Early Social Enrichment Modulates Tumor Progression and p53 Expression in Adult Mice.

Epidemiological evidence indicates that stress and aversive psychological conditions can affect cancer progression, while well-being protects against it. Although a large set of studies have addressed the impact of stress on cancer, not much is known about the mechanisms that protect from cancer in healthy psychological conditions. C57BL/6J mouse pups were exposed to an environmental enrichment condition consisting of being raised until weaning by the biological lactating mother plus a non-lactating virgin female (LnL = Lactating and non-Lactating mothers). The Control group consisted of mice raised by a single lactating mother (L = Lactating). Four months after weaning, mice from LnL and L conditions were exposed to intramuscular injection of 3-methylcolantrene (3MCA), a potent tumorigenic drug, and onset and progression of 3MCA-induced fibrosarcomas were monitored over time. Pups from the LnL compared to the L group received more parental care and were more resilient to stressful events during the first week of life. In association, the onset of tumors in LnL adults was significantly delayed. At the molecular level, we observed increased levels of wild-type p53 protein in tumor samples of LnL compared to L adults and higher levels of its target p21 in healthy muscles of LnL mice compared to the L group, supporting the hypothesis of potential involvement of p53 in tumor development. Our study sustains the model that early life care protects against tumor susceptibility.

Sexually Dimorphic Immune and Neuroimmune Changes Following Peripheral Nerve Injury in Mice: Novel Insights for Gender Medicine.

Neuropathic pain (NeP) in humans is often a life-long condition with no effective therapy available. The higher incidence of female gender in NeP onset is worldwide reported, and although the cause is generally attributed to sex hormones, the actual mechanisms and the players involved are still unclear. Glial and immune cells take part in NeP development, and orchestrate the neuroimmune and inflammatory response, releasing pro-inflammatory factors with chemoattractant properties that activate resident immune cells and recruit immune cells from circulation. The neuro-immune crosstalk is a key contributor to pain hypersensitivity following peripheral nervous system injury. Our previous works showed that in spite of the fact that female mice had an earlier analgesic response than males following nerve lesion, the recovery from NeP was never complete, suggesting that this difference could occur in the very early stages after injury. To further investigate gender differences in immune and neuroimmune responses to NeP, we studied the main immune cells and mediators elicited both in plasma and sciatic nerves by peripheral nerve lesion. After injury, we found a different pattern of distribution of immune cell populations showing either a higher infiltration of T cells in nerves from females or a higher infiltration of macrophages in nerves from males. Moreover, in comparison to male mice, the levels of cytokines and chemokines were differently up- and down-regulated in blood and nerve lysates from female mice. Our study provides some novel insights for the understanding of gender-associated differences in the generation and perseveration of NeP as well as for the isolation of specific neurodegenerative mechanisms underlying NeP. The identification of gender-associated inflammatory profiles in neuropathy is of key importance for the development of differential biomarkers and gender-specific personalized medicine.

Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice.

Recent preclinical and clinical evidence suggest that immune system has a role in the progression and prognosis of Amyotrophic Lateral Sclerosis (ALS), but the identification of a clear mechanism and immune players remains to be elucidated. Here, we have investigated, in 30 and 60 days (presymptomatic) and 120 days (symptomatic) old SOD1-G93A mice, systemic, peripheral, and central innate and adaptive immune and inflammatory response, correlating it with the progression of the neurodegeneration in neuromuscular junction, sciatic nerves, and spinal cord. Surprisingly, we found a very initial (45-60 days) presence of IgG in sciatic nerves together with a gradual enhancement of A20/TNFAIP3 (protein controlling NF-κB signalling) and a concomitantly significant increase and activation of circulating mast cells (MCs) as well as MCs and macrophages in sciatic nerve and an enhancement of IL-6 and IL-10. This immunological frame coincided with a myelin aggregation. The 30-60 days old SOD1-G93A mice didn't show real elements of neuroinflammation and neurodegeneration in spinal cord. In 120 days old mice macrophages and monocytes are widely diffused in sciatic nerves, peripheral neurodegeneration reaches the tip, high circulating levels of TNFα and IL-2 were found and spinal cord exhibits clear signs of neural damage and infiltrating immune cells. Our results underpin a clear immunological disorder at the origin of ALS axonopathy, in which MCs are involved in the initiation and sustaining of inflammatory events. These data cannot be considered a mere epiphenomenon of motor neuron degeneration and reveal new potential selective immune targets in ALS therapy.

Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma.

Following peripheral axon injury, dysregulation of non-coding microRNAs (miRs) occurs in dorsal root ganglia (DRG) sensory neurons. Here we show that DRG neuron cell bodies release extracellular vesicles, including exosomes containing miRs, upon activity. We demonstrate that miR-21-5p is released in the exosomal fraction of cultured DRG following capsaicin activation of TRPV1 receptors. Pure sensory neuron-derived exosomes released by capsaicin are readily phagocytosed by macrophages in which an increase in miR-21-5p expression promotes a pro-inflammatory phenotype. After nerve injury in mice, miR-21-5p is upregulated in DRG neurons and both intrathecal delivery of a miR-21-5p antagomir and conditional deletion of miR-21 in sensory neurons reduce neuropathic hypersensitivity as well as the extent of inflammatory macrophage recruitment in the DRG. We suggest that upregulation and release of miR-21 contribute to sensory neuron-macrophage communication after damage to the peripheral nerve.

17beta-estradiol counteracts neuropathic pain: a behavioural, immunohistochemical, and proteomic investigation on sex-related differences in mice.

Sex differences play a role in pain sensitivity, efficacy of analgesic drugs and prevalence of neuropathic pain, even if the underlying mechanisms are far from being understood. We demonstrate that male and female mice react differently to structural and functional changes induced by sciatic nerve ligature, used as model of neuropathic pain. Male mice show a gradual decrease of allodynia and a complete recovery while, in females, allodynia and gliosis are still present four months after neuropathy induction. Administration of 17ß-estradiol is able to significantly attenuate this difference, reducing allodynia and inducing a complete recovery also in female mice. Parallel to pain attenuation, 17ß-estradiol treated-mice show a functional improvement of the injured limb, a faster regenerative process of the peripheral nerve and a decreased neuropathy-induced gliosis. These results indicate beneficial effects of 17ß-estradiol on neuropathic pain and neuronal regeneration and focuses on the importance of considering gonadal hormones also in clinical studies.

Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain.

Severe pain is a common and debilitating complication of metastatic bone cancer. Current analgesics provide insufficient pain relief and often lead to significant adverse effects. In models of cancer-induced bone pain, pathological sprouting of sensory fibers at the tumor-bone interface occurs concomitantly with reactive astrocytosis in the dorsal horn of the spinal cord. We observed that calcitonin gene-related peptide (CGRP)-fiber sprouting in the bone was associated with an increase in CGRP content in sensory neuron cell bodies in the dorsal root ganglia (DRG) and increased basal and activity-evoked release of CGRP from their central terminals in the dorsal horn. Intrathecal administration of a peptide antagonist (α-CGRP8-37) attenuated referred allodynia in the hind paw ipsilateral to bone cancer. CGRP receptor components (CLR and RAMP1) were up-regulated in dorsal horn neurons and expressed by reactive astrocytes. In primary cultures of astrocytes, CGRP incubation led to a concentration-dependent increase of forskolin-induced cAMP production, which was attenuated by pretreatment with CGRP8-37. Furthermore, CGRP induced ATP release in astrocytes, which was inhibited by CGRP8-37. We suggest that the peripheral increase in CGRP content observed in cancer-induced bone pain is mirrored by a central increase in the extracellular levels of CGRP. This increase in CGRP not only may facilitate glutamate-driven neuronal nociceptive signaling but also act on astrocytic CGRP receptors and lead to release of ATP.

Estudio y análisis de las tecnologías de información y comunicación (TIC) en odontología en Rio Grande do Sul / Study and analysis of information and communication technology (TIC) in dentistry in Rio Grande do Sul

Objetivo: Analizar el uso de las tecnologías de información y comunicación (TIC) por odontólogos que egresaron a partir de 2002 en el estado de Rio Grande do Sul Brasil. Método: Análisis estadístico descriptivo de los datos de 217 cuestionarios on line con el software SPSS y Test Chi-Cuadrado para la obtención de los porcentajes de las variables de comparación (p<0,05). Resultados: El 61,8% son graduados en facultades públicas y 55,8% tiene, al menos, una especialidad. El consultorio particular como lugar de trabajo surge en 62,2% de las respuestas; 88,9% no utilizan la historia clínica electrónica, siendo la TIC que más desean incorporar a su práctica, constando en el 53,6% de las respuestas. El 87,2% considera que la informatización ayuda en la práctica clínica reconociendo “agilidad” el 78,9%. La mayor dificultad para la incorporación fue el alto costo (67%). Conclusión: La mayoría de los participantes posee equipamientos electrónicos, pero esa práctica no se extiende al consultorio y menos aún a servicios públicos. La informatización ayuda en la práctica clínica, brindando mayor agilidad y practicidad.

Objective: To analyze the use of Information and Communication Technologies (ICT) by dentists graduated since the year 2002 in the state of Rio Grande do Sul Brazil. Method: Descriptive statistical analysis of data from 217 on-line questionnaires with SPSS software, using the Chi-square test to obtain the percentages of variables compared (p < 0.05). Results: 61.8% graduated from public colleges and 55.8% have at least one specialty. Private practice as a workplace appeared in 62.2% of responses; 88.9% do not use electronic medical records, which is the ICT they desire most to incorporate to their practice, appearing in 53.6% of responses. 87.2% believe that computerization aids clinical practice, 78.9% reporting agility. The biggest difficulty for incorporation was the high cost (67%). Conclusion: Most participants have electronic equipment, but this practice does not extend to the office and even less to public services. Computerization aids clinical practice providing more flexibility and convenience.

Relación entre enfermedades crónicas y salud-enfermedad bucal en adultos brasileros de bajo nivel socioeconómico / Relationship between chronic diseases and oral health-disease in Brazilian adults of low socioeconomic status

El presente trabajo representó un estudio de prevalencia, transversal, de observación analítica, realizado en el barrio Figueirinha, en el municipio de Xangri-Lá, localizado en el litoral norte del Estado de Río Grande do Sul, Brasil. Objetivo del mismo fue realizar un relevamiento de las condiciones de salud bucal de los habitantes adultos registrados en el programa Salud de la Familia Figueirinha, portadores de diabetes mellitus, hipertensión arterial o ambas patologías y verificar la existencia de alguna correlación con la salud-enfermedad bucal. Material y Método. Se recogieron datos de 218 habitantes adultos, de los cuales 35 estaban registrados en el Programa Hiperdía (Estrategia Salud de la Familia Figueirinha) como portadores de las patologías sistémicas citadas anteriormente. Para la valoración del estado de salud bucal, se evaluó: presencia de placa bacteriana, sangrado gingival y el índice CPOD (dientes cariados, perdidos y obturados). Resultados: de los 218 habitantes adultos, el 11.5% eran pacientes hipertensos, el 2.3% portadores de diabetes mellitus y el 2.3% portaban ambas enfermedades. Del examen bucal resultó que el 67,9% presentaba placa bacteriana y el 58,7% sangrado gingival. Se verificó una correlación positiva entre el número de pérdidas dentarias, la hipertensión arterial y diabetes mellitus con un resultado estadísticamente significante (p≥0,015).Conclusiones: Es de suma importancia que las personas portadoras de enfermedades sistémicas como la diabetes mellitus y la hipertensión arterial estén integradas a un programa de promoción de salud que tenga en cuenta sus necesidades específicas para el mantenimiento de la salud bucal.

This work consisted of a prevalence study, cross-sectional analytical observation, made in the neighborhood Figueirinha, in the municipality of Xangri-La, located on the northern coast of the Rio Grande do Sul state, Brazil. Objective was to survey the oral health conditions of adult inhabitants registered as Figueirinha’s Family Health Program patients who have diabetes mellitus, hypertension, or both diseases. Another objective was to check for any correlation between health and mouth’s diseases.Material and Methods: Data were collected from 218 adult inhabitants, of which 35 were registered in Hiperdia Program of the Figueirinha’s Family Health Program as having systemic diseases mentioned above. For the assessment of oral health status the presence of plaque, gingival bleeding and DMFT (decayed, missing and filled) were evaluated.Results: Of the 218 adult inhabitants, 11.5% were hypertensive, 2.3% had diabetes mellitus and 2.3% carried both diseases. 67.9% had plaque and 58.7% gingival bleeding. A statistically positive correlation was verified between the number of tooth loss, hypertension and diabetes mellitus, with a significant result (p ≥ 0.015).Conclusions: It is vital that people living with systemic diseases such as diabetes mellitus and hypertension are integrated to a health promotion program that takes into account their specific needs for maintaining oral health.