Single-Center Prospective Cohort Study on the Histopathology, Genotype, and Postsurgical Outcomes of Patients With Primary Aldosteronism

Unilateral forms of primary aldosteronism are usually surgically treated to remove the source of aldosterone excess. After adrenalectomy, aldosteronism persists in some patients indicating abnormal aldosterone production from the unresected gland. Our objective was to investigate histopathology, genotype, and postsurgical outcomes in a 3-year prospective cohort of surgically treated patients for primary aldosteronism (from 2016 to 2018). The cohort comprised 60 consecutively operated patients categorized with classical or nonclassical histopathologic findings of unilateral primary aldosteronism. In the classical group were 45 solitary aldosterone-producing adenomas or dominant aldosterone-producing nodules; in the nonclassical group were 15 cases of multiple aldosterone-producing micronodules or nodules (12 cases) or aldosterone-producing diffuse hyperplasia (3 cases). The classical group displayed higher baseline plasma aldosterone concentrations (262 versus 155 pg/mL, P=0.008) and an increased aldosterone-to-renin ratio (81 versus 42, P=0.002). A high proportion of the classical group achieved complete biochemical success (97.6% versus 66.7% in the nonclassical group, P=0.002). The nonclassical versus classical group displayed an increased ratio of absolute aldosterone concentration in the contralateral adrenal vein to peripheral vein at adrenal venous sampling (3.8 versus 2.0, P=0.004). Variants in aldosterone-driver genes were identified in 85% of 41 aldosterone-producing adenomas and were excluded in the remaining 15% by CYP11B2 guided next-generation sequencing. There were no differences in clinical or biochemical outcomes in patients with a solitary aldosterone-producing adenoma categorized by KCNJ5 mutation status. In conclusion, adrenals with a nonclassical histopathology of unilateral primary aldosteronism are associated with a higher incidence of postsurgical disease persistence and increased aldosterone production from the unresected adrenal

Ghrelin drives GH secretion during fasting in man

OBJECTIVES: In humans, fasting leads to elevated serum GH concentrations. Traditionally, changes in hypothalamic GH-releasing hormone and somatostatin release are considered as the main mechanisms that induce this elevated GH secretion during fasting. Ghrelin is an endogenous ligand of the GH secretagogue receptor and is synthesized in the stomach. As ghrelin administration in man stimulates GH release, while serum ghrelin concentrations are elevated during fasting in man, this increase in ghrelin levels might be another mechanism whereby fasting results in stimulation of GH release. DESIGN AND SUBJECTS: In ten healthy non-obese males we performed a double-blind placebo-controlled crossover study comparing fasting with and fasting without GH receptor blockade. GH, ghrelin, insulin, glucose and free fatty acids were assessed. RESULTS: While ghrelin levels do not vary considerably in the fed state, fasting rapidly induced a diurnal rhythm in ghrelin concentrations. These changes in serum ghrelin concentrations during fasting were followed by similar, profound changes in serum GH levels. The rapid development of a diurnal ghrelin rhythm could not be explained by changes in insulin, glucos

Obese adolescents exhibit a constant ratio of GH isoforms after whole body vibration and maximal voluntary contractions

Background: Growth hormone (GH) is a heterogeneous protein composed of several molecular isoforms, the most abundant ones being the 22kDa- and 20kDa-GH. Exercise-induced secretion of GH isoforms has been extensively investigated in normal-weight individuals due to antidoping purposes, particularly recombinant human GH (rhGH) abuse. On the other hand, the evaluation of exercise-induced responses in GH isoforms has never been performed in obese subjects.Methods: The acute effects of whole body vibration (WBV) or maximal voluntary contraction (MVC) alone and the combination of MVC with WBV (MVC+WBV) on circulating levels of 22kDa- and 20kDa-GH were evaluated in 8 obese male adolescents [mean ageSD: 17.13.3yrs.;weight: 107.4 +/- 17.8kg;body mass index (BMI): 36.5 +/- 6.6kg/m(2);BMI standard deviation score (SDS): 3.1 +/- 0.6].Results: MVC (alone or combined with WBV) significantly stimulated 22kDa- and 20kDa-GH secretion, while WBV alone was ineffective. In particular, 22kDa- and 20kDa-GH peaks were significantly higher after MVC+WBV and MVC than WBV. In addition, 22kDa-GH (but not 20kDa-GH) peak was significantly higher after MVC+WBV than MVC. Importantly, the ratio of circulating levels of 22kDa- to 20kDa-GH was constant throughout the time window of evaluation after exercise and similar among the three different protocols of exercise.Conclusions The results of the present study confirm the ability of MVC, alone and in combination with WBV, to stimulate both 22kDa- and 20kDa-GH secretion in obese patients, these responses being related to the exercise workload. Since the ratio of 22kDa- to 20kDa-GH is constant after exercise and independent from the protocols of exercise as in normal-weight subjects, hyposomatotropism in obesity does not seem to depend on an unbalance of circulating GH isoforms. Since the present study was carried out in a small cohort of obese sedentary adolescents, these preliminary results should be confirmed in further future studies enrolling overweight/obese subjects with a wider age range

A Formal Proof of PAC Learnability for Decision Stumps

We present a formal proof in Lean of probably approximately correct (PAC) learnability of the concept class of decision stumps. This classic result in machine learning theory derives a bound on error probabilities for a simple type of classifier. Though such a proof appears simple on paper, analytic and measure-theoretic subtleties arise when carrying it out fully formally. Our proof is structured so as to separate reasoning about deterministic properties of a learning function from proofs of measurability and analysis of probabilities.Comment: 13 pages, appeared in Certified Programs and Proofs (CPP) 202

Thermosensitivity of the Saccharomyces cerevisiae gpp1gpp2 double deletion strain can be reduced by overexpression of genes involved in cell wall maintenance

A Saccharomyces cerevisiae strain in which the GPP1 and GPP2 genes, both encoding glycerol-3-phosphate phosphatase isoforms, are deleted, displays both osmo- and thermosensitive (ts) phenotypes. We isolated genes involved in cell wall maintenance as multicopy suppressors of the gpp1gpp2 ts phenotype. We found that the gpp1gpp2 strain is hypersensitive to cell wall stress such as treatment with β-1,3-glucanase containing cocktail Zymolyase and chitin-binding dye Calcofluor-white (CFW). Sensitivity to Zymolyase was rescued by overexpression of SSD1, while CFW sensitivity was rescued by SSD1, FLO8 and WSC3-genes isolated as multicopy suppressors of the gpp1gpp2 ts phenotype. Some of the isolated suppressor genes (SSD1, FLO8) also rescued the lytic phenotype of slt2 deletion strain. Additionally, the sensitivity to CFW was reduced when the cells were supplied with glycerol. Both growth on glycerol-based medium and overexpression of SSD1, FLO8 or WSC3 had additive suppressing effect on CFW sensitivity of the gpp1gpp2 mutant strain. We also confirmed that the internal glycerol level changed in cells exposed to cell wall perturbation. © 2007 Springer-Verlag

Mental health in the aged: prevalence, covariates and related neuroendocrine, cardiovascular and inflammatory factors of successful aging

<p>Abstract</p> <p>Background</p> <p>Although aging is accompanied by diminished functioning, many elderly individuals preserve a sense of well-being. While the concept of "successful aging" has been popular for many decades, little is known about its psycho-physiologic and endocrine underpinnings. KORA-Age is a population-based, longitudinal study designed to determine the prevalence of successfully aged men and women between 65 and 94 years old in the MONICA/KORA Augsburg cohort of randomly selected inhabitants. Specifically, we aim to identify predictors of successful aging and to elucidate bio-psychosocial mechanisms that maintain mental health and successful adaptation despite adverse experiences of life and aging.</p> <p>Methods/Design</p> <p>Components of successful aging were assessed in a telephone survey of 4,127 participants (2008-2009) enrolled in the MONICA/KORA cohort, on average, 13 years earlier. Psychosocial, somatic and behavioural predictors are used to determine factors that contribute to successful aging. An age-stratified random sub-sample (n = 1,079) participated in a personal interview where further psychological mechanisms that may underlie successful adaptation (resilience, social support, attachment) were examined. The interactions among neuroendocrine systems in the aging process are investigated by studying the cortisol/dehydroepiandrosterone-sulfate ratio, the level of insulin-like growth factor I, and oxytocin.</p> <p>Discussion</p> <p>Longitudinal determinants of successful aging can be assessed based on a follow-up of an average of 13 years. A comprehensive analysis of biological as well as physio-psychological information provides a unique opportunity to investigate relevant outcomes such as resilience and frailty in the elderly population.</p

Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations

Objective The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH). Participants A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry. Evidence Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues. Consensus process Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors. Conclusions LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations

Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients

An Extensive Circuitry for Cell Wall Regulation in Candida albicans

Protein kinases play key roles in signaling and response to changes in the external environment. The ability of Candida albicans to quickly sense and respond to changes in its environment is key to its survival in the human host. Our guiding hypothesis was that creating and screening a set of protein kinase mutant strains would reveal signaling pathways that mediate stress response in C. albicans. A library of protein kinase mutant strains was created and screened for sensitivity to a variety of stresses. For the majority of stresses tested, stress response was largely conserved between C. albicans, Saccharomyces cerevisiae, and Schizosaccharomyces pombe. However, we identified eight protein kinases whose roles in cell wall regulation (CWR) were not expected from functions of their orthologs in the model fungi Saccharomyces cerevisiae and Schizosaccharomyces pombe. Analysis of the conserved roles of these protein kinases indicates that establishment of cell polarity is critical for CWR. In addition, we found that septins, crucial to budding, are both important for surviving and are mislocalized by cell wall stress. Our study shows an expanded role for protein kinase signaling in C. albicans cell wall integrity. Our studies suggest that in some cases, this expansion represents a greater importance for certain pathways in cell wall biogenesis. In other cases, it appears that signaling pathways have been rewired for a cell wall integrity response