Prolactin secretory rhythm in women: immediate and long-term alterations after sexual contact

BACKGROUND Prolactin (PRL) is one of the most versatile hormones in the mammalian body, affecting reproductive, sexual and other functions. In rats, mating or vaginocervical stimulation activates a characteristic PRL secretory pattern for several days, which is essential for successful reproduction. Although the underlying mechanisms appear to be different, PRL is also crucial for human fertility. We have detected a PRL increase in women induced by sexual intercourse. Extending these findings, the current study aimed at analyzing the PRL secretory rhythm after sexual contact, in order to elucidate whether human females also show long-term alterations of the PRL secretory pattern. METHODS In a pilot study, serial blood samples were taken from women (n= 7) in mid-cycle to assess changes in PRL secretory rhythm induced by sexual intercourse, during a period of 32 h. RESULTS Compared with control condition, sexual intercourse with orgasm induced not only the well-established immediate PRL increase of ∼300% but also an additional PRL elevation around noon of the next day (P< 0.05). These fluctuations were measured on top of the regular circadian rhythm of PRL, manifested as a surge early in the morning. CONCLUSIONS We are able to demonstrate a long-term change in the PRL secretory rhythm after sexual intercourse with orgasm in females, suggesting memory effects. We hypothesize that the additionally secreted PRL could be beneficial for decidualization and implantation. Further studies with more participants are required to investigate in detail the implications of such effects on reproductive success in human

Working with patients’ treatment expectations – what we can learn from homeopathy

The usual homeopathic remedy, “globules,” does not contain any pharmacologically active ingredient. However, many patients and practitioners report beneficial effects of homeopathic treatment on various health outcomes. Experimental and clinical research of the last two decades analyzing the underlying mechanisms of the placebo effect could explain this phenomenon, with patients’ treatment expectations as the predominant mechanism. Treatment expectations can be optimized through various factors, such as prior information, communication, and treatment context. This narrative review analyses how homeopathy successfully utilizes these factors. Subsequently, it is discussed what evidence-based medicine could learn from homeopathic practice to optimize treatment expectations (e.g., using an empathic, patient-centered communication style, deliberately selecting objects in practice rooms, or using clear treatment rituals and salient contextual stimuli) and thereby treatment effectiveness. Homeopathic remedy does not work beyond the placebo effect but is recommended or prescribed as an active treatment by those who believe in it. Thus, practitioners need to understand the manner in which homeopathy (as an example of inert treatment) works and are advised to reintegrate its underlying effective placebo mechanisms into evidence-based medicine. This promises to increase treatment efficacy, tolerability, satisfaction, and compliance with evidence-based treatments, and addresses the desires patients are trying to satisfy in homeopathy in an ethical, fully informed way that is grounded in evidence-based medicine

Treatment with the calcineurin inhibitor and immunosuppressant cyclosporine A impairs sensorimotor gating in Dark Agouti rats

Rationale Calcineurin is a protein regulating cytokine expression in T lymphocytes and calcineurin inhibitors such as cyclosporine A (CsA) are widely used for immunosuppressive therapy. It also plays a functional role in distinct neuronal processes in the central nervous system. Disturbed information processing as seen in neuropsychiatric disorders is reflected by deficient sensorimotor gating, assessed as prepulse inhibition (PPI) of the acoustic startle response (ASR). Objective Patients who require treatment with immunosuppressive drugs frequently display neuropsychiatric alterations during treatment with calcineurin inhibitors. Importantly, knockout of calcineurin in the forebrain of mice is associated with cognitive impairments and symptoms of schizophrenia-like psychosis as seen after treatment with stimulants. Methods The present study investigated in rats effects of systemic acute and subchronic administration of CsA on sensorimotor gating. Following a single injection with effective doses of CsA, adult healthy male Dark Agouti rats were tested for PPI. For subchronic treatment, rats were injected daily with the same doses of CsA for 1 week before PPI was assessed. Since calcineurin works as a modulator of the dopamine pathway, activity of the enzyme tyrosine hydroxylase was measured in the prefrontal cortex and striatum after accomplishment of the study. Results Acute and subchronic treatment with the calcineurin inhibitor CsA disrupted PPI at a dose of 20 mg/kg. Concomitantly, following acute CsA treatment, tyrosine hydroxylase activity was reduced in the prefrontal cortex, which suggests that dopamine synthesis was downregulated, potentially reflecting a stimulatory impact of CsA on this neurotransmitter system. Conclusions The results support experimental and clinical evidence linking impaired calcineurin signaling in the central nervous system to the pathophysiology of neuropsychiatric symptoms. Moreover, these findings suggest that therapy with calcineurin inhibitors may be a risk factor for developing neurobehavioral alterations as observed after the abuse of psychomotor stimulant drugs

Taste-immune associative learning amplifies immunopharmacological effects and attenuates disease progression in a rat glioblastoma model

Mechanistic target of rapamycin (mTOR)-signaling is one key driver of glioblastoma (GBM), facilitating tumor growth by promoting the shift to an anti-inflammatory, pro-cancerogenic microenvironment. Even though mTOR inhibitors such as rapamycin (RAPA) have been shown to interfere with GBM disease progression, frequently chaperoned toxic drug side effects urge the need for developing alternative or supportive treatment strategies. Importantly, previous work document that taste-immune associative learning with RAPA may be utilized to induce learned pharmacological placebo responses in the immune system. Against this background, the current study aimed at investigating the potential efficacy of a taste-immune associative learning protocol with RAPA in a syngeneic GBM rat model. Following repeated pairings of a novel gustatory stimulus with injections of RAPA, learned immune-pharmacological effects could be retrieved in GBM-bearing animals when re-exposed to the gustatory stimulus together with administering 10 % amount of the initial drug dose (0.5 mg/kg). These inhibitory effects on tumor growth were accompanied by an up-regulation of central and peripheral pro-inflammatory markers, suggesting that taste-immune associative learning with RAPA promoted the development of a pro-inflammatory anti-tumor microenvironment that attenuated GBM tumor growth to an almost identical outcome as obtained after 100 % (5 mg/kg) RAPA treatment. Together, our results confirm the applicability of taste-immune associative learning with RAPA in animal disease models where mTOR overactivation is one key driver. This proof-of-concept study may also be taken as a role model for implementing learning protocols as alternative or supportive treatment strategy in clinical settings, allowing the reduction of required drug doses and side effects without losing treatment efficacy

Does Human Experimental Endotoxemia Impact Negative Cognitions Related to the Self?

A role of inflammatory processes in the pathophysiology of depression is increasingly recognized. Experimental endotoxemia offers an established model to induce transient systemic inflammation in healthy humans, and has been proposed as an experimental paradigm of depression. Indeed, different symptoms of depression can be observed during experimental endotoxemia, including negative mood or dysthymia as key symptoms of depression. Hopelessness and low self-esteem constitute common cognitive symptoms in depression, but have not been specifically assessed during endotoxemia. Thus, we pooled data from healthy volunteers who received low-dose endotoxin (i.e., 0.4 or 0.8 ng/kg lipopolysaccharide, LPS) or placebo in three randomized, controlled studies to investigate the effects of LPS on cognitive schemata related to depression. Validated questionnaires were used to assess self-esteem, hopelessness and the vulnerability factor intolerance of uncertainty after intravenous injection of LPS or placebo. Plasma tumor necrosis factor (TNF)-α and interleukin (IL)-6 were repeatedly assessed, along with self-reported mood. Because not all questionnaires were available from primary studies, data were analyzed in two separate data sets: In data set 1, self-esteem and intolerance of uncertainty were assessed in N = 87 healthy volunteers, who randomly received either 0.4 or 0.8 ng/kg LPS or placebo. In data set 2, hopelessness was measured in N = 59 volunteers who randomly received either LPS (0.8 ng/kg) or placebo. In both data sets, LPS-application led to significant increases in TNF-α and IL-6, reflecting systemic inflammation. Positive mood was significantly decreased in response to LPS, in line with inflammation-induced mood impairment. General self-esteem, intolerance of uncertainty and hopelessness did not differ between LPS- and placebo groups, suggesting that these negative cognitive schemata are not responsive to acute LPS-induced systemic inflammation. Interestingly, LPS-treated volunteers reported significantly lower body-related self-esteem, which was associated with increased TNF-α concentration. Thus, certain aspects of self-esteem related to physical attractiveness and sportiness were reduced. It is conceivable that this effect is primarily related to physical sickness symptoms and reduced physical ability during experimental endotoxemia. With respect to cognitive symptoms of depression, it is conceivable that LPS affects cognitive processes, but not negative cognitive schemata, which are rather based on learning and repeated experiences

Chemosensory Cues to Conspecific Emotional Stress Activate Amygdala in Humans

Alarm substances are airborne chemical signals, released by an individual into the environment, which communicate emotional stress between conspecifics. Here we tested whether humans, like other mammals, are able to detect emotional stress in others by chemosensory cues. Sweat samples collected from individuals undergoing an acute emotional stressor, with exercise as a control, were pooled and presented to a separate group of participants (blind to condition) during four experiments. In an fMRI experiment and its replication, we showed that scanned participants showed amygdala activation in response to samples obtained from donors undergoing an emotional, but not physical, stressor. An odor-discrimination experiment suggested the effect was primarily due to emotional, and not odor, differences between the two stimuli. A fourth experiment investigated behavioral effects, demonstrating that stress samples sharpened emotion-perception of ambiguous facial stimuli. Together, our findings suggest human chemosensory signaling of emotional stress, with neurobiological and behavioral effects

Altered temporal variance and functional connectivity of BOLD signal is associated with state anxiety during acute systemic inflammation

Systemic inflammation is accompanied by complex behavioral changes and disturbed emotion regulation that have been related to the pathophysiology of mood disorders including depression and anxiety. However, the causal role of systemic inflammation on mood disorders is still unclear. We herein investigated neural resting state patterns of temporal variance of the amygdala and functional connectivity within the salience network underlying changes in state anxiety during experimentally-induced systemic inflammation. In this randomized, double-blind study, N = 43 healthy men received an intravenous injection of either low-dose lipopolysaccharide (LPS, 0.4 ng/kg body weight) or saline. Resting state functional magnetic resonance imaging was assessed before and 3.5 h after injection. State anxiety, assessed with a standardized questionnaire, and plasma cytokine concentrations were repeatedly measured. LPS administration induced a transient systemic inflammatory response reflected in increases in plasma Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α concentration. Compared to placebo, state anxiety and temporal variance in the amygdala significantly increased while functional connectivity in the salience network decreased during LPS-induced systemic inflammation. Together, these data indicate that acute systemic inflammation alters temporal variance of the BOLD signal as well as functional connectivity in brain regions and networks implicated in emotion processing and regulation. These results are of translational importance to encourage further research on the role of inflammatory pathways in the pathophysiology of neuropsychiatric conditions including anxiety disorders

Технология сборки и дуговой сварки пластин из титанового сплава

Цель работы – является разработка технологии дуговой сварки пластин из сплава ВТ5-1. В процессе исследования проводился анализ повышения эффективности и сравнение способов сварки, ручной аргонодуговой сварки неплавящимся электродом и механизированной сварки плавящимся электродом в среде защитного газа. В результате работы были рассчитаны параметры и выбран наиболее производительный способ для сварки сплава ВТ5-1.The purpose of the work is to develop a technology for arc welding of plates made of VT5-1 alloy. In the course of the study, the analysis of efficiency improvement and comparison of welding methods, manual argon arc welding with a non-melting electrode and mechanized welding with a melting electrode in a protective gas environment were carried out. As a result of the work, the parameters were calculated and the most productive method for welding the VT5-1 alloy was selected