Descending thoracic aortic mural ulceration is associated with postoperative spinal cord ischemia after branched endovascular aortic aneurysm repair.

OBJECTIVE: Paraplegia is one of the most feared complications after thoracoabdominal aortic aneurysm repair. The purpose of this study is to determine whether aortic thrombus characteristics are associated with spinal cord ischemia (SCI) after branched endovascular aneurysm repair (BEVAR). METHODS: From April 2011 to April 2020, 62 patients underwent elective BEVAR for thoracoabdominal aortic aneurysm and pararenal aortic aneurysms using a low-profile device and had a complete preoperative computed tomography angiography of the aorta from the sinotubular junction to the aortic bifurcation. Aortic thrombus was evaluated for thrombus thickness ≥5 mm, thrombus >2/3 of aortic circumference, and the presence of an ulcer-like thrombus. One point was assigned at each 5 mm axial image if all 3 criteria were met, resulting in a total "shaggy score" for the entire aorta. Data on demographics, procedural details, and outcomes were collected prospectively. All patients underwent a standard spinal cord protection protocol, including routine cerebrospinal fluid drainage. In July 2016, an insulin infusion protocol (IIP) was initiated to maintain postoperative blood glucose levels <120 mg/dL for 48 hours. The primary clinical end point was postoperative SCI. RESULTS: 10 (16%) patients developed postoperative SCI: 6 with transient paraparesis, 2 with persistent paraparesis, and 2 with persistent paraplegia. Patients with SCI were older, had higher shaggy scores, and were less likely to have been on an IIP. There were no significant differences in demographics, aneurysm type, or operative parameters. In a logistic multivariate regression model for SCI, age (odds ratio [OR]: 1.2 [1.1-1.4], P = .02) and shaggy score (OR: 1.2 [1.1-1.4], P = .02) were independently associated with increased risk of SCI, whereas treatment with the IIP was associated with lower risk of SCI (OR: 0.04 [0.006-0.50], P = .05). Of the individual components of the shaggy score, higher descending thoracic aortic ulcer scores were the most strongly associated with postoperative SCI (P = .009). CONCLUSIONS: Preoperative characterization of aortic wall thrombus is an important adjunctive tool for individualized clinical decision-making and patient counseling about the risk of SCI after BEVAR.

Morning salivary dehydroepiandrosterone (DHEA) qualifies as the only neuroendocrine biomarker separating depressed patients with and without prior history of depression: An HPA axis challenge study.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depression (MDD) have been consistently reported in psychiatry and extend to several neurosteroids. However, recurrence and chronicity may heavily influence HPA axis dynamics in MDD along its course and also explain conflicting results in literature. Thus, the mechanistic understanding of HPA axis (re)activity changes over time could be of major importance for unravelling the dynamic pathophysiology of MDD. METHODS: This study simultaneously assessed several baseline and dynamic HPA-axis-related endocrine biomarkers in both saliva (dehydroepiandrosterone, DHEA; sulfated DHEA, DHEA-s; cortisol, CORT) and plasma (CORT; adrenocorticotropic hormone, ACTH; copeptin, CoP) over three consecutive days using overnight HPA axis stimulation (metyrapone) and suppression (dexamethasone) challenges in order to investigate differences between antidepressant-free MDD patients (n = 14) with and without history of prior depressive episodes (i.e., first vs. recurrent episode). RESULTS: Our results suggest group differences only with respect to saliva DHEA levels, with recurrent-episode MDD patients showing overall lower saliva DHEA levels across the three days, and statistically significant differences mainly at day 1 (baseline) across all three timepoints (awakening, +30 min, +60 min), even after adjustment for confounders. CONCLUSIONS: Our study supports that salivary DHEA levels could represent a significant biomarker of MDD progression and individual stress resilience. DHEA deserves additional attention in the research of pathophysiology, staging and individualized treatment of MDD. Prospective longitudinal studies are needed to evaluate HPA axis reactivity along MDD course and progression to better understand temporal effects on stress-system-related alterations, related phenotypes and appropriate treatment.

Inverse autonomic stress reactivity in depressed patients with and without prior history of depression.

BACKGROUND: There is a considerable association between major depressive disorder (MDD) and cardiovascular disease, most possibly relying on abnormalities in the autonomic nervous system (ANS)-related cardiac reactivity, although the exact underlying pathophysiological pathway is unclear. This study tends to shed some additional light on this background by investigating ANS reactivity in MDD with respect to previous depression history through an objective stress challenge paradigm. METHODS: The study assessed the effects of an overnight hypothalamus-pituitary-adrenal (HPA) axis stimulation with metyrapone (MET) on baseline ANS activity through linear and non-linear heart rate variability (HRV) measures in the morning of two continuous days in a group of 14 physically healthy, antidepressant-free patients with clinical, non-psychotic MDD, to investigate differences in autonomic reactivity with respect to prior MDD history. RESULTS: The main findings of this study include statistically significant time × group interactions with respect to several HRV measures, suggesting substantial differences on autonomic reactivity between patients with and without depression history. Hereby, recurrent-episode MDD patients showed lower vagal activity, while first-episode MDD patients increased PNS activity after HPA axis stimulation. CONCLUSIONS: These findings indicate that HPA axis stimulation in MDD patients leads to inverse vagal response according to MDD history. We suggest that chronic stress system overactivation, as found in MDD, might lead to a progressive inversion of the original stress response through HPA axis and ANS divergence over the course of a recurrent illness. HRV could, thus, represent a significant biomarker in MDD with temporal sensitivity.

Vasopressin Surrogate Marker Copeptin as a Potential Novel Endocrine Biomarker for Antidepressant Treatment Response in Major Depression: A Pilot Study.

BACKGROUND: Major depressive disorder (MDD) constitutes the leading cause of disability worldwide. Although efficacious antidepressant pharmacotherapies exist for MDD, only about 40-60% of the patients respond to initial treatment. However, there is still a lack of robustly established and applicable biomarkers for antidepressant response in everyday clinical practice. OBJECTIVE: This study targets the assessment of the vasopressin (AVP) surrogate marker Copeptin (CoP), as a potential peripheral hypothalamic-level biomarker of antidepressant treatment response in MDD. METHODS: We measured baseline and dynamic levels of plasma CoP along with plasma ACTH and cortisol (CORT) in drug-naive outpatients with MDD before and after overnight manipulation of the hypothalamic-pituitary-adrenal (HPA) axis [i.e., stimulation (metyrapone) and suppression (dexamethasone)] on three consecutive days and their association with treatment response to 4 weeks of escitalopram treatment. RESULTS: Our findings suggest significantly higher baseline and post-metyrapone plasma CoP levels in future non-responders, a statistically significant invert association between baseline CoP levels and probability of treatment response and a potential baseline plasma CoP cut-off level of above 2.9 pmol/L for future non-response screening. Baseline and dynamic plasma ACTH and CORT levels showed no association with treatment response. CONCLUSIONS: This pilot study provide first evidence in humans that CoP may represent a novel, clinically easily applicable, endocrine biomarker of antidepressant response, based on a single-measurement, cut-off level. These findings, underline the role of the vasopressinergic system in the pathophysiology of MDD and may represent a significant new tool in the clinical and biological phenotyping of MDD enhancing individual-tailored therapies.

Doping substances in dietary supplements. / Dopingmidler i kosttilskudd.

BACKGROUND: International studies have shown that 12-58 % of all dietary supplements intended for people who exercise and engage in sports contain substances prohibited by the World Anti-Doping Code (WADC). In some cases, the doping substances are not declared on the product label, and the consumer may therefore be unaware of what he/she ingests. Many of the substances may cause adverse health effects, and sale of such products is illegal in Norway. MATERIAL AND METHOD: To investigate the prevalence of doping substances in dietary supplements sold on the Norwegian market, a total of 93 high-risk products from online shops targeting Norwegian consumers were analysed for substances on the WADC Prohibited List and pharmaceutical drugs. All supplements were marketed as able to boost energy levels and/or having a muscle-building or fat-burning effect. The products were selected on the basis of tips received, online forums and/or international lists. RESULTS: Altogether 21 of 93 (23 %) products analysed contained prohibited substances, pharmaceutical drugs and/or illegal amounts of caffeine. Substances on the WADC Prohibited List were detected in 8 of the 93 (9 %) dietary supplements. All products containing doping substances were declared as containing one or more banned substances. INTERPRETATION: The results show that using apparently legal dietary supplements purchased in online shops targeting Norwegian consumers involves a risk of inadvertent doping and adverse health effects.

Vagal effects of endocrine HPA axis challenges on resting autonomic activity assessed by heart rate variability measures in healthy humans.

BACKGROUND: The hypothalamic-pituitary-adrenal axis (HPA axis) and the autonomic nervous system (ANS) are considered to play the most crucial role in the pathophysiology of stress responsiveness and are increasingly studied together. However, only few studies have simultaneously assessed HPA axis and ANS activity to investigate their direct interaction in pathophysiology, while no study so far has assessed the dynamic interplay between the two systems in healthy subjects through endocrine challenges. METHODS: The present study assessed the direct effects of overnight pharmacoendocrine HPA axis challenges with dexamethasone (suppression) and metyrapone (stimulation) on ANS activity at rest as determined by linear and nonlinear measures of heart rate variability (HRV) in 39 young healthy individuals. RESULTS: Findings indicated significant effects of metyrapone, but not dexamethasone on autonomic activity at rest based on HRV measures. HRV after metyrapone was overall significantly reduced in comparison to baseline or post-dexamethasone conditions, while the combined metyrapone-related reduction of HRV measures RMSSD, NN50(%) and HF(%) with concomitant increase of the unifractal scaling coefficient αfast value jointly indicated a specifically diminished vagal activity. CONCLUSIONS: We provide first data that HPA axis stimulation (metyrapone) is associated with reduced vagal tone, while HPA axis suppression (dexamethasone) has no effect on autonomic modulation of heart function. Our results support a vital role of the parasympathetic nervous system in the interplay between ANS and HPA axis and, thus, in the modulation of stress-related cardiovascular responsiveness and the susceptibility to stress-related disorders.

Synergistic stabilisation of NOsGC by cinaciguat and non-hydrolysable nucleotides: Evidence for sGC activator-induced communication between the heme-binding and catalytic domains.

Nitric oxide sensitive guanylyl cyclase (NOsGC) is a heterodimeric enzyme consisting of one α and one ß subunit. Each subunit consists of four domains: the N-terminal heme-nitric oxide oxygen binding (HNOX) domain, a PAS domain, a coiled-coil domain and the C-terminal catalytic domain. Upon activation by the endogenous ligand NO or activating drugs, NOsGC catalyses the conversion of GTP to cGMP. Although several crystal structures of the isolated domains are known, the structure of the full-length enzyme and the interdomain conformational changes during activation remain unsolved to date. In the current study, we performed protein thermal shift assays of purified NOsGC to identify discrete conformational states amenable to further analysis e.g. by crystallisation. A non-hydrolysable substrate analogue binding to the catalytic domain led to a subtle change in melting temperature. An activator drug binding to the HNOX domain led to a small increase. However, the combination of substrate analogue and activator drug led to a marked synergistic increase from 51 °C to 60 °C. This suggests reciprocal communication between HNOX domain and catalytic domain and formation of a stable activated conformation amenable to further biophysical characterization.

Methods to investigate structure and activation dynamics of GC-1/GC-2.

Soluble guanylyl cyclase (sGC) is a heterodimeric enzyme consisting of one α and one ß subunit. The α1ß1 (GC-1) and α2ß1 (GC-2) heterodimers are important for NO signaling in humans and catalyse the conversion from GTP to cGMP. Each sGC subunit consists of four domains. Several crystal structures of the isolated domains are available. However, crystals of full-length sGC have failed to materialise. In consequence, the detailed three dimensional structure of sGC remains unknown to date. Different techniques including stopped-flow spectroscopy, Förster-resonance energy transfer, direct fluorescence, analytical ultracentrifugation, chemical cross-linking, small-angle X-ray scattering, electron microscopy, hydrogen-deuterium exchange and protein thermal shift assays, were used to collect indirect information. Taken together, this circumstantial evidence from different groups brings forth a plausible model of sGC domain arrangement, spatial orientation and dynamic rearrangement upon activation. For analysis of the active conformation the stable binding mode of sGC activators has a significant methodological advantage over the transient, elusive, complex and highly concentration dependent effects of NO in many applications. The methods used and the results obtained are reviewed and discussed in this article.

BAY 60-2770 activates two isoforms of nitric oxide sensitive guanylyl cyclase: Evidence for stable insertion of activator drugs.

Nitric oxide sensitive guanylyl cyclase (NOsGC), a hemoprotein and the major physiological receptor for nitric oxide (NO), is a heterodimer with the α1/ß1 and α2/ß1 isoforms known to be important for NO-signaling and conversion of GTP to cGMP in humans. Two innovative classes of compounds modulating the NO/cGMP signaling pathway have been discovered: the heme-dependent sGC stimulators, that stimulate NOsGC directly and also increase the affinity towards NO, and the heme-independent sGC activators, that are thought to bind to oxidized and heme-free NOsGC in tissues exposed to oxidative stress. In the current study, we evaluate the effects of the sGC activators BAY 58-2667 (cinaciguat) and BAY 60-2770 on the isoforms α1/ß1 and α2/ß1 expressed in Sf9 cells. Western blot analysis of cytosolic fractions revealed a decrease in overexpressed NOsGC in the presence of sGC activators, which is dependent on an intact catalytic site of the enzyme. For both isoforms, we show a higher efficacy for BAY 60-2770 compared to cinaciguat after purification of NOsGC by affinity and size exclusion chromatography. Using a new experimental strategy of expression of NOsGC with activator and subsequent purification, we demonstrate a stable insertion of activator drugs into the enzyme during protein biosynthesis independent of the heme redox state. We postulate that the balance between stable insertion of activator during de novo synthesis and replacement of NOsGC ferric heme in tissues exposed to oxidative stress can be influenced by the dosage regimen.

Perioperative patient education improves long-term satisfaction rates of low-risk prostate cancer patients after radical prostatectomy.

PURPOSE: To evaluate patient-reported functional outcomes after radical prostatectomy (RP) and to analyse the effect of perioperative patient education on satisfaction rates among low-risk prostate cancer patients. METHODS: Inclusion criteria encompassed low-risk prostate cancer patients as defined by the D'Amico criteria, undergoing nerve-sparing RP without pelvic lymph node dissection. Patient-centred functional outcomes, subjective evaluation of perioperative counselling, and patient satisfaction rates were documented. Stress urinary incontinence (SUI) was assessed by daily pad usage. Erectile dysfunction (ED) was assessed using IIEF5 score. Patients' histories were attained from the electronic medical records. The effect of pre-defined predictive features for satisfaction rates was analysed in low-risk patients. Statistical analyses included Fisher's exact test, Mann-Whitney-U test, and binary logistic regression models (p < 0.05). RESULTS: 266 patients met the inclusion criteria. Median follow-up was 94 months (68-118). The global satisfaction rate was 75.1%. Regarding SUI, 69.5% of patients required no pads. 67.1% felt very well informed, while 11.7% felt poorly educated about postoperative SUI. Regarding ED, an IIEF score of ≥18 was reached by 33.7%. 59.6% felt very well educated, while 13.0% felt poorly informed. Poor patient counselling regarding SUI and ED led to significantly decreased long-term satisfaction rates [40.7, 33.3% (p < 0.001)]. In multivariate analysis, poor ED patient counselling [OR 0.190, 95% CI 0.055-0.652 (p = 0.008)], and postoperative IIEF5 score [OR 3.061, 95% CI 1.013-3.111 (p = 0.013)] could be confirmed as independent predictors for patient satisfaction. CONCLUSIONS: Patient-centred functional outcome analysis has illustrated the importance of perioperative patient education on long-term patient satisfaction rates after RP in low-risk prostate cancer patients.

Heterodimerization with the ß1 subunit directs the α2 subunit of nitric oxide-sensitive guanylyl cyclase to calcium-insensitive cell-cell contacts in HEK293 cells: Interaction with Lin7a.

Nitric oxide-sensitive guanylyl cyclase is a heterodimeric enzyme consisting of an α and a ß subunit. Two different α subunits (α1 and α2) give rise to two heterodimeric enzymes α1/ß1 and α2/ß1. Both coexist in a wide range of tissues including blood vessels and the lung, but expression of the α2/ß1 form is generally much lower and approaches levels similar to the α1/ß1 form in the brain only. In the present paper, we show that the α2/ß1 form interacts with Lin7a in mouse brain synaptosomes based on co-precipitation analysis. In HEK293 cells, we found that the overexpressed α2/ß1 form, but not the α1/ß1 form is directed to calcium-insensitive cell-cell contacts. The isolated PDZ binding motif of an amino-terminally truncated α2 subunit was sufficient for cell-cell contact localization. For the full length α2 subunit with the PDZ binding motif this was only the case in the heterodimer configuration with the ß1 subunit, but not as isolated α2 subunit. We conclude that the PDZ binding motif of the α2 subunit is only accessible in the heterodimer conformation of the mature nitric oxide-sensitive enzyme. Interaction with Lin7a, a small scaffold protein important for synaptic function and cell polarity, can direct this complex to nectin based cell-cell contacts via MPP3 in HEK293 cells. We conclude that heterodimerization is a prerequisite for further protein-protein interactions that direct the α2/ß1 form to strategic sites of the cell membrane with adjacent neighbouring cells. Drugs increasing the nitric oxide-sensitivity of this specific form may be particularly effective.

Mid-term outcomes after AdVanceXP male sling implantation.

OBJECTIVE: To describe efficacy and safety of the AdVanceXP (Boston Scientific, Marlborough, MA, USA) retrourethral transobturator male sling after a mean follow-up of almost 3 years. PATIENTS AND METHODS: A total of 41 patients underwent AdVanceXP implantation between July 2010 and March 2012 by a single surgeon. Patients were prospectively evaluated at baseline, after a mean follow-up of 12months and after an individual maximum follow-up. Efficacy was evaluated by daily pad usage, 24-h pad testing, and validated questionnaires (International Consultation on Incontinence questionnaire [ICIQ]). Patient satisfaction was determined using the Patient's Global Impression of Improvement score; quality of life was evaluated using the International Quality of Life (IQOL) score. Patients needing 0 or 1 safety pad with a daily urine loss <8 g were classified as cured. To assess the changes in outcome over time, a Wilcoxon signed-rank test was used. A P value <0.05 was taken to indicate statistical significance. RESULTS: The mean ± sd follow-up was 33.1 ± 8.1 months. A total of four patients (9.8%) were lost to follow-up. At follow-up, 56.1% of patients used 0 or 1 dry safety pad, 17.1% used 1 pad, and 17.1% used 2 pads. Mean pad use was 0.6 pads per day (P < 0.001 vs baseline) with a mean urine loss of 14 g per day. After nearly 3 years, 46.3% of the patients could be classified as cured and 29.3% could be classified as improved. When comparing respective outcomes after 1 and 3 years, no significant changes in mean daily pad use (0.8 at 1 year; P = 1.000), in ICIQ score (5.0 at 3 years vs 5.2 at 1 year; P = 0.500), or in IQOL score (89.2 at 3 years vs 86.8 at 1 year; P = 0.500) were observed. Patients lost less urine based on 24-h pad testing after nearly 3 years (14 g at 3 years vs 28 g at 1 year; P = 0.106). Subgroup analyses showed no significant differences in efficacy in patients who had previously received radiotherapy or in patients with mild preoperative incontinence. Between 1 and 3 years postoperatively, no complications were detected. CONCLUSIONS: The present study had the longest follow-up for AdVanceXP to date and is the first to show a high efficacy even after a mean follow-up of almost 3 years. The results indicate that late-onset complications are rare after AdVanceXP implantation.

Long-term Outcome of the Retrourethral Transobturator Male Sling After Transurethral Resection of the Prostate.

PURPOSE: To evaluate long-term outcomes of AdVance and AdVanceXP male slings in patients with persistent stress urinary incontinence (SUI) after transurethral resection of the prostate (TURP). METHODS: A total of 18 consecutive patients received AdVance (n=14) or AdVanceXP (n=4) male sling implantation between 2007 and 2013. Continence was determined by pad use, 24-hour pad testing and validated questionnaires (International Consultation on Incontinence Questionnaire Short Form, ICIQ-SF). Quality of life was evaluated by International Quality of Life (IQoL) score. Patient satisfaction was measured with patient's global impression of improvement score. Cure was defined as 0-5 g in the 24-hour pad test. Statistical analysis included Fisher exact and Wilcoxon test (P<0.05). RESULTS: Follow-up was available for 15 patients who underwent further analysis. After a median follow-up of 70 months (range, 18-83 months), mean daily pad usage was 1.8±2.1 pads (P=0.015 vs. baseline level). Mean IQoL score was 66.4±31.6 (P=0.050 vs. baseline level), and mean ICIQ-SF score was 9.5±6.6 (P=0.077 vs. baseline level). Based on 24-hour pad testing, mean daily urine loss was 31.2±64.5 g (median, 0 g; range, 0-209 g). Cure rate was 46.7%, and cure-and-improved rate was 60.0%. Assessing predictive features for success, better results were found in patients who needed up to 4 pads preoperatively (P=0.041) as well as for patients ≤71 years at the time of implantation (P=0.041). CONCLUSIONS: The findings indicate that AdVance and AdVanceXP implantation can be performed effectively and safely in men suffering from SUI after TURP. However, long-term success rates seem to be lower compared to SUI after radical prostatectomy and patients should be counseled accordingly.