Age-dependent Decrease in 11β-Hydroxysteroid Dehydrogenase Type 2 (11β-HSD2) Activity in Hypertensive Patients

Background The prevalence of arterial hypertension lacking a defined underlying cause increases with age. Age-related arterial hypertension is insufficiently understood, yet known characteristics suggest an aldosterone-independent activation of the mineralocorticoid receptor. Therefore, we hypothesized that 11β-HSD2 activity is age-dependently impaired, resulting in a compromised intracellular inactivation of cortisol (F) with F-mediated mineralocorticoid hypertension. Methods Steroid hormone metabolites in 24-h urine samples of 165 consecutive hypertensive patients were analyzed for F and cortisone (E), and their TH-metabolites tetrahydro-F (THF), 5αTHF, TH-deoxycortisol (THS), and THE by gas chromatography-mass spectroscopy. Apparent 11β-HSD2 and 11β-hydroxylase activity and excretion of F metabolites were assessed. Results In 72 female and 93 male patients aged 18-84 years, age correlated positively with the ratios of (THF + 5αTHF)/THE (P = 0.065) and F/E (P < 0.002) suggesting an age-dependent reduction in the apparent 11β-HSD2 activity, which persisted (F/E; P = 0.020) after excluding impaired renal function. Excretion of F metabolites remained age-independent most likely as a consequence of an age-dependent diminished apparent 11β-hydroxylase activity (P = 0.038). Conclusion Reduced 11β-HSD2 activity emerges as a previously unrecognized risk factor contributing to the rising prevalence of arterial hypertension in elderly. This opens new perspectives for targeted treatment of age-related hypertensio

Sea ice as a source of sea salt aerosol to Greenland ice cores: a model-based study

Abstract. Growing evidence suggests that the sea ice surface is an important source of sea salt aerosol and this has significant implications for polar climate and atmospheric chemistry. It also offers the opportunity to use ice core sea salt records as proxies for past sea ice extent. To explore this possibility in the Arctic region, we use a chemical transport model to track the emission, transport and deposition of sea salt from both the open ocean and the sea ice, allowing us to assess the relative importance of each. Our results confirm the importance of sea ice sea salt (SISS) to the winter Arctic aerosol burden. For the first time, we explicitly simulate the sea salt concentrations of Greenland snow and find they match high resolution Greenland ice core records to within a factor of two. Our simulations suggest that SISS contributes to the winter maxima in sea salt characteristic of ice cores across Greenland. A north-south gradient in the contribution of SISS relative to open ocean sea salt (OOSS) exists across Greenland, with 50 % of sea salt being SISS at northern sites such as NEEM, while only 10 % of sea salt is SISS at southern locations such as ACT10C. Our model shows some skill at reproducing the inter-annual variability in sea salt concentrations for 1991–1999 AD, particularly at Summit where up to 62 % of the variability is explained. Future work will involve constraining what is driving this inter-annual variability and operating the model under different paleoclimatic conditions. This work was supported by a European Commission Horizon 2020 Marie Sklodowska-Curie Individual Fellowship (no. 658120, SEADOG) to Rachael H. Rhodes. Eric W. Wolff is supported by a Royal Society Professorship

Machine Learning for Outcome Prediction in First-Line Surgery of Prolactinomas.

Background First-line surgery for prolactinomas has gained increasing acceptance, but the indication still remains controversial. Thus, accurate prediction of unfavorable outcomes after upfront surgery in prolactinoma patients is critical for the triage of therapy and for interdisciplinary decision-making. Objective To evaluate whether contemporary machine learning (ML) methods can facilitate this crucial prediction task in a large cohort of prolactinoma patients with first-line surgery, we investigated the performance of various classes of supervised classification algorithms. The primary endpoint was ML-applied risk prediction of long-term dopamine agonist (DA) dependency. The secondary outcome was the prediction of the early and long-term control of hyperprolactinemia. Methods By jointly examining two independent performance metrics - the area under the receiver operating characteristic (AUROC) and the Matthews correlation coefficient (MCC) - in combination with a stacked super learner, we present a novel perspective on how to assess and compare the discrimination capacity of a set of binary classifiers. Results We demonstrate that for upfront surgery in prolactinoma patients there are not a one-algorithm-fits-all solution in outcome prediction: different algorithms perform best for different time points and different outcomes parameters. In addition, ML classifiers outperform logistic regression in both performance metrics in our cohort when predicting the primary outcome at long-term follow-up and secondary outcome at early follow-up, thus provide an added benefit in risk prediction modeling. In such a setting, the stacking framework of combining the predictions of individual base learners in a so-called super learner offers great potential: the super learner exhibits very good prediction skill for the primary outcome (AUROC: mean 0.9, 95% CI: 0.92 - 1.00; MCC: 0.85, 95% CI: 0.60 - 1.00). In contrast, predicting control of hyperprolactinemia is challenging, in particular in terms of early follow-up (AUROC: 0.69, 95% CI: 0.50 - 0.83) vs. long-term follow-up (AUROC: 0.80, 95% CI: 0.58 - 0.97). It is of clinical importance that baseline prolactin levels are by far the most important outcome predictor at early follow-up, whereas remissions at 30 days dominate the ML prediction skill for DA-dependency over the long-term. Conclusions This study highlights the performance benefits of combining a diverse set of classification algorithms to predict the outcome of first-line surgery in prolactinoma patients. We demonstrate the added benefit of considering two performance metrics jointly to assess the discrimination capacity of a diverse set of classifiers

Sea ice as a source of sea salt aerosol to Greenland ice cores: a model-based study

Growing evidence suggests that the sea ice surface is an important source of sea salt aerosol and this has significant implications for polar climate and atmospheric chemistry. It also suggests the potential to use ice core sea salt records as proxies for past sea ice extent. To explore this possibility in the Arctic region, we use a chemical transport model to track the emission, transport, and deposition of sea salt from both the open ocean and the sea ice, allowing us to assess the relative importance of each. Our results confirm the importance of sea ice sea salt (SISS) to the winter Arctic aerosol burden. For the first time, we explicitly simulate the sea salt concentrations of Greenland snow, achieving values within a factor of two of Greenland ice core records. Our simulations suggest that SISS contributes to the winter maxima in sea salt characteristic of ice cores across Greenland. However, a north–south gradient in the contribution of SISS relative to open-ocean sea salt (OOSS) exists across Greenland, with 50 % of winter sea salt being SISS at northern sites such as NEEM (77° N), while only 10 % of winter sea salt is SISS at southern locations such as ACT10C (66° N). Our model shows some skill at reproducing the inter-annual variability in sea salt concentrations for 1991–1999, particularly at Summit where up to 62 % of the variability is explained. Future work will involve constraining what is driving this inter-annual variability and operating the model under different palaeoclimatic conditions

Nasopharyngeal Microbiota in Infants With Acute Otitis Media

Background. Interspecies interactions of the nasopharyngeal microbiota are likely to be involved in the pathogenesis of acute otitis media (AOM). Capturing the breadth of microbial interactions requires a detailed description of the microbiota during health and AOM. Methods. The nasopharyngeal microbiota of 163 infants with (n = 153) or without (n = 10) AOM was characterized using nasopharyngeal swabs and multiplexed pyrosequencing of 16S rRNA. Nasopharyngeal swab specimens were collected during 4 winter seasons from 2004 through 2010 for infants with AOM and during 2010 for controls. Results. Fifty-eight bacterial families were identified, of which Moraxellaceae, Streptococcaceae, and Pasteurellaceae were the most frequent. Commensal families were less prevalent in infants with AOM than in controls. In infants with AOM, prior exposure to antimicrobials and administration of the heptavalent conjugated pneumococcal polysaccharide vaccine (PCV7) were also associated with reduced prevalence of distinct commensal families (Streptococcaceae and Corynebacteriaceae). In addition, antimicrobial exposure increased the prevalence of Enterobacteriaceae and the abundance of Pasteurellaceae. Other factors, such as age, sex, day care, and a history of recurrent AOM, did not influence the microbiota. Conclusions. Infants' nasopharyngeal microbiota undergoes significant changes during AOM and after exposure to antimicrobials and PCV7, which is mainly attributable to reduced prevalence of commensal bacterial familie

Coexistence and Survival in Conservative Lotka-Volterra Networks

Analyzing coexistence and survival scenarios of Lotka-Volterra (LV) networks in which the total biomass is conserved is of vital importance for the characterization of long-term dynamics of ecological communities. Here, we introduce a classification scheme for coexistence scenarios in these conservative LV models and quantify the extinction process by employing the Pfaffian of the network's interaction matrix. We illustrate our findings on global stability properties for general systems of four and five species and find a generalized scaling law for the extinction time

Persistent bone impairment despite long-term control of hyperprolactinemia and hypogonadism in men and women with prolactinomas.

While prolactinoma patients have high bone turnover, current data are inconclusive when it comes to determining whether correction of hyperprolactinemia and associated hypogandism improves osteodensitometric data in men and women over the long term. In a large cohort of including 40 men and 60 women, we studied the long-term impact of prolactinoma treatment on bone mineral density (BMD) in men versus women, assessed adverse effects of a primary surgical or medical approach, and evaluated data for risk factors for impaired BMD at last follow-up using multivariate regression analyses. Median duration of follow-up was 79 months (range 13-408 months). Our data indicate that the prevalence of impaired BMD remained significantly higher in men (37%) than in women (7%, p < 0.001), despite the fact that hyperprolactinemia and hypogonadism are under control in the majority of men. We found that persistent hyperprolactinemia and male sex were independent risk factors for long-term bone impairment. Currently, osteoporosis prevention and treatment focus primarily on women, yet special attention to bone loss in men with prolactinomas is advised. Bone impairment as "end organ" reflects the full range of the disease and could become a surrogate marker for the severity of long-lasting hyperprolactinemia and associated hypogonadism

Comparison of continuous and intermittent renal replacement therapy for acute renal failure

Background. Mortality rates of critically ill patients with acute renal failure (ARF) requiring renal replacement therapy (RRT) are high. Intermittent and continuous RRT are available for these patients on the intensive care units (ICUs). It is unknown which technique is superior with respect to patient outcome. Methods. We randomized 125 patients to treatment with either continuous venovenous haemodiafiltration (CVVHDF) or intermittent haemodialysis (IHD) from a total of 191 patients with ARF in a tertiary-care university hospital ICU. The primary end-point was ICU and in-hospital mortality, while recovery of renal function and hospital length of stay were secondary end-points. Results. During 30 months, no patient escaped randomization for medical reasons. Sixty-six patients were not randomized for non-medical reasons. Of the 125 randomized patients, 70 were treated with CVVHDF and 55 with IHD. The two groups were comparable at the start of RRT with respect to age (62±15 vs 62±15 years, CVVHDF vs IHD), gender (66 vs 73% male sex), number of failed organ systems (2.4±1.5 vs 2.5±1.6), Simplified Acute Physiology Scores (57±17 vs 58±23), septicaemia (43 vs 51%), shock (59 vs 58%) or previous surgery (53 vs 45%). Mortality rates in the hospital (47 vs 51%, CVVHDF vs IHD, P = 0.72) or in the ICU (34 vs 38%, P = 0.71) were independent of the technique of RRT applied. Hospital length of stay in the survivors was comparable in patients on CVVHDF [median (range) 20 (6-71) days, n = 36] and in those on IHD [30 (2-89) days, n = 27, P = 0.25]. The duration of RRT required was the same in both groups. Conclusion. The present investigation provides no evidence for a survival benefit of continuous vs intermittent RRT in ICU patients with AR

Age-dependent decrease in 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity in hypertensive patients

BACKGROUND: The prevalence of arterial hypertension lacking a defined underlying cause increases with age. Age-related arterial hypertension is insufficiently understood, yet known characteristics suggest an aldosterone-independent activation of the mineralocorticoid receptor. Therefore, we hypothesized that 11beta-HSD2 activity is age-dependently impaired, resulting in a compromised intracellular inactivation of cortisol (F) with F-mediated mineralocorticoid hypertension. METHODS: Steroid hormone metabolites in 24-h urine samples of 165 consecutive hypertensive patients were analyzed for F and cortisone (E), and their TH-metabolites tetrahydro-F (THF), 5alphaTHF, TH-deoxycortisol (THS), and THE by gas chromatography-mass spectroscopy. Apparent 11beta-HSD2 and 11beta-hydroxylase activity and excretion of F metabolites were assessed. RESULTS: In 72 female and 93 male patients aged 18-84 years, age correlated positively with the ratios of (THF + 5alphaTHF)/THE (P = 0.065) and F/E (P < 0.002) suggesting an age-dependent reduction in the apparent 11beta-HSD2 activity, which persisted (F/E; P = 0.020) after excluding impaired renal function. Excretion of F metabolites remained age-independent most likely as a consequence of an age-dependent diminished apparent 11beta-hydroxylase activity (P = 0.038). CONCLUSION: Reduced 11beta-HSD2 activity emerges as a previously unrecognized risk factor contributing to the rising prevalence of arterial hypertension in elderly. This opens new perspectives for targeted treatment of age-related hypertension