Structural and Functional Insights into CRF Peptides and Their Receptors.

Corticotropin-releasing factor or hormone (CRF or CRH) and the urocortins regulate a plethora of physiological functions and are involved in many pathophysiological processes. CRF and urocortins belong to the family of CRF peptides (CRF family), which includes sauvagine, urotensin, and many synthetic peptide and non-peptide CRF analogs. Several of the CRF analogs have shown considerable therapeutic potential in the treatment of various diseases. The CRF peptide family act by interacting with two types of plasma membrane proteins, type 1 (CRF1R) and type 2 (CRF2R), which belong to subfamily B1 of the family B G-protein-coupled receptors (GPCRs). This work describes the structure of CRF peptides and their receptors and the activation mechanism of the latter, which is compared with that of other GPCRs. It also discusses recent structural information that rationalizes the selective binding of various ligands to the two CRF receptor types and the activation of receptors by different agonists.

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children.

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-ß in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-ω and/or IFN-α2.

Diurnal production of cortisol and prediction of treatment response in rheumatoid arthritis: a 6-month, real-life prospective cohort study.

OBJECTIVES: A reduced adrenal reserve-associated cortisol production relative to the enhanced needs of chronic inflammation (disproportion principle) has been observed in rheumatoid arthritis (RA). We examined the possible clinical value of diurnal cortisol measurements in active RA on treatment response prediction. METHODS: Diurnal cortisol production (measured at: 08-12:00/18:00-22:00) was assessed by electrochemiluminescence immunoassay in 28 consecutive patients with moderately/highly active RA, as well as 3 and 6 months after treatment initiation or/escalation. Twenty-eight COVID-19 patients and 28 age-matched healthy individuals (HC) served as controls. RESULTS: Saliva diurnal cortisol production in patients with RA was similar to that of HC, despite 12-fold higher serum C reactive protein (CRP) levels, and lower than COVID-19 patients (area under the curve: RA: 87.0±37.6 vs COVID-19: 146.7±14.3, p<0.001), having similarly high CRP. Moreover, a disturbed circadian cortisol rhythm at baseline was evident in 15 of 28 of patients with RA vs 4 of 28 and 20 of 28 of HC and COVID-19 patients, respectively. Treatment-induced minimal disease activity (MDA) at 6 months was achieved by 16 of 28 patients. Despite comparable demographics and clinical characteristics at baseline, non-MDA patients had lower baseline morning cortisol and higher adrenocorticotropic hormone (ACTH) levels compared with patients on MDA (cortisol: 10.9±4.0 vs 18.4±8.2 nmol/L, respectively, p=0.005 and ACTH: 4.8±3.3 vs 2.4±0.4 pmol/L, respectively, p=0.047). Baseline morning cortisol <13.9 nmol/L predicted non-MDA at 6 months (75% sensitivity, 92% specificity, p=0.006). Prospective measurements revealed that individualised diurnal cortisol production remained largely unchanged from baseline to 3 and 6 months. CONCLUSIONS: An impaired adrenal reserve is present in patients with RA. Further studies to confirm that assessment of diurnal cortisol production may be useful in guiding treatment decisions and/or predicting treatment response in RA are warranted. TRIAL REGISTRATION NUMBER: NCT05671627.

Functional MRI Techniques Suggesting that the Stress System Interacts with Three Large Scale Core Brain Networks to Help Coordinate the Adaptive Response: A Systematic Review.

OBJECTIVE: Synthesis of functional MRI (fMRI) and functional connectivity (FC) analysis data on human stress system (SS) function, as it relates to the dynamic function of the Salience (SN), Default Mode (DMN) and Central Executive (CEN) networks. METHODS: Systematic search of Medline, Scopus, Clinical Trials.gov, and Google Scholar databases of studies published prior to September 2022 resulted in 28 full-text articles included for qualitative synthesis. RESULTS: Acute stress changes the states of intra-/inter- neural network FCs and activities from those of resting, low arousal state in the SN, DMN and CEN, during which intra- and inter-network FCs and activities of all three networks are low. SS activation is positively linked to the activity of the SN and negatively to that of the DMN, while, in parallel, it is associated with an initial decrease and a subsequent increase of the intra- network FC and activity of the CEN. The FC between the DMN and the CEN increases, while those between the SN and the CEN decrease, allowing time for frontal lobe strategy input and "proper" CEN activity and task decision. SN activation is linked to sensory hypersensitivity, "impaired" memory, and a switch from serial to parallel processing, while trait mindfulness is associated with FC changes promoting CEN activity and producing a "task-ready state". CONCLUSION: SS activation is tightly connected to that of the SN, with stress hormones likely potentiating the intra-network FC of the latter, attenuating that of the DMN, and causing a biphasic suppression- to-activation response of the CEN, all adaptive changes favoring proper decisions and survival.

Inflammation in Posttraumatic Stress Disorder: Dysregulation or Recalibration?

Despite ample experimental data indicating a role of inflammatory mediators in the behavioral and neurobiological manifestations elicited by exposure to physical and psychologic stressors, causative associations between systemic low-grade inflammation and central nervous system inflammatory processes in posttraumatic stress disorder (PTSD) patients remain largely conceptual. As in other stress-related disorders, pro-inflammatory activity may play an equivocal role in PTSD pathophysiology, one that renders indiscriminate employment of anti-inflammatory agents of questionable relevance. In fact, as several pieces of preclinical and clinical research convergingly suggest, timely and targeted potentiation rather than inhibition of inflammatory responses may actually be beneficial in patients who are characterized by suppressed microglia function in the face of systemic low-grade inflammation. The deleterious impact of chronic stress-associated inflammation on the systemic level may, thus, need to be held in context with the - often not readily apparent - adaptive payoffs of low-grade inflammation at the tissue level.

Thyroid Diseases and Intestinal Microbiome.

The human microbiome plays an integral role in health. In particular, it is important for the development, differentiation, and maturation of the immune system, 70% of which resides in the intestinal mucosa. Microbiome studies conducted to date have revealed an association between disturbances in the microbiota (dysbiosis) and various pathological disorders, including changes in host immune status. Autoimmune thyroid diseases are one of the most common organ-specific autoimmune disorders, with a worldwide prevalence higher than 5%. The predominant autoimmune thyroid diseases are Hashimoto's thyroiditis and Grave's disease. Several factors, such as genetic and environmental ones, have been studied. In accordance with recent studies, it is assumed that the gut microbiome might play a significant role in triggering autoimmune diseases of the thyroid gland. However, the exact etiology has not yet been elucidated. The present review aims to describe the work carried out so far regarding the role of gut microflora in the pathogenesis of autoimmune thyroid diseases and its involvement in the appearance of benign nodules and papillary thyroid cancer. It appears that future work is needed to elucidate more precisely the mechanism for gut microbiota involvement in the development of autoimmune thyroid diseases.

Diet and metabolism are back: The oldest known Islamic medical manuscript bridges the gap from ancient to modern gout management.

Gout is a chronic disease frequently associated with lifestyle; its prevalence is increasing in Western societies, as well as in the Middle East. Apart from its partial genetic features, diet accounts for 12% of the causality of the disease, while purine-rich foods contribute decisively to its development and evaluation. The influential Persian physician of the medieval ages, Abu Bakr Muhammad Ibn Zakariya al-Razi (or by his Latin name Rhazes; 860-925 AD), wrote a short book (20 chapters) entitled 'Treatise on gout'. Rhazes adopted the Hippocratic humoralism, and suggested that the disease results from metabolic excess in the peripheral blood, presenting sex dimorphism and age-dependence. His therapeutic guidelines include a diet prescribed by a physician, the use of laxatives and emetics, counter-balancing excess or deficiency of bile or phlegm and analgesics, bloodletting, foot and steam baths, as well as salves and poultices as preventive measures. He appends differential dietary restrictions/suggestions for phlegmatic or choleric patients: Small rations and intake of good quality foods low in purine by 20% for phlegmatic and 28% for choleric patients, as well as the restriction of foods high in purine by 27% for phlegmatic and 22% for the choleric patients. Finally, the acidic to alkaloid food intake ratio suggested is 2/5 for choleric and 3/7 for phlegmatic patients. His suggested foods and drugs are vitamin C and B-rich complexes, thereby inhibiting the accumulation of tophi.

The human glucocorticoid receptor.

Glucocorticoids are members of steroid hormones that are biosynthesized in the intermediate cellular zone of the adrenal cortex (zona fasciculata) and released into the peripheral blood as final products of the hypothalamic-pituitary-adrenal (HPA) axis, as well as under the control of the circadian biologic system. These molecules regulate every physiologic function of the organism as they bind to an almost ubiquitous hormone-activated transcription factor, the glucocorticoid receptor (GR), which influences the rate of transcription of a huge number of target genes amounting to up to 20% of the mammalian genome. The evolving progress of cellular, molecular and computational-structural biology and the implication of epigenetics in every-day clinical practice have enabled us a deeper and ever-increasing understanding of how target tissues respond to natural and synthetic glucocorticoids. In this chapter, we summarize the current knowledge on the structure, expression, function and signaling of the human glucocorticoid receptor in normal and pathologic conditions.

Review of Disease-Specific microRNAs by Strategically Bridging Genetics and Epigenetics in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent human malignancies and a global health concern with a poor prognosis despite some therapeutic advances, highlighting the need for a better understanding of its molecular etiology. The genomic landscape of OSCC is well-established and recent research has focused on miRNAs, which regulate gene expression and may be useful non-invasive biomarkers or therapeutic targets. A plethora of findings regarding miRNA expression have been generated, posing challenges for the interpretation and identification of disease-specific molecules. Hence, we opted to identify the most important regulatory miRNAs by bridging genetics and epigenetics, focusing on the key genes implicated in OSCC development. Based on published reports, we have developed custom panels of fifteen major oncogenes and five major tumor suppressor genes. Following a miRNA/target gene interaction analysis and a comprehensive study of the literature, we selected the miRNA molecules which target the majority of these panels that have been reported to be downregulated or upregulated in OSCC, respectively. As a result, miR-34a-5p, miR-155-5p, miR-124-3p, miR-1-3p, and miR-16-5p appeared to be the most OSCC-specific. Their expression patterns, verified targets, and the signaling pathways affected by their dysregulation in OSCC are thoroughly discussed.

Pythagorean Self-Awareness Intervention Promoted Healthy Dietary Patterns, Controlled Body Mass Index, and Reduced Self-Reported Stress Levels of Primary School Children: Α One-Arm Pilot Study.

Stress is common in childhood and an important factor that affects behavior later in adulthood. The aim of this study was to assess the effects of the Pythagorean Self-Awareness Intervention (PSAI), a holistic "cognitive reconstruction" technique to assess primary school children's stress levels, adherence to the Mediterranean diet, and body mass index. Secondary outcome measures included relations with peers, sleep, and hair cortisol concentrations. This one-arm pilot study took place in a primary school, from February to June 2019. Participants were 32 pupils attending the second grade of primary school who received the 8-week PSAI to adopt healthy behaviors and lifestyle. Self-report measures were applied for the evaluation of various variables at the beginning and the end of the eight-week intervention. There were statistically significant reductions in stress levels (p = 0.00), nightmares' frequency (p = 0.00), body mass index (p = 0.03), and bully scale (p = 0.00), and improvement in Mediterranean diet quality (p = 0.00). Hair cortisol concentrations increased (p = 0.02). The social scale significantly increased. Bedtime remained the same after the intervention. This pilot trial showed that the PSAI promoted healthy dietary patterns, controlled children's body mass index, and reduced their self-reported stress levels. Further research on the implementation of this holistic program on children is suggested, in well-powered randomized controlled trials.

The Effect of Pythagorean Self-Awareness Intervention on Stress and Mental Health Characteristics of Civil Servants in Crete, Greece.

Evidence is limited regarding the effects of holistic programs on work-related stress, anxiety, and depressive symptomatology. This study aimed to evaluate the effects of the Pythagorean Self-Awareness Intervention (PSAI) on stress and mental health characteristics of civil servants in Crete, Greece. This was a single arm interventional study with PSAI outcome evaluation. Validated, self-reported scales were used to assess stress and mental health characteristics (PSS, DASS, UCLA, RSE, and STAXI). Hair samples were obtained to measure cortisol concentrations as a biological stress marker. Paired-samples t-test or Wilcoxon tests were used to evaluate pre- and post-intervention measures. Overall, 48 civil servants (56.3% women, mean age 51 years) participated in the study. Statistically significant reductions were observed in all self-reported stress scales (p < 0.05). Although hair cortisol decreased, this difference was not statistically significant (p = 0.109). Statistically significant improvements were also observed on depressive symptomatology (p < 0.001), self-esteem (p < 0.001), loneliness (p < 0.001), self-efficacy (p = 0.002), and anger (p = 0.017). The PSAI appeared beneficial with respect to all self-reported outcomes. Larger studies including control groups and further follow-up evaluations are needed to ascertain these findings.

Validation of the Greek Version of the State Shame and Guilt Scale (SSGS).

Both shame and guilt are self-conscious negative emotions claiming self-representations and self-awareness. Growing evidence indicates that these pessimistic emotions are associated to stress and stress-related disorders. The aim of this study was to translate and investigate the validity and reliability of the State Shame and Guilt Scale (SSGS) in a Greek adult population sample. A total of 181 adults (63% women) participated in the study. To validate the SSGS, correlations with the Depression Anxiety Stress Scales (DASS) and the Perceived Stress Scale (PSS) were also examined. Exploratory factor analysis was used to examine the factors of the Greek version of the SSGS. In addition, for greater validity, comparisons were made according to sex, marital status and level of education. The reliability assessment revealed that the index of internal consistency (Cronbach's alpha) was above the acceptable margin (0.7) for the three subscales (shame; 0.717, guilt; 0.770, pride; 0.874). The Greek version of the 15-item State Shame and Guilt Scale (SSGS) demonstrated good psychometric properties and could be proven useful for the assessment of shame, guilt, and pride.

Post-traumatic Stress Disorder as a Risk Factor for the Development of Risky Behavior Among Adolescent Offenders: A Systematic Review.

The purpose of this research study was to obtain greater insight into the associations of post-traumatic stress disorder (PTSD) and trauma-exposed experiences with the development of offending behavior in adolescents. Using the PubMed and Scopus databases, we performed a systematic review of recent cross-sectional studies between 2016 and 2022, investigating the associations of PTSD and trauma with the social and mental behavior of adolescents. Fifty-three articles were initially identified. Due to duplication, eight articles were excluded, leaving 45 remaining articles. In addition, 34 articles were excluded due to year of publication, review, abstract, or irrelevant title. Seven articles were included in this systematic review after excluding the remaining due to different study types or samples. Included studies primarily examined the associations of PTSD symptomatology and expression of externalizing symptoms with risky behavior and the commission of a crime. The strongest outcomes were increased levels of violent behavior, violent delinquency, and total risk in correlation with PTSD symptoms, emotional numbing, use of drugs, and in some cases maltreatment. The results of the systematic review suggest that PTSD symptoms and risky behavior, which can be also fueled by maltreatment activities in the family circle, are associated with criminal behavior. Future research is needed to confirm these findings.

Burnout in General Surgeons. A Systematic Review.

Occupational burnout is particularly widespread amongst surgical professionals. During the past 10 years, both the awareness and the ability to reliably measure and classify "burnout" in medical professionals have increased. The purpose of this systematic review was to summarize the current evidence on the burnout levels of general surgeons. Online searches were carried out using the scientific search engines PubMed, Embase, Cinahl, and Google scholar, from 2010 to 2020, before the COVID-19 pandemic. Articles that met the inclusion criteria were critically evaluated using the critical appraisal skills programme (CASP) tool. Five studies pertaining to 669 subjects were included in this review. As expected, "burnout syndrome" was mainly due to the exhaustive and demanding conditions of working life and was strongly observed in general surgeons. The incidence of the burnout syndrome increased with their years of service, compromised their quality of life, and had detrimental effects on their mental and physical health. Personal achievements and emotional satisfaction were protective for the occurrence of the syndrome. We conclude that valid recognition and prevention of the burnout syndrome are necessary. Further research is needed to manage this phenomenon within the healthcare settings and the surgical departments.

Mindfulness and Academic Performance of College and University Students: A Systematic Review.

Higher education's expectations place demands on students' attainment, leading them to experience stress and anxiety, which negatively affect their academic improvement and life satisfaction. The aim of this systematic review was to investigate (a) if mindfulness as an inner ability is related to academic attainment, through dependent variables, including compassion, engagement, stress or anxiety state, depression, self-efficacy, mindfulness's facets (non-reactivity, acting with awareness) and (b) if mindfulness-based interventions positively affect the academic performance of college and university students. The systematic review was conducted in accordance with the PRISMA statement. PubMed, Web of Science, and Cochrane Library Wiley were screened to identify studies published relevant to the topic. In total, 568 papers were retrieved in the initial search. Five papers met the eligibility criteria and were included in the systematic review: a randomized controlled trial, a non-randomized controlled trial, a quasi-experimental study, a quantitative exploratory pilot study, and a longitudinal randomized controlled study. Most interventional studies revealed a non-significant direct effect of practicing mindfulness technique on academic attainment. Further research, especially randomized controlled trials are necessary to clarify the effect of mindfulness on academic performance of college and university students.

How Does Meditation Affect the Default Mode Network: A Systematic Review.

This article provides a systematic review of studies evaluating the effect of meditation on the Default Mode Network (DMN). The review was conducted according to PRISMA guidelines. A literature search of PubMed, Scopus, and Embase was conducted up to June 2020. Search terms included default mode network or DMN and meditation.A total of 306 articles were identified, of which 16 controlled trials with a total of 853 experienced (in Mindfulness, Samatha, Raja Yoga, Transcendental Meditation, Vipassana, Insight meditation Theravada tradition) and non-experienced mediators were finally included in this systematic review. The results showed that meditative interventions affect the operation of DMN and there are differences in functional connectivity between networks. Further research should be undertaken to establish meditation as an effective intervention strategy for well-being.

Brain Activity of Professional Dancers During Audiovisual Stimuli Exposure: A Systematic Review.

Many studies have shown the effect of dance to the brain. It seems that long-term practice modulates brain plasticity and visuomotor skills, as it activates the Action Observation Network (AON). The aim of this systematic review was to evaluate potential differences in the brain activity (visuomotor skills) between professional dancers and non-dancer adults, measured by electroencephalography (EEG), during the observation of an individual who is dancing (video dance stimuli). This literature search was conducted from February to June 2022, according to the PRISMA guidelines, in the PubMed database using advanced search, mesh terms, and extensive manual search. The included articles were published in English. Specifically, case-control studies were selected, which used healthy adults, professional dancers, and non-dancers as participants, who were exposed to video dance clips and measured by EEG. The articles were excluded if they were based on different type of study, unhealthy population, control group with athletic background, different type of stimuli (rhythmic), or different type of task and procedure. The ratings of quality of evidence were conducted using the Joanna Briggs Institute's (JBI) critical appraisal tool. Five case-control studies were included with 193 participants in total, 87% females. The participating groups of professional dancers (n = 12-25) had mean age 25.14 years, with at least 9-19 years of professional training, whereas control groups had the same sample size, mean age of 24.14 years, and no experience in dancing. Most of the studies presented high methodological quality. All studies showed significant differences in dancers' brain activity, especially regarding the visuomotor skills. The results showed faster activation of AON demonstrated by higher P300 at the frontocentral regions and increased sensitivity of the occipital temporal cortex. Dancers could cope easier with familiar-unfamiliar and effortful-effortless movements. They also demonstrated faster alpha band peak frequency, stronger synchrony over the bands theta, beta, gamma during the audiovisual stimuli, and the ability to encode faster the visual information. The results demonstrate that dancers had better visuomotor skills suggesting dance-enhanced neuroplasticity, as professional dancers processed their actions easier. Dance, which includes visuomotor tasks, could help in prevention, therapy, and rehabilitation of neurodegenerative diseases or movement disorders.

A Systematic Review on the Adult Alpha Brainwave Activity After Essential Oil Inhalation.

Aroma extracts from plant species have been utilized since ancient times for a variety of discomforting circumstances. Aromatherapy is a recognized complementary therapeutic treatment performed in various ways such as massage or dermal application, with its main uses involving relaxation, pain relief, and stress management. Several studies have outlined that inhalation of fragrance may influence the brain function since their components can cross the blood-brain barrier and interact with central nervous system receptors. The aim of this review was to systematically present findings regarding alpha brain wave activity reported exclusively by electroencephalography. The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed and Scopus databases were screened for relevant papers, based on specific eligibility criteria. The final step of the process resulted in 13 studies published between 1998 and 2021, using different essential oils. Most of the studies revealed the increase of alpha brainwave activity post-essential oil inhalation. Given the proven positive outcomes of increased alpha wave activity on several domains such as cognitive performance and better mental state, further research on the impact of essential oil inhalation is warranted.

Glucocorticoid Signaling Pathway: From Bench to Bedside.

Glucocorticoids were named by Hans Hugo Bruno Selye, the modern father of stress concepts, for their important role in glucose metabolism [...].