Fasting Modulates GABAergic Synaptic Transmission to Arcuate Kisspeptin Neurons in Female Mice.

It is well-established that the hypothalamic-pituitary-gonadal (HPG) axis is suppressed due to negative energy balance. However, less information is available on whether kisspeptin neuronal activity contributes to fasting-induced responses. In the present study, female and male mice were fasted for 24 hours or provided food ad libitum (fed group) to determine whether acute fasting is sufficient to modulate kisspeptin neuronal activity. In female mice, fasting attenuated luteinizing hormone (LH) and prolactin (PRL) serum levels and increased follicle-stimulating hormone levels compared with the fed group. In contrast, fasting did not affect gonadotropin or PRL secretion in male mice. By measuring genes related to LH pulse generation in micropunches obtained from the arcuate nucleus of the hypothalamus (ARH), we observed that fasting reduced Kiss1 mRNA levels in female and male mice. In contrast, Pdyn expression was upregulated only in fasted female mice, whereas no changes in the Tac2 mRNA levels were observed in both sexes. Interestingly, the frequency and amplitude of the GABAergic postsynaptic currents recorded from ARH kisspeptin neurons (ARHKisspeptin) were reduced in 24-hour fasted female mice but not in males. Additionally, neuropeptide Y induced a hyperpolarization in the resting membrane potential of ARHKisspeptin neurons of fed female mice but not in males. Thus, the response of ARHKisspeptin neurons to fasting is sexually dependent with a female bias, associated with changes in gonadotropins and PRL secretion. Our findings suggest that GABAergic transmission to ARHKisspeptin neurons modulates the activity of the HPG axis during situations of negative energy balance.

Vasoactive intestinal peptide exerts an excitatory effect on hypothalamic kisspeptin neurons during estrogen negative feedback.

Hypothalamic kisspeptin neurons are the primary modulators of gonadotropin-releasing hormone (GnRH) neurons. It has been shown that circadian rhythms driven by the suprachiasmatic nucleus (SCN) contribute to GnRH secretion. Kisspeptin neurons are potential targets of SCN neurons due to reciprocal connections with the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) and the arcuate nucleus of the hypothalamus (ARH). Vasoactive intestinal peptide (VIP), a notable SCN neurotransmitter, modulates GnRH secretion depending on serum estradiol levels, aging or time of the day. Considering that kisspeptin neurons may act as interneurons and mediate VIP's effects on the reproductive axis, we investigated the effects of VIP on hypothalamic kisspeptin neurons in female mice during estrogen negative feedback. Our findings indicate that VIP induces a TTX-independent depolarization of approximately 30% of AVPV/PeN kisspeptin neurons in gonad-intact (diestrus) and ovariectomized (OVX) mice. In the ARH, the percentage of kisspeptin neurons that were depolarized by VIP was even higher (approximately 90%). An intracerebroventricular infusion of VIP leds to an increased percentage of kisspeptin neurons expressing the phosphoSer133 cAMP-response-element-binding protein (pCREB) in the AVPV/PeN. On the other hand, pCREB expression in ARH kisspeptin neurons was similar between saline- and VIP-injected mice. Thus, VIP can recruit different signaling pathways to modulate AVPV/PeN or ARH kisspeptin neurons, resulting in distinct cellular responses. The expression of VIP receptors (VPACR) was upregulated in the AVPV/PeN, but not in the ARH, of OVX mice compared to mice on diestrus and estradiol-primed OVX mice. Our findings indicate that VIP directly influences distinct cellular aspects of the AVPV/PeN and ARH kisspeptin neurons during estrogen negative feedback, possibly to influence pulsatile LH secretion.

Influence of the AT1 Receptor Antagonists Telmisartan and Losartan on Reproduction and Offspring After Paternal Exposure to Ionizing Radiation.

This study evaluated the repercussions of paternal exposure to radiation on reproduction and offspring in rats, as well as whether treatment with the angiotensin II type 1 (AT1) receptor antagonists telmisartan and losartan has a mitigating effect. Rats were randomly divided into 6 groups: control, radiation, telmisartan, losartan, radiation + telmisartan, and radiation + losartan. A single 5 Gy dose of radiation was administered directly into the scrotum, followed by treatment with telmisartan (12 mg/kg/d) or losartan (34 mg/kg/2 times per day) for 60 days in the groups receiving these medications. The reproductive ability of the test animals was assessed before and after exposure to radiation via fertility tests. The resulting offspring were analyzed for the presence of external and internal anomalies. Ionizing radiation significantly affected the rates of fertility, pre- and postimplantation losses, and implantation. Telmisartan and losartan did not significantly prevent this radiation-induced damage. The frequency of fetal anomalies was similar in offspring produced before and after paternal radiation exposure. Moreover, irradiated rats that received treatments and were able to generate offspring did not produce fetuses with morphological changes; this may represent a possible radioprotective effect AT1 antagonists have on offspring development, although few fetuses survived and were evaluated for malformations. Although the study findings indicate that these medications have a positive effect, further studies with longer treatment periods (extending beyond 1 rat spermatogenic cycle) are needed to determine whether these drugs significantly improve reproductive rates after paternal exposure to radiation, which may also reflect an increase in the number of viable fetuses.

Potential radioprotective effect of AT1 receptor antagonists against morphological and ultrastructural changes in the testes induced by ionizing radiation / Potencial efecto radioprotector de antagonistas del receptor AT1 contra los daños morfológicos y ultraestructurales en los testículos inducido por la radiación ionizante

Radiotherapy is a source of human exposure to ionizing radiation. This pure energy causes deleterious effects on tissues, which result from oxidative stress, a phenomenon in which there is the participation of the Renin-Angiotensin System (RAS). The male genital organs are extremely radiosensitive and the action of radiation in the testes can significantly affect spermatogenesis. In search of potential radioprotective for male genital system, this study investigated whether the AT1 receptor antagonists minimize radiation-induced damage to reproductive tissues, by decreasing oxidative stress. Male Wistar rats were divided into six groups: 0 Gray (Gy) (control), 5 Gy (single dose in the scrotal area), telmisartan, losartan, 5Gy+telmisartan and 5Gy+losartan. The treatment started the day after irradiation with losartan 34 mg/kg (two times/day) and telmisartan 12 mg/kg (one time/day) during 60 days. For ultrastructural analysis, the testis fragments were fixed in 2 % glutaraldehyde and 4 % paraformaldehyde in 0.1 M phosphate buffer, pH 7.3. The material was postfixed for 2 h in 1 % osmium tetroxide. For collagen evaluation, the sections were stained with Picrosirius-red method. Serum testosterone was determined. The date showed the deleterious effects of gamma radiation on testicular ultrastructure. Rich accumulation of collagen fibers in the interstitium was observed in the irradiated groups, especially the irradiated and nontreated testes. No significant difference was detected in serum testosterone concentration among the studied experimental groups. Treatments with telmisartan and losartan influenced the onset of attenuation on ultrastructural damages arising from ionizing radiation. Although the data strongly suggest that AT1 receptor antagonists may promote radioprotection to the testes, further studies with a longer duration of treatment are required for these potentially positive effects to be maximized and, therefore, to better characterize radioprotection to reproductive parameters.

El tratamiento radioterápico es una fuente de exposición del ser humano a la radiación ionizante. Esta energía pura causa efectos deletéreos en los tejidos, debido al estrés oxidativo, fenómeno donde hay participación del Sistema Renina-Angiotensina. Los órganos genitales masculinos son extremadamente radiosensibles y la acción de la radiación en los testículos puede afectar significativamente la espermatogénesis. En la búsqueda de potenciales radioprotectores, este estudio ha investigado fármacos antagonistas del receptor AT1 que minimizan los daños radioinduzidos en los tejidos reproductivos, por medio de la disminución del estrés oxidativo. Ratones Wistar machos fueron distribuidos en seis grupos: grupo 0 Gray (Gy) (control), grupo 5 Gy (dosis única en el área escrotal), grupo telmisartán, grupo losartán, grupo 5Gy+telmisartán y grupo 5Gy+losartán. El tratamiento empezó en el día siguiente a la irradiación con losartán 34 mg/kg (2x/día) y telmisartán 12 mg/kg (1x/día), durante 60 días. Para el análisis ultraestructural, los testículos se fijaron en glutaraldehido (2 %) y paraformaldehido (4 %) con tampón de fosfato 0,1 M, pH 7,3. El material fue post-fijado en tetróxido de osmio (1 %). Para evaluar el colágeno fue utilizado el método Picrosirius Red. Fue determinada la concentración sérica de testosterona. Los datos mostraron los efectos deletéreos de los rayos gamma sobre la ultraestructura testicular. Fue observada una rica deposición de colágeno en el intersticio en los grupos irradiados, especialmente en el irradiado y no tratado. Entre los grupos, no se detectó ninguna diferencia significativa en la concentración sérica de testosterona. Los tratamientos con telmisartán y losartán influenciaron el comienzo de la atenuación de los cambios en la ultraestructura testicular de la radiación. A pesar de que los datos sugieren que los antagonistas del receptor AT1 pueden promover radioprotección a los testículos, estudios complementarios con una duración de tratamiento más extendida son necesarios para que los efectos potencialmente positivos sean maximizados y, por supuesto, puedan mejorar la caracterizacion de la radioprotección a los parámetros reproductivos.

Qualidade de vida de pacientes adultos e idosos com artrite reumatoide / Quality of life in adults and elderly patients with rheumatoid arthritis

Objetivo: Analisar e comparar a qualidade de vida (QV) de pacientes adultos e idosos com artrite reumatoide (AR). Métodos: Trata-se de um estudo transversal, quantitativo. Os instrumentos aplicados incluem o Medical Outcomes Study-36 Short Form (SF-36), o Disease Activity Score 28 (DAS-28), o Health Assestment Questionnaire (HAQ), o inventário de depressão de Beck e o Teste de Caminhada de 6 Minutos (TC6). A análise dos dados foi feita por estatística descritiva, teste t de student e teste de regressão linear, sendo adotado nível de significância de p<0,05. Resultados: A amostra foi constituída por 99 pacientes com diagnóstico de AR, divididos em adultos e idosos. Foram considerados adultos aqueles de 18 a 59 anos, e idosos aqueles com 60 anos ou mais. No SF-36 os grupos apresentaram o domínio dor como o mais comprometido e o domínio aspectos emocionais como menos comprometido. Ambos apresentaram nível moderado de atividade da doença e deficiência leve. Aplicando-se o teste t, constatou-se que não há diferença significativa entre os grupos no que diz respeito à QV, capacidade funcional, depressão e atividade da doença. A diferença foi significativa no TC6, no qual os idosos obtiveram uma média de 330,8 m, e os adultos 412,2m, com um p=0,000. Na regressão linear houve correlação significativa (r=-0,31) entre a distância percorrida no TC6 e o aumento da idade. Conclusão: A QV e a capacidade funcional na AR mostrou-se afetada nos adultos e nos idosos; porém, os resultados mostraram que não há diferença entre os grupos com exceção do TC6. .

Objective: To analyze and compare quality of life (QoL) in adults and elderly patients with rheumatoid arthritis (RA). Methods: This was a cross-sectional quantitative study. The tools include the Medical Outcomes Study Short Form-36 (SF-36), the Disease Activity Score 28 (DAS-28), the Assessment Health Questionnaire (HAQ), the Beck Depression Inventory (BDI) and the 6-Minute Walk Test (6MWT). Data analysis was done by descriptive statistics, Student's t test and linear regression test, with significance level of p <0.05. Results: The sample consisted of 99 patients diagnosed with RA, divided into adults and elderly. Those considered adults were 18-59 years-old and those with 60 years or older where considered elderly. In SF-36, the groups showed the pain domain as the most compromised and the emotional aspects domain as the less compromised. Both showed moderate level of disease activity and mild disability. Applying the t test, it was found that there was no significant difference between groups with respect to QoL, functional ability, depression and disease activity. The difference was significant in the 6MWT, in which the elderly achieved an average of 330.8 m, and the adults, 412.2 m (p=0.000). In linear regression, a significant correlation (r=-0.31) between the 6MWT and increasing age was noted. Conclusion: QoL and functional capacity in RA were affected in adults and the elderly. However, the results showed no significant difference between groups, with the exception of the 6MWT. .

[Quality of life in adults and elderly patients with rheumatoid arthritis]. / Qualidade de vida de pacientes adultos e idosos com artrite reumatoide.

OBJECTIVE: To analyze and compare quality of life (QoL) in adults and elderly patients with rheumatoid arthritis (RA). METHODS: This was a cross-sectional quantitative study. The tools include the Medical Outcomes Study Short Form-36 (SF-36), the Disease Activity Score 28 (DAS-28), the Assessment Health Questionnaire (HAQ), the Beck Depression Inventory (BDI) and the 6-Minute Walk Test (6MWT). Data analysis was done by descriptive statistics, Student's t test and linear regression test, with significance level of p <0.05. RESULTS: The sample consisted of 99 patients diagnosed with RA, divided into adults and elderly. Those considered adults were 18-59 years-old and those with 60 years or older where considered elderly. In SF-36, the groups showed the pain domain as the most compromised and the emotional aspects domain as the less compromised. Both showed moderate level of disease activity and mild disability. Applying the t test, it was found that there was no significant difference between groups with respect to QoL, functional ability, depression and disease activity. The difference was significant in the 6MWT, in which the elderly achieved an average of 330.8 m, and the adults, 412.2 m (p=0.000). In linear regression, a significant correlation (r=-0.31) between the 6MWT and increasing age was noted. CONCLUSION: QoL and functional capacity in RA were affected in adults and the elderly. How-ever, the results showed no significant difference between groups, with the exception of the 6MWT.