No abstract

Hypertension is a leading cause of premature death worldwide and the most important modifiable risk factor for cardiovascular disease. Effective screening programs, communication with patients, regular monitoring, and adherence to treatment are essential to successful management but may be challenging in health systems facing resource constraints. This qualitative study explored patients’ knowledge, attitudes, behaviour and health care seeking experiences in relation to detection, treatment and control of hypertension in Colombia. We conducted in-depth interviews and focus group discussions with 26 individuals with hypertension and 4 family members in two regions. Few participants were aware of ways to prevent high blood pressure. Once diagnosed, most reported taking medication but had little information about their condition and had a poor understanding of their treatment regime. The desire for good communication and a trusting relationship with the doctor emerged as key themes in promoting adherence to medication and regular attendance at medical appointments. Barriers to accessing treatment included co-payments for medication; costs of transport to health care facilities; unavailability of drugs; and poor access to specialist care. Some patients overcame these barriers with support from social networks, family members and neighbours. However, those who lacked such support, experienced loneliness and struggled to access health care services. The health insurance scheme was frequently described as administratively confusing and those accessing the state subsidized system believed that the treatment was inferior to that provided under the compulsory contributory system. Measures that should be addressed to improve hypertension management in Colombia include better communication between health care professionals and patients, measures to improve understanding of the importance of adherence to treatment, reduction of co-payments and transport costs, and easier access to care, especially in rural areas.

Heptapeptide microcystin and pentapeptide motuporin (nodularin-V) are equipotent inhibitors of type-1 and type-2A protein phosphatase catalytic subunits (PP-1c and PP-2Ac). Herein we describe elucidation of the molecular mechanisms involved in the interaction of these structurally similar hepatotoxins with PP-1c/PP-2Ac and identification of an important functional difference between their mode of interaction with these enzymes. Microcystin-LR, microcystin-LA, and microcystin-LL were found to interact with PP-2Ac and PP-1c by a two-step mechanism involving rapid binding and inactivation of the protein phosphatase (PPase) catalytic subunit, followed by a slower covalent interaction (within hours). Covalent adducts comprising PPase-toxin complexes were separated from free PPase by C-18 reverse-phase liquid chromatography, thus allowing the time course of covalent adduct formation to be quantitated. In contrast to microcystins, motuporin (nodularin-V) and nodularin-R were unable to form covalent complexes with either PP-1c or PP-2Ac even after 96 h incubation. Specific reduction of microcystin-LA to dihydromicrocystin-LA abolished the ability of the toxin to form a covalent adduct with PP-2Ac. Specific methyl esterification of the single Glu residue in microcystin-LR rendered this toxin inactive as a PPase inhibitor and abolished subsequent formation of a covalent adduct. Our data indicate that inactivation of PP-2Ac/PP-1c by microcystins precedes covalent modification of the PPases via a Michael addition reaction between a nucleophilic phosphatase residue and Mdha in the heptapeptide toxin. In contrast, following rapid inactivation of PP-2Ac/PP-1c by motuporin, the equivalent N-methyldehydrobutyrine residue in this toxin is unreactive and does not form a covalent bond with the PPases. These results are consistent with structural data for (i) the NMR solution structures of microcystin-LR and motuporin, which indicate a striking difference in the relative positions of their corresponding dehydroamino acids in the toxin peptide backbone, and (ii) X-ray crystallographic data on an inactive complex between PP-1c and microcystin-LR, which show a covalent bond between Cys-273 and the bound toxin.