibliográfica al respecto

Proximal humerus fractures constitute the third osteoporotic fracture in frequency. With an increasingly elderly population and with osteoporosis as one of the main risk factors for osteosynthesis failure, new fixation improvement techniques are required that prevent varus displacement of the humeral head. In recent years, not only have plate systems been improved by adding locking screws, but techniques such as inferomedial screw supplementation, screw cementation or structural grafting have also been developed. In this study, we present two cases of fractures of the proximal humerus in patients with poor bone quality who were treated with structural allograft of the intramedullary fibula and we make a bibliographic review in this regard

High-dose intramyocardial HMGB1 induces long-term cardioprotection in sheep with myocardial infarction.

In rodents with acute myocardial infarction (AMI), high mobility group box 1 (HMGB1) injection has produced controversial results. Given the lack of data in large mammals, we searched the dose that would promote angiogenesis and expression of specific regenerative genes in sheep with AMI (protocol 1) and, subsequently, use this dose to study long-term effects on infarct size and left ventricular (LV) function (protocol 2). Protocol 1: Sheep with AMI received 250 µg (high-dose, n = 7), 25 µg (low-dose, n = 7) HMGB1, or PBS (placebo, n = 7) in 10 intramyocardial injections (0.2 ml each) in the peri-infarct area. Seven days later, only the high-HMGB1-dose group exhibited higher microvascular densities, Ki67-positive cardiomyocytes, and overexpression of VEGF, Ckit, Tbx20, Nkx2.5, and Gata4. Protocol 2: Sheep with AMI received HMGB1 250 µg (n = 6) or PBS (n = 6). At 60 days, HMGB1-treated sheep showed smaller infarcts (8.5 ± 2.11 vs. 12.2 ± 1.97% LV area, P < 0.05, ANOVA-Bonferroni) and higher microvascular density (capillaries, 1798 ± 252 vs. 1266 ± 250/mm2; arterioles, 18.3 ± 3.9 vs. 11.7 ± 2.2/mm2; both P < 0.01). Echocardiographic LV ejection fraction, circumferential shortening, and wall thickening increased from day 3 to 60 with HMGB1 (all P < 0.05). Conclusion: in ovine AMI, high-dose HMGB1 induces angio-arteriogenesis, reduces infarct size, and improves LV function at 2 months post-treatment.

Cervical Cord Compression by Exostosis.

A 51-year-old woman presented to physical therapy with complaints of weakness in her left arm, progressive numbness in both hands, and mild progressive neck pain radiating into the left upper arm. She reported that her condition had started after playing in an amateur tennis tournament 4 weeks prior and progressed to inability to play tennis. Following examination by the physical therapist, the patient was referred to her physician, who ordered magnetic resonance imaging of the spine, which showed a bony exostosis at C1-2 with myelopathy. J Orthop Sports Phys Ther 2019;49(2):112. doi:10.2519/jospt.2019.7942.

Targeting the Cardiomyocyte Cell Cycle for Heart Regeneration.

Adult mammalian cardiomyocytes (CMs) exhibit limited proliferative capacity, as cell cycle activity leads to an increase in DNA content, but mitosis and cytokinesis are infrequent. This makes the heart highly inefficient in replacing with neoformed cardiomyocytes lost contractile cells as occurs in diseases such as myocardial infarction and dilated cardiomyopathy. Regenerative therapies based on the implant of stem cells of diverse origin do not warrant engraftment and electromechanical connection of the new cells with the resident ones, a fundamental condition to restore the physiology of the cardiac syncytium. Consequently, there is a growing interest in identifying factors playing relevant roles in the regulation of the CM cell cycle to be targeted in order to induce the resident cardiomyocytes to divide into daughter cells and thus achieve myocardial regeneration with preservation of physiologic syncytial performance. Despite the scientific progress achieved over the last decades, many questions remain unanswered, including how cardiomyocyte proliferation is regulated during heart development in gestation and neonatal life. This can reveal unknown cell cycle regulation mechanisms and molecules that may be manipulated to achieve cardiac self-regeneration. We hereby revise updated data on CM cell cycle regulation, participating molecules and pathways recently linked with the cell cycle, as well as experimental therapies involving them.

Effect of poly (l-lactic acid) scaffolds seeded with aligned diaphragmatic myoblasts overexpressing connexin-43 on infarct size and ventricular function in sheep with acute coronary occlusion.

Diaphragmatic myoblasts (DM) are stem cells of the diaphragm, a muscle displaying high resistance to stress and exhaustion. We hypothesized that DM modified to overexpress connexin-43 (cx43), seeded on aligned poly (l-lactic acid) (PLLA) sheets would decrease infarct size and improve ventricular function in sheep with acute myocardial infarction (AMI). Sheep with AMI received PLLA sheets without DM (PLLA group), sheets with DM (PLLA-DM group), sheets with DM overexpressing cx43 (PLLA-DMcx43) or no treatment (control group, n = 6 per group). Infarct size (cardiac magnetic resonance) decreased ∼25% in PLLA-DMcx43 [from 8.2 ± 0.6 ml (day 2) to 6.5 ± 0.7 ml (day 45), p < .01, ANOVA-Bonferroni] but not in the other groups. Ejection fraction (EF%) (echocardiography) at 3 days post-AMI fell significantly in all groups. At 45 days, PLLA-DM y PLLA-DMcx43 recovered their EF% to pre-AMI values (PLLA-DM: 61.1 ± 0.5% vs. 58.9 ± 3.3%, p = NS; PLLA-DMcx43: 64.6 ± 2.9% vs. 56.9 ± 2.4%, p = NS), but not in control (56.8 ± 2.0% vs. 43.8 ± 1.1%, p < .01) and PLLA (65.7 ± 2.1% vs. 56.6 ± 4.8%, p < .01). Capillary density was higher (p < .05) in PLLA-DMcx43 group than in the remaining groups. In conclusion, PLLA-DMcx43 reduces infarct size in sheep with AMI. PLLA-DMcx43 and PLLA-DM improve ventricular function similarly. Given its safety and feasibility, this novel approach may prove beneficial in the clinic.

Direct-acting antivirals are effective and safe in HCV/HIV-coinfected liver transplant recipients who experience recurrence of hepatitis C: A prospective nationwide cohort study.

Direct-acting antivirals have proved to be highly efficacious and safe in monoinfected liver transplant (LT) recipients who experience recurrence of hepatitis C virus (HCV) infection. However, there is a lack of data on effectiveness and tolerability of these regimens in HCV/HIV-coinfected patients who experience recurrence of HCV infection after LT. In this prospective, multicenter cohort study, the outcomes of 47 HCV/HIV-coinfected LT patients who received DAA therapy (with or without ribavirin [RBV]) were compared with those of a matched cohort of 148 HCV-monoinfected LT recipients who received similar treatment. Baseline characteristics were similar in both groups. HCV/HIV-coinfected patients had a median (IQR) CD4 T-cell count of 366 (256-467) cells/µL. HIV-RNA was <50 copies/mL in 96% of patients. The DAA regimens administered were SOF + LDV ± RBV (34%), SOF + SMV ± RBV (31%), SOF + DCV ± RBV (27%), SMV + DCV ± RBV (5%), and 3D (3%), with no differences between the groups. Treatment was well tolerated in both groups. Rates of SVR (negative serum HCV-RNA at 12 weeks after the end of treatment) were high and similar for coinfected and monoinfected patients (95% and 94%, respectively; P = .239). Albeit not significant, a trend toward lower SVR rates among patients with advanced fibrosis (P = .093) and genotype 4 (P = .088) was observed. In conclusion, interferon-free regimens with DAAs for post-LT recurrence of HCV infection in HIV-infected individuals were highly effective and well tolerated, with results comparable to those of HCV-monoinfected patients.

Breit corrections to individual atomic and molecular orbital energies.

Several issues concerning Breit correction to electron-electron interaction in many-electron systems, which are important in precise atomic and molecular calculations, are presented. At first, perturbative versus self-consistent calculations of Breit correction were studied in selected cases. Second, the Z-dependence of Breit contribution per subshell is shown, based on values calculated for selected atoms with 30 ≤ Z ≤ 118. Third, the relations between magnetic and retardation parts of Breit interaction are analyzed. Finally, Gaunt contribution calculated for Kr, Xe, and Rn noble gas atoms and its iso-electronic HBr, HI, and HAt diatomic molecules has been compared to full-Breit atomic calculations. We found that Breit corrections should be treated by self-consistent calculations and that there is a functional dependence of those corrections for subshells as εnlBreit(Z)≃a×Zb. We also found that molecular Gaunt corrections are close to their atomic counterparts for inner electrons though they are not for outer orbitals. In any case, accurate calculations must include retardation correction in addition to Gaunt.

Influence of the nuclear charge distribution and electron correlation effects on magnetic shieldings and spin-rotation tensors of linear molecules.

The nuclear charge distribution effects (NChDE) on two response properties, the NMR magnetic shielding ( σ ) and the nuclear spin-rotation (SR) constants ( M ), are analyzed. We do it employing point-like and Gaussian-like models for describing the nuclear charge density of three linear molecules: HBr, HI and HAt. According to our results, both properties are sensitive to the NChDE. We show that the NChDE are almost completely relativistic, i.e., they nearly vanish in the non-relativistic limit of both properties. We calculated the NChDE on σ and M , and analyzed the differences between them in terms of a relativistic relation between these two properties. Using that relation we found that the electronic core mechanisms are the main ones for the NChDE on the shielding of nuclei of both, molecules and free atoms. The NChDE are smaller on SR constants than on shieldings. Nevertheless, within the relativistic polarization propagator formalism at the RPA level of approach they are very important for SR constants of nuclei in heavy-atom-containing compounds. Astatine in HAt has the largest influence: M At = -9.95 kHz for a point-like model and -50.10 kHz for a Gaussian-like model. Correlation effects must be included and we do it using different DFT schemes. The PBE0 functional gives results that are closest to experiments for Br and I, though the LDA gives the closest for hydrogen. The value of the SR constant of At is reduced among 350 kHz and 500 kHz from its RPA value, when different and usual functionals are applied. Given that the NChDE on M and σ are mostly relativistic in their origin, these effects are also dependent on electron correlation. They have also a nonvanishing dependence with the Gaunt electron-electron interactions.

Aligned ovine diaphragmatic myoblasts overexpressing human connexin-43 seeded on poly (L-lactic acid) scaffolds for potential use in cardiac regeneration.

Diaphragmatic myoblasts (DMs) are precursors of type-1 muscle cells displaying high exhaustion threshold on account that they contract and relax 20 times/min over a lifespan, making them potentially useful in cardiac regeneration strategies. Besides, it has been shown that biomaterials for stem cell delivery improve cell retention and viability in the target organ. In the present study, we aimed at developing a novel approach based on the use of poly (L-lactic acid) (PLLA) scaffolds seeded with DMs overexpressing connexin-43 (cx43), a gap junction protein that promotes inter-cell connectivity. DMs isolated from ovine diaphragm biopsies were characterized by immunohistochemistry and ability to differentiate into myotubes (MTs) and transduced with a lentiviral vector encoding cx43. After confirming cx43 expression (RT-qPCR and Western blot) and its effect on inter-cell connectivity (fluorescence recovery after photobleaching), DMs were grown on fiber-aligned or random PLLA scaffolds. DMs were successfully isolated and characterized. Cx43 mRNA and protein were overexpressed and favored inter-cell connectivity. Alignment of the scaffold fibers not only aligned but also elongated the cells, increasing the contact surface between them. This novel approach is feasible and combines the advantages of bioresorbable scaffolds as delivery method and a cell type that on account of its features may be suitable for cardiac regeneration. Future studies on animal models of myocardial infarction are needed to establish its usefulness on scar reduction and cardiac function.

Allogeneic Mesenchymal Stromal Cells Overexpressing Mutant Human Hypoxia-Inducible Factor 1-α (HIF1-α) in an Ovine Model of Acute Myocardial Infarction.

BACKGROUND: Bone marrow mesenchymal stromal cells (BMMSCs) are cardioprotective in acute myocardial infarction (AMI) because of release of paracrine angiogenic and prosurvival factors. Hypoxia-inducible factor 1-α (HIF1-α), rapidly degraded during normoxia, is stabilized during ischemia and upregulates various cardioprotective genes. We hypothesized that BMMSCs engineered to overexpress mutant, oxygen-resistant HIF1-α would confer greater cardioprotection than nontransfected BMMSCs in sheep with AMI. METHODS AND RESULTS: Allogeneic BMMSCs transfected with a minicircle vector encoding mutant HIF1-α (BMMSC-HIF) were injected in the peri-infarct of sheep (n=6) undergoing coronary occlusion. Over 2 months, infarct volume measured by cardiac magnetic resonance (CMR) imaging decreased by 71.7±1.3% (P<0.001), and left ventricular (LV) percent ejection fraction (%EF) increased near 2-fold (P<0.001) in the presence of markedly decreased end-systolic volume. Sheep receiving nontransfected BMMSCs (BMMSC; n=6) displayed less infarct size limitation and percent LVEF improvement, whereas in placebo-treated animals (n=6), neither parameters changed over time. HIF1-α-transfected BMMSCs (BMMSC-HIF) induced angio-/arteriogenesis and decreased apoptosis by HIF1-mediated overexpression of erythropoietin, inducible nitrous oxide synthase, vascular endothelial growth factor, and angiopoietin-1. Cell tracking using paramagnetic iron nanoparticles in 12 additional sheep revealed enhanced long-term retention of BMMSC-HIF. CONCLUSIONS: Intramyocardial delivery of BMMSC-HIF reduced infarct size and improved LV systolic performance compared to BMMSC, attributed to increased neovascularization and cardioprotective effects induced by HIF1-mediated overexpression of paracrine factors and enhanced retention of injected cells. Given the safety of the minicircle vector and the feasibility of BMMSCs for allogeneic application, this treatment may be potentially useful in the clinic.