Mesocorticolimbic and Cardiometabolic Diseases-Two Faces of the Same Coin?

The risk behaviors underlying the most prevalent chronic noncommunicable diseases (NCDs) encompass alcohol misuse, unhealthy diets, smoking and sedentary lifestyle behaviors. These are all linked to the altered function of the mesocorticolimbic (MCL) system. As the mesocorticolimbic circuit is central to the reward pathway and is involved in risk behaviors and mental disorders, we set out to test the hypothesis that these pathologies may be approached therapeutically as a group. To address these questions, the identification of novel targets by exploiting knowledge-based, network-based and disease similarity algorithms in two major Thomson Reuters databases (MetaBase™, a database of manually annotated protein interactions and biological pathways, and IntegritySM, a unique knowledge solution integrating biological, chemical and pharmacological data) was performed. Each approach scored proteins from a particular approach-specific standpoint, followed by integration of the scores by machine learning techniques yielding an integrated score for final target prioritization. Machine learning identified characteristic patterns of the already known targets (control targets) with high accuracy (area under curve of the receiver operator curve was ~93%). The analysis resulted in a prioritized list of 250 targets for MCL disorders, many of which are well established targets for the mesocorticolimbic circuit e.g., dopamine receptors, monoamino oxidases and serotonin receptors, whereas emerging targets included DPP4, PPARG, NOS1, ACE, ARB1, CREB1, POMC and diverse voltage-gated Ca2+ channels. Our findings support the hypothesis that disorders involving the mesocorticolimbic circuit may share key molecular pathology aspects and may be causally linked to NCDs, yielding novel targets for drug repurposing and personalized medicine.

Vestibular Stimulation May Drive Multisensory Processing: Principles for Targeted Sensorimotor Therapy (TSMT).

At birth, the vestibular system is fully mature, whilst higher order sensory processing is yet to develop in the full-term neonate. The current paper lays out a theoretical framework to account for the role vestibular stimulation may have driving multisensory and sensorimotor integration. Accordingly, vestibular stimulation, by activating the parieto-insular vestibular cortex, and/or the posterior parietal cortex may provide the cortical input for multisensory neurons in the superior colliculus that is needed for multisensory processing. Furthermore, we propose that motor development, by inducing change of reference frames, may shape the receptive field of multisensory neurons. This, by leading to lack of spatial contingency between formally contingent stimuli, may cause degradation of prior motor responses. Additionally, we offer a testable hypothesis explaining the beneficial effect of sensory integration therapies regarding attentional processes. Key concepts of a sensorimotor integration therapy (e.g., targeted sensorimotor therapy (TSMT)) are also put into a neurological context. TSMT utilizes specific tools and instruments. It is administered in 8-weeks long successive treatment regimens, each gradually increasing vestibular and postural stimulation, so sensory-motor integration is facilitated, and muscle strength is increased. Empirically TSMT is indicated for various diseases. Theoretical foundations of this sensorimotor therapy are discussed.

Selective Inhibition of the Serotonin Transporter in the Treatment of Depression: Sertraline, Fluoxetine and Citalopram.

Discovery and development of the selective serotonin reuptake inhibitors mark a milestone in neuropharmacology. Drugs from this class alter the functioning of the serotonin system by the potentiation of serotonin through the negative allosteric modulation of its neuronal uptake by the human serotonin transporter. Selective serotonin reuptake inhibitors show few side effects compared to those caused by traditional antidepressants and they vary in the binding interactions formed during binding. Generally, their binding involves three specific regions of the drug structures, each participating in vital interactions, such as salt bridge formation and additional hydrophobic interactions with conserved residues in the central binding site of the target protein. Side effects, however, such as the initial lack of response to treatment, or drowsiness, nausea, and sexual dysfunction occasionally may arise. Additional binding studies, furthermore, highlighted the importance of enantioselectivity in the binding of these compounds, raising concerns about the beneficial application of racemate mixtures of some of these compounds. Therefore, additional characterisation of binding and further structural improvement of this class of drugs is necessary. The recently synthesized sertraline salts, and functional derivatives of fluoxetine and citalopram show promising results in delivering antidepressant activity as well as in effectively overcoming anorexigenic side-effects in rodent models. Hence, despite certain non-desired effects associated with selective serotonin reuptake inhibitor applications, this class of drugs is considered as first-line medication in the management of major depression, and is carrying an excellent potential for the development and refinement of the currently available and novel antidepressant therapies.

Altered irisin/BDNF axis parallels excessive daytime sleepiness in obstructive sleep apnea patients.

STUDY OBJECTIVES: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a sleep-related breathing disorder, characterized by excessive daytime sleepiness (EDS), paralleled by intermittent collapse of the upper airway. EDS may be the symptom of OSAHS per se but may also be due to the alteration of central circadian regulation. Irisin is a putative myokine and has been shown to induce BDNF expression in several sites of the brain. BDNF is a key factor regulating photic entrainment and consequent circadian alignment and adaptation to the environment. Therefore, we hypothesized that EDS accompanying OSAHS is reflected by alteration of irisin/BDNF axis. METHODS: Case history, routine laboratory parameters, serum irisin and BDNF levels, polysomnographic measures and Epworth Sleepiness Scale questionnaire (ESS) were performed in a cohort of OSAHS patients (n = 69). Simple and then multiple linear regression was used to evaluate data. RESULTS: We found that EDS reflected by the ESS is associated with higher serum irisin and BDNF levels; ß: 1.53; CI: 0.35, 6.15; p = 0.012 and ß: 0.014; CI: 0.0.005, 0.023; p = 0.02, respectively. Furthermore, influence of irisin and BDNF was significant even if the model accounted for their interaction (p = 0.006 for the terms serum irisin, serum BDNF and their interaction). Furthermore, a concentration-dependent effect of both serum irisin and BDNF was evidenced with respect to their influence on the ESS. CONCLUSIONS: These results suggest that the irisin-BDNF axis influences subjective daytime sleepiness in OSAS patients reflected by the ESS. These results further imply the possible disruption of the circadian regulation in OSAHS. Future interventional studies are needed to confirm this observation.

Blind Spot for Sedentarism: Redefining the Diseasome of Physical Inactivity in View of Circadian System and the Irisin/BDNF Axis.

Introduction: The term "diseasome of physical inactivity" was coined by Pedersen to explain clustering of chronic diseases linked to physical inactivity. Accordingly, physical inactivity per se contributes to the accumulation of visceral fat, which, generates chronic low-grade systemic inflammation, contributes to emergence of chronic, non-communicable diseases. Diversity of these disorders posits the possible involvement of a supraphysiological system. Methods: Hypothesis driven literature search and deductive reasoning was used to review relevant literature and formulate a novel theory. Results: We have identified the circadian system, omnipresent in virtually every cell, as a possible vehicle for brain muscle crosstalk, explaining some aspects of the diseasome of physical inactivity This system is hierarchically organized, with the suprachiasmatic nucleus (SCN) being the master clock that entrains to the dark/light cycle and synchronizes subsidiary molecular clocks in the periphery. Insufficient photic entrainment also causes chronic disease evolution. The recently identified irisin, was shown to induce brain-derived neurotrophic factor (BDNF) production in several brain areas. BDNF assumes significant role in gating light's influence in the retinohypothalamic synapse, by having a permissive effect on glutamate signal transduction underlying photic entrainment. Conclusions: Here we provide theoretical evidence to support the hypothesis that irisin may facilitate photic entrainment of the SCN, via BDNF. By this irisin opens up possible pathways for peripheral non-photic entrainment signals to exert influence on the master clock that is otherwise resistant to these. Furthermore, we suggest that intertwining processes of circadian, redox, inflammatory, and myokine systems lay underneath the diseasome of physical inactivity.

[Total laparoscopic hysterectomy with the coagulation of the uterine arteries at their origin]. / Totális laparoszkópos hysterectomia az arteria uterinák eredésüknél történo ellátásával.

INTRODUCTION: Hysterectomy is one of the most frequently performed gynecological operations worldwide. Due to patient perceived advantages of technical development laparoscopic hysterectomy has become a widely used method. The attitude of patients, surgeons and service providers to laparoscopic procedures is not uniform, but total laparoscopic hysterectomy has prevailed due to its advantages from other types of laparoscopic hysterectomies. Coagulation of the uterine arteries at their origin during the standardized method of total laparoscopic hysterectomy provides further benefits for this procedure. AIM: Our aim was the presentation of our experience together with a review of the relevant literature. METHOD: Operations were performed with the coagulation of the uterine arteries at their origin right at the beginning of the procedure. Inclusion criteria were the use of the standardized method, video documentation of the surgery, and pre- and postoperative haemostatus results. RESULTS: Our results confirm that the procedure involves an acceptable operating time that is comparable to that of open abdominal and vaginal hysterectomies, minimal blood loss that is far less than that in open procedures, a much shorter duration of hospitalization and a low complication rate. CONCLUSION: In skilled hands with proper knowledge of the anatomy the standardized method of total laparoscopic hysterectomy with the coagulation of the uterine arteries at their origin is a safe and reproducible technique which suitably utilizes the advantages of minimally invasive surgery. Orv. Hetil., 2017, 158(8), 298-303.

UNANSWERED QUESTIONS IN THE TRANSCRANIAL MAGNETIC STIMULATION TREATMENT OF PATIENTS WITH DEPRESSION.

According to the WHO fact sheet depression is a common mental disorder affecting 350 million people of all ages worldwide. Transcranial Magnetic Stimulation (TMS) is a technique which allows the investigator to stimulate and study cortical functions in healthy subjects and patients suffering from various mental and neurological disorders. In the early 1990s, studies revealed that it is possible to evoke long term mood changes in healthy volunteers by rapid rate repetitive, TMS (rTMS) over the frontal cortex. Subsequent studies involving depressed patients found frontal cortical rTMS administered daily to be clinically effective. In the past two decades, numerous trials examined the therapeutic potential of rTMS application in the treatment of mood disorders with constantly evolving treatment protocols. The aim of this paper is to review the literature of the past two decades, focusing on trials addressing the efficacy and safety of rTMS in depressed patients. Our primary goal is to evaluate the results in order to direct future studies which may help investigators in the development of treatment protocols suitable in hospital settings. The time is not far when TMS devices will be used routinely by practitioners primarily for therapeutic purpose rather than clinical research. To our knowledge, a widely accepted "gold standard" that would offer the highest efficacy, with the best tolerability has not been established yet. In order to approach this goal, the most important factors to be addressed by further studies are: localization, frequency, intensity, concurrent medication, maintenance treatments, number of pulses, trains, unilateral, or bilateral mode of application.

Thrombin generation and low-molecular-weight heparin prophylaxis in pregnant women with thrombophilia.

Pregnancy is associated with increased risk of venous thromboembolism, especially in the presence of thrombophilia. However, there is no consensus on the optimal approach for thromboprophylaxis in this population. Recent evidence suggests that thrombin generation correlates with the overall procoagulant state of the plasma. Our aim was to evaluate thrombin generation in a prospective cohort of thrombophilic pregnant women, and investigate the effectiveness of low-molecular-weight heparin (LMWH) prophylaxis in pregnancy. Women with severe (n=8), mild (n=47) and no (n=15) thrombophilia were followed throughout their pregnancies. Thrombin generation was evaluated in each trimester as well as five days and eight weeks postpartum (as a reference category). In women undergoing LMWH prophylaxis, thrombin generation and anti-Factor-Xa activity were measured just before and 4 hours after administration (peak effect). Thrombin generation was determined using Technothrombin TGA assay system. For the analysis, median peak thrombin and endogenous thrombin potential were used. Peak thrombin and endogenous thrombin potential were increased during pregnancy compared to the non-pregnant state with the highest results in the severe thrombophilia group. In women receiving LMWH prophylaxis a decrease was observed in thrombin generation at peak effect but over the progression of pregnancy the extent of this decrease reduced in a stepwise fashion. Our results show that thrombin generation demonstrates the hypercoagulable state in thrombophilic pregnancies. In addition, we found the effect of LMWH prophylaxis to progressively decrease with advancing stages of pregnancy.

Enhancement of creative expression and entoptic phenomena as after-effects of repeated ayahuasca ceremonies.

Studying the effect of psychedelic substances on expression of creativity is a challenging problem. Our primary objective was to study the psychometric measures of creativity after a series of ayahuasca ceremonies at a time when the acute effects have subsided. The secondary objective was to investigate how entoptic phenomena emerge during expression of creativity. Forty individuals who were self-motivated participants of ayahuasca rituals in Brazil completed the visual components of the Torrance Tests of Creative Thinking before and the second day after the end of a two-week long ceremony series. Twenty-one comparison subjects who did not participate in recent psychedelic use also took the Torrance tests twice, two weeks apart. Repeated ingestion of ayahuasca in the ritual setting significantly increased the number of highly original solutions and phosphenic responses. However, participants in the ayahuasca ceremonies exhibited more phosphenic solutions already at the baseline, probably due to the fact that they had more psychedelic experiences within six months prior to the study than the comparison subjects did. This naturalistic study supports the notion that some measures of visual creativity may increase after ritual use of ayahuasca, when the acute psychoactive effects are receded. It also demonstrates an increased entoptic activity after repeated ayahuasca ingestion.

The effects of pregnancy and lactation on hormonal status and biochemical markers of bone turnover.

INTRODUCTION: Biochemical markers of bone turnover are reliable indices for measuring changes in bone formation and bone resorption. Due to limitations in the use of bone densitometry during pregnancy biochemical markers of bone turnover provide an excellent alternative to examine the state of the skeleton during this physiologic state. STUDY DESIGN: We performed a prospective study in 20 women, during their first full term pregnancy until 12 months postpartum, intending to breast feed for 12 (mean, 9.1; range, 7-12) months postpartum. Morning blood and urine samples were obtained for laboratory tests: within 3 months before conception (baseline); between 22 and 24 gestational weeks; after delivery, and 6 and 12 months postpartum. Serum 25-hydroxyvitamin D (25-OH-D), parathyroid hormone (PTH), bone specific alkaline phosphatase, osteocalcin (OC), procollagen I carboxypeptides, calcium, phosphate and creatinine in addition to urine deoxypyridinoline crosslinks and calcium were measured. RESULTS: There was no significant difference in the values of urinary calcium/creatinine and serum calcium, phosphate and 25-OH-D between the different visits during the study. In our patients there was a significant increase in PTH levels at 12 months postpartum as compared to baseline, although the mean values remained in the PTH reference range. All bone turnover markers increased during pregnancy and failed to reach baseline level even 12 months postpartum. CONCLUSION: The high maternal bone turnover may suggest that the calcium needed for infant growth during pregnancy and lactation may be drawn at least in part from the maternal skeleton.