Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis

The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90: MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity. In addition to disrupting the eHSP90:MMP2 complex and terminally inactivating MMP2, TIMP2 loads the client to eHSP90, keeping the protease in a transient inhibitory state. Secreted activating co-chaperone AHA1 displaces TIMP2 from the complex, providing a "reactivating'' mechanism for MMP2. Gene knockout or blocking antibodies targeting TIMP2 and AHA1 released by HT1080 cancer cells modify their gelatinolytic activity. Our data suggest that TIMP2 and AHA1 co-chaperones function as a molecular switch that determines the inhibition and reactivation of the eHSP90 client protein MMP2

Development of a quality indicator set to measure and improve quality of ICU care in low- and middle-income countries

PURPOSE: To develop a set of actionable quality indicators for critical care suitable for use in low- or middle-income countries (LMICs). METHODS: A list of 84 candidate indicators compiled from a previous literature review and stakeholder recommendations were categorised into three domains (foundation, process, and quality impact). An expert panel (EP) representing stakeholders from critical care and allied specialties in multiple low-, middle-, and high-income countries was convened. In rounds one and two of the Delphi exercise, the EP appraised (Likert scale 1–5) each indicator for validity, feasibility; in round three sensitivity to change, and reliability were additionally appraised. Potential barriers and facilitators to implementation of the quality indicators were also reported in this round. Median score and interquartile range (IQR) were used to determine consensus; indicators with consensus disagreement (median < 4, IQR ≤ 1) were removed, and indicators with consensus agreement (median ≥ 4, IQR ≤ 1) or no consensus were retained. In round four, indicators were prioritised based on their ability to impact cost of care to the provider and recipient, staff well-being, patient safety, and patient-centred outcomes. RESULTS: Seventy-one experts from 30 countries (n = 45, 63%, representing critical care) selected 57 indicators to assess quality of care in intensive care unit (ICU) in LMICs: 16 foundation, 27 process, and 14 quality impact indicators after round three. Round 4 resulted in 14 prioritised indicators. Fifty-seven respondents reported barriers and facilitators, of which electronic registry-embedded data collection was the biggest perceived facilitator to implementation (n = 54/57, 95%) Concerns over burden of data collection (n = 53/57, 93%) and variations in definition (n = 45/57, 79%) were perceived as the greatest barrier to implementation. CONCLUSION: This consensus exercise provides a common set of indicators to support benchmarking and quality improvement programs for critical care populations in LMICs

Olfactory and trigeminal interaction of menthol and nicotine in humans

The purpose of the study was to investigate the interactions between two stimuli—menthol and nicotine—both of which activate the olfactory and the trigeminal system. More specifically, we wanted to know whether menthol at different concentrations modulates the perception of burning and stinging pain induced by nicotine stimuli in the human nose. The study followed an eightfold randomized, double-blind, cross-over design including 20 participants. Thirty phasic nicotine stimuli at one of the two concentrations (99 and 134 ng/mL) were applied during the entire experiment every 1.5 min for 1 s; tonic menthol stimulation at one of the three concentrations (0.8, 1.5 and 3.4 μg/mL) or no-menthol (placebo control conditions) was introduced after the 15th nicotine stimulus. The perceived intensities of nicotine’s burning and stinging pain sensations, as well as perceived intensities of menthol’s odor, cooling and pain sensations, were estimated using visual analog scales. Recorded estimates of stinging and burning sensations induced by nicotine initially decreased (first half of the experiment) probably due to adaptation/habituation. Tonic menthol stimulation did not change steady-state nicotine pain intensity estimates, neither for burning nor for stinging pain. Menthol-induced odor and cooling sensations were concentration dependent when combined with low-intensity nicotine stimuli. Surprisingly, this dose dependency was eliminated when combining menthol stimuli with high-intensity nicotine stimuli. There was no such nicotine effect on menthol’s pain sensation. In summary, we detected interactions caused by nicotine on menthol perception for odor and cooling but no effect was elicited by menthol on nicotine pain sensation

A qualitative study exploring perceptions and attitudes of community pharmacists about extended pharmacy services in Lahore, Pakistan

Background In recent decades, community pharmacies reported a change of business model, whereby a shift from traditional services to the provision of extended roles was observed. However, such delivery of extended pharmacy services (EPS) is reported from the developed world, and there is scarcity of information from the developing nations. Within this context, the present study was aimed to explore knowledge, perception and attitude of community pharmacists (CPs) about EPS and their readiness and acceptance for practice change in the city of Lahore, Pakistan. Methods A qualitative approach was used to gain an in-depth knowledge of the issues. By using a semi-structured interview guide, 12 CPs practicing in the city of Lahore, Pakistan were conveniently selected. All interviews were audio-taped, transcribed verbatim, and were then analyzed for thematic contents by the standard content analysis framework. Results Thematic content analysis yielded five major themes. (1) Familiarity with EPS, (2) current practice of EPS, (3) training needed to provide EPS, (4) acceptance of EPS and (5) barriers toward EPS. Majority of the CPs were unaware of EPS and only a handful had the concept of extended services. Although majority of our study respondents were unaware of pharmaceutical care, they were ready to accept practice change if provided with the required skills and training. Lack of personal knowledge, poor public awareness, inadequate physician-pharmacist collaboration and deprived salary structures were reported as barriers towards the provision of EPS at the practice settings. Conclusion Although the study reported poor awareness towards EPS, the findings indicated a number of key themes that can be used in establishing the concept of EPS in Pakistan. Over all, CPs reported a positive attitude toward practice change provided to the support and facilitation of health and community based agencies in Pakistan

Population Genetics of GYPB and Association Study between GYPB*S/s Polymorphism and Susceptibility to P. falciparum Infection in the Brazilian Amazon

Merozoites of Plasmodium falciparum invade through several pathways using different RBC receptors. Field isolates appear to use a greater variability of these receptors than laboratory isolates. Brazilian field isolates were shown to mostly utilize glycophorin A-independent invasion pathways via glycophorin B (GPB) and/or other receptors. The Brazilian population exhibits extensive polymorphism in blood group antigens, however, no studies have been done to relate the prevalence of the antigens that function as receptors for P. falciparum and the ability of the parasite to invade. Our study aimed to establish whether variation in the GYPB*S/s alleles influences susceptibility to infection with P. falciparum in the admixed population of Brazil.Two groups of Brazilian Amazonians from Porto Velho were studied: P. falciparum infected individuals (cases); and uninfected individuals who were born and/or have lived in the same endemic region for over ten years, were exposed to infection but have not had malaria over the study period (controls). The GPB Ss phenotype and GYPB*S/s alleles were determined by standard methods. Sixty two Ancestry Informative Markers were genotyped on each individual to estimate admixture and control its potential effect on the association between frequency of GYPB*S and malaria infection.GYPB*S is associated with host susceptibility to infection with P. falciparum; GYPB*S/GYPB*S and GYPB*S/GYPB*s were significantly more prevalent in the in the P. falciparum infected individuals than in the controls (69.87% vs. 49.75%; P<0.02). Moreover, population genetics tests applied on the GYPB exon sequencing data suggest that natural selection shaped the observed pattern of nucleotide diversity.Epidemiological and evolutionary approaches suggest an important role for the GPB receptor in RBC invasion by P. falciparum in Brazilian Amazons. Moreover, an increased susceptibility to infection by this parasite is associated with the GPB S+ variant in this population

Parental Burnout Around the Globe: a 42-Country Study

High levels of stress in the parenting domain can lead to parental burnout, a condition that has severe consequences for both parents and children. It is not yet clear, however, whether parental burnout varies by culture, and if so, why it might do so. In this study, we examined the prevalence of parental burnout in 42 countries (17,409 parents; 71% mothers; M_{age} = 39.20) and showed that the prevalence of parental burnout varies dramatically across countries. Analyses of cultural values revealed that individualistic cultures, in particular, displayed a noticeably higher prevalence and mean level of parental burnout. Indeed, individualism plays a larger role in parental burnout than either economic inequalities across countries, or any other individual and family characteristic examined so far, including the number and age of children and the number of hours spent with them. These results suggest that cultural values in Western countries may put parents under heightened levels of stress