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Humanity is plagued by many diseases. Beside environmental influences, many --- if not all --- diseases are also subject to genetic predisposition and then display molecular alterations such as proteomic or metabolic aberrations. The elucidation of the molecular principles underlying human diseases is one of the prime goals of biomedical research. To this end, there has been an advent of large-scale omics profiling studies. While the field of molecular biology has experienced tremendous development, data analysis remains a bottleneck. In the context of this thesis, we developed a number of analysis strategies for different types of omics data resulting from different experimental settings. These include approaches for associations studies for plasma miRNAs and time-resolved plasma omics data. Furthermore, we devised analyses of different RNA-Seq transcriptome profiling studies coping with problems such as lack of replicates or multifactorial experimental design. We also designed machine learning frameworks for the identification of discriminatory biomolecular signatures analysing case-control or time-to-event data. All of the strategies mentioned above were developed and applied in the contexts of multi-disciplinary endeavours. They aided in the identification of plasma miRNAs associated with age, sex, and BMI as well as plasma miRNAs bearing potential as diagnostic biomarkers for non-alcoholic fatty liver disease (NAFLD). This thesis significantly contributed to a study demonstrating the utility of plasma miRNAs as prognostic biomarkers for major cardiovascular events such as ST-elevation myocardial infarction. Our approaches for analysing RNA-Seq data aided in the characterisation of murine models for Alzheimers disease and the transcriptional response of human gingiva fibroblasts to ionizing radiation exposure. Furthermore, the developed approaches were applied for studying a human model for thyrotoxicosis and for the successful identification of a multi-omics plasma biomarker signature of thyroid status. We are only beginning to understand the molecular principles underlying human diseases. The approaches and results presented in this thesis will contribute to improved understanding of biomolecular processes involved in common diseases such as Alzheimers disease, NAFLD, and cardiovascular diseases.
Geistige Behinderung ist eine der häufigsten Formen von erblich bedingten kognitiven Beeinträchtigungen. Definiert wird sie durch einen Intelligenzquotienten unter 70 und obwohl ihre genetischen Ursachen sehr heterogen sein können, gibt es unter ihnen eine beachtliche Menge Gene, die am Aufbau der Glycocalyx beteiligt sind [1, 2]. Die Glycocalyx besteht aus Zuckerbausteinen, die Teil von Lipiden und Proteinen der Zelloberfläche oder der extrazellulären Matrix sind. Vor kurzem konnten wir belegen, dass Mutationen im ST3GAL3-Gen, welches für die Golgi-lokalisierte β-Galactosid-α2,3-sialyltransferase-III codiert, zu verschiedenen klinischen Befunden führt. Zwei unabhängige Mutationen (p.Ala13Asp and p.Asp370Tyr), gefunden in iranischen Familien, konnten mit relativ milden Formen nicht-syndromaler geistiger Behinderung (NSARID) in Verbindung gebracht werden [5]. Eine dritte Punktmutation (p.Ala320Pro), gefunden in einer palästinensischen Familie, verursachte hingegen eine schwere, altersabhängige epileptische Enzephalopathie, das West-Syndrom. Dieses Syndrom ist mit einem Arrest der geistigen Entwicklung oder sogar, wie in unserem Fall, einer Regression assoziiert [3, 4]. ST3GAL3 bildet im Menschen unter anderem das Sialyl Lewis-a (sLea)-Epitop auf Proteinen. Exogene Expression der Volllängen-c-MYC-Fusionsproteine, der Mutationsvarianten in LMTK—Zellen, zeigte, dass alle Varianten eine gestörte subzellulare Lokalisierung zeigen und zwei von ihnen (p.Ala13ASp und p.ALA320Pro) kaum mehr messbare Aktivität besitzen [5]. Um die molekularen und zellulären Mechanismen näher zu beleuchten, die dem ST3GAL3-bedingten West-Syndrom zugrunde liegen, haben wir erfolgreich ein patientenspezifisches, induzertes pluripotentes Stammzellmodell etabliert. Hierfür wurden Fibroblasten der Patientin, die eine Mutation im Exon 12 (c.958G>C, p.Ala320Pro) des ST3GAL3-Gens trägt, und einer gesunden Schwester mittels eines lentiviralen Vektorsystems reprogrammiert. Da ST3GAL3 die höchsten Expressionswerte im frontalen Kortex zeigte, und dies auch in Übereinstimmung mit dem vorgeschlagenen Ursprung epileptischer Anfälle steht, wurde ein Differenzierungsprotokoll für kortikale Neuronen etabliert und erfolgreich für beide Zelllinien durch geführt. Einer der größten Vorteile dieses Protokolls ist, dass hier die Neurogenese in vitro nach demselben temporalen Muster abläuft wie die Neurogenese in vivo. Die iPSC und die daraus differenzierten Neuronen wurden anschließend mittels Lectinblot, mRNA-Sequenzierung, Adhärenzassays und FACS untersucht. Während keine Unterschiede zwischen den iPSC und den Fibroblasten festgestellt wurden, konnten für die kortikalen Neuronen der Patientin eine zusätzliche Bande im Lektinblot (70 kDa), ein verändertes Adhärenzverhalten auf poly-L-Orinithin/Laminin-beschichteter Oberfläche und eine deutlich reduzierte Menge T-box-transcription factor-brain-1-exprimierende Neuronen festgestellt werden. Unsere Ergebnisse zeigen, dass die ST3GAL3-Aktivität wichtig für die normale Entwicklung und Funktion des Gehirns ist.
The thyroid as the largest endocrine gland mainly produces and secretes the thyroid hormones (TH): 3,3’,5-triiodo-L-thyronine (T3) and its pro-hormone L-thyroxine (T4). Besides the impact on growth, normal development, bone marrow structure, the cardiovascular system, body weight and thermogenesis, TH play a vivid role in many metabolic regulatory mechanisms in almost all tissues. Thyroid diseases are relatively prevalent and cause, due to the resulting TH imbalances, a broad spectrum of effects. Many of them manifest in pathologically increased or decreased TH levels defined as hyperthyroidism or hypothyroidism, respectively. Routinely, determination of the thyroid state is based on the assessment of the classical markers TSH and free T4. However, this practice has several drawbacks. Moreover, elucidation of the pleiotropic effects of TH on multiple molecular pathways is mostly based on cell culture, tissue and rodent models. Analysis of animal biofluids like serum and urine using metabolomics approaches demonstrated the extensive impact of TH on other body compartments. In contrast, proteome profiling has not been exploited for the comprehensive characterization of the general metabolic effects of TH. Plasma as a large and diverse compartment of the human proteome provides a great opportunity to identify novel protein markers of thyroid function as well as to characterize metabolic effects of TH in humans.
Therefore, a study of experimental thyrotoxicosis was performed with 16 male volunteers treated with 0.25 mg/d levothyroxine (L-T4) for 8 weeks to induce a hyperthyroid state. Plasma samples were collected before the L-T4 application started, two times during the treatment and additionally two times after withdrawal. Proteome analysis revealed remarkable alterations including increased levels of two known proteins known to correlate with TH levels (sex hormone-binding globulin and cystatin C). The correlation with free T4 levels revealed 76 out of 437 detected proteins with a Pearson correlation coefficient of r ≥ |0.9|. One prominent signature included 10 coagulation cascade proteins exhibiting significantly increased plasma levels during thyrotoxicosis, thereby revealing a trend towards a hypercoagulative state in hyperthyroidism. To overcome the statistical drawbacks of the Pearson correlation analysis, additionally a mixed-effect linear regression model using serum free T4 concentrations as exposure and protein abundances as outcome while controlling for age, BMI, and batch was implemented. Application of this model resulted in the detection of 63 proteins with significant associations to free T4 levels. Besides the already mentioned augmented coagulation, a significant drop in the amounts of three apolipoproteins (ApoD, ApoB-100 and ApoC3) was observed. Furthermore, an increased abundance of proteins assigned to the complement system was detected.
Experimental studies in humans were complemented by corresponding analyses in murine models. In the current work, plasma samples of two murine studies including male C57BL/6 wildtype mice were analyzed to elucidate the impact of thyroid dysfunction on the plasma proteome. The first study was similarly designed as the human model of experimentally induced thyrotoxicosis and assigned the animals to three groups: a control group, a T4 treatment group, and a T4 recovery group, whereupon the latter first received T4 followed by a subsequent TH normalization period. A high proportion of plasma proteins exhibited significantly different protein levels during T4 application (n = 120), where 90 of these also showed a corresponding reverse trend after T4 withdrawal (T4 recovery vs. T4), thereby displaying transient alterations. The molecular pattern of hyperthyroidism in the murine model indicated, as in the human study, a pronounced decrease in apolipoproteins. However, in clear contrast to the human data, the levels of proteins related to the coagulation cascade and complement system were also transiently decreased in mice, while being increased in humans.
The second murine analysis focused on the impact of hyper- and hypothyroidism caused by T3 or T4 treatment and MMI/KClO4 application, respectively. In general, compared to the first murine study less clear alterations of protein levels were detected. Proteins related to the complement system revealed fewer changes in the T3 group and only marginal changes after T4 induction. Unexpectedly, the MMI/KClO4-induced hypothyroidism caused a reduction of the levels of several proteins assigned to the complement system, although different components and factors were affected.
Generally, rodent studies partially provided a divergent picture of TH action as compared to human studies. However, in spite of inconsistent results in studies regarding the effects of TH that are possibly due to species-specific differences, an important role of TH on several metabolic and other pathways, e.g. in the process of blood coagulation and apolipoprotein regulation, is evident. The results from both murine and human studies presented here provide novel insights into changes in the plasma proteome in the context of thyroid diseases which might contribute to a better understanding of TH action on metabolism and other pathways.
Transfusion-related acute lung injury (TRALI) is an adverse transfusion reaction and the major cause of transfusion-related mortality. The syndrome occurs within six hours after transfusion and is characterized by acute respiratory distress and the occurrence of a non-cardiogenic, bilateral lung edema. TRALI is almost entirely induced by leukocyte-reactive substances which are present in the blood product and get transferred to the recipient during transfusion. The majority of cases (~80%) is caused by leukocyte-reactive immunoglobulins and is accordingly classified as immune-mediated TRALI. The responsible antibodies are generated via alloimmunization and are directed against human leukocyte antigens of class I and II or human neutrophil alloantigens (HNA). Within the HNA class, HNA-3a antibodies have an exceptional clinical relevance as they are most frequently involved in severe and fatal TRALI cases. The high mortality was associated with their characteristic ability to induce a strong neutrophil aggregation response. The described clinical relevance of HNA-3a antibody-mediated TRALI motivates the screening for new strategies for preventive or acute pharmacologic intervention. Knowledge of the molecular pathomechanisms is a crucial prerequisite and thus, respective investigations are required. In order to achieve this goal, HNA-3a antibody-induced cytotoxicity and aggregation were assessed on the molecular level by usage of flow cytometry, the granulocyte agglutination test and by phosphoproteome analysis. The current study provides insight into molecular processes during HNA-3a antibody-induced neutrophil responses and is the first to assess neutrophils using global, gel-free phosphoproteome analyses. Accordingly, it is the first to provide neutrophil phosphoproteome data in the context of TRALI. Gel-free phosphoproteome analyses of primary neutrophils required the highly selective and sensitive phosphopeptide enrichment from stable and sufficiently large protein extracts. However, an appropriate workflow did not exist and was hence developed by sequential protocol optimization steps. The developed workflow was finally proven suitable for comparative gel-free phosphoproteomics when detecting the formyl-methionyl-leucyl-phenylalanine-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in a proof-of-principle experiment. The following single parameter analyses were conducted to investigate neutrophils for their responses to HNA-3a antibodies in absence and presence of proinflammatory priming conditions. Results revealed that the direct stimulation of neutrophils with HNA-3a antibodies will likely not cause the induction of cytotoxic effector functions. In contrast, neutrophils react predominantly by aggregation, a process which is potentially mediated by integrins and causes a secondary, subthreshold activation of solely ERK2. Accordingly, only the neutrophil aggregation response could also be enhanced by an appropriate priming. Taken together, the single parameter analyses proved neutrophil aggregation as the main pathomechanism in HNA-3a antibody-mediated TRALI and thus, the underlying signaling pathways were investigated by global, gel-free phosphoproteomics. The following phosphoproteome analyses indicated the induction of a biphasic signaling during 30 minutes of HNA-3a antibody treatment and signaling pathways of Rho family GTPases could be associated with the first and the second phase. Additionally, the involvement of ERK signaling was indicated in the second phase and this result corroborated thus the data of the previous single parameter analyses. The comprehensive analysis of the identified signaling pathways revealed Rho, Rac and Cdc42 as central regulators and the specific inhibition of Rho in the following validating experiments led very intriguingly to a significant enhancement of HNA-3a antibody-mediated neutrophil aggregation. Hence, this result indicated a potential inhibitory effect of HNA-3a antibodies on Rho activity. Therefore, Rho inhibition was suggested to occur in parallel to an adhesion-inducing signaling pathway and might hence be involved in the stabilization of neutrophil aggregates in HNA-3a antibody-induced TRALI. The results from this doctoral thesis contributed to the generation of a new pathogenesis model for HNA-3a antibody-mediated TRALI. In this model, neutrophils respond to direct HNA-3a antibody exposure predominantly by homotypic aggregation. These potentially very stable and primed aggregates accumulate in the lung and are susceptible to parallel, proinflammatory stimulation. Subsequently, this cascade leads to full neutrophil activation and finally to TRALI induction.
Staphylococcus aureus (S. aureus) is the leading cause of serious diseases in human both from hospital and community associated infections. Some clinical manifestations of S. aureus infections are infective endocarditis (IE), osteoarticular infections, skin and soft tissue, pleuropulmonary, and device-related infections. In Germany, S. aureus is the second most common cause of hospital-acquired (HA) infections. About 16.7% of these nosocomial infections are caused by HA-MRSA clinical isolates. It has been a huge threat for the clinicians/scientists to control the emergence of such infections caused by S. aureus. S. aureus exhibits increasing virulence and resistance to various antibiotics, complicating prevention and treatment of infections. Eventually, active and passive vaccines might be the alternative strategy to deal with S. aureus related diseases. An effective S. aureus vaccine would provide great potential security and many societal benefits. However, so far vaccine trials have failed often due to limited number of available antigen candidates (monovalent/single antigen) in the clinical trials. Efforts to develop not only S. aureus vaccine but also prognosis or diagnosis tools are challenging tasks. That was the motivation point for the current thesis to identify potential antigen candidates for the aid of vaccine development using immunoproteomics approaches. From the earlier studies, passive immunisation with CP5, CP8, PNAG, ClfA, SdrG, alpha-hemolysin and active immunisation with IsdB, SEB, ClfA, CP5, CP8 were examined during preclinical trials and found to be the best examples for potential vaccine candidates. The antibody responses against S. aureus infections are heterogenous, still it is possible to identify the antibody signatures to a number of corresponding S. aureus antigens, whose abundance and presence could correlate to the disease state and may predict treatment outcome. To support this hypothesis, goals were set to develop and validate serological assay by indirect detection using suspension array technology (SAT). During the study, an antigen library of 140 recombinant S. aureus antigens was generated. Further serological assay were developed and validated to monitor the insights of antibody mediated humoral responses during S. aureus infection from various episodes of S. aureus infection. As an outcome, potential immunogenic antigen candidates were identified which may be used as candidates in active/passive vaccination and to stratify the patient. In total, three studies were carried out using serum and plasma samples from S. aureus nasal colonised healthy individuals (carriers and non-carriers) and bacteraemia patients (control, complicated and uncomplicated sepsis). Bead-based assays were performed and subsequent statistical analyses were done to identify immunogenic antigens that might discriminate between the different clinical status and outcome. Screening of healthy individuals (study-1) have shown significantly higher IgG responses against 14 antigens in S. aureus nasal carriers compared to non-carriers. Furthermore, the clonal complex 30 group of healthy carriers has shown significantly higher IgG responses against toxic shock syndrome toxin-1 (Tsst1) in comparison to non-clonal complex 30 healthy carriers. Study-2 have shown extensively higher IgG responses against 67 antigens in control samples compared to sepsis patients. 50% of the antigens eliciting different immune responses belonged to the extracellular components of S. aureus. The IgG responses against MSCRAMM proteins such as FnbA, FnbB, Efb-1 have been shown to be significantly higher in complicated sepsis. Study-3 have shown notably higher IgG responses against 8 antigens (Plc, SspB, IsaA, SEM, GlpQ, HlgC, SACOL0444, SACOL0985) at baseline in uncomplicated sepsis patients compared to patients subsequently developing complicated sepsis. In summary, the group of immunogenic antigens that have been identified in these studies using immunoproteomics approach could be a starting point for the development of S. aureus vaccines. Moreover, the suspension array technology approach facilitated the identification of new S. aureus antigen candidates in addition to earlier reports. The current results of this study support the hypothesis that it is possible to identify a serological response to potential S. aureus antigens that correlate to progression of S. aureus infections.
Die vorliegende Arbeit adressiert die Nutzbarkeit des humanen Speichelproteoms als diagnostisches Instrument im Kontext einer oralen Mukositis bei Kopf- und Halskarzinoms. Als häufigste Nebenwirkung einer Radio(chemo)therapie kann die Mukositis therapielimitierend sein und hat für betroffene Patienten meist eine Einschränkung ihrer Lebensqualität zur Folge. Trotz der guten Verfügbarkeit von Speichel existieren wenige Studien, welche zeigen, dass das Speichelproteom für die Diagnostik einer Krankheit oder zur Therapieentscheidung nutzbar ist. Das hat unter anderem seinen Grund in der Komplexität der massenspektrometrischen Methode. Die erste Veröffentlichung (Golatowski et al. 2013) erarbeitete deshalb einen Standard in der Probengewinnung von Speichel. Als Ergebnis steht die Empfehlung zur Nutzung eines Paraffin-Kaugummis, aufgrund des hohen Speichelvolumens und der guten Vergleichbarkeit mit der nichtstimulierten Salivation beim identifizierten Proteom. In einer zweiten Veröffentlichung (Jehmlich & Golatowski et al. 2014) wurden C18 Mikrosäulen verschiedener Hersteller bezüglich ihres Einflusses auf die Proteinidentifizierung verglichen. Die Säulen sind notwendig für die Entsalzung und Aufreinigung eines Peptidgemisches. Mit allen verwendeten Säulen konnten ähnliche Ergebnisse erzielt werden, wobei die ZipTip® µC18 sowie C18 Systeme der OASIS® HLB μElution 96er Well Platte und TopTip® C18 Pipettenspitzen leicht überlegen sind. In der letzten Arbeit (Jehmlich et al. 2015) wurden die gewonnenen Erkenntnisse genutzt, um die Speichelproben von Patienten mit Kopf- und Halskarzinom zu untersuchen. Insgesamt zeigten wir die Möglichkeit, alterierte Proteine zwischen zwei Patientengruppen massenspektrometrisch zu detektieren. Mit den gefundenen Daten konnte demonstrieren werden, dass massenspektrometrische Techniken geeignet sind, um schon vor Behandlungsbeginn Patienten zu identifizieren, die für die Entwicklung einer oralen Mukositis prädisponiert sind. Es ist hierbei die Proteinklasse der Metalloproteinasen hervorzuheben, da diese für einen therapeutischen Ansatz gegen Mukositis interessant sind. In Zukunft werden jedoch größere und voraussichtlich multizentrische Studien erforderlich sein, um ausreichend große Patientenkohorten zusammenzustellen und die Klassifikation speziell für Patienten ohne Mukositisrisiko sensitiver zu gestalten.
For the normal development of pregnancy, a balance between immune tolerance and defense is crucial. However, the mechanisms mediating such a balance are not fully understood. CD83 is a transmembrane protein whose expression has been linked to anti-inflammatory functions of T and B cells. The soluble form of CD83, released by cleavage of the membrane-bound protein, has strong anti-inflammatory properties and was successfully tested in different mouse models. It is assumed that this molecule contributes to the establishment of immune tolerance. Therefore, we postulated that the expression of CD83 is crucial for immune tolerance during pregnancy in mice. Here, we demonstrated that the membrane-bound form of CD83 was upregulated in T and B cells during allogeneic murine pregnancies. An upregulation was also evident in the main splenic B cell subtypes: marginal zone, follicular zone, and transitional B cells. We also showed that there was an augmentation in the number of CD83+ cells toward the end of pregnancy within splenic B and CD4+ T cells, while CD83+ dendritic cells were reduced in spleen and inguinal lymph nodes of pregnant mice. Additionally, B lymphocytes in late-pregnancy presented a markedly higher sensitivity to LPS in terms of CD83 expression and sCD83 release. Progesterone induced a dosis-dependent upregulation of CD83 on T cells. Our data suggest that the regulation of CD83 expression represents a novel pathway of fetal tolerance and protection against inflammatory threats during pregnancy.
Background: Despite optimized medical therapy, severe idiopathic pulmonary arterial hypertension (IPAH) is a devastating disease with a poor outcome. Autoantibodies have been detected in IPAH that can contribute to worsening of the disease. Objectives: The objective of this prospective, open-label, single-arm, multicenter trial was to evaluate the safety and efficacy of immunoadsorption (IA) as an add-on to optimized medical treatment for patients with IPAH. Methods: A total of 10 IPAH patients received IA over 5 days. Their clinical parameters, including hemodynamics measured by right heart catheter, were assessed at baseline and after 3 and 6 months. The primary endpoint was the change in pulmonary vascular resistance (PVR). Secondary endpoints included the change in 6-min walking distance, quality of life, safety, and plasma levels of IgG and autoantibodies. Results: The evaluation of the 10 IPAH patients (75% female; 51 ± 12 years; 166 ± 10 cm; WHO functional class III; 53% on combination therapy) revealed that IA was a safe procedure that efficiently removed IgG and autoantibodies from the circulation. After 3 months, the mean PVR improved significantly by 13.2% (p = 0.03) and the cardiac index improved by 13.1%, but no significant changes were found in 6-min walking distance. The quality of life physical functioning subscale score significantly improved after 6 months. The serious adverse events in 3 patients were possibly related to IA and included pneumonia, temporary disturbance in attention, and thrombocytopenia. Conclusions: IA as an add-on to targeted medical treatment for IPAH is a safe procedure with beneficial effects on hemodynamics, especially in patients with high levels of autoantibodies. Larger-scale controlled studies are needed to assess its efficacy in IPAH and to identify responders.
Resource and cost constraints in hospitals demand thorough planning of operating room schedules. Ideally, exact start times and durations are known in advance for each case. However, aside from the first case’s start, most factors are hard to predict. While the role of the start of the first case for optimal room utilization has been shown before, data for to-follow cases are lacking. The present study therefore aimed to analyze all elective surgery cases of a university hospital within 1 year in search of visible patterns. A total of 14,014 cases scheduled on 254 regular working days at a university hospital between September 2015 and August 2016 underwent screening. After eliminating 112 emergencies during regular working hours, 13,547 elective daytime cases were analyzed, out of which 4,346 ranked first, 3,723 second, and 5,478 third or higher in the daily schedule. Also, 36% of cases changed start times from the day before to 7:00 a.m., with half of these (52%) resulting in a delay of more than 15 min. After 7:00 a.m., 87% of cases started more than 10 min off schedule, with 26% being early and 74% late. Timeliness was 15 ± 72 min (mean ± SD) for first, 21 ± 84 min for second, and 25 ± 93 min for all to-follow cases, compared to preoperative day planning, and 21 ± 45, 23 ± 61, and 19 ± 74 min compared to 7:00 a.m. status. Start time deviations were also related to procedure duration, with cases of 61–90 min duration being most reliable (deviation 9.8 ± 67 min compared to 7:00 a.m.), regardless of order. In consequence, cases following after 61–90 min long cases had the shortest deviations of incision time from schedule (16 ± 66 min). Taken together, start times for elective surgery cases deviate substantially from schedule, with first and second cases falling into the highest mean deviation category. Second cases had the largest deviations from scheduled times compared to first and all to-follow cases. While planned vs. actual start times differ among specialties, cases of 61–90 min duration had the most reliable start times, with neither shorter nor longer cases seeming to improve timeliness of start times.
Activation of trace amine-associated receptor 1 (TAAR1) in endocrine pancreas is involved in weight regulation and glucose homeostasis. The purpose of this study was the identification and characterization of potential TAAR1 variants in patients with overweight/obesity and disturbed glucose homeostasis. Screening for TAAR1 variants was performed in 314 obese or overweight patients with impaired insulin secretion. The detected variants were functionally characterized concerning TAAR1 cell surface expression and signaling properties and their allele frequencies were determined in the population-based Study of Health in Pomerania (SHIP). Three heterozygous carriers of the single nucleotide missense variants p.Arg23Cys (R23C, rs8192618), p.Ser49Leu (S49L, rs140960896), and p.Ille171Leu (I171L, rs200795344) were detected in the patient cohort. While p.Ser49Leu and p.Ille171Leu were found in obese/overweight patients with slightly impaired glucose homeostasis, p.Arg23Cys was identified in a patient with a complete loss of insulin production. Functional in vitro characterization revealed a like wild-type function for I171L, partial loss of function for S49L and a complete loss of function for R23C. The frequency of the R23C variant in 2018 non-diabetic control individuals aged 60 years and older in the general population-based SHIP cohort was lower than in the analyzed patient sample. Both variants are rare in the general population indicating a recent origin in the general gene pool and/or the consequence of pronounced purifying selection, in line with the obvious detrimental effect of the mutations. In conclusion, our study provides hints for the existence of naturally occurring TAAR1 variants with potential relevance for weight regulation and glucose homeostasis.
Existing literature evidences the association between adolescents’ school self-concept and engagement, both concepts being related to students’ perception of teachers and peers as motivators. However, few longitudinal studies explore the interplay of these factors. The present study aims to close this gap, applying latent cross-lagged panel design to two-wave data from German adolescent students [1088 8th grade students at T1 (Mage = 13.7, SD = 0.53; 53.9% girls) and 845 9th grade students at T2 (Mage = 14.86; SD = 0.57; 55% girls) from the initial sample]. Besides direct effects, three cross-lagged over-time paths were found to be significant: students’ perception of peers as positive motivators (PPMs) at the beginning of 8th grade (T1) positively predicts their behavioral school engagement at the end of 9th grade (T2), as well as emotional school engagement at the beginning of 8th grade positively predicts students’ perception of PPMs 1.5 years later. Furthermore, behavioral school engagement at T1 functions as a predictor of a student’s school self-concept at T2.
Longitudinal Effects of Student-Perceived Classroom Support on Motivation – A Latent Change Model
(2017)
This two-wave longitudinal study examined how developmental changes in students’ mastery goal orientation, academic effort, and intrinsic motivation were predicted by student-perceived support of motivational support (support for autonomy, competence, and relatedness) in secondary classrooms. The study extends previous knowledge that showed that support for motivational support in class is related to students’ intrinsic motivation as it focused on the developmental changes of a set of different motivational variables and the relations of these changes to student-perceived motivational support in class. Thus, differential classroom effects on students’ motivational development were investigated. A sample of 1088 German students was assessed in the beginning of the school year when students were in grade 8 (Mean age = 13.70, SD = 0.53, 54% girls) and again at the end of the next school year when students were in grade 9. Results of latent change models showed a tendency toward decline in mastery goal orientation and a significant decrease in academic effort from grade 8 to 9. Intrinsic motivation did not decrease significantly across time. Student-perceived support of competence in class predicted the level and change in students’ academic effort. The findings emphasized that it is beneficial to create classroom learning environments that enhance students’ perceptions of competence in class when aiming to enhance students’ academic effort in secondary school classrooms.
Background
Signs of an inflammatory process have been described in major depression.
Methods
In a double-blind, randomized study of celecoxib or placebo add-on to reboxetine in 40 depressed patients, celecoxib treatment has beneficial effects. In order to evaluate the tryptophan/kynurenine metabolism and to identify predictors for remission, tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN) were estimated in the serum of 32 patients before and after treatment and in a group of 20 healthy controls.
Results
KYN levels were significantly lower in patients (p = 0.008), and the QUIN/KYN ratios were significantly higher (p = 0.028). At baseline, the higher KYN/TRP ratio was predictive for remission during celecoxib add-on treatment (p = 0.04) as well as for remission in the overall patient group (p = 0.01). In the placebo group, remitters showed a higher KYNA/QUIN ratio (p = 0.032). In the overall group, remitters showed lower KYNA/KYN (p = 0.035) and QUIN/KYN (p = 0.011) ratios. The lower the formation of downstream metabolites, especially QUIN, the better the treatment outcome.
Conclusion
The high KYN/TRP ratio predicted remission after treatment with celecoxib in this small sample of depressed patients. Eventually, the KYN/TRP ratio might be a marker for those patients, which benefit from an additional anti-inflammatory treatment.
Purpose
Due to the demographic change morbidity raises the demand for medical hospital services as well as a need for medical specialization, while economic and human resources are diminishing. Unlike other industries hospitals do not have sufficient data and adequate models to relate growing demands and increasing performance to growth in staff capacity and to increase in staff competences.
Method
Based on huge medical data sample covering the years from 2010 to 2014 with more than 150,000 operations of the Department for Anesthesiology at the University Hospital Muenster, Germany, comparisons are drawn between the development of medical services and the development of personnel capacity and expertise.
Results
The numbers of surgical operations increased by 21% and “skin incision to closure” time by 17%. Simultaneously, personnel capacity grew by 16% largely resting upon recruiting first-time employees. Expertise measured as “years of professional experience” dwindled from 10 years to 5.4 years on average and staff turnover accelerated.
Conclusion
Static benchmark data collected at fixed reference dates do not sufficiently reflect the nexus between capacity and competence and do not reflect the dynamic changes in a hospital’s requirements for expertise and specialization, at all. Staff turnover leads to a loss of experience, which jeopardizes patient safety and hampers medical specialization. In consequence of the dramatic shortage of medical specialists, drop-off rates must be reduced and retention rates must be increased. To that end, working conditions need to be fundamentally converted for a multigeneration, multicultural, and increasingly female workforce.
Introduction
Primary immunodeficiency disorders (PIDs) are a heterogeneous group of more than 200 rare diseases. Timely diagnosis is of uttermost importance. Therefore, we aimed to develop a diagnostic questionnaire with computerized pattern-recognition in order to support physicians to identify suspicious patient histories.
Materials and methods
Standardized interviews were conducted with guardians of children with PID. The questionnaire based on parental observations was developed using Colaizzis’ framework for content analysis. Answers from 64 PID patients and 62 controls were analyzed by data mining methods in order to make a diagnostic prediction. Performance was evaluated by k-fold stratified cross-validation.
Results
The diagnostic support tool achieved a diagnostic sensitivity of up to 98%. The analysis of 12 interviews revealed 26 main phenomena observed by parents in the pre-diagnostic period. The questions were systematically phrased and selected resulting in a 36-item questionnaire. This was answered by 126 patients with or without PID to evaluate prediction. Item analysis revealed significant questions.
Discussion
Our approach proved suitable for recognizing patterns and thus differentiates between observations of PID patients and control groups. These findings provide the basis for developing a tool supporting physicians to consider a PID with a questionnaire. These data support the notion that patient’s experience is a cornerstone in the diagnostic process.
Structural alterations in the corpus callosum (CC), the major white matter tract connecting functionally related brain regions in the two hemispheres, have been shown to be associated with emotional instability, impulsivity and suicidality in various mental disorders. To explore whether structural alterations of the CC would be similarly associated with emotional instability, impulsivity and suicidality in borderline personality disorder (BPD), we used diffusion tensor imaging (DTI) to assess the structural integrity of the CC in 21 BPD and 20 healthy control (HC) participants. Our hypothesis-driven analyses revealed a positive correlation between BPD participants’ suicidal behavior and fractional anisotropy (FA) in the splenium and genu of the CC and a negative correlation between BPD participants’ suicidal behavior and mean diffusivity (MD) in the splenium of CC. Our exploratory analyses suggested that suicidal BPD participants showed less FA and more MD in these regions than HC participants but that non-suicidal BPD participants showed similar FA and MD in these regions as HC participants. Taken together, our findings suggest an association between BPD participants’ suicidal behavior and structural alterations in regions of the CC that are connected with brain regions implicated in emotion regulation and impulse control. Structural alterations of the CC may, thus, account for deficits in emotion regulation and impulse control that lead to suicidal behavior in BPD. However, these findings should be considered as preliminary until replicated and extended in future studies that comprise larger samples of suicidal and non-suicidal BPD participants.
In healthy older adults, resveratrol supplementation has been shown to improve long-term glucose control, resting-state functional connectivity (RSFC) of the hippocampus, and memory function. Here, we aimed to investigate if these beneficial effects extend to individuals at high-risk for dementia, i.e., patients with mild cognitive impairment (MCI). In a randomized, double-blind interventional study, 40 well-characterized patients with MCI (21 females; 50–80 years) completed 26 weeks of resveratrol (200 mg/d; n = 18) or placebo (1,015 mg/d olive oil; n = 22) intake. Serum levels of glucose, glycated hemoglobin A1c and insulin were determined before and after intervention. Moreover, cerebral magnetic resonance imaging (MRI) (3T) (n = 14 vs. 16) was conducted to analyze hippocampus volume, microstructure and RSFC, and neuropsychological testing was conducted to assess learning and memory (primary endpoint) at both time points. In comparison to the control group, resveratrol supplementation resulted in lower glycated hemoglobin A1c concentration with a moderate effect size (ANOVARM p = 0.059, Cohen's d = 0.66), higher RSFC between right anterior hippocampus and right angular cortex (p < 0.001), and led to a moderate preservation of left anterior hippocampus volume (ANOVARM p = 0.061, Cohen's d = 0.68). No significant differences in memory performance emerged between groups. This proof-of-concept study indicates for the first-time that resveratrol intake may reduce glycated hemoglobin A1c, preserves hippocampus volume, and improves hippocampus RSFC in at-risk patients for dementia. Larger trials with longer intervention time should now determine if these benefits can be validated and extended to cognitive function.
Multiple evidence in animal models and in humans suggest a beneficial role of cold physical
plasma in wound treatment. Yet, risk assessment studies are important to further foster therapeutic
advancement and acceptance of cold plasma in clinics. Accordingly, we investigated the long-term
side effects of repetitive plasma treatment over 14 consecutive days in a rodent full-thickness ear
wound model. Subsequently, animals were housed for 350 days and sacrificed thereafter. In blood,
systemic changes of the pro-inflammatory cytokines interleukin 1β and tumor necrosis factor α
were absent. Similarly, tumor marker levels of α-fetoprotein and calcitonin remained unchanged.
Using quantitative PCR, the expression levels of several cytokines and tumor markers in liver,
lung, and skin were found to be similar in the control and treatment group as well. Likewise,
histological and immunohistochemical analysis failed to detect abnormal morphological changes
and the presence of tumor markers such as carcinoembryonic antigen, α-fetoprotein, or the neighbor
of Punc 11. Absence of neoplastic lesions was confirmed by non-invasive imaging methods such as
anatomical magnetic resonance imaging and positron emission tomography-computed tomography.
Our results suggest that the beneficial effects of cold plasma in wound healing come without apparent
side effects including tumor formation or chronic inflammation.