Sacral neuromodulation for treatment of overactive bladder: a review

Sacral neuromodulation (SNM) therapy is an established third line therapeutic option for the treatment of urgency urinary incontinence, urgency-frequency and chronic non-obstructive urinary retention. The continuous stimulation of the sacral root S3 with an electrode connected to an implanted pulse generator (IPG) may influence detrusor and sphincter activity and improve lower urinary tract symptoms. The mechanism of action is not completely understood and seems to be based on the modulation of spinal cord reflexes and brain centers involved in lower urinary tract function. It is implanted with a minimally invasive technique that can be performed under local anesthesia and includes a test phase that precedes the definitive implantation of the pulse generator. When compared to the standard pharmacological therapy, neuromodulation promoted better results both in the partial improvement of overactive bladder (OAB) symptoms and total continence. Moreover, sexual function, quality of life and depressive symptoms may also improve in patients with OAB that undergo SNM. However, SNM is associated with significant rates of adverse events and need for surgical revisions, requiring continuous medical attention.A neuromodulação sacral (NMS) é uma opção bem estabelecida de tratamento de terceira linha da bexiga hiperativa, incluindo as indicações de urgência-frequência, incontinência urinária de urgência e também a retenção urinária crônica não obstrutiva. A estimulação contínua da raiz sacral S3, através de um eletrodo conectado a um gerador de pulsos implantado, pode influenciar a função do detrusor e do esfíncter uretral e melhorar os sintomas do trato urinário inferior. O mecanismo de ação não é totalmente conhecido e parece basear-se na modulação dos reflexos medulares e dos centros cerebrais envolvidos no controle da função do trato urinário inferior. O eletrodo sacral é implantado com técnica minimamente invasiva, que pode ser realizada com anestesia local, e inclui uma fase de teste que precede o implante definitivo do gerador de pulsos. Em comparação com o tratamento farmacológico padrão da bexiga hiperativa, a NMS promove melhores resultados na melhora dos sintomas e nas taxas de cura. Além disso, a função sexual, a qualidade de vida e os sintomas depressivos também podem melhorar nos pacientes com bexiga hiperativa que são submetidos à NMS. No entanto, a NMS acompanha-se de significativas taxas de eventos adversos e de necessidade de revisões cirúrgicas, requerendo acompanhamento clínico periódico

Impairment of the Plasmodium falciparum Erythrocytic Cycle Induced by Angiotensin Peptides

Plasmodium falciparum causes the most serious complications of malaria and is a public health problem worldwide with over 2 million deaths each year. The erythrocyte invasion mechanisms by Plasmodium sp. have been well described, however the physiological aspects involving host components in this process are still poorly understood. Here, we provide evidence for the role of renin-angiotensin system (RAS) components in reducing erythrocyte invasion by P. falciparum. Angiotensin II (Ang II) reduced erythrocyte invasion in an enriched schizont culture of P. falciparum in a dose-dependent manner. Using mass spectroscopy, we showed that Ang II was metabolized by erythrocytes to Ang IV and Ang-(1–7). Parasite infection decreased Ang-(1–7) and completely abolished Ang IV formation. Similar to Ang II, Ang-(1–7) decreased the level of infection in an A779 (specific antagonist of Ang-(1–7) receptor, MAS)-sensitive manner. 10−7 M PD123319, an AT2 receptor antagonist, partially reversed the effects of Ang-(1–7) and Ang II. However, 10−6 M losartan, an antagonist of the AT1 receptor, had no effect. Gs protein is a crucial player in the Plasmodium falciparum blood cycle and angiotensin peptides can modulate protein kinase A (PKA) activity; 10−8 M Ang II or 10−8 M Ang-(1–7) inhibited this activity in erythrocytes by 60% and this effect was reversed by 10−7 M A779. 10−6 M dibutyryl-cAMP increased the level of infection and 10−7 M PKA inhibitor decreased the level of infection by 30%. These results indicate that the effect of Ang-(1–7) on P. falciparum blood stage involves a MAS-mediated PKA inhibition. Our results indicate a crucial role for Ang II conversion into Ang-(1–7) in controlling the erythrocytic cycle of the malaria parasite, adding new functions to peptides initially described to be involved in the regulation of vascular tonus

Impairment of the Plasmodium falciparum Erythrocytic Cycle Induced by Angiotensin Peptides

Plasmodium falciparum causes the most serious complications of malaria and is a public health problem worldwide with over 2 million deaths each year. The erythrocyte invasion mechanisms by Plasmodium sp. have been well described, however the physiological aspects involving host components in this process are still poorly understood. Here, we provide evidence for the role of renin-angiotensin system (RAS) components in reducing erythrocyte invasion by P. falciparum. Angiotensin II (Ang II) reduced erythrocyte invasion in an enriched schizont culture of P. falciparum in a dose-dependent manner. Using mass spectroscopy, we showed that Ang II was metabolized by erythrocytes to Ang IV and Ang-(1–7). Parasite infection decreased Ang-(1–7) and completely abolished Ang IV formation. Similar to Ang II, Ang-(1–7) decreased the level of infection in an A779 (specific antagonist of Ang-(1–7) receptor, MAS)-sensitive manner. 10−7 M PD123319, an AT2 receptor antagonist, partially reversed the effects of Ang-(1–7) and Ang II. However, 10−6 M losartan, an antagonist of the AT1 receptor, had no effect. Gs protein is a crucial player in the Plasmodium falciparum blood cycle and angiotensin peptides can modulate protein kinase A (PKA) activity; 10−8 M Ang II or 10−8 M Ang-(1–7) inhibited this activity in erythrocytes by 60% and this effect was reversed by 10−7 M A779. 10−6 M dibutyryl-cAMP increased the level of infection and 10−7 M PKA inhibitor decreased the level of infection by 30%. These results indicate that the effect of Ang-(1–7) on P. falciparum blood stage involves a MAS-mediated PKA inhibition. Our results indicate a crucial role for Ang II conversion into Ang-(1–7) in controlling the erythrocytic cycle of the malaria parasite, adding new functions to peptides initially described to be involved in the regulation of vascular tonus

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements