Recurrences of depressive episodes in major depressive disorder (MDD) can be explained by the diathesis-stress model, suggesting that stressful life events (SLEs) can trigger MDD episodes in individuals with pre-existing vulnerabilities. However, the longitudinal neurobiological impact of SLEs on gray matter volume (GMV) in MDD and its interaction with early-life adversity remains unresolved. In 754 participants aged 18-65 years (362 MDD patients; 392 healthy controls; HCs), we assessed longitudinal associations between SLEs (Life Events Questionnaire) and whole-brain GMV changes (3 Tesla MRI) during a 2-year interval, using voxel-based morphometry in SPM12/CAT12. We also explored the potential moderating role of childhood maltreatment (Childhood Trauma Questionnaire) on these associations. Over the 2-year interval, HCs demonstrated significant GMV reductions in the middle frontal, precentral, and postcentral gyri in response to higher levels of SLEs, while MDD patients showed no such GMV changes. Childhood maltreatment did not moderate these associations in either group. However, MDD patients who had at least one depressive episode during the 2-year interval, compared to those who did not, or HCs, showed GMV increases in the middle frontal, precentral, and postcentral gyri associated with an increase in SLEs and childhood maltreatment. Our findings indicate distinct GMV changes in response to SLEs between MDD patients and HCs. GMV decreases in HCs may represent adaptive responses to stress, whereas GMV increases in MDD patients with both childhood maltreatment and a depressive episode during the 2-year interval may indicate maladaptive changes, suggesting a neural foundation for the diathesis-stress model in MDD recurrences.

ObjectiveThe degree of substitution (DS) of HES describes the average proportion of substituted glucose molecules in a starch molecule. Although no quantitative studies of the in vivo behavior of the DS have been conducted so far, most pharmacokinetic studies to date have measured HES concentrations using the enzymatic method. This method assumes that at any point in time after an infusion, the DS in a serum remains constant and is identical to the DS in the infused solution. In the present study, we examined the changes in the DS of HES 130/0.42 in vivo in an animal model and compared two methods of measuring HES concentrations in plasma (the enzymatic and the o-Toluidine method).MethodologyWe randomized 22 pigs into 2 groups. After induction of anesthesia, the pigs received 500 ml or 1000 ml of HES 130/0.42 (Tetraspan®). The DS was measured directly after the infusion, then after 30, 60, 120 and 240 minutes. In determining the DS, the hydroxyethyl starch was extracted from the plasma and hydrolyzed with hydrochloric acid to form non-substituted glucose and hydroxyethyl glucose. Subsequently, the concentration of free unsubstituted glucose was determined enzymatically and the total concentration of all (i.e., substituted and unsubstituted) glucose molecules was determined using the o-Toluidine method. From this, the concentration of the substituted glucose (hydroxyethyl glucose) and the DS could be calculated. In addition, the HES concentration was measured first in vitro and then in vivo at any point after the infusion by both the enzymatic method and the o-Toluidine method.ResultsThe DS increased significantly directly after the infusion from 0.42 to 0.53 (for 500ml) or to 0.50 (for 1000ml); 4 hours later this had further increased to 0.55 and 0.54, respectively (p <0.0001). The HES concentration in vitro showed no significant difference (p = 0.17) when determined with the enzymatic and the o-Toluidine method. In contrast, the serum concentrations in vivo displayed significant differences (p<0.0001) between the two measurement methods. Immediately after the infusion of 500ml HES, the concentration measured with the o-Toluidine method was 31% higher than the one measured with the enzymatic method; 4 hours later, this discrepancy was still at 25%. For 1000 ml HES, the differences amounted to 16% and 25%, respectively.ConclusionThe DS of HES in vivo increases significantly over time. As a result, an HES concentration measured with the enzymatic method in vivo will be significantly lower than the same concentration determined with the o-Toluidine method. In future pharmacokinetic studies, HES concentrations should be measured using a method that takes into account changes in the DS in vivo.

OBJECTIVE:To examine the predictive value of unremarkable nonstimulated highly sensitive thyroglobulin (hsTg) measurement with regard to the results of stimulated thyroglobulin (Tg) measurement, diagnostic whole-body scintigraphy, recurrence and differentiated thyroid cancer (DTC)-related death.DESIGN, PATIENTS AND MEASUREMENTS:We retrospectively analysed the data of all 461 (410 without anti-Tg-antibodies [TgAbs], 51 with) DTC patients who were referred to our department for treatment and follow-up care of differentiated thyroid cancer from 2004 onwards, and in whom at least one posttreatment Tg value was measured in our hospital at least 3 months after I-131 ablation.RESULTS:In the group of TgAb-negative patients, 2.0% of patients with an unstimulated Tg < 0.1 ng/ml showed a stimulated Tg ≥ 1.0 ng/ml, whereas this happened in 77.6% with an unstimulated Tg ≥ 0.1 but <1.0 ng/ml. An unstimulated hsTg ≥ 0.1 ng/ml had a sensitivity specificity positive and negative predictive value of 90.0%, 94.1%, 77.6% and 97.6%, respectively, for a stimulated Tg ≥ 1.0 ng/ml. In TgAb-positive patients, this was 75%, 97%, 75% and 97%, respectively. An unstimulated Tg ≥ 0.1 ng/ml did not significantly discriminate with regard to the risk of DTC-related death (p = .06), but ≥1.0 ng/ml did (p = .012), as did a stimulated Tg ≥ 1.0 ng/ml (p = .029). Excluding patients with distant metastases at diagnosis nullifies this significance.CONCLUSION:Except for patients with distant metastases, both TgAb negative and TgAb positive patients with an undetectable nonstimulated hsTg measurement have a very good prognosis. The high net present value of unstimulated hsTg testing means that further diagnostic procedures can be omitted in such patients.

Definition Untersuchung der in der Gasphase oberhalb einer Lösung enthaltenen (flüchtigen) Bestandteile.Beschreibung Die Probe wird in einem mit einem Septum gasdicht verschlossenen Glasgefäß bei einer bestimmten Tem-

EC 1.1.1.37▶ Malatdehydrogenase EC 1.1.1.42▶ Isocitrat-Dehydrogenase EC 1.1.1.48Transferasen EC 2.6.1.1 ▶ Aspartat-Aminotransaminase EC 2.6.1.2▶ Alanin-Aminotransaminase 740 EC 1.1.1.37EC 2.7.1.1 ▶ Hexokinase EC 2.7.1.3▶ Fruktokinase EC 2.7.1.6 ▶ Galaktokinase EC 2.7.7.12 ▶ Galaktose-1-Phosphat-Uridyltransferase EC 3.1.1.3▶ Lipase, hepatische ▶ Lipase, pankreatische EC 3.1.1.4▶ Phospholipase A2 EC 3.1.1.8▶ Pseudocholinesterase EC 3.1.1.47▶ Phospholipase A2, Lipoprotein-assoziierte EC 3.1.3.1 ▶ Phosphatase, alkalische EC 3.1.3.5 ▶ 5'-Nukleotidase EC 3.1.3.9 ▶ Glukose-6-Phosphatase EC 3.2.1.1 ▶ Amylase, pankreasspezifische EC 3.2.1.17▶ Lysozym EC 3.2.1.22▶ a-Galaktosidase EC 3.2.1.30▶ N-Acetyl-beta-D-glukosaminidase EC 3.4.11.

EC 1.1.1.37▶ Malatdehydrogenase EC 1.1.1.42▶ Isocitrat-Dehydrogenase EC 1.1.1.48Transferasen EC 2.6.1.1 ▶ Aspartat-Aminotransaminase EC 2.6.1.2▶ Alanin-Aminotransaminase 740 EC 1.1.1.37EC 2.7.1.1 ▶ Hexokinase EC 2.7.1.3▶ Fruktokinase EC 2.7.1.6 ▶ Galaktokinase EC 2.7.7.12 ▶ Galaktose-1-Phosphat-Uridyltransferase EC 3.1.1.3▶ Lipase, hepatische ▶ Lipase, pankreatische EC 3.1.1.4▶ Phospholipase A2 EC 3.1.1.8▶ Pseudocholinesterase EC 3.1.1.47▶ Phospholipase A2, Lipoprotein-assoziierte EC 3.1.3.1 ▶ Phosphatase, alkalische EC 3.1.3.5 ▶ 5'-Nukleotidase EC 3.1.3.9 ▶ Glukose-6-Phosphatase EC 3.2.1.1 ▶ Amylase, pankreasspezifische EC 3.2.1.17▶ Lysozym EC 3.2.1.22▶ a-Galaktosidase EC 3.2.1.30▶ N-Acetyl-beta-D-glukosaminidase EC 3.4.11.

A central reason behind the poor clinical outcome of patients with high-grade serous carcinoma (HGSC) of the ovary is the difficulty in reliably detecting early occurrence or recurrence of this malignancy. Biomarkers that provide reliable diagnosis of this disease are therefore urgently needed. Systematic proteomic methods that identify HGSC-associated molecules may provide such biomarkers. We applied the antibody-based proximity extension assay (PEA) platform (Olink) for the identification of proteins that are upregulated in the plasma of OC patients. Using binders targeting 368 different plasma proteins, we compared 20 plasma samples from HGSC patients (OC-plasma) with 20 plasma samples from individuals with non-malignant gynecologic disorders (N-plasma). We identified 176 proteins with significantly higher levels in OC-plasma compared to N-plasma by PEA (p < 0.05 by U-test; Benjamini-Hochberg corrected), which are mainly implicated in immune regulation and metastasis-associated processes, such as matrix remodeling, adhesion, migration and proliferation. A number of these proteins have not been reported in previous studies, such as BCAM, CDH6, DDR1, N2DL-2 (ULBP2), SPINT2, and WISP-1 (CCN4). Of these SPINT2, a protease inhibitor mainly derived from tumor cells within the HGSC microenvironment, showed the highest significance (p < 2 × 10-7) similar to the previously described IL-6 and PVRL4 (NECTIN4) proteins. Results were validated by means of the aptamer-based 1.3 k SOMAscan proteomic platform, which revealed a high inter-platform correlation with a median Spearman ρ of 0.62. Likewise, ELISA confirmed the PEA data for 10 out of 12 proteins analyzed, including SPINT2. These findings suggest that in contrast to other entities SPINT2 does not act as a tumor suppressor in HGSC. This is supported by data from the PRECOG and KM-Plotter meta-analysis databases, which point to a tumor-type-specific inverse association of SPINT2 gene expression with survival. Our data also demonstrate that both the PEA and SOMAscan affinity proteomics platforms bear considerable potential for the unbiased discovery of novel disease-associated biomarkers.