Characterization of wild and captive baboon gut microbiota and their antibiotic resistomes

Antibiotic exposure results in acute and persistent shifts in the composition and function of microbial communities associated with vertebrate hosts. However, little is known about the state of these communities in the era before the widespread introduction of antibiotics into clinical and agricultural practice. We characterized the fecal microbiota and antibiotic resistomes of wild and captive baboon populations to understand the effect of human exposure and to understand how the primate microbiota may have been altered during the antibiotic era. We used culture-independent and bioinformatics methods to identify functional resistance genes in the guts of wild and captive baboons and show that exposure to humans is associated with changes in microbiota composition and resistome expansion compared to wild baboon groups. Our results suggest that captivity and lifestyle changes associated with human contact can lead to marked changes in the ecology of primate gut communities.Environmental microbes have harbored the capacity for antibiotic production for millions of years, spanning the evolution of humans and other vertebrates. However, the industrial-scale use of antibiotics in clinical and agricultural practice over the past century has led to a substantial increase in exposure of these agents to human and environmental microbiota. This perturbation is predicted to alter the ecology of microbial communities and to promote the evolution and transfer of antibiotic resistance (AR) genes. We studied wild and captive baboon populations to understand the effects of exposure to humans and human activities (e.g., antibiotic therapy) on the composition of the primate fecal microbiota and the antibiotic-resistant genes that it collectively harbors (the “resistome”). Using a culture-independent metagenomic approach, we identified functional antibiotic resistance genes in the gut microbiota of wild and captive baboon groups and saw marked variation in microbiota architecture and resistomes across habitats and lifeways. Our results support the view that antibiotic resistance is an ancient feature of gut microbial communities and that sharing habitats with humans may have important effects on the structure and function of the primate microbiota

Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy

Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca(2+) handling is a key feature of HF pathophysiology. Restoring the Ca(2+) regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies. Here, we study antisense oligonucleotides (ASOs) as a therapeutic modality, interfering with the PLN/SERCA2a interaction by targeting Pln mRNA for downregulation in the heart of murine HF models. Mice harboring the PLN R14del pathogenic variant recapitulate the human dilated cardiomyopathy (DCM) phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. In another genetic DCM mouse model, unrelated to PLN (Cspr3/Mlp(−/−)), PLN-ASO also reverses the HF phenotype. Finally, in rats with myocardial infarction, PLN-ASO treatment prevents progression of left ventricular dilatation and improves left ventricular contractility. Thus, our data establish that antisense inhibition of PLN is an effective strategy in preclinical models of genetic cardiomyopathy as well as ischemia driven HF

Sickness absence following coronary revascularisation. A national study of women and men of working age in Sweden 1994-2006.

BACKGROUND: Evidence based and gender specific knowledge about sickness absence following coronary revascularisation is lacking. The objective was to investigate sickness absence after a first coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) among women and men in a national Swedish study. MATERIALS AND METHODS: All patients 30-63 years of age, who underwent a first CABG (n = 22,985, 16% women) or PCI (40,891, 22% women) in Sweden between 1994 and 2006 were included. Information on sickness absence, co-morbidity, and other patient characteristics was obtained from national registers. Long-term sickness absence (LTSA) was defined as >180 and >90 sick-leave days in the first sick-leave spell following CABG and PCI, respectively. Prevalence ratio (PR) and 95% confidence interval (CI) of LTSA were calculated. FINDINGS: LTSA followed the interventions in 41% and 36% for CABG and PCI patients, respectively. Women had more often LTSA compared with men, (CABG PR = 1.23: 95% CI 1.19-1.28 and PCI PR = 1.19; 95% CI 1.16-1.23). A history of sickness absence the year before the intervention increased the risk for LTSA after the intervention in both genders. Among women, older age, or being self employed or unemployed was associated with a lower risk for LTSA. Among men previous cardiovascular disease, diabetes and low socio-economic position increased the risk. During the observation period, there was no change in sickness absence rates among PCI patients but an increase among CABG patients adjusting for patient characteristics. CONCLUSION: This national study covering a 13-year period shows that long-term sickness absence following coronary revascularisation is common in Sweden, especially among women, and is associated with socio-economic position, co-morbidity, and sickness absence during the year before the intervention. Gender specific scientific knowledge about use and effects of sickness absence following coronary revascularisation is warranted for the patients, the treating physicians, the healthcare sector, and the society

Patient characteristics, and the five-year (or up through 2006) all-cause mortality, number (n) and percentages (%), aged 30–64 years, on disability pension (DP) or not on DP at the time of first percutaneous coronary intervention (PCI) during the year 1994–2006 and alive 30 days after the intervention.

<p>¹ Percentage of all in each sub-group.</p><p>² Non-ST-elevated or ST-elevated myocardial infarction.</p><p>Patient characteristics, and the five-year (or up through 2006) all-cause mortality, number (n) and percentages (%), aged 30–64 years, on disability pension (DP) or not on DP at the time of first percutaneous coronary intervention (PCI) during the year 1994–2006 and alive 30 days after the intervention.</p

Crude and adjusted hazard ratio (HR) with 95% confidence interval (CI) for all-cause mortality within five years following a first percutaneous coronary intervention (PCI), among women and men, with disability pension (DP) or no DP (reference group), at time of revascularisation, for all and within each subpopulation.

<p>Model I = Adjusted for Age; model II = Adjusted for: age, level of education, country of birth, type of living area, year of intervention, indication for intervention, diabetes mellitus, in-patient care within 5 years up to one day before intervention, and re-intervention.</p><p>^1. In model II adjusted for all except age.</p><p>Crude and adjusted hazard ratio (HR) with 95% confidence interval (CI) for all-cause mortality within five years following a first percutaneous coronary intervention (PCI), among women and men, with disability pension (DP) or no DP (reference group), at time of revascularisation, for all and within each subpopulation.</p

Patient characteristics, stratified by type of intervention and gender, of all patients in Sweden (N = 65,676), 30–63 years of age, with a first coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI) within the year 1994–2006, and with disability pension (DP) (n = 15,497) at time of intervention.

<p>¹ Proportion of patients with disability pension at the time of first coronary revascularisation</p><p>² Acute Coronary Syndrome: Non-ST-elevated myocardial infarction or ST-elevated myocardial infarction</p><p>Patient characteristics, stratified by type of intervention and gender, of all patients in Sweden (N = 65,676), 30–63 years of age, with a first coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI) within the year 1994–2006, and with disability pension (DP) (n = 15,497) at time of intervention.</p

Disability pension (DP) at the time of first coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI), frequencies (n), proportions (%), crude and adjusted odds ratio (OR) with 95% confidence intervals (CI), by gender and type of intervention.

<p>Model I = adjusted for age; Model II = adjusted for age and level of education; Model III = adjusted for gender.</p><p>Disability pension (DP) at the time of first coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI), frequencies (n), proportions (%), crude and adjusted odds ratio (OR) with 95% confidence intervals (CI), by gender and type of intervention.</p

Prevalence ratio of a sick-leave spell >90 days following PCI for <i>all patients</i> and for <i>patients with ≤90 sick-leave days</i> immediately before the intervention.

1<p>Adjusted for age and >90 sick-leave days <i>in total</i> during the year before PCI.</p>2<p>Myocardial infarction.</p>3<p>Acute myocardial infarction, heart failure, cerebrovascular disease and transient cerebral ischeamic attacks.</p>4<p>Including non-manual employees at intermediate level.</p>5<p>Not adjusted for >90 sick-leave days <i>in total</i> during the year before PCI.</p>*<p>p-value <0.05;</p>**<p>p-value <0.01;</p>***<p>p-value <0.001.</p