The analytical performance and the clinical utility of a thyrotropin receptor (TSHR)-stimulating immunoglobulin (TSI) bioassay were compared with those of a TSHR-binding inhibitory immunoglobulin ...(TBII) assay. Limits of detection (LoD) and quantitation (LoQ), assay cutoff, and the half-maximal effective concentration (EC(50)) were measured. Dilution analysis was performed in sera of hyperthyroid patients with Graves disease (GD) during antithyroid treatment (ATD). Titer was defined as the first dilution step at which measurement of TSI or TBII fell below the assay cutoff. The LoD, LoQ, cutoff, and EC(50) of the bioassay were 251-, 298-, 814-, and 827-fold lower than for the TBII assay. There were 22%, 42%, 23%, and 14% more positive samples in the TSI bioassay at dilutions of 1:3, 1:9, 1:27, and 1:81 (P < .0001), respectively. Responders to ATD demonstrated marked differences in titers compared with nonresponders. The bioassay detected lower levels of TSHR autoantibodies, and the dilution analysis provided similar predictive values of both assays in GD.
Depression is associated with an increased risk for type 2 diabetes mellitus. However, depression may take different courses, and it is not fully understood how these affect the development of ...diabetes. It is further to be determined whether sex modifies the association between depression and type 2 diabetes.
We analyzed data from the Gutenberg Health Study, a longitudinal and population-based cohort study (N = 15,010) in Germany. Depressive symptoms (measured by PHQ-9), history of depression, diabetes mellitus, and relevant covariates were assessed at baseline, and the outcomes of prediabetes and type 2 diabetes mellitus were evaluated 5 years later. Logistic regression was used to estimate odds ratios of incident prediabetes and type 2 diabetes mellitus, adjusting for potential confounders as identified in a Directed Acyclic Graph.
In the confounder adjusted model, current depression (PHQ-9 ≥ 10 at baseline; OR = 1.79, 95% CI = 1.11 to 2.74, p = 0.011), and persistent depression had a statistically significant (OR = 2.44, 95% CI = 1.62 to 3.54, p = 0.005) effect on incident type 2 diabetes mellitus. A history of depression without current depression had no statistically significant effect on type 2 diabetes (OR = 1.00, 95% CI = 0.68 to 1.43, p = 0.999). The effect of depression on incident diabetes did not differ significantly between women (OR = 2.02; 95% CI = 1.32 to 3.09) and men (OR = 2.16; 95% CI = 1.41 to 3.31; p-value for interaction on the multiplicative scale p = 0.832 and on the additive scale p = 0.149). Depression did not have a significant effect on incident prediabetes.
This study shows how the history and trajectory of depression shape the risk for diabetes. This raises interesting questions on the cumulative effects of depression trajectories on diabetes and body metabolism in general. Depression can negatively affect physical health, contributing to increased morbidity and mortality in people with mental disorders.
Most presently known breast cancer susceptibility genes have been linked to DSB repair. To identify novel markers that may serve as indicators for breast cancer risk, we performed DSB repair analyses ...using a case‐control design. Thus, we examined 35 women with defined familial history of breast and/or ovarian cancer (first case group), 175 patients with breast cancer (second case group), and 245 healthy women without previous cancer or family history of breast cancer (control group). We analyzed DSB repair in peripheral blood lymphocytes (PBLs) by a GFP‐based test system using 3 pathway‐specific substrates. We found increases of microhomology‐mediated nonhomologous end joining (mmNHEJ) and nonconservative single‐strand annealing (SSA) in women with familial risk vs. controls (P=0.0001‐0.0022) and patients with breast cancer vs. controls (P=0.0004‐0.0042). Young age (<50) at initial diagnosis of breast cancer, which could be indicative of genetic predisposition, was associated with elevated SSA using two different substrates, amounting to similar odds ratios (ORs=2.54‐4.46, P= 0.0059‐0.0095) as for familial risk (ORs=2.61‐4.05, P=0.0007‐0.0045). These findings and supporting validation data underscore the great potential of detecting distinct DSB repair activities in PBLs as method to estimate breast cancer susceptibility beyond limitations of genotyping and to predict responsiveness to therapeutics targeting DSB repair‐dysfunctional tumors.—Keimling, M., Deniz, M., Varga, D., Stahl, A., Schrezenmeier, H., Kreienberg, R., Hoffmann, I., König, J., Wiesmüller, L. The power of DNA double‐strand break (DSB) repair testing to predict breast cancer susceptibility. FASEB J. 26, 2094‐2104 (2012). www.fasebj.org
Spontaneous intracerebral hemorrhage (ICH) causes, besides the primary brain injury, a secondary brain injury (SBI), which is induced, amongst other things, by oxidative stress (OS) and inflammation, ...determining the patient's outcome. This study aims to assess the impact of OS in plasma and cerebrospinal fluid (CSF) on clinical outcomes in patients with ICH. A total of 19 ICH (volume > 30 cc) patients and 29 control patients were included. From day one until seven, blood and CSF samples were obtained, and ICH volume was calculated. OS markers, like malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione-sulfhydryl (GSH), and the total antioxidant status (TAS) were measured. Clinical data on treatment and outcome were determined. Patients with mRS ≤ 4 showed significantly elevated SOD and GSH-Px levels in plasma compared to patients with poor CO (
= 0.004;
= 0.002). Initial increased TAS in plasma and increased MDA in CSF were linked to an unfavorable outcome after six months (
= 0.06, r = 0.45;
= 0.05, r = 0.44). A higher ICH volume was associated with a worse outcome at week six (
= 0.04, r = 0.47). OS plays a significant role in SBI. Larger ICHs, elevated MDA in CSF, and TAS in plasma were associated with a detrimental outcome, whereas higher plasma-SOD and -GSH-Px were associated with a favorable outcome.
While a bidirectional relationship between diabetes and depression has been established, there is little knowledge if the associations are due to somatic-affective or cognitive-affective dimensions ...of depression.
In a population-based, representative survey of 15.010 participants we therefore studied the associations of the two dimensions of depression with diabetes and health care utilization among depressed and diabetic participants. Depression was assessed by the Patient Health Questionnaire PHQ-9.
We found a linear and consistent association between the intensity of depression and the presence of diabetes increasing from 6.9% in no or minimal depression to 7.6% in mild, 9% in moderate and 10.5% in severe depression. There was a strong positive association between somatic-affective symptoms but not with cognitive-affective symptoms and diabetes. Depression and diabetes were both independently related to somatic health care utilisation.
Diabetes and depression are associated, and the association is primarily driven by the somatic-affective component of depression. The main limitation of our study pertains to the cross-sectional data acquisition. Further longitudinal work on the relationship of obesity and diabetes should differentiate the somatic and the cognitive symptoms of depression.
The objective of the present study is to assess the influence of extent of resection (EoR), use of intraoperative imaging, and awake surgery on health-related quality of life (HRQoL) in high-grade ...glioma (HGG) patients in a prospective multicenter study. We analyzed 170 surgeries of patients suffering from a HGG. During the first year after resection, HRQoL was evaluated using the European Organization of Research and Treatment of Cancer Core Questionnaire C30 and Brain Neoplasm 20 questionnaires. We assessed the influence of EoR; awake surgery; and use of 5-aminolevulinic acid (5-ALA), intraoperative MRI (iMRI), and their combination on sum scores for function and symptoms as well as several neurological single items. In mixed-model analyses, adjustments for age, Karnofsky performance status (KPS), and eloquent location were performed. In the mixed model, EoR generally did not significantly influence HRQoL (
p
= 0.10). Yet, patients receiving subtotal resection (STR) vs. patients with biopsy showed significantly better QoL and role and cognitive functions (
p
= 0.04,
p
= 0.02, and
p
< 0.01, respectively). The combination of iMRI and 5-ALA reached the highest EoR (95%) followed by iMRI alone (94%), 5-ALA alone (74%), and no imaging (73%). Thereby, neurological symptoms were lowest and functioning score highest after combined use of iMRI and 5-ALA, without reaching significance (
p
= 0.59). Despite lower scores in emotional function (59 vs. 46,
p
= 0.24), no significant impact of awake surgery on HRQoL was found (
p
= 0.70). In HGG patients, STR compared to biopsy was significantly associated with better HRQoL and fewer neurological symptoms in this series. An escalated use of intraoperative imaging increased EoR with stable or slightly better HRQoL and fewer neurological symptoms. Based on HRQoL, awake surgery was a well-tolerated and safe method in our series.
Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as an alternative therapy for spontaneous intracerebral hemorrhage (ICH). Optimal dose and schedule are still unclear. ...The aim of this study was to create a reliable in vitro blood clot model for investigation of optimal drug dose and timing. An in vitro clot model was established, using 25 mL and 50 mL of human blood. Catheters were placed into the clots and three groups, using intraclot application of rtPA, placebo, and catheter alone, were analyzed. Dose-response relationship, repetition, and duration of rtPA treatment and its effectiveness in aged clots were investigated. A significant relative end weight difference was found in rtPA treated clots compared to catheter alone (p=0.002) and placebo treated clots (p<0.001). Dose-response analysis revealed 95% effective dose around 1 mg rtPA in 25 and 50 mL clots. Approximately 80% of relative clot lysis could be achieved after 15 min incubation. Lysis of aged clots was less effective. A new clot model for in vitro investigation was established. Our data suggest that current protocols for rtPA based ICH therapy may be optimized by using less rtPA at shorter incubation times.
Children are often treated off-label and are at a disadvantage in pharmacotherapy. The aim of this study was to implement and evaluate a quality assurance measure (PaedPharm) for pediatric ...pharmacotherapy whose purpose is to reduce medication-related hospitalizations among children and adolescents.
PaedPharm consisted of the digital pediatric drug information system PaedAMIS, pediatric pharmaceutical quality circles (PaedZirk), and an adverse drug event (ADE) reporting system (PaedReport). The intervention was implemented in a cluster-randomized trial (DRKS 00013924) in 12 regions, with a pediatric and adolescent medicine clinic in each and a total of 152 surrounding private practitioners, in 6 sequences over 8 quarters. In addition to the proportion of ADE-related hospital admissions (primary endpoint), comprehensive process evaluation included other endpoints such as coverage, user acceptance, and relevance to practice.
41 829 inpatient admissions were recorded, of which 5101 were patients of physicians who participated in our study. 4.1% of admissions were ADE-related under control conditions, and 3.1% under intervention conditions (95% CI: 2.3; 5.9 and 1.8; 4.5, respectively). A model-based comparison yielded an intervention effect of 0.73 (population-based odds ratio; 0.39; 1.37; p = 0.33). PaedAMIS achieved moderate user acceptance and PaedZirk achieved high user acceptance.
The introduction of PaedPharm was associated with a decrease in medicationrelated hospitalizations that did not reach statistical significance. The process evaluation revealed broad acceptance of the intervention in outpatient pediatrics and adolescent medicine.
The measurement of TSH receptor (TSHR) antibodies is warranted for diagnosis of Graves' disease (GD).
The performance, detection sensitivity, and specificity of 6 TSHR immunoassays were compared.
Two ...bioassays and 4 binding assays (Kronus, Immulite, Kryptor, Dynex) were compared in a dilution study performed in patients with autoimmune thyroid disease. Both bioassays were compared to 2 binding assays using stimulatory (M22) and blocking (K1-70) monoclonal antibody (MAb) mixtures.
Thirty samples from stimulatory (TSAb)-positive/blocking (TBAb)-negative patients with GD were diluted serially and measured in all assays. Samples were positive until dilution 1:2,187 in the TSAb bioassay, 1:81 in the Immulite (
< 0.002 vs. bioassay) and Kronus ELISA (
= 0.039) assays, and 1:27 in the Kryptor and Dynex ELISA (
< 0.001 vs. bioassay). Ten samples from TBAb-positive/TSAb-negative patients with GD or Hashimoto's thyroiditis were positive in all binding assays. None of the binding assays differentiated between TSAb and TBAb. Mixtures of 100% K1-70 (200 ng/mL), 80% K1-70 + 20% M22, 60% K1-70 + 40% M22, 40% K1-70 + 60% M22, 20% K1-70 + 80% M22, and 100% M22 (20 ng/mL) tested positive in both Immulite (26.4, 20.2, 15.2, 10.5, 6.3, 2.00 IU/L) and Kronus assays (27.1, 23.3, 19.3, 12.0, 5.7, 2.2 IU/L). These MAb mixtures were tested in the TBAb bioassay and showed 82, 61, 24 (negative), -26 (negative), -77 (negative), and -95% (negative) inhibition, respectively.
The sample dilution study showed higher detection sensitivity for the TSAb bioassay, and the antibody mixture study demonstrated exclusive specificity of the bioassays over all automated and ELISA binding assays.
Studies in immigrant youth have suggested differences in parenting patterns by immigration status. Knowledge of variation in recalled parenting pattern and its distinctive impact on mental health in ...adult immigrants, however, is limited. Therefore, the purpose of the current study was to investigate similarities and differences in recalled maternal and paternal rearing behavior and its association with depressiveness in adult 1st generation immigrants compared to non-immigrants.
Seven hundred and forty-three 1st generation immigrants (M = 57.4, SD = 10.1 years) and 6518 non-immigrants (M = 60.3, SD = 10.7 years) participated in a population-based study. Regarding countries of origin, the largest subgroups were immigrants from Eastern-Europe, Former-SU, and Arabic-Islamic countries. All participants completed the ultra-short version of The Recalled Parental Rearing Behavior-questionnaire and the PHQ-9 assessing depressiveness. Multiple linear regressions with depressiveness as outcome variable were analyzed separately for each facet of parental rearing behavior adjusting for socio-demographic and migration-related variables.
In addition to differences in depressiveness and socioeconomic status, 1st generation immigrants recalled both their mothers and fathers as more controlling and overprotecting than non-immigrants. Parental emotional warmth was negatively associated with depressiveness across all groups. The relationship between parental control, respectively parental rejection and depressiveness, however, varied in direction and severity between the groups.
The results support the notion that parental warmth is a universal protective factor against depressiveness, whereas the impact of parental control on mental health might be more culturally influenced. Analyses point to the importance of considering the unique contribution of fathers' rearing behavior on mental health, particularly in immigrant samples.
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