Long-term use of prescription opioids for non-cancer pain and mortality: a population-based, propensity-weighted cohort study.

OBJECTIVE: The objective of this study was to identify factors associated with long-term opioid use and to assess the association between long-term use and death. STUDY DESIGN: Retrospective cohort study combining several population-wide databases and covering a population of five million inhabitants, including all adults who were initiated on opioid treatment from 2014 to 2018 for non-cancer pain. METHODS: We used logistic regression models to identify factors associated with chronic opioid use and carried out survival analyses using multivariable Cox regression modelling for all-cause mortality during follow-up using inverse probability of treatment weighting (IPTW) and propensity scores based on the probability of using opioids chronically. RESULTS: Among 760,006 patients, 82,423 (10.85%) used opioids for 90 days or more after initiation. Initial therapy characteristics associated with higher risk for long-term use were initiating with long- and short-acting opioids (when compared to tramadol, odds ratio [OR]: 2.63, 95% confidence interval [CI]: 2.57, 2.69 and OR: 1.60, 95%CI: 1.46, 1.76, respectively), using higher daily doses (when compared to 50 morphine milligramme equivalent [MME] or less, prescribing 50 to 89 daily MME, OR: 1.76, 95%CI: 1.65, 1.87; 90 to 119 daily MME, OR: 2.44, 95%CI: 1.99, 3.01; and more than 120 daily MME, OR: 1.77, 95%CI: 1.64, 1.91), and overlapping with gabapentinoids (OR: 2.26, 95%CI: 2.20, 2.32), benzodiazepines (OR: 1.32, 95%CI: 1.30, 1.35), and antipsychotics (OR: 1.21, 95%CI: 1.16, 1.26). After IPTW, chronic opioid use was associated with higher risk of all-cause mortality when compared to short-term use (Hazard Ratio (HR): 1.37, 95%CI: 1.32, 1.42). Sensitivity analyses provided similar results. CONCLUSION: These findings may help healthcare managers to identify and address patients at higher risk of long-term use and riskier prescription patterns.

Impairment of sperm maturation and capacitation due to diet-dependent cholesterol overload.

BACKGROUND: Lipid metabolic disorders (dyslipidemia) are constantly increasing in occidental societies and lead to the development of pathologies such as obesity, diabetes, and metabolic syndrome. It has been demonstrated that dyslipidemia can alter the reproductive function. Animal models have recently been used to show that the offspring of dyslipidemic males could also develop such pathologies and that the transgenerational transmission involved post-testicular sperm maturation. These data targeted the essential role of male gamete epididymal maturation and its importance for the health of the offspring. OBJECTIVES: This publication summarizes in the first place experimental data obtained using a mouse model of dyslipidemia-induced post-testicular infertility, knockout mice for the two isoforms of the 'Liver X Receptors' (Lxrα;ß-/- ), the major regulators of cholesterol homeostasis. The impact of a high cholesterol diet (HCD) on the protein YWHAZ (14-3-3 ζ or tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein Zeta) was also investigated in our model. MATERIALS AND METHODS: In our mouse model, when young fertile Lxrα;ß-/- males aged three months were fed four weeks with a HCD, they developed an epididymal phenotype leading to infertility. The level of sperm YWHAZ was evaluated by Western blot and its tyrosine phosphorylation state by immunoprecipitation followed by Western blot. RESULTS: Our data revealed that sperm lipid composition and structure were altered, leading to defects of the capacitation-associated signaling pathway. They also showed that both the level and the tyrosine phosphorylation state of YWHAZ were affected by the HCD in sperm cells from Lxrα;ß-/- males. DISCUSSION AND CONCLUSION: YWHAZ could be a new important regulator of capacitation-associated tyrosine phosphorylation and a marker of dyslipidemia-induced infertility.

Of vessels and cells: the spatial organization of the epididymal immune system.

BACKGROUND: One third of infertility cases in couples worldwide has an exclusive male origin and immune disorders, essentially due to repetitive infections, are emerging an cause of male infertility. As the place of sperm maturation, epididymis must be preserved from excessive immune responses that may arise following infections of the male genital tract. At the same time, epididymis must set and maintain a tolerogenic environment in order not to destroy sperm cells that enter the tissue at puberty, long after the immune system has been taught to recognize self pathogens. The immune cells that populate the epididymis have raised growing interest over the last thirty years but they may be not sufficient to understand the immune balance existing in this organ, between immune response to pathogens and tolerance to spermatozoa. Indeed, immune cells are the most motile cells in the organism and need blood and lymphatic vessels to traffic between lymphoid organs and sites of infection to induce efficient responses. OBJECTIVES: To review the literature on the blood and lymphatic vessels, and on the immune cells present at steady state in the rodent epididymis (rat and mouse). MATERIALS AND METHODS: PubMed database was searched for studies reporting on the spatial organization of the rodent epididymal vasculature and immune cell types at steady state. This search was combined with recent findings from our team. RESULTS: At steady state, the rodent epididymis presents with dense blood and lymphatic networks, and a large panel of immune cells distributed across the interstitum and epithelium along the organ. CONCLUSIONS: The immune system of the rodent epididymis is highly organized. Exploring its functions, especially in an infectious context, is the essential coming step before any transposition to human.

Increase of germ cell nuclear factor expression in globozoospermic Gopc-/- knockout mice.

BACKGROUND: Golgi-associated PDZ and coiled-coil motif-containing protein (GOPC) is a Golgi protein that plays a role in vesicular transport and intracellular protein trafficking and degradation. Mice deficient in GOPC protein have globozoospermia and are infertile. The germ cell nuclear factor (GCNF) is a member of the nuclear receptor superfamily which is expressed in male germ cells, from spermatocytes and spermatids, both in the nucleus and the acrosomal region. It is not known if its expression could be altered in Gopc-/- mice with defective acrosomes. OBJECTIVES: The aim of the present work was to analyze the distribution of GCNF protein in spermatids of Gopc-/- knockout mice. MATERIALS AND METHODS: We have analyzed the expression and distribution during spermatogenesis of GCNF and its deregulation in Gopc-/- mutant mice by RT-qPCR, Western blot, immunohistochemistry and immunogold. RESULTS: Germ cell nuclear factor was localized in the nucleus of all the cell types in the seminiferous tubules. Despite being a nuclear protein, it was also located in the acrosome and in the manchette of elongating spermatids. We have found that in the absence of GOPC, the expression of GCNF was increased in the nucleus of spermatocytes, mainly in leptotene, and in the nucleus and the manchette during the spermatid elongation. DISCUSSION AND CONCLUSION: Gopc-/- mice have defective acrosome and manchette. The manchette is involved in the transport of proteins through the cytoplasm and the nucleus. Considering that the GCNF protein is normally transported to the acrosome and the nucleus, it can be thought that transport deficiencies in Gopc-/- mice are responsible for the increased expression of this protein.

Dyslipidemia alters sperm maturation and capacitation in LXR-null mice.

Lipid metabolism disorders (dyslipidemia) are causes of male infertility, but little is known about their impact on male gametes when considering post-testicular maturation events, given that studies concentrate most often on endocrine dysfunctions and testicular consequences. In this study, three-month-old wild-type (wt) and Liver-X-Receptors knock out (Lxrα;ß-/- ) males were fed four weeks with a control or a lipid-enriched diet containing 1.25% cholesterol (high cholesterol diet (HCD)). The HCD triggered a dyslipidemia leading to sperm post-testicular alterations and infertility. Sperm lipids were analyzed by LC-MS and those from Lxrα;ß-/- males fed the HCD showed higher chol/PL and PC/PE ratios compared to wt-HCD (P < 0.05) and lower oxysterol contents compared to wt (P < 0.05) or Lxrα;ß-/- (P < 0.05). These modifications impaired membrane-associated events triggering the tyrosine phosphorylation normally occurring during the capacitation process, as shown by phosphotyrosine Western blots. Using flow cytometry, we showed that a smaller subpopulation of spermatozoa from Lxrα;ß-/- -HCD males could raise their membrane fluidity during capacitation (P < 0.05 vs wt or wt-HCD) as well as their intracellular calcium concentration (P < 0.05 vs Lxrα;ß-/- and P < 0.001 vs wt). The accumulation of the major sperm calcium efflux pump (PMCA4) was decreased in Lxrα;ß-/- males fed the HCD (P < 0.05 vs Lxrα;ß-/- and P < 0.001 vs wt). This study is the first showing an impact of dyslipidemia on post-testicular sperm maturation with consequences on the capacitation signaling cascade. It may lead to the identification of fertility prognostic markers in this pathophysiological situation, which could help clinicians to better understand male infertilities which are thus far classified as idiopathic.

Morphofunctional basis of the different types of angiogenesis and formation of postnatal angiogenesis-related secondary structures.

We review the morpho-functional basis of the different types of angiogenesis and report our observations, including the formation of angiogenesis-related secondary structures. First of all, we consider the following issues: a) conceptual differences between angiogenesis and vasculogenesis, b) incidence of angiogenesis in pre- and postnatal life, c) regions of vascular tree with angiogenic capacity, d) cells (endothelial cells, pericytes, CD34+ adventitial stromal cells of the microvasculature and inflammatory cells) and extracellular matrix components involved in angiogenesis, e) events associated with angiogenesis, f) different types of angiogenesis, including sprouting and intussusceptive angiogenesis, and other angiogenic or vascularization forms arising from endothelial precursor cells (postnatal vasculogenesis), vasculogenesis mimicry, vessel co-option and piecemeal angiogenesis. Subsequently, we consider the specific morpho-functional characteristics of each type of angiogenesis. In sprouting angiogenesis, we grouped the events in three phases: a) activation phase, which includes vasodilation and increased permeability, EC, pericyte and CD34+ adventitial stromal cell activation, and recruitment and activation of inflammatory cells, b) sprouting phase, encompassing EC migration (concept and characteristics of endothelial tip cells, tip cell selection, lateral inhibition, localized filopodia formation, basal lamina degradation and extracellular changes facilitating EC migration), EC proliferation (concept of endothelial stalk cells), pericyte mobilization, proliferation, recruitment and changes in CD34+ adventitial stromal cells and inflammatory cells, tubulogenesis, formation of a new basal lamina, and vascular anastomosis with capillary loop formation, and c) vascular remodelling and stabilization phase (concept of phalanx cells). Subsequently, the concept, incidence, events and mechanisms are considered in the other forms of angiogenesis. Finally, we contribute the formation of postnatal angiogenesis-related secondary structures: a) intravascular structures through piecemeal angiogenesis, including intravascular papillae in vessel tumours and pseudotumours (intravascular papillary endothelial hyperplasia, vascular transformation of the sinus in lymph nodes, papillary intralymphatic angioendothelioma or Dabska tumour, retiform hemangioendothelioma, hemangiosarcoma and lymphangiosarcoma), vascular septa in hemorrhoidal veins and intravascular projections in some tumours; b) arterial intimal thickening; c) intravascular tumours and pseudotumours (e.g. intravenous pyogenic granulomas and intravascular myopericytoma); d) vascular glomeruloid proliferations; and e) pseudopalisading necrosis in glioblastoma multiform.

Correction of chin ptosis.

Chin ptosis is described as a descent of the soft tissue from the symphyseal region to a position under the lower contour of the mandible. Given its multifactorial causes, treatment must be determined on a patient-by-patient basis. While augmentation of the submental crease is a versatile option for the correction of chin ptosis, this only corrects the soft tissue component. A technical modification to treat dynamic chin ptosis, associated with bone reduction in the mandibular symphysis, is presented here.

Telocyte Behaviour During Inflammation, Repair and Tumour Stroma Formation.

In this chapter, we outline the role of human CD34+ stromal cells/telocytes (CD34+ SC/TCs) as progenitor cells during repair. The in vivo activation phenomena of CD34+ SC/TCs in this process include increased size; separation from the neighbouring structures (mainly of the vascular walls); association with inflammatory cells, predominantly macrophages; development of the organelles of synthesis (rough endoplasmic reticulum and Golgi apparatus); cell proliferation with presence of mitosis and high proliferative index (transit-amplifying cells); and fibroblastic and myofibroblastic differentiation. A procedure to study these tissue-resident cells, comparison of their behaviour in vivo and in vitro and different behaviour depending on location, time, type of injury (including tumour stroma) and greater or lesser proximity to the injury are also considered.

[The mind-brain problem (I): onto-epistemological foundations]. / El problema mente-cerebro (I): fundamentos ontoepistemologicos.

INTRODUCTION: Throughout the history of thought, science and philosophy have addressed the problem of mind-brain from different epistemic perspectives. The first covers specific areas of reality and constructs hypotheses with limited scope and multiple inter-scientific connectivity with the aim of validating theoretical models; the second extends its systemic architecture to all that is real (including scientific activity). DEVELOPMENT: The complexity of the mind-brain problem requires the generation of a link connecting the disciplines of philosophy and science; our onto-epistemological presuppositions therefore fall within the framework of a scientifically-oriented philosophy (scientific philosophy). Emergentist materialism is defended as a coherent and verifiable philosophical-scientific solution, as opposed to other proposals developed on the basis of different ontological models (for example, interactionist dualism, functionalism, theory of identity, epiphenomenalism, and so on). CONCLUSIONS: An answer to the mind-brain problem is only feasible if based on a philosophically grounded cognitive neuroscience: emergentist materialism -an ontological postulate- holds that the mind is an emergent property (qualitative novelty) of the brain; scientific realism -an epistemological postulate- holds that cognitive neuroscience is the basic theoretical-experimental tool that allows cognitive access to both the brain and its neurocognitive processes. We consider that on the basis of this philosophical reasoning, cognitive neuroscience acquires epistemic legitimacy to be able to undertake the study of the most genuinely human mental process: consciousness.

TITLE: El problema mente-cerebro (I): fundamentos ontoepistemologicos.Introduccion. La ciencia y la filosofia han abordado a lo largo de la historia del pensamiento y desde diferentes perspectivas epistemicas el problema mente-cerebro. La primera de ellas acota areas especificas de la realidad y construye hipotesis de corto alcance y multiple conectividad intercientifica con el objetivo de validar modelos teoricos; la segunda extiende su arquitectura sistemica al conjunto de lo real (incluida la actividad cientifica). Desarrollo. La complejidad del problema mente-cerebro exige generar un vinculo de conexion disciplinar entre la filosofia y la ciencia; nuestros presupuestos ontoepistemologicos se erigen, por lo tanto, en el marco de una filosofia orientada cientificamente (filosofia cientifica). Se defiende el materialismo emergentista como solucion filosofico-cientifica coherente y contrastable en contraposicion a otras propuestas desarrolladas desde diferentes modelos ontologicos (por ejemplo, dualismo interaccionista, funcionalismo, teoria de la identidad, epifenomenalismo...). Conclusiones. La respuesta al problema mente-cerebro solo es factible desde una neurociencia cognitiva fundamentada filosoficamente: el materialismo emergentista ­postulado ontologico­ afirma que la mente es una propiedad emergente (novedad cualitativa) del cerebro; el realismo cientifico ­postulado epistemologico­ sostiene que la neurociencia cognitiva es la herramienta teorico-experimental basica que posibilita el acceso cognoscitivo tanto al cerebro como a sus procesos neurocognitivos. Consideramos que a partir de esta fundamentacion filosofica, la neurociencia cognitiva adquiere legitimidad epistemica para acometer el estudio del proceso mental mas genuinamente humano: la conciencia.

[The mind-brain problem (II): about consciousness]. / El problema cerebro-mente (II): sobre la conciencia.

INTRODUCTION: Consciousness is the result of a series of neurobiological processes in the brain and is, in turn, a feature of the level of its complexity. In fact, being conscious and being aware place us before what Chalmers called the 'soft problem' and the 'hard problem' of consciousness. The first refers to aspects such as wakefulness, attention or knowledge, while the second is concerned with such complex concepts as self-awareness, 'neural self' or social cognition. In this sense it can be said that the concept of consciousness as a unitary thing poses problems of approaching a highly complex reality. DEVELOPMENT: We outline the main models that have addressed the topic of consciousness from a neuroscientific perspective. On the one hand, there are the conscious experience models of Crick, Edelman and Tononi, and Llinas, and, on the other, the models and neuronal bases of self-consciousness by authors such as Damasio (core and extended consciousness), Tulving (autonoetic and noetic consciousness and chronesthesia), the problem of qualia (Dennett, Popper, Ramachandran) and the cognit model (Fuster). CONCLUSIONS: All the stimuli we receive from the outside world and from our own internal world are converted and processed by the brain so as to integrate them, and from there they become part of our identity. The perception of a dog and being able to recognise it as such or the understanding of our own consciousness are the result of the functioning of brain, neuronal and synaptic structures. The more complex processes of consciousness, such as self-awareness or empathy, are probably emergent brain processes.

TITLE: El problema cerebro-mente (II): sobre la conciencia.Introduccion. La conciencia es el resultado de una serie de procesos neurobiologicos en el cerebro y a su vez es un rasgo del nivel de su complejidad. En realidad, el estar y el ser consciente nos situan ante lo que Chalmers ha denominado el 'problema blando' y el 'problema duro' de la conciencia. El primero hace referencia a aspectos como la vigilia, la atencion o el conocimiento, y el segundo a conceptos tan complejos como autoconciencia, 'yo neural' o cognicion social. En este sentido se puede afirmar que el concepto de conciencia como algo unitario plantea problemas de acercamiento a una realidad sumamente compleja. Desarrollo. Planteamos los principales modelos que desde una perspectiva neurocientifica han abordado el tema de la conciencia. Por un lado, los modelos de experiencia consciente de Crick, Edelman y Tononi, y Llinas, y por otro, los modelos y las bases neuronales de la autoconciencia de autores como Damasio (conciencia central y extendida), Tulving (conciencia autonoetica, noetica y cronestesia), el problema de los qualia (Dennett, Popper, Ramachandran) y el modelo de los cognitos (Fuster). Conclusiones. Todos los estimulos que recibimos del mundo externo y de nuestro mundo interno son convertidos y tratados por el cerebro para integrarlos y que formen parte de nuestra identidad. Desde la percepcion de un perro y reconocerlo como tal hasta la comprension de la propia conciencia responden al funcionamiento de estructuras cerebrales, neuronas y sinapsis. Ahora bien, los procesos mas complejos de la conciencia, como la autoconciencia o la empatia, son probablemente procesos emergentes del cerebro.

Intravascular papillary endothelial hyperplasia (IPEH). Evidence supporting a piecemeal mode of angiogenesis from vein endothelium, with vein wall neovascularization and papillary formation.

Intravascular papillary endothelial hyperplasia (IPEH) is a reactive process of questioned pathogenesis (primary proliferation of endothelial cells/ECs versus organizing thrombi). The aim of this study is to assess the organization of morphologic patterns, with precise location of neovascularization and papillary distribution in IPEH to clarify the role of the vein wall (mainly vein intimal ECs) in lesion development and papillary formation. We studied 12 cases of IPEH in skin and subcutaneous veins by serial histological sections and immunohistochemical procedures. In four well-structured cases (the remaining cases showed overlapping events), we found four principal histological patterns organized by zone: 1) invaginated vein wall zone with microvascular networks. The intraparietal microvessels presented CD34+ and CD31+ ECs arising from ECs of the vein intima, and αSMA+ pericyte-like cells originating from modified SMCs of the media layer. 2) Papillary zone, generally with myriad papillae, formed by ECs of intraparietal microvessel networks encircling vein wall components (parietal papillae). 3) Organizing thrombotic zone from microvascular networks of invaginated vein wall zone. 4) Unorganized thrombotic zone partially covered by ECs, also originating from vein intimal endothelium and arranged in a monolayer or encircling thrombotic fibrin (thrombotic papillae). In conclusion, the capacity of vein intimal ECs and those originating from them (in newly-formed microvessels in the vein itself and covering the unorganized thrombi) to encircle vein wall components or fibrin, and to form papillae (ECs form the cover and encircled components the core) supports a piecemeal mode of angiogenesis as a pathogenic basis of IPEH. This mechanism encompasses the two histogenetic hypotheses outlined above.

Can customized implants correct enophthalmos and delayed diplopia in post-traumatic orbital deformities? A volumetric analysis.

The purpose of this study was to determine whether orbital reconstruction with customized implants can correct post-traumatic orbital deformities such as late enophthalmos and delayed diplopia. The hypothesis proposed was that an overcorrection of the orbital volume is needed to resolve enophthalmos. A retrospective observational descriptive study was conducted. Patients with a major trauma who required customized orbital implants for the delayed treatment of unilateral orbital fractures that had initially been operated on using titanium mesh and/or osteosynthesis plates were included. The orbital volumes of the unaffected contralateral side, of the affected orbit after initial reconstruction with mesh, and of the affected orbit subsequently reconstructed with the customized implant were calculated. All of the patients included in this study had diplopia in the gaze position prior to the installation of the implant. In addition, they all had severe enophthalmos. After surgery, no patient with a customized implant showed diplopia. The enophthalmos was corrected in all but one case. On average, orbits reconstructed with customized implants had lower volumes compared to the unaffected contralateral side. In cases where the enophthalmos was resolved, the volume was reduced by an average of 8.55%. Further studies using a larger number of cases and with controlled volumetric corrections using CAD/CAM are needed.

Cellular changes in the hamster testicular interstitium with ageing and after exposure to short photoperiod.

The aim of this study was to evaluate the cellular changes that occur in the hamster testicular interstitium in two very different physiological situations involving testicular involution: ageing and exposure to a short photoperiod. The animals were divided into an 'age group' with three subgroups - young, adult and old animals - and a 'regressed group' with animals subjected to a short photoperiod. The testicular interstitium was characterised by light and electron microscopy. Interstitial cells were studied histochemically with regard to their proliferation, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP in situ nick end labelling (TUNEL+) and testosterone synthetic activity. We identified two types of Leydig cell: Type A cells showed a normal morphology, while Type B cells appeared necrotic. With ageing, pericyte proliferation decreased but there was no variation in the index of TUNEL-positive Leydig cells. In the regressed group, pericyte proliferation was greater and TUNEL-positive cells were not observed in the interstitium. The testicular interstitium suffered few ultrastructural changes during ageing and necrotic Leydig cells were observed. In contrast, an ultrastructural involution of Leydig cells with no necrosis was observed in the regressed group. In conclusion, the testicular interstitium of Mesocricetus auratus showed different cellular changes in the two groups (age and regressed), probably due to the irreversible nature of ageing and the reversible character of changes induced by short photoperiod.

Changes in Testicular Interstitial Connective Tissue of Hamsters (Mesocricetus auratus) During Ageing and After Exposure to Short Photoperiod.

The testicular interstitium of Syrian hamster (Mesocricetus auratus) was studied during ageing and in testicular regression after exposure to a short photoperiod, in relation to the interstitial cells and their connective tissue. This tissue was assessed histochemically using Masson's trichrome technique and the expression of Heat Shock Protein 47 (HSP-47) and collagen IV (α5) was assessed in Leydig cells. Finally, an ultrastructural analysis of some cells of the testicular interstitium was made. Leydig cells were positive for HSP-47 and collagen IV (α5). Ageing did not change the parameters studied while the short photoperiod altered the synthetic activity of Leydig cells. The positivity index of these cells for HSP-47 was significantly higher in the regressed testis, but was lower for collagen IV (α5). During ageing no change were observed. Ultrastructural Leydig cells showed a discontinuous basal lamina that did not change during ageing. The basal lamina was not identified in Leydig cells regressed by exposure to a short photoperiod. In conclusion; the intertubular connective tissue suffers little change with age. By contrast, in the testis regressed after exposure to a short photoperiod the studied parameters related to the intertubular connective tissue were altered. These changes are probably related with the low synthetic activity of regressed Leydig cell.

Mediterranean diet and childhood asthma.

BACKGROUND: The incidence of bronchial hyperreactivity has increased to one-third of the population in developed countries, which requires the adoption of preventive and therapeutic measures. The objective of the present study was to assess the effects of a traditional Mediterranean diet on patients diagnosed with childhood asthma and determine if there is a beneficial effect from this dietary intervention. METHODS: Prospective before-after comparison study of 50 girls and 54 boys aged 1-5 years, who were enrolled in the 1-year programme "Learning to Eat from the Mediterranean", designed to promote the adoption of a traditional Mediterranean diet. We studied the clinical and therapeutic variables and anthropometric measurements. RESULTS: All studied symptomatic indicators (number and intensity of asthmatic attack, infections and hospital admissions) showed a positive and statistically significant evolution of bronchial hyperreactivity from the first weeks of the intervention onwards. Throughout the treatment, 32.2% of patients remained free of crisis, 35.3% of the patients only had one attack throughout the year and 24.9% had two episodes, compared to 4.73 episodes on average in the previous year. The use of inhaled corticosteroids markedly decreased from 3.92 ± 1.61 to 1.11 ± 1.09 times per patient per year (P<0.001) and that of inhaled bronchodilators decreased from 4.14 ± 1.61 to 1.12 ± 1.40 (P<0.001). As a result, the families involved in the programme reported a high level of satisfaction. CONCLUSIONS: The adoption of a traditional Mediterranean diet could contribute significantly to the improvement of patients diagnosed with childhood asthma.

Sinusitis maxilar por osteonecrosis asociada a bisfosfonatos en pacientes con cáncer de mama: serie de casos / Maxillary sinusitis associated to bisphosphonate-related osteonecrosis in patients with breast cancer: case series

Los bisfosfonatos (BF) son fármacos ampliamente utilizados como estabilizadores óseos en el tratamiento de metástasis óseas, osteoporosis, enfermedad de Paget, entre otras patologías, debido a sus efectos anti-tumorales y a la característica de inhibir la actividad osteoclástica. La osteonecrosis maxilar asociada a BF, hoy en día osteonecrosis maxilar asociada a fármacos (ONMF) es definida como la presencia de hueso expuesto, no-vascularizado y necrótico en la cavidad oral por un periodo mayor a ocho semanas, con una historia positiva de tratamiento con fármacos anti-reabsorción ósea (BP, inhibidores del ligando RANKL) y/o anti-angiogénicos y sin antecedentes de tratamiento con radiación o metástasis obvia en los maxilares. La frecuencia de ONMF es incierta. La mandíbula es más frecuentemente afectada por ONMF que el maxilar. Pocos casos de ONMF en el maxilar han sido descritos con un diagnostico de sinusitis maxilar simultáneo. Tres casos con sinusitis maxilar asociada a ONMF son presentados en este trabajo. Todos los pacientes fueron mujeres con una historia positiva de cáncer de mama y tratamiento con bisfosfonatos. Los primeros dos casos, desarrollaron ONMF después de una extracción del tercer molar maxilar. El tercer caso con ONMF en el maxilar, sólo tenía antecedentes de curetaje periodontal. Una tomografía computada fue realizada y mostró compromiso del seno maxilar en todos los pacientes. Modalidades diagnósticas para evaluar la extensión de la necrosis y el compromiso del seno, como también alternativas de tratamiento son descritas en este estudio. Finalmente, una revisión actualizada de la literatura es presentada.

Bisphosphonates are widely used as bone-stabilizers in the treatment of osseous metastases, osteoporosis, Paget's disease and others,due to their ability to inhibit osteoclast activity and anti-tumor effects. Bisphosphonate-related osteonecrosis of the jaw, nowadays medication-related osteonecrosis of the jaw (MRONJ), is defined as the presence of exposed, non-vascularized and necrotic bone tissue in the oral cavity over a period of 8 weeks with a current or previous history of treatment with antiresorptive (bisphosphonates, RANKL ligand inhibitor) and/or antiangiogenic agents, and no history of radiation therapy to the jaws or obvious metastatic disease to the jaws. The frequency of MRONJ is unclear. The mandible appears to be more frequently affected by MRONJ than the maxilla. Isolated cases of maxillary MRONJ have been described in wich a simultaneous sinusitis maxillaris was diagnosed. Three cases of MRONJ associated with maxillaris sinusitis are presented. All cases were females with a positive history of breast cancer and bisphosphonate therapy. The first two, developed MRONJ after a third molar upper extraction. The third case with MRONJ, had a history of periodontal curettage. A computed tomography was performed and showed a maxillary sinus compromise in all patients. Imaging modalities to evaluate the extent of the necrosis and the sinus compromise, as also treatment options were described in this study. Finally, an updated literature review is presented.

Activation of annexin A1 signalling in renal fibroblasts exerts antifibrotic effects.

AIM: The anti-inflammatory protein annexin A1 (AnxA1) and its formyl peptide receptor 2 (FPR2) have protective effects in organ fibrosis. Their role in chronic kidney disease (CKD) has not yet been elucidated. Our aim was to characterize the AnxA1/FPR2 system in models of renal fibrosis. METHODS: Rats were treated with angiotensin receptor antagonist during the nephrogenic period (ARAnp) to induce late-onset hypertensive nephropathy and fibrosis. Localization and regulation of AnxA1 and FPR2 were studied by quantitative real-time PCR and double labelling immunofluorescence. Biological effects of AnxA1 were studied in cultured renal fibroblasts from AnxA1(-/-) and wild-type mice. RESULTS: Angiotensin receptor antagonist during the nephrogenic period kidneys displayed matrix foci containing CD73(+) fibroblasts, alpha-smooth muscle actin (a-SMA)(+) myofibroblasts and CD68(+) macrophages. TGF-ß and AnxA1 mRNAs were ~threefold higher than in controls. AnxA1 was localized to macrophages and fibroblasts; myofibroblasts were negative. FPR2 was localized to fibroblasts, myofibroblasts, macrophages and endothelial cells. AnxA1 and FPR2 immunoreactive signals were increased in the foci, with fibroblasts and macrophages expressing both proteins. AnxA1(-/-) fibroblasts revealed higher α-SMA (sevenfold) and collagen 1A1 (Col1A1; 144-fold) mRNA levels than controls. Treatment of murine WT fibroblasts with TGF-ß (22.5 ng mL 24 h(-1)) increased mRNA levels of α-SMA (9.3-fold) and Col1A1 (fourfold). These increases were greatly attenuated upon overexpression of AnxA1 (1.5- and 1.7-fold, respectively; P < 0.05). Human fibroblasts reacted similarly when receiving the FPR2 inhibitor WRW4. CONCLUSION: Our results demonstrate that AnxA1 and FPR2 are abundantly expressed in the renal interstitium and modulate fibroblast phenotype and extracellular matrix synthesis activity.

Testicular histomorphometry and the proliferative and apoptotic activities of the seminiferous epithelium in Syrian hamster (Mesocricetus auratus) during regression owing to short photoperiod.

During the non-breeding season some animals exhibit testicular atrophy, decreased testicular weight and reduced seminiferous tubule diameter accompanied by depletion of the seminiferous epithelium. Some cellular factors involved in this depletion are changes in germ cell proliferation and apoptosis. In the Syrian hamster this depletion has been studied histologically and in terms of the involvement of proliferation and apoptosis in the seminiferous epithelium of fully regressed testes. The objectives of this study included the histomorphometrical characterization of the testis and the determination of the proliferative and apoptotic activity of germ cells in the seminiferous epithelium during testicular regression owing to short photoperiod. The study was performed using conventional light microscopy (hematoxylin and eosin), proliferating cell nuclear antigen and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP in situ nick end labelling staining, image analysis software, and transmission electron microscopy in three established regression groups: mild regression (MR), strong regression (SR), and total regression (TR). Morphometrically a gradual decrease in total tubular area and in the testicular, tubular, and epithelial volumes was observed during testicular regression. Interstitial and luminal volumes decreased from the MR group onwards. The tubular length decreased from MR to SR. As regards spermatogonial proliferation, only an initial decrease in proliferative activity was observed, whereas apoptotic germ cell activity increased throughout regression. The number of germ cells studied decreased throughout the process of testicular regression. In conclusion, testicular regression in Syrian hamster comprises two histomorphometrical phases, the first involving a decrease in seminiferous tubular diameter and volume and the second involving shortening of the seminiferous tubule and a decrease in interstitial volume. At the cellular level, there is an initial decrease in proliferation and increase in apoptosis involving all germ cells. At the end of regression, the proliferative and apoptotic activities of the spermatogonia recover the values observed prior to regression in preparation for recrudescence.

Human resident CD34+ stromal cells/telocytes have progenitor capacity and are a source of αSMA+ cells during repair.

We studied the progenitor capacity of human resident CD34+ stromal cells/telocytes (SC/TCs) in the enteric wall affected by inflammatory/repair processes (appendicitis, diverticulitis of large bowel and Crohn's disease of the terminal ileum) at different stages of evolution (inflammatory, proliferative and remodelling). In these conditions, CD34+ SC/TCs are activated, showing changes, which include the following overlapping events: 1) separation from adjacent structures (e.g., from vascular walls) and location in oedematous spaces, 2) morphological modifications (in cell shape and size) with presence of transitional cell forms between quiescent and activated CD34+ SC/TCs, 3) rapid proliferation and 4) loss of CD34 expression and gain of αSMA expression. These events mainly occur in the inflammatory and proliferative stages. During the loss of CD34 expression, the following findings are observed: a) irregular cell labelling intensity for anti-CD34, b) co-localization of CD34 and actin, c) concurrent irregular labelling intensity for αSMA and d) αSMA expression in all stromal cells, with total loss of CD34 expression. While CD34 expression was conserved, a high proliferative capacity (Ki-67 expression) was observed and vice versa. In the segments of the ileum affected by Crohn's disease, the stromal cells around fissures were αSMA+ and, in the transitional zones with normal enteric wall, activated CD34+ SC/TCs were observed. In conclusion, human resident CD34+ SC/TCs in the enteric wall have progenitor capacity and are activated with or without differentiation into αSMA+ stromal cells during inflammatory/repair processes.