RESUMEN

Alkaptonuria is a rare autosomal recessive disease caused by a mutation in the homogentisate 1,2-dioxygenase (HGO) gene, leading to the accumulation of homogentisic acid (HGA). HGA polymerizes to form a black pigment that accumulates in connective tissue and joints (ochronosis), causing their destruction. In this work, we report a case of Achilles tendon rupture in a patient with a prior diagnosis of alkaptonuria. A 71-year-old man presented to the emergency department reporting pain in his posterior right ankle and dysfunction, evolving over three weeks after falling down a short flight of stairs. He had previously been diagnosed with alkaptonuria and had undergone five joint prostheses and an aortic valve replacement. A physical examination revealed right ankle edema, pain upon palpation, a palpable gap at the insertion of the tendon, and a positive Thompson test. An MRI confirmed an avulsive rupture at the insertion of the Achilles tendon. During surgical exploration, black pigmentation was observed in the tendon, which was reinserted using a double-row system reinforced with a percutaneous Bunnel stitch. The patient was discharged the following day with a cast splint, maintaining the foot in physiological plantar flexion for two weeks. In the subsequent two weeks, he used a non-weight-bearing walker boot, and finally, in the following two weeks, he began weight-bearing. Two months post-operation, he was walking without support. Twelve months after the intervention, the patient regained their previous functional status, being able to walk on tiptoes without difficulty. Spontaneous Achilles tendon rupture without associated trauma in patients with ochronosis is rare, with limited literature demonstrating successful outcomes post-surgery. Since the tendon becomes more fragile due to pigment accumulation, it was reinserted using a double-row system, increasing the contact area and more effectively distributing the load. There is no standard technique for treating these patients, but the patient's previous functional capacity was restored, with no new ruptures to date. The significant morbidity of alkaptonuria and potential complications, such as tendon ruptures, warrant future studies to discover and develop new prophylactic and therapeutic treatments.

RESUMEN

In the avian retina, ADP induces the proliferation of late developing glia progenitors. Here, we show that in serum-containing retinal cell cultures, ADP-induced increase in [3H]-thymidine incorporation can be prevented by the IGF-1 receptor antagonists AG1024 and I-OMe-Tyrphostin AG 538, suggesting the participation of IGF-1 in ADP-mediated progenitor proliferation. In contrast, no increase in [3H]-thymidine incorporation is observed in retinal cultures treated only with IGF-1. Under serum starvation, while no increase in cell proliferation is detected in cultures treated only with ADP or IGF-1, a significant increase in [3H]-thymidine incorporation and number of PCNA expressing cells is observed in cultures treated concomitantly with ADP plus IGF-1, suggesting that both molecules are required to induce proliferation of retinal progenitors. In serum-starved cultures, although an increase in cell viability is detected by MTT assays in IGF-1-treated cultures, no significant increase in viability of [3H]-thymidine labeled progenitors is observed, suggesting that IGF-1 may contribute to survival of postmitotic cells in culture. While only ADP increases intracellular calcium, only IGF-1 induces the phosphorylation of Akt in the retinal cultures. IGF-1 through the PI3K/Akt pathway induces a significant increase in the transcription and expression of CDK1 with a decrease in phospho-histone H3 expression that is concomitant with an increase in the expression of cyclins D1 and E and CDK2. These findings suggest that IGF-1 stimulates CDK-1 mRNA and protein expression that enable progenitors to progress through the cell cycle. However, signaling of ADP in the presence IGF-I seems to be required for DNA synthesis.

RESUMEN

The active principles of Cannabis sativa are potential treatments for several diseases, such as pain, seizures and anorexia. With the increase in the use of cannabis for medicinal purposes, a more careful assessment of the possible impacts on embryonic development becomes necessary. Surveys indicate that approximately 3.9% of pregnant women use cannabis in a recreational and/or medicinal manner. However, although the literature has already described the presence of endocannabinoid system components since the early stages of CNS development, many of their physiological effects during this stage have not yet been established. Moreover, it is still uncertain how the endocannabinoid system can be altered in terms of cell proliferation and cell fate, neural migration, neural differentiation, synaptogenesis and particularly cell death. In relation to cell death in the CNS, knowledge about the effects of cannabinoids is scarce. Thus, the present work aims to review the role of the endocannabinoid system in different aspects of CNS development and discuss possible side effects or even opportunities for treating some conditions in the development of this tissue.

Asunto(s)

Cannabinoides , Cannabis , Embarazo , Femenino , Humanos , Cannabinoides/farmacología , Endocannabinoides/metabolismo , Cannabis/metabolismo , Convulsiones/inducido químicamente , Proliferación Celular

RESUMEN

Optimization is at the heart of machine learning, statistics, and many applied scientific disciplines. It also has a long history in physics, ranging from the minimal action principle to finding ground states of disordered systems such as spin glasses. Proximal algorithms form a class of methods that are broadly applicable and are particularly well-suited to nonsmooth, constrained, large-scale, and distributed optimization problems. There are essentially five proximal algorithms currently known, each proposed in seminal work: Forward-backward splitting, Tseng splitting, Douglas-Rachford, alternating direction method of multipliers, and the more recent Davis-Yin. These methods sit on a higher level of abstraction compared to gradient-based ones, with deep roots in nonlinear functional analysis. In this paper we show that all of these methods are actually different discretizations of a single differential equation, namely, the simple gradient flow which dates back to Cauchy (1847). An important aspect behind many of the success stories in machine learning relies on "accelerating" the convergence of first-order methods. However, accelerated methods are notoriously difficult to analyze, counterintuitive, and without an underlying guiding principle. We show that similar discretization schemes applied to Newton's equation with an additional dissipative force, which we refer to as accelerated gradient flow, allow us to obtain accelerated variants of all these proximal algorithms-the majority of which are new although some recover known cases in the literature. Furthermore, we extend these methods to stochastic settings, allowing us to make connections with Langevin and Fokker-Planck equations. Similar ideas apply to gradient descent, heavy ball, and Nesterov's method which are simpler. Our results therefore provide a unified framework from which several important optimization methods are nothing but simulations of classical dissipative systems.

RESUMEN

Energy statistics was proposed by Székely in the 80's inspired by Newton's gravitational potential in classical mechanics and it provides a model-free hypothesis test for equality of distributions. In its original form, energy statistics was formulated in euclidean spaces. More recently, it was generalized to metric spaces of negative type. In this paper, we consider a formulation for the clustering problem using a weighted version of energy statistics in spaces of negative type. We show that this approach leads to a quadratically constrained quadratic program in the associated kernel space, establishing connections with graph partitioning problems and kernel methods in machine learning. To find local solutions of such an optimization problem, we propose kernel k-groups, which is an extension of Hartigan's method to kernel spaces. Kernel k-groups is cheaper than spectral clustering and has the same computational cost as kernel k-means (which is based on Lloyd's heuristic) but our numerical results show an improved performance, especially in higher dimensions. Moreover, we verify the efficiency of kernel k-groups in community detection in sparse stochastic block models which has fascinating applications in several areas of science.

RESUMEN

AIM: We investigated the effects of high-intensity interval and continuous short-term exercise on body composition and cardiac function after myocardial ischemia-reperfusion injury (IRI) in obese rats. METHODS: Rats fed with a standard chow diet (SC) or high-fat diet (HFD) for 20 weeks underwent systolic blood pressure (SBP), glycemia and dual-energy X-ray absorptiometry analyses. Then, animals fed with HFD were subdivided into three groups: sedentary (HFD-SED); moderate-intensity continuous training (HFD-MICT); and high-intensity interval training (HFD-HIIT). Exercised groups underwent four isocaloric aerobic exercise sessions, in which HFD-MICT maintained the intensity continuously and HFD-HIIT alternated it. After exercise sessions, all groups underwent global IRI and myocardial infarct size (IS) was determined histologically. Fat and muscle mass were weighted, and protein levels involved in muscle metabolism were assessed in skeletal muscle. RESULTS: HFD-fed versus SC-fed rats reduced lean body mass by 31% (P < 0.001), while SBP, glycemia and body fat percentage were increased by 10% (P = 0.04), 30% (P = 0.006) and 54% (P < 0.001); respectively. HFD-induced muscle atrophy was restored in exercised groups, as only HFD-SED presented lower gastrocnemius (32%; P = 0.001) and quadriceps mass (62%; P < 0.001) than SC. PGC1-α expression was 2.7-fold higher in HFD-HIIT versus HFD-SED (P = 0.04), whereas HFD-HIIT and HFD-MICT exhibited 1.7-fold increase in p-mTORSer2481 levels compared to HFD-SED (P = 0.04). Although no difference was detected among groups for IS (P = 0.30), only HFD-HIIT preserved left-ventricle developed pressure after IRI (+0.7 mmHg; P = 0.9). SIGNIFICANCE: Short-term exercise, continuous or HIIT, restored HFD-induced muscle atrophy and increased mTOR expression, but only HIIT maintained myocardial contractility following IRI in obese animals.

Asunto(s)

Composición Corporal/fisiología , Miocardio/metabolismo , Animales , Glucemia/metabolismo , Presión Sanguínea , Dieta Alta en Grasa , Regulación de la Expresión Génica , Pruebas de Función Cardíaca , Entrenamiento de Intervalos de Alta Intensidad , Humanos , Estudios Longitudinales , Masculino , Modelos Animales , Músculo Esquelético/metabolismo , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/etiología , Obesidad/etiología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Condicionamiento Físico Animal , Ratas , Ratas Wistar , Sarcopenia/etiología

RESUMEN

Development of progenitors in the embryonic retina is modulated by signaling molecules, and cannabinoid receptors are highly expressed in the early developing retina. Here, we investigated whether the CB1/CB2 receptor agonist WIN 5212-2 (WIN) modulated the proliferation, viability, and calcium responses in chick embryo retinal progenitors in culture. A decline in [3H]-thymidine incorporation was observed when cultures were incubated with 0.5-1.0 µM WIN, an effect that was mimicked by URB602 and URB597, inhibitors of the monoacylglycerol lipase and fatty acid amide hydrolase, respectively. A reduction in the number of proliferating cell nuclear antigen-positive nuclei was also noticed in WIN-treated cultures, suggesting that activation of cannabinoid receptors decreases the proliferation of cultured retinal progenitors. WIN (0.5-5.0 µM), but not capsaicin, decreased retinal cell viability, an effect that was blocked by CB1 and CB2 receptor antagonists and by the P2X7 receptor antagonist A438079, implicating this nucleotide receptor in the cannabinoid-mediated cell death. Treatment with WIN also induced an increase in mitochondrial superoxide and P2X7 receptor-mediated uptake of sulforhodamine B in the cultured cells. While a high proportion of cultured cells responded to glutamate, GABA, and 50 mM KCl with intracellular calcium shifts, very few cells responded to the activation of P2X7 receptors by ATP. Noteworthy, while decreasing the number of cells responding to glutamate, GABA, and KCl, treatment of the cultures with WIN induced a significant increase in the number of cells responding to 1 mM ATP, suggesting that activation of cannabinoid receptors primes P2X7 receptor calcium signaling in retinal progenitors in culture.

Asunto(s)

Apoptosis/efectos de los fármacos , Cannabinoides/farmacología , Neuroglía/citología , Receptores Purinérgicos P2X7/metabolismo , Retina/citología , Transducción de Señal/efectos de los fármacos , Células Madre/metabolismo , Animales , Benzoxazinas/farmacología , Calcio/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Embrión de Pollo , Colorantes Fluorescentes/metabolismo , Morfolinas/farmacología , Naftalenos/farmacología , Nestina/metabolismo , Fenotipo , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Células Madre/efectos de los fármacos

RESUMEN

Acetabular retroversion (AR) consists of a malorientation of the acetabulum in the sagittal plane. AR is associated with changes in load transmission across the hip, being a risk factor for early osteoarthrosis. The pathophysiological basis of AR is an anterior acetabular hyper-coverage and an overall pelvic rotation.The delay or the non-diagnosis of AR could have an impact in the overall management of femoroacetabular impingement (FAI). AR is a subtype of (focal) pincer deformity.The objective of this review was to clarify the pathophysiological, diagnosis and treatment fundaments inherent to AR, using a current literature review.Radiographic evaluation is paramount in AR: the cross-over, the posterior wall and ischial spine signs are classic radiographic signs of AR. However, computed tomography (CT) evaluation permits a three-dimensional characterization of the deformity, being more reliable in its recognition.Acetabular rim trimming (ART) and periacetabular osteotomy (PAO) are the best described surgical options for the treatment of AR.The clinical outcomes of both techniques are dependent on the correct characterization of existing lesions and adequate selection of patients. Cite this article: EFORT Open Rev 2018;3:595-603. DOI: 10.1302/2058-5241.3.180015.

RESUMEN

Abstract AIM To compare the amount of cardioprotection induced by a single exercise session with those achieved after an 8-week aerobic exercise training following ischemia reperfusion injury in rats. METHODS Twenty-five male Wistar rats (250-300g) were assigned into a group submitted to physical training (TR; n=12) or a single maximal exercise session (EXE; n=13). Following sedentarism or physical training (8 weeks, 5 sessions/wk, 1h/session at 70% of maximal speed) both groups performed a maximal exercise test. Then, groups were submitted to ischemia reperfusion injury (30 min/1h) through an isolated heart protocol, in which left ventricle developed pressure was measured. RESULTS The TR group presented greater maximal oxygen consumption compared to the EXE group (77.25±20.41 vs 41.32±25.86 ml/Kg/min; P=0.003). Regarding left ventricle developed pressure, no differences were detected between groups at baseline (TR: 89.78±24.40 vs EXE: 81.37±31.84 mmHg; P=0.48). However, after reperfusion, the TR group presented superior intraventricular pressure than EXE group (37.94±18.34 vs 21.59±13.67 mmHg; P=0.03). CONCLUSION Eight-week aerobic training induced greater cardioprotection against ischemia reperfusion injury in rats compared to a single exercise session, due to an increased cardiac function. This suggests that exercise-induced cardioprotection is a multifactorial process that may involve different mediators according to the exercise duration.(AU)

Asunto(s)

Animales , Masculino , Ratas , Ejercicio Físico , Daño por Reperfusión Miocárdica/inducido químicamente , Ratas Wistar

RESUMEN

When retinal cell cultures were mechanically scratched, cell growth over the empty area was observed. Only dividing and migrating, 2 M6-positive glial cells were detected. Incubation of cultures with apyrase (APY), suramin, or Reactive Blue 2 (RB-2), but not MRS 2179, significantly attenuated the growth of glial cells, suggesting that nucleotide receptors other than P2Y1 are involved in the growth of glial cells. UTPγS but not ADPßS antagonized apyrase-induced growth inhibition in scratched cultures, suggesting the participation of UTP-sensitive receptors. No decrease in proliferating cell nuclear antigen (PCNA(+)) cells was observed at the border of the scratch in apyrase-treated cultures, suggesting that glial proliferation was not affected. In apyrase-treated cultures, glial cytoplasm protrusions were smaller and unstable. Actin filaments were less organized and alfa-tubulin-labeled microtubules were mainly parallel to scratch. In contrast to control cultures, very few vinculin-labeled adhesion sites could be noticed in these cultures. Increased Akt and ERK phosphorylation was observed in UTP-treated cultures, effect that was inhibited by SRC inhibitor 1 and PI3K blocker LY294002. These inhibitors and the FAK inhibitor PF573228 also decreased glial growth over the scratch, suggesting participation of SRC, PI3K, and FAK in UTP-induced growth of glial cells in scratched cultures. RB-2 decreased dissociated glial cell attachment to fibronectin-coated dishes and migration through transwell membranes, suggesting that nucleotides regulated adhesion and migration of glial cells. In conclusion, mechanical scratch of retinal cell cultures induces growth of glial cells over the empty area through a mechanism that is dependent on activation of UTP-sensitive receptors, SRC, PI3K, and FAK.

Asunto(s)

Movimiento Celular/efectos de los fármacos , Neuroglía/citología , Nucleótidos/metabolismo , Retina/efectos de los fármacos , Animales , Apirasa/farmacología , Movimiento Celular/fisiología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Pollos , Cromonas/farmacología , Morfolinas/farmacología , Neurogénesis/efectos de los fármacos , Neuroglía/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Quinolonas/farmacología , Retina/lesiones , Transducción de Señal/efectos de los fármacos , Sulfonas/farmacología , Suramina/farmacología

RESUMEN

Sustained chronic inflammation induces activation of genes involved in cellular proliferation and apoptosis, thereby causing skeletal muscle degeneration. To investigate in vitro effects of isolated pentacyclic triterpenes from Eugenia punicifolia (Ep-CM) upon signaling pathways involved in the regulation of skeletal muscle cell line proliferation, and in vivo muscular tissue remodeling. C2C12 cells were seeded on eight-well plates and [(3)H]-thymidine incorporation, TUNEL assays, mitochondria viability, zymography for matrix metalloproteases (MMPs), Western blot analysis for MAPKinase signaling pathway, NFκB activation and HMGB1 production subsequently determined under basal conditions and after Ep-CM treatment. A polymer containing Ep-CM was implanted on the volar surface of gastrocnemius muscles subjected to acute injury induced by bupivacaine for local slow and gradual release of bioactive compounds, and mice killed 4 days after surgery. Ep-CM inhibited proliferation of C2C12 myoblast cell line in a dose-dependent manner, confirmed by reduction of [(3)H]-thymidine uptake without affecting cell viability or inducing apoptosis. The cytostatic effect of Ep-CM occurred mainly via inhibition of phosphorylated extracellular signal-regulated kinase (pERK) activation and DNA synthesis, possibly inhibiting the G1 phase of the cell cycle, since Ep-CM increased pAkt and p27(kip1) but reduced Cyclin D1. Ep-CM in vitro treatment increased MMP-9 and MMP-2 activities of C2C12 myoblast cells, but reduced in vivo MMP-9 activity and acute muscular inflammation. Besides cytostatic and anti-inflammatory effects, Ep-CM pentacyclic triterpenes also contributed to degradation of basement membrane components by activating mechanisms of skeletal muscle remodeling in response to local injury.

Asunto(s)

Inflamación/prevención & control , Músculo Esquelético/efectos de los fármacos , Triterpenos Pentacíclicos/administración & dosificación , Syzygium/química , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Microambiente Celular/efectos de los fármacos , Implantes de Medicamentos/química , Proteína HMGB1/metabolismo , Inflamación/patología , Inflamación/fisiopatología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Mioblastos Esqueléticos/citología , Mioblastos Esqueléticos/efectos de los fármacos , FN-kappa B/metabolismo , Triterpenos Pentacíclicos/aislamiento & purificación , Fitoterapia , Polímeros/química

RESUMEN

ATP is an important mitogen in the developing retina and its proliferative response decreases as chick retinal cells differentiate in culture. Both non-stimulated or ATP-induced proliferative response was abolished if cycling cells were cocultured with cells from older embryos or cultured with conditioned medium (CM) from postmitotic cells. The effect of CM was dose-dependent and reversible, as removal of CM from the cultures restored both basal and ATP-induced incorporation of [3H]-thymidine. The effect of CM was also dependent on the developmental stage of the retina used to prepare the medium. As tissues from older embryos were used, inhibition of the basal and ATP-induced proliferative response of the cells increased. Similar inhibition of ATP-induced increase in [3H]-thymidine incorporation was observed using CM from purified glial cultures. Neither ARL 67156, an ecto-ATPase inhibitor, prevented nor TGF-beta1 and TGF-beta2 mimicked the inhibitory effect of conditioned medium. Incubation of cells with CM or ATP for 24 h completely abolished the formation of [3H]-phosphoinositides induced by ATP. These effects were blocked by the P2 receptor antagonist PPADS and were not observed with dialysed CM, suggesting that agonist-dependent desensitization of P2 receptors occurred in cultures incubated with CM. However, removal of small molecules such as nucleotides by dialysis did not affect the decline in the proliferative activity induced by CM, suggesting that desensitization is not responsible for the conditioned medium-dependent cell cycle arrest of early developing retinal cells in culture. These results suggest that factors released from postmitotic cells induce the arrest of retinal cells in the mitotic state, a phenomenon that is concomitant with agonist-dependent P2 receptor desensitization.

Asunto(s)

Adenosina Trifosfato/farmacología , Proliferación Celular/efectos de los fármacos , Mitosis/fisiología , Retina/citología , Adenosina Trifosfato/análogos & derivados , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Embrión de Pollo , Medios de Cultivo Condicionados , Neuroglía/metabolismo , Fosfatidilinositoles/metabolismo , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacología , Receptores Purinérgicos P2/metabolismo , Retina/efectos de los fármacos , Timidina/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Factor de Crecimiento Transformador beta2/farmacología