Etiopathophysiological role of the renin-angiotensin-aldosterone system in age-related muscular weakening: RAAS-independent beneficial role of ACE2 in muscle weakness.

Aging is accompanied by major changes in body composition that can negatively affect functional status in older adults, including a progressive decrease in muscle mass, strength, and quality. The prevalence of sarcopenia has varied considerably, depending on the definition used and the population surveyed-a 2014 meta-analysis across several countries found estimates ranging from 1% to 29% for people aged 60 years or older, who live independently. The potentially relevant studies were retrieved from the ScienceDirect/Medline/PubMed/Public library of science/Mendeley/Springer link and Google Scholar. Multiple keywords were used for the literature search both alone and in combination. Some of the important keywords used for literature search were as follows: "Epidemiology of muscle weakness/muscle disorders," "Pathogenesis of RAAS in muscle weakness," "Role of Angiotensin 1-7/ACE-2/Mas R axis in muscle weakness," and "Correction pathophysiology of muscle weakness via ACE2." The renin-angiotensin system (RAAS), a major blood pressure regulatory system, is a candidate mediator that may promote aging-associated muscle weakness. Previously, studies explored the proof concept for RAAS inhibition as a therapeutic target. Furthermore, in RAAS, angiotensin II, and angiotensin-converting enzyme 2 (ACE2) have been reported to induce endoplasmic reticulum (ER) stress via glucose-regulated protein 78/eukaryotic translation initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)/CHOP axis in the liver. In addition, other mitochondria and ER physical interactions contribute to skeletal muscle dysfunction. However, very few studies have investigated the relationship between RAAS and ER stress-associated pathophysiological events and ACE2-mediated biological consequences in muscle weakness. Thus, the study has been designed to investigate the RAAS-independent beneficial role of ACE2 in muscle weakness.

Mainz II urinary diversion in low-resource settings: patient outcomes in women with irreparable fistula in Malawi.

BACKGROUND: Obstructed labor leading to a vesicovaginal fistula remains a devastating outcome of childbirth in low-resource countries. Women with an irreparable vesicovaginal fistula may be candidates for a urinary diversion, such as the Mainz II modified ureterosigmoidostomy procedure. Previous reviews state that the procedure should be considered in low-resource countries. However, given the limited duration of postoperative follow-up, these studies do not adequately represent the long-term morbidity and mortality that is likely associated with this procedure. We present data that strongly support avoiding the procedure in low-resource countries. OBJECTIVE: This study aimed to evaluate the postoperative status of the patient (dead, alive, lost to follow-up) and time to death following the Mainz II procedure. STUDY DESIGN: This is a case series including 21 patients who underwent a Mainz II urinary diversion from April 2013 to June 2015 for management of irreparable vesicovaginal fistula at the Fistula Care Centre in Lilongwe, Malawi. Patients were seen postoperatively at 3, 6, 9, and 12 months, followed by every 6 to 12 months thereafter. Descriptive statistics were performed to summarize the data. RESULTS: During the postoperative period, 8 (38.1%; 8/21) patients died, 5 (23.8%; 5/21) were lost to follow-up, and 8 (38.1%; 8/21) are currently alive and followed up at the Fistula Care Centre. We strongly suspect that 7 of the 8 deaths were related to the procedure given that the patients had illnesses that exacerbated the metabolic consequences of the procedure. The eighth patient died after being attacked by robbers. Unfortunately, the exact cause of death could not be determined for these patients. Given that most of the suspected illnesses would be treatable in an otherwise healthy patient, even in this low-resource setting, we surmised that the metabolic compromise from the Mainz II procedure likely contributed to their untimely death. The average time from procedure to death was 58 months, with the earliest death at 10 months and the most recent at 7 years after the procedure. CONCLUSION: The Mainz II procedure is an option for patients with irreparable fistula. However, it should likely not be performed in low-resource countries given the long-term complications that often cannot be adequately addressed in these settings, leading to significant morbidity and mortality.

Dissecting the role of TRPV1 in detecting multiple trigeminal irritants in three behavioral assays for sensory irritation.

Polymodal neurons of the trigeminal nerve innervate the nasal cavity, nasopharynx, oral cavity and cornea. Trigeminal nociceptive fibers express a diverse collection of receptors and are stimulated by a wide variety of chemicals. However, the mechanism of stimulation is known only for relatively few of these compounds. Capsaicin, for example, activates transient receptor potential vanilloid 1 (TRPV1) channels. In the present study, wildtype (C57Bl/6J) and TRPV1 knockout mice were tested in three behavioral assays for irritation to determine if TRPV1 is necessary to detect trigeminal irritants in addition to capsaicin. In one assay mice were presented with a chemical via a cotton swab and their response scored on a 5 level scale. In another assay, a modified two bottle preference test, which avoids the confound of mixing irritants with the animal's drinking water, was used to assess aversion. In the final assay, an air dilution olfactometer was used to administer volatile compounds to mice restrained in a double-chambered plethysmograph where respiratory reflexes were monitored. TRPV1 knockouts showed deficiencies in the detection of benzaldehyde, cyclohexanone and eugenol in at least one assay. However, cyclohexanone was the only substance tested that appears to act solely through TRPV1.