Publications

Personalized medicine incorporates genetic information into medical practice so as to optimize the management of chronic diseases. In rare diseases, such as heart cancer (incidence 0.0017–0.33%), this may be elusive. Ninety-five percent of the cases are due to secondary involvementwith the neoplasm originating in the lungs, breasts, kidney, blood, or skin. The clinical manifestations of heart tumors (benign or malignant) include heart failure, hypertension, and cardiac arrhythmias of varying severity, frequently resulting in blood vessel emboli, including strokes. This study aims to explain the pathophysiology and contribute to a P4 medicine model for use by cardiologists, pathologists, and oncologists. We created six gene/protein heart-related and tumor-related targets high-confidence interactomes, which unfold the main pathways that may lead to cardiac diseases (heart failure, hypertension, coronary artery disease, arrhythmias), i.e., the sympathetic nervous system, the renin-angiotensin-aldosterone axis and the endothelin pathway, and excludes others, such as the K oxidase or cytochrome P450 pathways. We concluded that heart cancer patients could be affected by beta-adrenergic blockers, ACE inhibitors, QT-prolonging antiarrhythmic drugs, antibiotics, and antipsychotics. Interactomes may elucidate unknown pathways, adding to patient/survivor wellness during/after chemo- and/or radio-therapy.

Nelson's syndrome develops in 10–15% of patients with Cushing's disease who undergo bilateral adrenalectomy. Whether the pituitary tumors of Nelson's syndrome are autonomous or are regulated by hypothalamic signals or glucocorticoids is controversial. We, therefore, compared the plasma ACTH responses to synthetic ovine corticotropin-releasing hormone (CRH) in l i patients with Nelson's syndrome, 1 patient with Cushing's disease who had had bilateral adrenalectomy and did not have Nelson's syndrome, 14 patients with Cushing's disease, and 27 normal subjects. The plasma ACTH response to CRH in 10 patients with Nelson's syndrome was markedly increased and prolonged compared to the responses of normal subjects or patients with Cushing's disease. In 4 patients with Nelson's syndrome, plasma ACTH and cortisol concentrations also were determined at frequent intervals for 10–24 h during continuous infusions of 0.15 M saline or CRH (1 ¼g/kg-h). There was no desensitization of ACTH secretion during short term continuous infusion of CRH. Exogenous cortisol inhibited CRHstimulated ACTH secretion. These findings suggest that the ACTH response to CRH of patients with ACTH-secreting tumors of Nelson's syndrome differs from the response of those who have the microadenomas of Cushing's disease in two ways: the magnitude is greater, and the response is prolonged. These differences can be explained by the greater size of the tumor and the reduced glucocorticoid feedback in adrenalectomized patients with Nelson's syndrome.

No abstract is provided for this article.

A simplified view of robustness and redundancy is presented for the seismic assessment and design of structures. It is argued that the topological simplicity of the seismic load, i.e., its highly correlated nature of application for practically every component in all but the ultra-long structures, means that simpler formulations can be devised compared to blast, wave or wind hazards. In that sense, robustness may be considered to express the influence of structural uncertainties on the seismic performance of the structure, in essence showing the available margin of safety subject to material variability. Quantitatively, a pertinent robustness/redundancy index is defined as the ratio of two different estimates of the mean annual frequency (MAF) of exceeding a limit-state of interest, such as global collapse: On the denominator lies the MAF estimate that incorporates all sources of variability while on the nominator is the estimate that neglects structural uncertainties. It is shown that a simple closed form solution is available that directly relates robustness to the dispersion of response due to model parameter uncertainty. As an example, a steel frame where only beams are allowed to yield is shown to be more robust compared to another version where columns become the sacrificial element. Structural robustness and redundancy are highly desirable structural properties that are understood to be related to structural safety, especially against collapse. Qualitatively, one may think of robustness as the property of the system that prevents isolated local failures from progressing unchecked to become extensive or even global. According to EN1990, robustness in design is enforced by mandating that “a structure should be designed and executed in such a way that it will not be damaged to an extent disproportionate to the original cause”. Quantitatively, this is a difficult concept to capture, as it pertains to the level and magnitude of loading, structural typology, member properties and even the consequences of failure (e.g. loss, time-to-repair etc.). Various robustness indices have been proposed at times, each carrying its own combination of factors that contribute to increased structural safety. In general, the focus has been on assessing either the consequences or the safety associated with a locally damaged structure. For example, Baker et al (2008), suggest separating the consequences (e.g. losses) due damage into (a) the direct losses of the damaged components and (b) the indirect ones due to cascading failures of other components or loss of functionality. Then the ratio of direct over the total losses defines a robustness index. Another approach sees the comparison of the global safety of the damaged structure versus the intact, where a wealth of different indices is available to supply quantification; see for example Sorensen (2011), Mondal and Tesfamariam (2013), Starossek and Haberland (2011) and references therein for a more comprehensive review. Redundancy is a concept quite similar to robustness. For example, Frangopol and Curley (1987) define it as the absence of critical components whose failure would cause global collapse. It is also generally taken to be associated to the presence of alternate load paths within the structure, and thus the presence of multiple elements to resist a given load. It has also received a fair share of attention, especially in seismic engineering, due to the inclusion of an explicit redundancy factor in US codes (ICBO 1997) that favors some structural configurations 12 International Conference on Applications of Statistics and Probability in Civil Engineering, ICASP12 Vancouver, Canada, July 12-15, 2015 2 over others, an issue that has received considerable criticism (Wen and Song, 2002, Liao et al 2007). In the end, as elaborately argued by Kanno and Ben-Heim (2011), redundancy and robustness can be thought as two faces of the same coin, conveying the ability of the system to transfer loads with safety in face of the uncertainty in the structure itself and its environment. 1. CONCEPTUAL DEVELOPMENT Existing approaches to determine robustness and redundancy need to be comprehensive, and thus often undeniably complex, mainly due to the need to examine the potential failure of many different components due to localized loads. In this particular case, though, the focus is on structures under seismic loads. This is a highly specific situation where topology is not necessarily important. It is quite different in comparison to, e.g., a lifeline network under seismic loads. There, having multiple alternate routes connecting a given node often confers an advantage, as each may experience different loading levels due to the spatial variability of the ground motion. It would also be different for the blast assessment of a building where the highly localized effects of an explosion become important. Then, having a large number of widely-spaced structural elements working in unison improves the survivability. Topology becomes important for such cases because the damaging loads have a very distinct spatial distribution. A single structure subject to an earthquake, instead, generally experiences the same (or a highly correlated) ground motion in all of its components (with the probable exception of long bridges). Based on the above, it can be reliably stipulated that for any single structure we can define a seismic robustness index that does not need to account for topology per se. Then, structural robustness becomes a simpler issue of quantifying how the safety margin of capacity versus demand is influenced by the uncertainty arising from the structure itself. In that sense, robustness is not far from the notion of a reliability index that pertains to the influence of epistemic and aleatory uncertainties inherent to the structure, rather than the method of analysis or the seismic hazard. Following this mode of thinking, a simple definition for a seismic robustness index is proposed to characterize the “resistance” of structural systems to uncertainty. Specifically, the uncertainty robustness index (URI) is defined as the ratio of two estimates of the mean annual frequency (MAF) of exceeding a limit-sate of interest. At the nominator is the MAF that includes only (aleatory) record-to-record randomness, λR, while the denominator is the MAF estimate that also incorporates (aleatory or epistemic) structural uncertainties, λRU:

A simplified approach is presented for the seismic performance assessment of liquid storage tanks. The proposed methodology relies on a nonlinear static analysis, in conjunction with suitable “strength ratio-ductility-period” relationships, to derive the associated structural demand for the desired range of seismic intensities. In the absence of available relationships that are deemed fit to represent the nonlinear-elastic response of liquid storage tanks, several incremental dynamic analyses are performed for variable post-yield hardening ratios and periods in order to form a set of data that enables the fitting of the response. Following the identification of common modes of failure such as elephant's foot buckling (EFB), base plate plastic rotation, and sloshing wave damage, the aforementioned relationships are employed to derive the 16%, 50%, and 84% percentiles for each of the respective response parameters. Fragility curves are extracted for the considered failure modes, taking special care to appropriately quantify both the median and the dispersion of capacity and demand. A comparison with the corresponding results of incremental dynamic analysis (IDA) reveals that the pushover approach offers a reasonable agreement for the majority of failure modes and limit states considered.

In Adrenal Disorders, a panel of distinguished physicians and researchers select the most relevant new findings and integrate them into the existing body of clinical knowledge on adrenal pathologies.

The focus of this paper is on the probabilistic estimation of the buckling capacity of single-bolted members from plain or lipped angle sections with stochastic geometric imperfections. A joint experimental-stochastic mechanics approach is adopted, employing in-house imperfection measurements of angle members in combination with detailed numerical models. Different slenderness values, plain and lipped angle sections, as well as single-brace or X-bracing diagonals are investigated in all cases accounting for the single-bolt connection. The member buckling loads are obtained via numerical analyses considering geometric and material nonlinearities with initial imperfections. The random variables are the geometric imperfections, the material properties, and the lateral load (wind pressure) on the member. Quatro-variate single-dimensional stochastic processes (the spectral representation method in connection with the method of separation) are used for the modeling of the geometric imperfections. It is shown that the influence of imperfections for typical lattice tower angle members is 3–6 times lower than the influence of material properties and lateral loading. All in all, current EU and US design provisions are found to be mostly conservative for the design of such members, while the use of equivalent imperfections in a numerical model can provide a more rational safety margin.

In a previous issue of Clinical Endocrinology, Leow et al.1 describe a post-SARS (severe acute respiratory syndrome) condition characterized by mild sickness syndrome manifestations (malaise, anorexia, fatigue, myalgia) and transient, mild hypoactivation of the hypothalamic–pituitary–adrenal (HPA) axis. The authors have provided well-collected and analysed data obtained in difficult clinical circumstances on an infectious condition that is potentially lethal. The phenomenon described is robust and reminiscent of other postviral infection syndromes. However, some of the endocrine findings in this study are of uncertain value and some of the secondary conclusions conjectural. In this brief editorial, we will try to put the phenomenon described in this remarkable study into a more general perspective. The symptomatology of the post-SARS sickness syndrome manifestations can hardly be contested, given that they were of sufficient severity to warrant presentation to the caring physicians. In addition, one can hardly contest the concurrent mild hypocortisolism examined by the well-accepted time-integrated measure of 24-h urinary free cortisol excretion.2 Caution should, however, be exercised on conclusions based on HPA axis evaluation during the morbid state of SARS, and the validity of single, low-dose ACTH stimulation tests is dubious as an unquestionable index of low or high HPA axis activity.2 This is because the initial test was performed during a time of major physical and emotional stress, while subsequent short synacthen tests used a single submaximal dose of the peptide. The short, low-dose synacthen test has considerable intraindividual variability, even when a stress-producing condition is stable.3,4 This assessment would have been more valid if a number of doses of synacthen were used to span the dose–response curve. The findings of Leow et al.1 have added the post-SARS sickness syndrome and hypocortisolism to a long list of mostly transient conditions that are characterized by sudden reversal of a state of chronic cortisol hypersecretion (Table 1). These include prolonged regular exercise, states of chronic stress, treatment of Cushing's syndrome and cessation of exogenous glucocorticoids.5–7 In the same list one could include the premenstrual, postpartum and perimenopausal periods, the post-traumatic stress disorder in adults, the abrupt cessation of chronic smoking, the chronic fatigue syndrome (CFS) and fibromyalgia (FM) and other chronic pain and fatigue syndromes.5–7 Sickness syndrome is generated primarily by activated immune and immune-related cells via proinflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α), the interleukins (IL)-1, IL-6 and IL-8, and other nonpeptide mediators of inflammation.8 It includes symptoms such as malaise, somnolence, fatigue, anorexia with or without nausea, and hyperalgesia with or without headache (Table 2). As a product of active systemic inflammation, sickness syndrome is accompanied by activation of the acute-phase reaction and the pain and fatigue system, with which it represents an extremely important composite biological programme responsible for generating behaviours and somatic responses that protect us from tissue damage and allow time and energy for a speedy and efficient tissue repair.8 An immune and inflammatory reaction of sufficient magnitude, however, through the proinflammatory cytokines, also activates the HPA axis, which to some extent serves as a valuable negative feedback system that prevents this reaction from overshooting.8 Indeed, the HPA axis, a major component of the stress system of the organism, suppresses the secretion of the proinflammatory cytokines and other mediators of inflammation and renders their target tissues resistant to these proinflammatory molecules8,9 (Fig. 1). Hence, when properly activated, this axis diminishes the manifestations of sickness syndrome and the activity of the pain and fatigue response.8 Acute Addison's disease is associated with varying degrees of sickness syndrome manifestations because the intrinsic levels of cortisol are insufficient to counteract the proinflammatory molecules that generate the syndrome.8,10,11,12 These manifestations may vary from a very mild sickness syndrome all the way to circulatory collapse and death, when an immune and inflammatory reaction has become unconstrained and uncompensated. Even slight hypocortisolism of the degree detected in the post-SARS period could explain the presence of the mild sickness syndrome manifestations in these patients. (a) Activation of the immune and inflammatory response of any aetiology leads to peripheral production and/or circulation of proinflammatory agents, which, through endocrine or neural afferent signals, stimulate a central nervous system (CNS) inflammatory cascade, cause manifestations of the sickness syndrome and spur the hypothalamic–pituitary–adrenal (HPA) axis at all levels. Note the involvement of NF-κB, a major proinflammatory transcription factor in both CNS and peripheral inflammation. On the other hand, the activated HPA axis, through its end-hormone, cortisol, and its receptor (GR), inhibits CNS and peripheral inflammation, as well as its own activity. (b) The presence of increased proinflammatory cytokines and other agents in the vicinity of peripheral somatic and autonomic afferent nerves decreases the pain and fatigue threshold of an individual and hence produces hyperalgesia and fatigue. This is further accentuated by post-stress hypocortisolism and diminished by cortisol elevations or administration. iCRH, immune corticotropin-releasing hormone; Sms, somatostatin; TLR, Toll-like receptor. If we rule out persistent infection by the SARS virus or residual post-SARS myopathy as two nonmutually exclusive explanations for the post-SARS syndrome described in this study, the sickness syndrome manifestations and the hypocortisolism demonstrated may represent a generic, transient adaptive response following a major stressful event, which improves the speed and quality of recovery of the organism after major stress. What are the mechanisms that generate this post-stress syndrome, and is it possible that some patients are more prone to develop it than others? In our opinion, this syndrome is produced by a period of prolonged central nervous system suppression of the HPA axis that results when a major stressor, in this case the virus, is of sufficient magnitude and duration that it causes sustained hypercortisolism. The degree and duration of this post-stress neuroendocrine HPA axis alteration, the activity of the immune system that generates the sickness syndrome and the sensitivity of the pertinent target tissues to glucocorticoids and cytokines are defined by genetic and developmental/constitutional factors, which determine whether an individual is more prone or more resistant to developing the syndrome. It is quite likely that syndromes such as CFS, FM, and other chronic pain and fatigue states represent pathological conditions in which such an important adaptive biological programme has gone awry, has lost its adaptive value, and in fact prevents healthy functioning of the suffering individual.6 The real practical question is on what should be done with patients with post-SARS sickness syndrome manifestations and hypocortisolism. It is obvious that patients with a truly subnormal standard, high-dose ACTH test should be treated for adrenal insufficiency with glucocorticoids, as the current standards of care dictate.2 However, in all others, who appear to be the majority of those with the syndrome, in the absence of data, a conservative approach should be taken. We do not treat patients with the euthyroid sick syndrome, which is an adaptive state that conserves energy in an individual that is under stress. On the same logical basis, we should probably not administer exogenous glucocorticoids for what is essentially an adaptive response of the HPA axis after major or prolonged stress. We recognize that there are no data to support this opinion at the present time and that properly designed, double-masked and placebo-controlled studies should be undertaken to test this hypothesis.