Insulin resistance (IR) and obesity are common features of the polycystic ovary syndrome (PCOS). Insulin-sensitizing agents have been shown to improve both reproductive and metabolic aspects of PCOS, ...but it remains unclear whether it is also beneficial in lean patients without pre-treatment IR. The aim of this study was to determine the influence of metformin on the clinical and biochemical parameters of PCOS irrespective of the presence of basal obesity and IR.
The effect of 6 months of metformin treatment was prospectively assessed in 188 PCOS patients, divided into three groups according to body mass index (BMI; lean: BMI<25 kg/m2, overweight: BMI 25-29 kg/m2, and obese: BMI30 kg/m2). Outcome parameters, which were also assessed in 102 healthy controls, included body weight, homeostasis model assessment for IR (HOMA-IR), fasting glucose and insulin levels, area under the curve of insulin response (AUCI), hyperandrogenism, and menstrual irregularities.
In comparison with the respective BMI-appropriate control groups, only obese but not lean and overweight PCOS patients showed differences in fasting insulin and HOMA-IR. Metformin therapy significantly improved all outcome parameters except fasting glucose levels. Subgroup analyses revealed that in the group of lean PCOS patients without pre-treatment IR, metformin significantly improved HOMA-IR (1.7+/-1.0 vs 1.1+/-0.7 micromol/lxmmol/l2) and fasting insulin levels (7.7+/-4.2 vs 5.4+/-3.9 mU/l), in addition to testosterone levels (2.6+/-0.9 vs 1.8+/-0.7 nmol/l), anovulation rate (2.3 vs 59.5%), and acne (31.8 vs 11.6%; all P<0.017). In the overweight and obese PCOS groups, metformin also showed the expected beneficial effects.
Metformin improves parameters of IR, hyperandrogenemia, anovulation, and acne in PCOS irrespective of pre-treatment IR or obesity.
Data from clinical and cross-sectional studies suggest that inflammation contributes to psychomotor slowing and attentional deficits found in depressive disorder. However, experimental evidence is ...still lacking. The aim of this study was to clarify the effect of inflammation on psychomotor slowing using an experimental and acute model of inflammation, in which twenty-two healthy volunteers received an intravenous injection of lipopolysaccharide (LPS, dose: 0.8 ng/kg body weight) and of placebo, in a randomized order following a double-blind within-subject crossover design. A reaction time test and a go/no-go test were conducted 3 h after the LPS/placebo injection and interleukin (IL)-6 and tumor necrosis factor (TNF)-α concentrations were assessed. No effect of experimental inflammation on reaction times or errors for either test was found. However, inflammation was related to worse self-rated performance and lower effort put in the tasks. Exploratory analyses indicated that reaction time fluctuated more over time during acute inflammation. These data indicate that acute inflammation has only modest effects on psychomotor speed and attention in healthy subjects objectively, but alters the subjective evaluation of test performance. Increased variability in reaction time might be the first objective sign of altered psychomotor ability and would merit further investigation.
•The effect of experimental inflammation on psychomotor slowing was assessed.•Acute inflammation does not affect psychomotor speed in two reaction time tasks.•Inflammation altered the subjective evaluation of test performance.•In exploratory analyses, the variability of reaction time over time was affected.
Bacterial colonisation in wounds delays healing, mandating regular bacterial removal through cleaning and debridement. Real‐time monitoring of the efficacy of mechanical debridement has recently ...become possible through fluorescence imaging. Red fluorescence, endogenously produced during bacterial metabolism, indicates regions contaminated with live bacteria (>104 CFU/g). In this prospective study, conventional and fluorescence photos were taken of 25 venous leg ulcers before and after mechanical debridement, without use of antiseptics. Images were digitally segmented into wound bed and the periwound regions (up to 1.5 cm outside bed) and pixel intensity of red fluorescence evaluated to compute bacterial area. Pre‐debridement, bacterial fluorescence comprised 10.4% of wound beds and larger percentages of the periwound area (~25%). Average bacterial reduction observed in the wound bed after a single mechanical debridement was 99.4% (p<0.001), yet periwound bacterial reduction was only 64.3%. On average, across bed and periwound, a single mechanical debridement left behind 29% of bacterial fluorescence positive tissue regions. Our results show the substantial effect that safe, inexpensive, mechanical debridement can have on bacterial load of venous ulcers without antiseptic use. Fluorescence imaging can localise bacterial colonised areas and showed persistent periwound bacteria post‐debridement. Fluorescence‐targeted debridement can be used quickly and easily in daily practice.
Objective. Polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance (IR), key features of nonalcoholic steatohepatitis (NASH). Cytokeratin 18 fragments (M30) have been ...established as a serum marker for NASH. The insulin sensitizer metformin improves hepatic IR. This study evaluates the influence of MF on serologic NASH (sNASH) in patients with PCOS. Patients and Methods. In 89 patients, metabolic parameters, liver injury indicating fatty liver (LIFL), and M30 were assessed at baseline and after metformin treatment. Patients with initial IR were subdivided into dissolved (PCOS-exIR) and persistent IR (PCOS-PIR) after treatment and compared to an initially insulin sensitive PCOS group (PCOS-C). Results. Improvement of LIFL prevalence could be seen in PCOS-C and PCOS-exIR compared to PCOS-PIR (−19.4, resp., −12.0% versus 7.2%, Chi2 = 29.5, P < 0.001 ) without change in sNASH prevalence. In PCOS-PIR, ALT levels increased significantly accompanied by a nominal, nonsignificant M30 increase. Conclusions. Metformin improves LIFL in subgroups of patients with PCOS without influencing sNASH. This could either indicate a missing effect of metformin on NAFLD or slowed disease progression. Further studies are needed to elucidate NAFLD in the context of PCOS and potential therapeutic options.
The immune system and the central nervous system exchange information continuously. This communication is a prerequisite for adaptive responses to physiological and psychological stressors. While the ...implicate relationship between inflammation and pain is increasingly recognized in clinical cohorts, the underlying mechanisms and the possibilities for pharmacological and psychological approaches aimed at neuro-immune communication in pain are not fully understood yet. This calls for preclinical models which build a bridge from clinical research to laboratory research. Experimental models of systemic inflammation (experimental endotoxemia) in humans have been increasingly recognized as an approach to study the direct and causal effects of inflammation on pain perception. This narrative review provides an overview of what experimental endotoxemia studies on pain have been able to clarify so far. We report that experimental endotoxemia results in a reproducible increase in pain sensitivity, particularly for pressure and visceral pain (deep pain), which is reflected in responses of brain areas involved in pain processing. Increased levels of blood inflammatory cytokines are required for this effect, but cytokine levels do not always predict pain intensity. We address sex-dependent differences in immunological responses to endotoxin and discuss why these differences do not necessarily translate to differences in behavioral measures. We summarize psychological and cognitive factors that may moderate pain sensitization driven by immune activation. Together, studying the immune-driven changes in pain during endotoxemia offers a deeper mechanistic understanding of the role of inflammation in chronic pain. Experimental endotoxemia models can specifically help to tease out inflammatory mechanisms underlying individual differences, vulnerabilities, and comorbid psychological problems in pain syndromes. The model offers the opportunity to test the efficacy of interventions, increasing their translational applicability for personalized medical approaches.
Highlights • We compared psychological and physiological responses to endotoxin between sexes. • Profound sex differences in inflammatory and neuroendocrine responses were observed. • Women mounted a ...more pronounced pro-inflammatory response compared to men. • Men and women did not differ in the severity of sickness symptoms. • Compensatory mechanisms may prevent exaggerated sickness responses in women.
•Vulnerability factors of inflammation-induced hyperalgesia remain unclear.•LPS-induced systemic inflammation leads to musculoskeletal hyperalgesia.•Hyperalgesia was predicted by TNF-alpha and ...pre-existing anxiety symptoms.•Subclinical anxiety may increase risk for inflammation-induced hyperalgesia.
Despite broad clinical implications, the mechanisms linking inflammation and pain remain incompletely understood. Using human experimental endotoxemia as a translational model of systemic inflammation, we aimed to elucidate putative vulnerability factors of inflammation-induced musculoskeletal hyperalgesia.
We pooled data from three published randomized controlled trials, resulting in a sample of N = 98 healthy volunteers who received either low-dose endotoxin (lipopolysaccharide) or vehicle (saline) intravenously. As measure of musculoskeletal pain sensitivity, pressure pain thresholds (PPTs) were assessed at baseline and 3 h post injection with a handheld algometer for the low back (erector spinae muscle), calf (gastrocnemius muscle), and shoulder region (deltoid muscle). Implementing multiple regression models, we tested the contribution of putative vulnerability factors on musculoskeletal hyperalgesia during systemic inflammation, including acute changes in pro-inflammatory cytokines, state anxiety and mood, as well as pre-existing symptoms of anxiety and depression.
Endotoxin application led to significant increases in plasma cytokines, state anxiety, and negative mood, and significantly decreased PPTs for all muscle groups. Regression models revealed that greater M. erector spinae PPT changes were predicted by higher HADS-anxiety scores. Higher TNF-α concentration emerged as predictor for M. gastrocnemius PPT changes, and more pronounced TNF-α increase and higher HADS-anxiety were predictive for M. deltoideus PPTs. HADS scores emerged as predictor for a mean PPT score (computed across all body sites).
Together, our results indicate that musculoskeletal hyperalgesia during systemic inflammation is related to pro-inflammatory cytokines, specifically TNF-α. Importantly, subclinical anxiety symptoms (even though in a low and normal range in this cohort of healthy volunteers) may contribute to inflammation-induced hyperalgesia, making individuals more vulnerable to the detrimental effects of systemic inflammation.
Context: In patients with severe acute respiratory syndrome coronavirus type 2 infection, diabetes is associated with poor COVID-19 prognosis. However, case detection strategy is divergent and ...reported prevalence varies from 5% to 35%. Objective: We examined how far the choice of screening tools affects the detection rate of dysglycemia and in consequence the estimation of diagnosis-associated risk for moderate (mo) or severe (s) COVID-19. Methods: Non--intensive care unit inpatients with COVID-19 were screened systematically at admission for diabetes (D) and prediabetes (PreD) by glycated hemoglobin A.sub.1c (HbA.sub.1c) (A), random blood glucose (B), and known history (C) from November 1, 2020 to March 8, 2021. Dysglycemia rate and effect on COVID-19 outcome were analyzed in 2 screening strategies (ABC vs BC). Results: A total of 578 of 601 (96.2%) of admitted patients were screened and analyzed. In ABC, prevalence of D and PreD was 38.2% and 37.5%, respectively. D was significantly associated with an increased risk for more severe COVID-19 (adjusted odds ratio aOR moCOVID-19: 2.27, 95% CI, 1.16-4.46 and aOR sCOVID-19: 3.26, 95% CI, 1.56-6.38). Patients with PreD also presented more often with more severe COVID-19 than those with normoglycemia (aOR moCOVID-19: 1.76, 95% CI, 1.04-2.97 and aOR sCOVID-19: 2.41, 95% CI, 1.37-4.23). Screening with BC failed to identify only 96% of PreD (206/217) and 26.2% of D diagnosis (58/221) and missed associations of dysglycemia and COVID-19 severity. Conclusion: Pandemic conditions may hamper dysglycemia detection rate and in consequence the awareness of individual patient risk for COVID-19 severity. A systematic diabetes screening including HbA.sub.1c reduces underdiagnosis of previously unknown or new-onset dysglycemia, and enhances the quality of risk estimation and access of patients at risk to a diabetes-specific intervention. Key Words: COVID-19, SARS-CoV-2, prediabetes, diabetes, inflammation, screening
There is evidence to suggest a role of emotions in placebo and nocebo effects, but whether acute psychological stress changes the magnitude of placebo or nocebo responses has not been tested. In a ...clinically relevant model of visceroception, we assessed effects of acute psychological stress on changes in urgency and pain in response to positive or negative treatment suggestions. In 120 healthy volunteers, perceived urge-to-defecate and pain in response to individually calibrated rectal distensions were measured with visual analogue scales during a BASELINE. Participants then underwent the Trier Social Stress Test (N = 60) or a simple cognitive task (control, N = 60) and were randomized to positive (placebo), negative (nocebo), or neutral treatment information regarding intravenous administration of saline. The series of distensions was repeated, and changes in visual analogue scales from BASELINE to TEST were compared between groups using analysis of covariance and planned post hoc tests. Treatment information emerged as a main factor (P <0.001), supporting treatment information effects for both urgency and pain. Effects for urgency were modulated by stress (interaction effect: P <0.05): Positive information reduced urgency (P = 0.025), while negative information increased urgency (P = 0.026) only in stressed groups. For pain, effects of stress emerged for nocebo responses, which were only evident in stressed groups (P = 0.009). This is the first experimental study supporting effects of acute psychological stress on placebo and nocebo responses in visceroception. Results call for mechanistic as well as patient studies to assess how psychological stress shapes patients' treatment expectations and thereby affects health outcomes.
•Inflammation and depressed mood interact as vulnerability factors for pain.•States of inflammation and acute sadness impacted on pain unpleasantness.•Interaction effects observed for anticipatory ...activation of caudate and hippocampus.•This may reflect a nocebo mechanism relevant to hypervigilance and hyperalgesia.
Inflammation and depressed mood constitute clinically relevant vulnerability factors for enhanced interoceptive sensitivity and chronic visceral pain, but their putative interaction remains untested in human mechanistic studies. We tested interaction effects of acute systemic inflammation and sad mood on the expectation and experience of visceral pain by combining experimental endotoxemia with a mood induction paradigm.
The double-blind, placebo-controlled, balanced crossover fMRI-trial in N = 39 healthy male and female volunteers involved 2 study days with either intravenous administration of low-dose lipopolysaccharide (LPS, 0.4 ng/kg body weight; inflammation condition) or saline (placebo condition). On each study, day two scanning sessions were conducted in an experimentally induced negative (i.e., sad) and in a neutral mood state, accomplished in balanced order. As a model of visceral pain, rectal distensions were implemented, which were initially calibrated to be moderately painful. In all sessions, an identical series of visceral pain stimuli was accomplished, signaled by predictive visual conditioning cues to assess pain anticipation. We assessed neural activation during the expectation and experience of visceral pain, along with unpleasantness ratings in a condition combining an inflammatory state with sad mood and in control conditions. All statistical analyses were accomplished using sex as covariate.
LPS administration led to an acute systemic inflammatory response (inflammation X time interaction effects for TNF-α, IL-6, and sickness symptoms, all p <.001). The mood paradigm effectively induced distinct mood states (mood X time interaction, p <.001), with greater sadness in the negative mood conditions (both p <.001) but no difference between LPS and saline conditions. Significant main and interaction effects of inflammation and negative mood were observed for pain unpleasantness (all p <.05). During cued pain anticipation, a significant inflammation X mood interaction emerged for activation of the bilateral caudate nucleus and right hippocampus (all pFWE < 0.05). Main effects of both inflammation and mood were observed in multiple regions, including insula, midcingulate cortex, prefrontal gyri, and hippocampus for inflammation, and midcingulate, caudate, and thalamus for mood (all pFWE < 0.05).
Results support an interplay of inflammation and sad mood on striatal and hippocampal circuitry engaged during visceral pain anticipation as well as on pain experience. This may reflect a nocebo mechanism, which may contribute to altered perception and interpretation of bodily signals. At the interface of affective neuroscience and the gut-brain axis, concurrent inflammation and negative mood may be vulnerability factors for chronic visceral pain.
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