Paolo Prolo

IL-6 and Its Circadian Secretion in Humans

Interleukin-6 (IL-6) is a pleiotropic cytokine produced by numerous types of immune and nonimmune cells and is involved in many pathophysiologic mechanisms in humans. Many studies suggest that IL-6 is a putative ‘sleep factor’ and its circadian secretion correlates with sleep/sleepiness. IL-6 is elevated in disorders of excessive daytime sleepiness such as narcolepsy and obstructive sleep apnea. It correlates positively with body mass index and may be a mediator of sleepiness in obesity. Also the secretion of this cytokine is stimulated by total acute or partial short-term sleep loss reflecting the increased sleepiness experienced by sleep-deprived individuals. Studies that evaluated the 24-hour secretory pattern of IL-6 in healthy young adults suggest that IL-6 is secreted in a biphasic circadian pattern with two nadirs at about 08.00 and 21.00, and two zeniths at about 19.00 and 05.00 h. In contrast, following sleep deprivation or in disorders of sleep disturbance, e.g., insomnia, IL-6 peaks during the day and, based on the level of stress system activity, i.e., cortisol secretion, contributes to either sleepiness and deep sleep (low cortisol) or feelings of tiredness and fatigue and poor sleep (high cortisol). In order to address concerns about the potential impact of differences of IL-6 levels between the beginning and the end of the 24-hour blood-drawing experiment, we proceeded with a cosinor analysis of ‘detrended’ data in young and old healthy individuals. This new analysis did not affect the biphasic circadian pattern of IL-6 secretion in young adults, while it augmented the flattened circadian pattern in old individuals in whom the difference was greater. Finally, IL-6 appears to be somnogenic in rats and exhibits a diurnal rhythm that follows the sleep/wake cycle in these animals. We conclude that IL-6 is a mediator of sleepiness and its circadian pattern reflects the homeostatic drive for sleep.

Brain iNOS: current understanding and clinical implications

Nitric oxide (NO) is a unique informational substance first identified as the endothelium-derived relaxing factor. It is generated by NO synthases and plays a prominent role in controlling a variety of organ functions in the cardiovascular, immune, reproductive and nervous systems. Inducible nitric oxide synthase (iNOS) is not normally present in the brain in youth but it can be detected in the brain after inflammatory, infectious or ischemic damage, as well as in the normal, aging brain. Brain iNOS seems to contribute to the pathophysiology of many diseases that involve the central nervous system, but the role of iNOS appears to go beyond tissue damage. Brain iNOS might be required for adequate repair following injury or damage. The effects of brain iNOS on the balance between damage and repair make this enzyme a promising therapeutic target in human disease.

Evidence-based Research in Complementary and Alternative Medicine I: History

Contemporary Western medicine has witnessed a fragmentation of our conceptualization of the medical endeavor into ‘traditional medicine’ and ‘non-traditional medicine’. The former is meant to refer to the Western medical tradition, the latter encompasses both ‘complementary’ and ‘alternative’ medical practices. Complementary medicine complements conventional medical treatments, and alternative modes of medical interventions are meant to replace traditional Western medicine. Evidence-based research must be directed at establishing the best available evidence in complementary and alternative medicine. This paper is the first of a set of four ‘lectures’ that reviews the process of evidence-based research, and discusses its implications and applications for the early decades of the 21st century. The purpose of this paper is to introduce the series by examining some of the historical and philosophical foundations of this research endeavor.

Injury severity differentially affects short- and long-term neuroendocrine outcomes of traumatic brain injury.

Having reported that traumatic brain injury (TBI), produced by moderate lateral controlled cortical impact (CCI), causes long-term dysregulation of the neuroendocrine stress response, the aim of this study was to assess short- and long-term effects of both moderate and mild CCI on stress-induced hypothalamic-pituitary-adrenal (HPA) function. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths to produce either a moderate or mild CCI. Controls underwent sham surgery without injury. Commencing at one week after recovery from surgery, rats were exposed to stressors: 30-min restraint (days 7, 34, and 70) or 15-min forced swim (days 21 and 54). Tail vein blood was analyzed for corticosterone (CORT) content by radioimmunoassay. On days 7 and 21, the stress-induced HPA responses were significantly attenuated by both mild and moderate CCI. Significant attenuation of the CORT response to stress persisted through day 70 after moderate CCI. In contrast, stress-induced CORT levels on days 34, 54, and 70 were significantly enhanced after mild CCI. Differential effects of injury severity were also observed on motor function in a forelimb test on post-injury day 12 and on cortical lesion volume and hippocampal cell loss at day 70, but not on working memory in a radial maze on day 15. The differing short- and long-term stress-induced HPA responses may be mediated by differential effects of moderate and mild CCI on the efficiency of glucocorticoid negative feedback or signaling among hypothalamic and extrahypothalamic components of the neuroendocrine stress-response system.

Interactions between Glucocorticoids and Cytokines in the Bone Microenvironment

Abstract: Cytokines belonging to the so‐called interleukin‐6 (IL‐6) or gp130 cytokine family, notably IL‐6 and IL‐11, are known as pro‐resorptive cytokines, in that they promote osteoclastogenesis. Glucocorticoid (GC)‐induced osteoporosis is admittedly the most frequent secondary osteoporosis. The pathogenesis still has many unresolved issues. Although the effects of GCs on cytokine production and recognition have been extensively studied, little is known about the effects of cytokines on GC action at the target level. We have focused on the effects of IL‐6 and IL‐11 on specific binding by type II GC receptors (GRs) in two human osteoblast‐like cell lines (Saos‐2 and MG‐63) that have remarkably different constitutive expression of these cytokines and GRs as well. We have provided evidence that IL‐6 upregulates GR binding sites, while IL‐11 downregulates these sites, as determined by radioligand binding assay and Scatchard analysis. GR affinity (Kd) did not change after exposure to both cytokines. A number of experiments were consistent with the view that in human osteoblast‐like cells, cytokines of the IL‐6 family have autocrine modulatory effects on GRα (GRβ is a variant that does not bind specifically in our method). Complex effects of GCs on the system(s) of proinflammatory/anti‐inflammatory cytokines and conversely of these cytokines on GC action could account for the dynamics of bone loss in patients given GCs and conceivably having high concentrations of these cytokines in the bone microenvironment.

Evidence-Based Research in Complementary and Alternative Medicine II: The Process of Evidence-Based Research

It is a common practice in contemporary medicine to follow stringently the scientific method in the process of validating efficacy and effectiveness of new or improved modes of treatment intervention. It follows that these complementary or alternative interventions must be validated by stringent research before they can be reliably integrated into Western medicine. The next decades will witness an increasing number of evidence-based research directed at establishing the best available evidence in complementary and alternative medicine (CAM). This second paper in this lecture series examines the process of evidence-based research (EBR) in the context of CAM. We outline the fundamental principles, process and relevance of EBR, and its implication to CAM. We underscore areas of future development in EBR. We note that the main problem of applying EBR to CAM at present has to do with the fact that the contribution of EBR can be significant only to the extent to which studies used in the process of EBR are of good quality. All too often CAM research is not of sufficient quality to warrant the generation of a consensus statement. EBR, nevertheless, can contribute to CAM by identifying current weaknesses of CAM research. We present a revised instrument to assess quality of the literature.

Post-Traumatic Stress Disorder: Evidence-Based Research for the Third Millennium

The stress that results from traumatic events precipitates a spectrum of psycho-emotional and physiopathological outcomes. Post-traumatic stress disorder (PTSD) is a psychiatric disorder that results from the experience or witnessing of traumatic or life-threatening events. PTSD has profound psychobiological correlates, which can impair the persons daily life and be life threatening. In light of current events (e.g. extended combat, terrorism, exposure to certain environmental toxins), a sharp rise in patients with PTSD diagnosis is expected in the next decade. PTSD is a serious public health concern, which compels the search for novel paradigms and theoretical models to deepen the understanding of the condition and to develop new and improved modes of treatment intervention. We review the current knowledge of PTSD and introduce the role of allostasis as a new perspective in fundamental PTSD research. We discuss the domain of evidence-based research in medicine, particularly in the context of complementary medical intervention for patients with PTSD. We present arguments in support of the notion that the future of clinical and translational research in PTSD lies in the systematic evaluation of the research evidence in treatment intervention in order to insure the most effective and efficacious treatment for the benefit of the patient.

Evidence-Based Research in Complementary and Alternative Medicine III: Treatment of Patients with Alzheimer's Disease

This paper presents the novel domain of evidence-based research (EBR) in the treatment of patients with Alzheimers disease (AD) from the perspective of traditional medicine and of complementary and alternative medicine. In earlier lectures we have described the process of evidence-based medicine as a methodological approach to clinical practice that is directed to aid clinical decision-making. Here, we present a practical example of this approach with respect to traditional pharmacological interventions and to complementary and alternative treatments for patients with AD.

Salivary biomarkers in psychobiological medicine

The value of salivary biomarkers for diagnostic and prognostic assessments has become increasingly well established in medicine, pharmacology, and dentistry. Certain salivary components mirror the neuro-endocrine status of the organism. Other saliva products are protein in nature, and can serve to reflect immune surveillance processes. The autonomic nervous system regulates the process of salivation, and the concentration of yet other salivary components, such as α-amylase, which provide a reliable outcome measure of the sympathetic response. Here, we discuss molecular technologies that have permitted giant steps in the utilization of salivary samples and micro-fluidics for the benefit of diagnostic medicine and dentistry, and their putative role in springing forward research in psychobiology.

Emergent Oscillations in Mathematical Model of the Human Menstrual Cycle

BACKGROUND The aim of this study was to develop a mathematical model of the hypothalamo-pituitary-gonadal axis that would reflect available data in humans. METHODS A model of hormonal relationships at the early follicular and midluteal phases of the human menstrual cycle is proposed. FINDINGS Two distinct temporal patterns of oscillatory behavior have been demonstrated for both pituitary and gonadal steroids in the early follicular phase: first, rapid oscillations in gonadotropin releasing hormone, follicle stimulating hormone and luteinizing hormone (Q approximate to 1 hour) that were an immediate consequence of the programmed equations. Second, there were slower, undulating, emergent rhythms in luteinizing hormone and follicle stimulating hormone, and also in estrogen, having oscillatory periods of 2-12 hours. There was also a longer-period (Q2-3 days) emergent rhythm in progesterone. In the mid-luteal phase, estrogen and progesterone rhythms were correlated, and all hormones showed an approximately 6-hour periodicity. CONCLUSIONS To our knowledge, the oscillatory behavior of peripheral sex steroids in the follicular phase has not been previously noted.