Connectome-based predictive modeling of brain pathology and cognition in Autosomal Dominant Alzheimer's Disease.

INTRODUCTION: Autosomal Dominant Alzheimer's Disease (ADAD) through genetic mutations can result in near complete expression of the disease. Tracking AD pathology development in an ADAD cohort of Presenilin-1 (PSEN1) E280A carriers' mutation has allowed us to observe incipient tau tangles accumulation as early as 6 years prior to symptom onset. METHODS: Resting-state functional Magnetic Resonance Imaging (fMRI) and Positron-Emission Tomography (PET) scans were acquired in a group of PSEN1 carriers (n=32) and non-carrier family members (n=35). We applied Connectome-based Predictive Modeling (CPM) to examine the relationship between the participant's functional connectome and their respective tau/amyloid-ß levels and cognitive scores (word list recall). RESULTS: CPM models strongly predicted tau concentrations and cognitive scores within the carrier group. The connectivity patterns between the temporal cortex, default mode network, and other memory networks were the most informative of tau burden. DISCUSSION: These results indicate that resting-state fMRI methods can complement PET methods in early detection and monitoring of disease progression in ADAD.

[Translated article] Real-world persistence with dolutegravir/lamivudine versus bictegravir/emtricitabine/tenofovir-alafenamide among persons with HIV.

OBJETIVES: The main objective was to compare the persistence between dolutegravir/lamivudine (DTG/3TC) and bictegravir/emtricitabine/tenofovir-alafenamide (BIC/FTC/TAF) and to analyze reasons for discontinuation. METHODS: We conducted a retrospective, non-interventional, descriptive, and longitudinal study. All human immunodeficiency virus (HIV) patients over 18 years treated with DTG/3TC or BIC/FTC/TAF in our center were included. Persistence after first year was compared using the χ2 test. Kaplan-Meier survival analysis was performed. RESULTS: Three hundred fifty-eight patients were included. 99.5% versus 90.99% of patients were persistent after the first year for DTG/3TC and BIC/FTC/TAF respectively (p=.001). Persistence with DGT/3TC was 1237 days (IC95% 1216-1258) and persistence with BIC/FTC/TAF was 986 days [(IC95% 950-1021); p<.001]. The difference was remained after adjusting for covariates with the cox regression model [HR=8.2 (IC95% 1.03-64.9), p=.047]. The main reasons for discontinuation for BIC/FTC/TAF were toxicity/tolerability. CONCLUSION: In our study, patients have a high persistence. Patients on DTG/3TC treatment are more persistent compared to BIC/FTC/TAF, although BIC/FTC/TAF have worse baseline characteristics. The main reason for discontinuation of BIC/FTC/TAF is tolerability/toxicity.

Effects of Parity and Somatic Cell Count Threshold on Udder Morphology, Milkability Traits, and Milk Quality in Canarian Goats.

The effects of parity and somatic cell count in milk (SCC) threshold on the udder morphology, milkability traits, and milk composition was evaluated in 41 Canarian goats in mid-lactation. The animals were divided according to parity (1st, 2nd, and 3rd), and a SCC threshold of 2000 × 103 cells/mL in milk was set to evaluate the effect of this factor on the different measured parameters. Results showed that primiparous goats had the udder smaller and less distended than multiparous goats, but no differences were detected on milk flow parameters. Furthermore, SCC and total bacterial count (TBC) tended to be higher when the parity increased. On the other hand, goats with SCC ≤ 2000 × 103 had higher cistern-floor distance (CF) and lower TBC values compared with those goats with a count above the predetermined threshold. The results suggest that a reduction in SCC can be achieved by a selection of udder morphological traits. Moreover, milk flow parameters do not seem to be a tool to determine the udder health status in Canarian goats, but long-term studies are needed to verify it.

Is reduction necessary in overriding metaphyseal distal radius fractures in children under 11 years: a systematic review and meta-analysis of comparative studies.

OBJECTIVE: To determine the necessity of reduction in the treatment of overriding metaphyseal distal radius fractures (DRF) in children under 11 years. METHODS: In this systematic review and meta-analysis, PubMed, Embase, and Cochrane databases were searched to retrieve studies published from inception to 2023. Two reviewers independently screened for studies with observational or randomized control design comparing two treatments for overriding metaphyseal DRF in patients under 11 years: simple casting without reduction (SC group) versus closed reduction plus casting or pin fixation (CRC/F group); with varying outcomes reported (CRD471761). The risk of bias was assessed using the ROBINS-I tool. RESULTS: Out of 3,024 screened studies, three met the inclusion criteria, 180 children (mean age 7.1 ± 0.9 years) with overriding metaphyseal DRF: SC-group (n = 79) versus CRC/F-group (n = 101). Both treatment groups achieved 100% fracture consolidation without requiring further manipulation. The SC-group showed significantly fewer complications (mean difference [MD] 0.08; 95% CI [0.01, 0.53]; I2 = 22%; P < 0.009) and trends towards better sagittal alignment (MD 5.11; 95% CI [11.92, 1.71]; I2 = 94%; P < 0.14), less reinterventions (MD 0.31; 95% CI [0.01, 8.31]; P < 0.48), and fewer patients with motion limitation at the end of follow-up (MD 0.23; 95% CI [0.03,  1.98]; P < 0.18), although these findings were not statistically significant. CONCLUSIONS: Despite a limited number of studies comparing SC versus CRC/F in overriding DRF in children under 11 years, this study suggests that anatomical reduction is not necessary. Treating these fractures with SC, even when presenting with an overriding position, leads to reduced complications, shows a trend towards fewer reinterventions, improved sagittal alignment, and less limitation in patient motion. LEVEL OF EVIDENCE: Level III, Systematic review of Level-III studies.

What's in a name? Political and economic concepts differ in social media references to harmful algae blooms.

Policies and management decisions in the marine environment are driven in part by public sentiment which can grow more intense during hazard events like Harmful Algae Blooms (HABs). The public conversations on social media sites like Twitter (before X) reveal the polarized nature of HABs through nuanced language and sentiment. This article uses mixed methods of machine learned topic modeling and inductive qualitative coding to describe the ways the long-term 2017-2019 Karenia brevis "red tide" bloom were politicized across Florida's South West coast. It finds that there are topical differences in keywords related to place (e.g. beach, Florida, coast), agent (individual or organization), and epistemic values (reliance on scientific and/or media reports). These topical differences demonstrate different levels of politicization and partisanship in qualitative analysis. Conceptually, this research demonstrates the ways different dimensions of a long-duration marine hazard can be polarized. Regarding management, this research provides insights to political and organizational stakeholders and the gaps in the discourse shaping marine hazards which can be used to strategically guide future social media engagement to manage politicization. What if all the careful work that resource and environmental managers do can be undone by simple, seemingly uncontroversial words? In an era of increased environmental and marine distress-coupled with short format communication-the ways environmental managers choose their words is crucial, even between ostensibly inconsequential nouns like "red tide" or "algae bloom." Policies and management decisions in the marine environment are driven in part by public sentiment which can grow more intense during hazard events like Harmful Algae Blooms (HABs). The public conversations on social media sites like Twitter (before X) reveal the polarized nature of HABs through nuanced language and sentiment. This article relies on mining social media posts, and uses mixed methods of machine-learned topic modeling and human-driven inductive qualitative coding to describe the ways the long-term 2017-2019 Karenia brevis "red tide" blooms were politicized across Florida's South West coast. It finds that there are topical differences in keywords related to place (e.g. beach, Florida, coast), agent (individual or organization), and epistemic values (reliance on scientific and/or media reports). These topical differences demonstrate different levels of politicization and partisanship in qualitative analysis. Conceptually, this research demonstrates the ways different dimensions of a long-duration marine hazard can be polarized. Regarding management, this research provides insights to political and organizational stakeholders and the gaps in the discourse shaping marine hazards which can be used to strategically guide future social media engagement to manage politicization.

Real-world persistence with dolutegravir/lamivudine versus bictegravir/emtricitabina/tenofovir-alafenamide among people with HIV. / Persistencia de los tratamientos con dolutegravir/lamivudina y bictegravir/emtricitabina/tenofovir-alafenamida en personas con VIH en la práctica real.

OBJETIVES: The main objective was to compare the persistence between dolutegravir/lamivudine (DTG/3TC) and bictegravir/emtricitabine/tenofovir-alafenamide (BIC/FTC/TAF) and to analyze reasons for discontinuation. METHODS: We conducted a retrospective, non-interventional, descriptive and longitudinal study. All human immunodeficiency virus (HIV) patients over 18 years treated with DTG/3TC or BIC/FTC/TAF in our center were included. Persistence after first year was compared using the χ2 test. Kaplan-Meier survival analysis was performed. RESULTS: Three hundred fifty-eight patients were included. 99.5% versus 90.99% of patients were persistent after the first year for DTG/3TC and BIC/FTC/TAF respectively (p = 0.001). Persistence with DGT/3TC was 1,237 days (IC95% 1,216-1,258) and persistence with BIC/FTC/TAF was 986 days ([IC95% 950-1,021]; p < 0.001). The difference was remained after adjusting for covariates with the cox regression model (HR= 8.2 [IC95% 1.03-64.9], p = 0.047). The main reasons for discontinuation for BIC/FTC/TAF were toxicity/tolerability. CONCLUSION: In our study patients had a high persistence. Patients on DTG/3TC treatment were more persistent compared to BIC/FTC/TAF, although BIC/FTC/TAF have worse baseline characteristics. The main reason for discontinuation of BIC/FTC/TAF was tolerability/toxicity.

Ray resection in pediatric population after trauma injuries.

The aim of this study is to assess the functional, emotional, and social adaptation of pediatric patients submitted to a hand ray resection to treat a traumatic hand injury. Retrospective study of pediatric patients undergoing hand ray resection, in the period 2013-2022, performed in two hospital institutions. Inclusion criteria: age less than 18 years, primary/secondary resection due to traumatic etiology and follow-up time of more than 1 year. Data concerning demographic information, lesion location, traumatic mechanism and surgical description were collected. Functional outcomes (QuickDASH Score), social and emotional integration (PEDSQL) and satisfaction were evaluated. Seven patients were included, with male predominance (n = 4) and the right side was the most affected (n = 5). Median age at the time of surgery was 10 years (2-15). Primary ray resection, without previous revascularization, was performed in three patients. Secondary ray resection was performed in four patients. Three patients with an unsuccessful revascularization procedure attempt another patient with a sequela with severe deformity. All patients presented a good adaptation to daily living activities, with good pinch and grip function. The median follow-up was 4 years (min:1; max:9). The scores were collected on six out of seven patients. Median QuickDASH score of 14 (min:11; max:22), and PEDSQL[physical] of 95.31 (min:78.13; max:100) and PEDSQL[social] of 93.47 (min:66.3; max:100). Hand ray resection is a rare procedure in pediatric age and usually difficult for patients and parents to accept. However, it is a useful and safe technique that allows for an improvement in overall hand function and psychosocial readaptation in specific and selected cases. Level of evidence: Level of evidence IV - case series.

Carbon footprint and employment generation produced by ICT networks for Internet deployment: A multi-regional input-output analysis.

Internet is widely regarded as a necessary resource for economic and social development. The availability of this technology requires the deployment of ICT networks which have implications not only on the natural surroundings but also on the human environment. Understanding the impact generated on key areas of socio-ecological concern such as carbon footprint and employment generation is essential to ensure well-informed decision-making. This investigation utilized multiregional environmentally extended input-output (MRIO) methodology to evaluate the carbon footprint and the employment generation associated with providing internet to six geo-demographic scenarios, from urban to remote rural, using Peru as a reference site. The results showed that most of the carbon emissions (289-340 kg CO2 eq./subs./yr.) and employment (7-8 jobs/subs./yr.) associated with larger ICT networks intended for urban and suburban areas was attributable to the manufacturing of end-user devices. The sustainability of smaller ICT networks for rural areas was dominated by the construction of shared infrastructures (mainly 4G LTE equipment), while the contribution of the energy consumed was in all cases limited. Although the analysis considered ICT networks deployed in Peru, most impacts were generated in China, where the manufacturing of the electronic components was assumed to take place. This analysis highlights the value of econometric methods for sustainability assessment such as MR-EEIO, which are complementary to the more conventional process-based E-LCA.

Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents.

We report here the virtual screening design, synthesis and activity of eight new inhibitors of SphK1. For this study we used a pre-trained Graph Convolutional Network (GCN) combined with docking calculations. This exploratory analysis proposed nine compounds from which eight displayed significant inhibitory effect against sphingosine kinase 1 (SphK1) demonstrating a high level of efficacy for this approach. Four of these compounds also displayed anticancer activity against different tumor cell lines, and three of them (5), (6) and (7) have shown a wide inhibitory action against many of the cancer cell line tested, with GI50 below 5 µM, being (5) the most promising with TGI below 10 µM for the half of cell lines. Our results suggest that the three most promising compounds reported here are the pyrimidine-quinolone hybrids (1) and (6) linked by p-aminophenylsulfanyl and o-aminophenol fragments respectively, and (8) without such aryl linker. We also performed an exhaustive study about the molecular interactions that stabilize the different ligands at the binding site of SphK1. This molecular modeling analysis was carried out by using combined techniques: docking calculations, MD simulations and QTAIM analysis. In this study we also included PF543, as reference compound, in order to better understand the molecular behavior of these ligands at the binding site of SphK1.These results provide useful information for the design of new inhibitors of SphK1 possessing these structural scaffolds.

Non-linear impacts of harmful algae blooms on the coastal tourism economy.

Harmful algae blooms (HABs) occur in water bodies throughout the globe and can have multi-faceted impacts on tourism. However, little is known of the magnitude of economic losses to the tourism sector as a result of HABs. There is limited understanding of the empirical relationships between HAB intensity and duration, and the effects of this phenomenon on the tourism sector. This study is based in the state of Florida, USA, a notable sun, sand, and sea destination in the western hemisphere, where blooms of a marine harmful algae are a recurrent threat to coastal tourism. The empirical framework is based on a month and county-level panel database that combines sales by tourism-related businesses with observations from the official HAB surveillance system of the state of Florida. We use time and space fixed-effects regressions to estimate the loss in tourism revenue associated with one additional day of red tide. Results indicate that impacts of HABs on tourism do not follow a linear pattern with increasing HAB concentrations, but rather appear to follow an inverted-U pattern. In other words, higher concentrations of the HAB organism do not necessarily imply higher economic losses, suggesting that the impacts of HABs on tourism are not driven solely by the biophysical element of cell density. Rather, these impacts appear to be mediated and amplified by human dimensions. The loss to tourism-related businesses due to the 2018 Florida red tide bloom was estimated to be $2.7 billion USD, which implies that HABs and their impact on tourism can be considered as a potential 'billion-dollar' disaster.

[Giant tongue leading to dysphagia in light chain amyloidosis patient]. / Lengua gigante condicionante de disfagia en paciente con amiloidosis de cadenas ligeras.

Introduction: Macroglossia as a clinical manifestation of systemic amyloidosis is a rare condition, occurring in less than 9% of all types of amyloidosis. The aim of this report is to present the diagnostic approach of a patient with macroglossia, providing a systematic approach and considering relevant diagnostic possibilities during their evaluation. Clinical case: We present the case of a 60-year-old man who presented with a progressively enlarging giant tongue for six months, causing dysphagia and reduced oral opening. A tongue biopsy was taken, which histopathologically exhibited homogenous eosinophilic amyloid-like material. Congo red staining showed amyloid material with red dye under light microscopy and apple-green birefringence under polarized light. Bone marrow biopsy showed 30% plasma cells, allowing for a definitive diagnosis of soft tissue amyloidosis. Although it is a benign lesion, localized amyloidosis should be differentiated from systemic forms. Conclusions: The approach of patients with macroglossia is complex due to the diagnostic possibilities, from endocrinological causes, neoplastic, and even by deposit; Being an isolated sign in a patient is a challenge in its approach, because the involvement of the airway is the main complication to avoid in these patients.

Introducción: la macroglosia, como manifestación clínica de la amiloidosis sistémica, es una condición poco frecuente, ya que ocurre en menos del 9% de todos los tipos de amiloidosis. El objetivo de este informe es presentar el abordaje diagnóstico de un paciente con macroglosia, proporcionando un enfoque sistemático y considerando las posibilidades diagnósticas relevantes durante su evaluación. Caso clínico: presentamos el caso de un hombre de 60 años que presentó una lengua gigante de crecimiento progresivo durante seis meses, lo que causó disfagia y reducción en la apertura oral. Se realizó una biopsia de la lengua, la cual histopatológicamente exhibió material homogéneo similar a un amiloide eosinofílico. La tinción de rojo Congo mostró material amiloide con colorante rojo bajo microscopía óptica y con birrefringencia verde manzana bajo luz polarizada. La biopsia de médula ósea mostró un 30% de células plasmáticas, lo que permitió realizar un diagnóstico definitivo de amiloidosis de tejidos blandos. Aunque se trata de una lesión benigna, la amiloidosis localizada debe diferenciarse de las formas sistémicas. Conclusiones: el abordaje de pacientes con macroglosia es complejo, debido a las diversas posibilidades diagnósticas, que incluyen causas endocrinológicas, neoplásicas e, incluso, por deposición de sustancias. Cuando se presenta como un signo aislado en un paciente, se convierte en un reto en su abordaje, ya que la principal complicación a evitar en estos pacientes es el compromiso de la vía aérea.

Rapid ozone depletion after humidification of the stratosphere by the Hunga Tonga Eruption.

The eruption of the Hunga Tonga-Hunga Ha'apai volcano on 15 January 2022 offered a good opportunity to explore the early impacts of tropical volcanic eruptions on stratospheric composition. Balloon-borne observations near Réunion Island revealed the unprecedented amount of water vapor injected by the volcano. The enhanced stratospheric humidity, radiative cooling, and expanded aerosol surface area in the volcanic plume created the ideal conditions for swift ozone depletion of 5% in the tropical stratosphere in just 1 week. The decrease in hydrogen chloride by 0.4 parts per million by volume (ppbv) and the increase in chlorine monoxide by 0.4 ppbv provided compelling evidence for chlorine activation within the volcanic plume. This study enhances our understanding of the effect of this unusual volcanic eruption on stratospheric chemistry and provides insights into possible chemistry changes that may occur in a changing climate.

Unexpectedly rapid aerosol formation in the Hunga Tonga plume.

The Hunga Tonga-Hunga Ha'apai (HT-HH) volcanic eruptions on January 13 and 15, 2022, produced a plume with the highest signal in stratospheric aerosol optical depth observed since the eruption of Mt. Pinatubo in 1991. Suites of balloon-borne instruments on a series of launches from Réunion Island intercepted the HT-HH plume between 7 and 10 d of the eruptions, yielding observations of the aerosol number and size distribution and sulfur dioxide (SO2) and water vapor (H2O) concentrations. The measurements reveal an unexpected abundance of large particles in the plume, constrain the total sulfur injected to approximately 0.2 Tg, provide information on the altitude of the injection, and indicate that the formation of sulfuric acid aerosol was complete within 3 wk. Large H2O enhancements contributed as much as ~30% to ambient aerosol surface area and likely accelerated SO2 oxidation and aerosol formation rates in the plume to approximately three times faster than under normal stratospheric conditions.

Study of the Total Antioxidant Capacity (TAC) in Native Cereal-Pulse Flours and the Influence of the Baking Process on TAC Using a Combined Bayesian and Support Vector Machine Modeling Approach.

During the last few years, the increasing evidence of dietary antioxidant compounds and reducing chronic diseases and the relationship between diet and health has promoted an important innovation within the baked product sector, aiming at healthier formulations. This study aims to develop a tool based on mathematical models to predict baked goods' total antioxidant capacity (TAC). The high variability of antioxidant properties of flours based on the aspects related to the type of grain, varieties, proximal composition, and processing, among others, makes it very difficult to innovate on food product development without specific analysis. Total phenol content (TP), oxygen radical absorbance capacity (ORAC), and ferric-reducing antioxidant power assay (FRAP) were used as markers to determine antioxidant capacity. Three Bayesian-type models are proposed based on a double exponential parameterized curve that reflects the initial decrease and subsequent increase as a consequence of the observed processes of degradation and generation, respectively, of the antioxidant compounds. Once the values of the main parameters of each curve were determined, support vector machines (SVM) with an exponential kernel allowed us to predict the values of TAC, based on baking conditions (temperature and time), proteins, and fibers of each native grain.

Enhancing Distributed Neural Network Training Through Node-Based Communications.

The amount of data needed to effectively train modern deep neural architectures has grown significantly, leading to increased computational requirements. These intensive computations are tackled by the combination of last generation computing resources, such as accelerators, or classic processing units. Nevertheless, gradient communication remains as the major bottleneck, hindering the efficiency notwithstanding the improvements in runtimes obtained through data parallelism strategies. Data parallelism involves all processes in a global exchange of potentially high amount of data, which may impede the achievement of the desired speedup and the elimination of noticeable delays or bottlenecks. As a result, communication latency issues pose a significant challenge that profoundly impacts the performance on distributed platforms. This research presents node-based optimization steps to significantly reduce the gradient exchange between model replicas whilst ensuring model convergence. The proposal serves as a versatile communication scheme, suitable for integration into a wide range of general-purpose deep neural network (DNN) algorithms. The optimization takes into consideration the specific location of each replica within the platform. To demonstrate the effectiveness, different neural network approaches and datasets with disjoint properties are used. In addition, multiple types of applications are considered to demonstrate the robustness and versatility of our proposal. The experimental results show a global training time reduction whilst slightly improving accuracy. Code: https://github.com/mhaut/eDNNcomm.

Insights into the Nitrogen Footprint of food consumption in Spain: Age and gender impacts on product choices and sustainability.

The reactive nitrogen released to the environment caused by food consumption can be quantified through the Nitrogen Footprint (NF). Spain has been traditionally regarded to follow the worldwide recognized healthy Mediterranean diet. However, dietary changes among the population have started to shift from the traditional Spanish food consumption. Based on the established method for quantifying the NF from the consumer perspective, this study aimed to estimate the NF from food consumption in Spain, distinguishing between different age groups and gender. The results show that the food NF in Spain was 12.78 kg of N/cap/year and 601 Gg N/year in total. The main food contributors to the overall food NF in Spain were cereals, beef, and pork, while the food products oilseeds and oil, fruits, and legumes presented a lower contribution to the Spanish food NF. Additionally, differences in the food NF among the Spanish population were also observed. Younger age groups (<10 years) and the elderly (>65 years) presented lower food NF per capita than the rest of the population. In relation to gender, it was observed that women have a food NF slightly lower than men. It was seen that food production NF contributes 91 % to the overall food NF in Spain compared to the total food consumption NF. Key strategies based on improving the N use efficiency of crops and livestock, recycling and avoiding food waste, and implementing more sustainable eating patterns can be applied to reduce the food NF in Spain.

Melanoma cells with acquired resistance to vemurafenib have decreased autophagic flux and display enhanced ability to transfer resistance.

Over the last years, the incidence of melanoma, the deadliest form of skin cancer, has risen significantly. Nearly half of the melanoma patients exhibit the BRAFV600E mutation. Although the use of BRAF and MEK inhibitors (BRAFi and MEKi) showed an impressive success rate in melanoma patients, durability of response remains an issue because tumor quickly becomes resistant. Here, we generated and characterized Lu1205 and A375 melanoma cells resistant to vemurafenib (BRAFi). Resistant cells (Lu1205R and A375R) exhibit higher IC50 (5-6 fold increase) and phospho-ERK levels and 2-3 times reduced apoptosis than their sensitive parents (Lu1205S and A375S). Moreover, resistant cells are 2-3 times bigger, display a more elongated morphology and have a modulation of migration capacity. Interestingly, pharmacological inhibition of sphingosine kinases, that prevents sphingosine-1-phosphate production, reduces migration of Lu1205R cells by 50 %. In addition, although Lu1205R cells showed increased basal levels of the autophagy markers LC3II and p62, they have decreased autophagosome degradation and autophagy flux. Remarkably, expression of Rab27A and Rab27B, which are involved in the release of extracellular vesicles are dramatically augmented in resistant cells (i.e. 5-7 fold increase). Indeed, conditioned media obtained from Lu1205R cells increased the resistance to vemurafenib of sensitive cells. Hence, these results support that resistance to vemurafenib modulates migration and the autophagic flux and may be transferred to nearby sensitive melanoma cells by factors that are released to the extracellular milieu by resistant cells.

Intraosseous injection of mesenchymal stem cells for the treatment of osteonecrosis of the immature femoral head and prevention of head deformity: A study in a pig model.

BACKGROUND: Cell therapy has been proposed as part of the therapeutic arsenal to assist bone formation and remodeling in the early stages of osteonecrosis of the femoral head. The purpose of this study is to determine the effects of intraosseous inoculation of mesenchymal stem cells on bone formation and remodeling in an established experimental model of osteonecrosis of the femoral head in immature pigs. METHODS: Thirty-one 4-week-old immature Yorkshire pigs were used. Experimental osteonecrosis of the femoral head was created in the right hip of all included animals (n = 31). The month after surgery, hip and pelvis radiographs were taken to confirm osteonecrosis of the femoral head. Four animals were excluded following surgery. Two groups were established: (A) mesenchymal stem cell-treated group (n = 13) and (B) saline-treated group (n = 14). One month after surgery the mesenchymal stem cell-group received an intraosseous injection of 10 × 106 mesenchymal stem cell (5 cc) and the saline-treated group of 5 cc of physiological saline solution. Osteonecrosis of the femoral head progression was assessed by monthly X-rays (1-, 2-, 3- and 4-months post-surgery). The animals were sacrificed 1 or 3 months following the intraosseous injection. Repair tissue and osteonecrosis of the femoral head were histologically evaluated immediately after sacrifice. RESULTS: At time of sacrifice, radiographic images showed evident osteonecrosis of the femoral head with associated severe femoral head deformity in 11 of the 14 animals (78%) in the saline group and in only 2 of the 13 animals (15%) in the mesenchymal stem cell group. Histologically, the mesenchymal stem cell group showed less osteonecrosis of the femoral head and less flattening. In the saline group, there was pronounced femoral head flattening and the damaged epiphyseal trabecular bone was largely replaced with fibrovascular tissue. CONCLUSION: Intraosseous mesenchymal stem cells inoculation improved bone healing and remodeling in our immature pig osteonecrosis of the femoral head model. This work supports further investigation to determine whether mesenchymal stem cells enhance the healing process in immature osteonecrosis of the femoral head.

Neurite outgrowth induced by stimulation of angiotensin II AT2 receptors in SH-SY5Y neuroblastoma cells involves c-Src activation.

Neuroblastoma, the most common extracranial solid tumor occurring in childhood, originates from the aberrant proliferation of neural crest cells. Accordingly, the mechanism underling neuronal differentiation could provide new strategies for neuroblastoma treatment. It is well known that neurite outgrowth could be induced by Angiotensin II (Ang II) AT2 receptors; however, the signaling mechanism and its possible interaction with NGF (neural growth factor) receptors remain unclear. Here, we show that Ang II and CGP42112A (AT2 receptor agonist) promote neuronal differentiation by inducing neurite outgrowth and ßIII-tubulin expression in SH-SY5Y neuroblastoma cells. In addition, we demonstrate that treatment with PD123319 (AT2 receptor antagonist) reverts Ang II or CGP42112A-induced differentiation. By using specific pharmacological inhibitors we established that neurite outgrowth induced by CGP42112A requires the activation of MEK (mitogen-activated protein kinase kinase), SphK (sphingosine kinase) and c-Src but not PI3K (phosphatidylinositol 3-kinase). Certainly, CGP42112A stimulated a rapid and transient (30 s, 1 min) phosphorylation of c-Src at residue Y416 (indicative of activation), following by a Src deactivation as indicated by phosphorylation of Y527. Moreover, inhibition of the NGF receptor tyrosine kinase A (TrkA) reduced neurite outgrowth induced by Ang II and CGP42112A. In summary, we demonstrated that AT2 receptor-stimulated neurite outgrowth in SH-SY5Y cells involves the induction of MEK, SphK and c-Src and suggests a possible transactivation of TrkA. In that regard, AT2 signaling pathway is a key player in neuronal differentiation and might be a potential target for therapeutic treatments.

Guided Growth for the Treatment of Cubitus Varus in Children: Medium- to Long-Term Results.

Correction of cubitus varus is commonly attempted through supracondylar humeral osteotomy. We hypothesized that lateral distal humeral hemiepiphysiodesis (LDHH) could be used to gradually correct this deformity in children. We conducted a retrospective study including all patients who underwent LDHH with the eight-Plate system between 2008 and 2018, with a minimum 4-year follow-up. We collected demographic, fracture-related, pre- and postoperative clinical (carrying angle (CA), ROM), and radiological data (humeral-ulnar angle (HUA), Baumann angle (BA), shaft-condylar angle (SCA), lateral capitellohumeral angle (LCHA)), as well as data on complications and satisfaction at last follow-up. Fifteen patients were included, with a median follow-up of 81 (64-103) months. All the variables had improved significantly as follows: CA -16 (-18 to -9)°, HUA -16 (-19 to -12)°, BA -11 (-17 to -7)°, SCA 7.5 (3.3 to 13.8)°, LCHA -4.8 (-6.8 to 0.6), flexion 10 (0 to 24)°, and extension 10 (0 to 10)°. The annual correction rate in terms of HUA was 2.41° (1.9 to 3.2). There were 5 cases of aseptic screw loosening, 4 of them requiring replacement, without relation to age at surgery (p = 0.324). Most patients (86.67%) were satisfied, and a relationship was found with younger age at surgery (p = 0.037). In conclusion, preliminary results show that LDHH with the eight-Plate system is an effective technique for mild to moderate cubitus varus deformity correction in children. Patients should be advised of the relatively long duration of implant retention and the possibility of reoperation for screw replacement or implant removal.