PORTAL: Pilot study on the safety and tolerance of preoperative melatonin application in patients undergoing major liver resection: a double-blind randomized placebo-controlled trial

<p>Abstract</p> <p>Background</p> <p>Major surgical procedures facilitate systemic endotoxinemia and formation of free radicals with subsequent inflammatory changes that can influence the postoperative course. Experimental data suggest that preoperative supraphysiological doses of melatonin, a potent immuno-modulator and antioxidant, would decrease postoperative infectious and non-infectious complications induced by major abdominal surgery.</p> <p>Methods/Design</p> <p>A randomized controlled double blind single center clinical trial with two study arms comprising a total of 40 patients has been designed to assess the effects of a single preoperative dose of melatonin before major liver resection. Primary endpoints include the determination of safety and tolerance of the regimen as well as clinical parameters reflecting pathophysiological functions of the liver. Furthermore, data on clinical outcome (infectious and non-infectious complications) will be collected as secondary endpoints to allow a power calculation for a randomized clinical trial aiming at clinical efficacy.</p> <p>Discussion</p> <p>Based on experimental data, this ongoing clinical trial represents an advanced element of the research chain from bench to bedside in order to reach the highest level of evidence-based clinical facts to determine if melatonin can improve the general outcome after liver resection.</p> <p>Trial Registration</p> <p>EudraCT200600530815</p

Melatonin protects rats from radiotherapy-induced small intestine toxicity

Radiotherapy-induced gut toxicity is among the most prevalent dose-limiting toxicities following radiotherapy. Prevention of radiation enteropathy requires protection of the small intestine. However, despite the prevalence and burden of this pathology, there are currently no effective treatments for radiotherapy-induced gut toxicity, and this pathology remains unclear. The present study aimed to investigate the changes induced in the rat small intestine after external irradiation of the tongue, and to explore the potential radio-protective effects of melatonin gel. Male Wistar rats were subjected to irradiation of their tongues with an X-Ray YXLON Y.Tu 320-D03 irradiator, receiving a dose of 7.5 Gy/day for 5 days. For 21 days post-irradiation, rats were treated with 45 mg/day melatonin gel or vehicle, by local application into their mouths. Our results showed that mitochondrial oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in the development of radiotherapy-induced gut toxicity. Oral treatment with melatonin gel had a protective effect in the small intestine, which was associated with mitochondrial protection and, consequently, with a reduced inflammatory response, blunting the NF-κB/NLRP3 inflammasome signaling activation. Thus, rats treated with melatonin gel showed reduced intestinal apoptosis, relieving mucosal dysfunction and facilitating intestinal mucosa recovery. Our findings suggest that oral treatment with melatonin gel may be a potential preventive therapy for radiotherapy-induced gut toxicity in cancer patients.This study was partially supported by grant no. SAF2009-14037 from the Spanish Ministry of Economy and Competitivity (MINECO), GREIB.PT_2010_04 from the CEIBiotic Program of the University of Granada, Spain, and CTS-101 from the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Spain

Is there a role for melatonin in fibromyalgia?

Fibromyalgia, characterised by persistent pain, fatigue, sleep disturbance and cognitive dysfunction, is a central sensitivity syndrome that also involves abnormality in peripheral generators and in the hypothalamic pituitary adrenal axis. Heterogeneity of clinical expression of fibromyalgia with a multifactorial aetiology has made the development of effective therapeutic strategies challenging. Physiological properties of the neurohormone melatonin appear related to the symptom profile exhibited by patients with fibromyalgia and thus disturbance of it’s production would be compatible with the pathophysiology. Altered levels of melatonin have been observed in patients with fibromyalgia which are associated with lower secretion during dark hours and higher secretion during daytime. However, inconsistencies of available clinical evidence limit conclusion of a relationship between levels of melatonin and symptom profiles in patients with fibromyalgia. Administration of melatonin to patients with fibromyalgia has demonstrated suppression of many symptoms and an improved quality of life consistent with benefit as a therapy for the management of this condition. Further studies with larger samples, however, are required to explore the potential role of melatonin in the pathophysiology of fibromyalgia and determine the optimal dosing regimen of melatonin for the management of fibromyalgia

The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications

The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Primjena i kompozicija individualiziranih zaštitnih elemenata linijske grafike u projektiranju novčanica

Proces stvaranja novčanica je dugotrajan i složen, što rezultira kompleksnim rješenjima koja predstavljaju pravo remek djelo grafike. Novčanice su prožete brojnim detaljima i prenose različite informacije koje se analiziraju u teorijskom dijelu rada. Prvotno se postavljaju kriteriji po kojima se izrađuje detaljna analiza velikog broja zaštitnih i konceptualnih elemenata na primjerima novčanica. Time je prikazan okvirni povijesni pregled razvoja novčanica i utjecaji kojima je bio izložen. Analizira se međuovisnost dizajna o sigurnosnim značajkama, te se ispituje razina informiranosti javnosti o zaštitama na novčanicama. Zaključuje se koje metode zaštite su najučinkovitije, te kako šira javnost najčešće provjerava autentičnost novčanica. U eksperimentalnom dijelu rada se na temelju donesenih zaključaka iz teorijskog dijela izrađuje prototip novčanice koja je u najvećoj mjeri prožeta individualiziranim PostScript programskim rješenjima elemenata linijske grafike (rozete, mikrotekst, zaštitne linije, brojevi apoena), a od ostalih zaštita modeliran je individualizirani raster transformacijom matematičkog izraza u PostScript programski kod. Sve ostale zaštite tipične za novčanice simulirane su alatima za rastersku i vektorsku grafiku. U radu se ispituje utjecaj kompozicije zaštitnih elemenata na prepoznavanje autentičnosti novčanica, te efikasnost samih individualiziranih programskih rješenja