Study area, the Eskipazar Basin, is located in the western part of the North Anatolian Fault System. It is a 3-5 km wide, 10 km long and NWSE trending depression, bounded by a complex array of oblique-slip normal faults and strike-slip faults. The Eskipazar Basin is interpreted to be a superimposed basin. The basin fill is composed of two different units deposited under the control of different tectonic regimes, namely the paleotectonic and the neotectonic regimes. The latest paleotectonic fill of the basin is the fluvio-lacustrine deposits of the paleotectonic Eskipazar formation. This formation is unconformably overlain by a group of neotectonic units namely, the Budaklar, the Karkin and the imanlar formations. The unconformity in between these paleotectonic and neotectonic units represents the time interval during which the paleotectonic period comes to end and the neotectonic period started. Thus, onset age of the strike-slip neotectonic regime in the study area is Late Pliocene (&amp / #8764 / 2.6 My). Common basin margin-bounding faults of the Eskipazar Basin are the Kadilar fault set, the Beytarla Fault Zone, the Budaklar fault set, the Arslanlar fault set, the Dibek fault, the Karkin fault, the Boztepe fault and the Acisu fault. These faults display well preserved fault scarps, in places. Morphological expressions of these faults and their geometrical relationships to regional stress system indicate that these faults are mostlystrike-slip faults with normal component. However the Kadilar fault set displays a different characteristic, being the major fault controlling the basin to the west and it is indeed an oblique slip normal fault. Long term seismicity and their epicentral distribution in and very close to the study area suggest that the Eskipazar basin is located in an area of seismic quiescence, nevertheless the morphotectonic expressions of the faults exposing in the basin suggest that these faults are active. Since the most of settlements are located on different lithologies of poorly consolidated deposits of the Eskipazar formation susceptible to landslides, the area is open to future earthquake hazard. Therefore, structures and settlements have to be constructed on strong ground away from active faults.

Background: Community acquired pneumonia (CAP) is a high incidence disease resulting in about 260,000 hospital admissions per year in Germany, more than myocardial infarction or stroke. Worldwide, CAP is the most frequent infectious disease with high lethality ranging from 1.2 % in those 20–29 years old to over 10 % in patients older than 70 years, even in industrial nations. CAP poses numerous medical challenges, which the PROGRESS (Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) network aims to tackle: Operationalization of disease severity throughout the course of disease, outcome prediction for hospitalized patients and prediction of transitions from uncomplicated CAP to severe CAP, and finally, to CAP with sepsis and organ failure as a life-threatening condition. It is a major aim of PROGRESS to understand and predict patient heterogeneity regarding outcome in the hospital and to develop novel treatment concepts. Methods: PROGRESS was designed as a clinical, observational, multi-center study of patients with CAP requiring hospitalization. More than 1600 patients selected for low burden of co-morbidities have been enrolled, aiming at a total of 3000. Course of disease, along with therapy, was closely monitored by daily assessments and long-term follow-up. Daily blood samples allow in depth molecular-genetic characterization of patients. We established a well-organized workflow for sample logistics and a comprehensive data management system to collect and manage data from more than 50 study centers in Germany and Austria. Samples are stored in a central biobank and clinical data are stored in a central data base which also integrates all data from molecular assessments. Discussion: With the PROGRESS study, we established a comprehensive data base of high quality clinical and molecular data allowing investigation of pressing research questions regarding CAP. In-depth molecular characterization will contribute to the discovery of disease mechanisms and establishment of diagnostic and predictive biomarkers. A strength of PROGRESS is the focus on younger patients with low burden of co-morbidities, allowing a more direct look at host biology with less confounding. As a resulting limitation, insights from PROGRESS will require validation in representative patient cohorts to assess clinical utility. Trial registration: The PROGRESS study was retrospectively registered on May 24th, 2016 with ClinicalTrials.gov: NCT02782013

Purpose: To investigate if apparent diffusion coefficient (ADC) values within primary central nervous system lymphoma correlate with cellularity and proliferative activity in corresponding histological samples. Materials and Methods: Echo-planar diffusion-weighted magnetic resonance images obtained from 21 patients with primary central nervous system lymphoma were reviewed retrospectively. Regions of interest were drawn on ADC maps corresponding to the contrast enhancing parts of the tumors. Biopsies from all 21 patients were histologically analyzed. Nuclei count, total nuclei area and average nuclei area were measured. The proliferation index was estimated as Ki-67 positive nuclei divided by total number of nuclei. Correlations of ADC values and histopathologic parameters were determined statistically. Results: Ki-67 staining revealed a statistically significant correlation with ADCmin (r = -0.454, p = 0.038), ADCmean (r = -0.546, p = 0.010) and ADCmax (r = -0.515, p = 0.017). Furthermore, ADCmean correlated in a statistically significant manner with total nucleic area (r = -0.500, p = 0.021). Conclusion: Low ADCmin, ADCmean and ADCmax values reflect a high proliferative activity of primary cental nervous system lymphoma. Low ADCmean values—in concordance with several previously published studies—indicate an increased cellularity within the tumor.

Background: Subjective cognitive decline (SCD), i.e., the self-perceived feeling of worsening cognitive function, may be the first notable syndrome of preclinical Alzheimer’s disease and other dementias. However, not all individuals with SCD progress. Stability of SCD, i.e., repeated reports of SCD, could contribute to identify individuals at risk, as stable SCD may more likely reflect the continuous neurodegenerative process of Alzheimer’s and other dementias. Methods: Cox regression analyses were used to assess the association between stability of SCD and progression to MCI and dementia in data derived from the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). Results: Of 453 cognitively unimpaired individuals with a mean age of 80.5 years (SD = 4.2), 139 (30.7 %) reported SCD at baseline. Over the study period (M = 4.8 years, SD = 2.2), 84 (18.5 %) individuals had stable SCD, 195 (43.1 %) unstable SCD and 174 (38.4 %) never reported SCD. Stable SCD was associated with increased risk of progression to MCI and dementia (unadjusted HR = 1.8, 95 % CI = 1.2–2.6; p < .01), whereas unstable SCD yielded a decreased progression risk (unadjusted HR = 0.5, 95 % CI = 0.4–0.7; p < .001) compared to no SCD. When adjusted for baseline cognitive functioning, progression risk in individuals with stable SCD was significantly increased in comparison to individuals with unstable SCD, but not compared to individuals without SCD. Conclusions: Our results, though preliminary, suggest that stable SCD, i.e., repeated reports of SCD, may yield an increased risk of progression to MCI and dementia compared to unstable SCD. Baseline cognitive scores, though within a normal range, seem to be a driver of progression in stable SCD. Future research is warranted to investigate whether stability could hold as a SCD research feature.

Background: Tumor cells are highly dependent on glucose even in the presence of oxygen. This concept called the Warburg effect is a hallmark of cancer and strategies are considered to therapeutically exploit the phenomenon such as ketogenic diets. The success of such strategies is dependent on a profound understanding of tumor cell metabolism. With new techniques it is now possible to thoroughly analyze the metabolic responses to the withdrawal of substrates and their substitution by others. In the present study we used gas chromatography coupled to mass spectrometry (GC-MS) to analyze how glioblastoma brain tumor cells respond metabolically when glucose is withdrawn and substituted by pyruvate. Methods: Glioblastoma brain tumor cells were cultivated in medium with high (25 mM), medium (11 mM) or low (5.5 mM) glucose concentration or with pyruvate (5 mM). After 24 h GC-MS metabolite profiling was performed. Results: The abundances of most metabolites were dependent on the supply of glucose in tendency but not in a linear manner indicating saturation at high glucose. Noteworthy, a high level of sorbitol production and release was observed at high concentrations of glucose and high release of alanine, aspartate and citrate were observed when glucose was substituted by pyruvate. Intermediates of the TCA cycle were present under all nutritional conditions and evidence was found that cells may perform gluconeogenesis from pyruvate. Conclusions: Our experiments reveal a high plasticity of glioblastoma cells to changes in nutritional supply which has to be taken into account in clinical trials in which specific diets are considered for therapy.

High-intensity interval training (HIIT) consists of short intervals of exercise at high intensity intermitted by intervals of lower intensity and is associated with improvement of body composition and metabolic health in adults. Studies in overweight adolescents are scarce. We conducted a randomized controlled trial in overweight adolescents to compare acceptance and attendance of HIIT with or without weekly motivational encouragement through text messages and access to a study website. HIIT was offered for six months (including summer vacation) twice a week (60 min/session). Participation rates were continuously assessed and acceptance was measured. Clinical parameters were assessed at baseline and after six months. Twenty-eight adolescents participated in this study (age 15.5 +/- 1.4; 54% female). The standard deviation score for body mass index over all participants was 2.33 at baseline and decreased by 0.026 (95% CI - 0.048 to 0.10) units, p = 0.49. Waist to height ratio was 0.596 at baseline and decreased by 0.013 (95% CI 0.0025 to 0.024), p = 0.023. Participation within the first two months ranged from 65% to 75%, but fell to 15% within the last three months. Attendance in the intervention group was 14% (95% CI - 8 to 37), p = 0.18, higher than the control group. Overall program content was rated as \"good\" by participants, although high drop-out rates were observed. Summer months constitute a serious problem regarding attendance. The use of media support has to be assessed further in appropriately powered trials.

Study area, the Yeni&ccedil / aga Basin, is located in the western part of the North Anatolian Fault System. It is a 1-5-km-wide and 14-km-long WSWENE- trending depression bounded by a complex array of strike-slip faults. The Yeni&ccedil / aga Basin is interpreted to be a fault &ndash / wedge basin with the North Anatolian Fault&rsquo / s System Master Strand, namely the Gerede Fault, cutting across the basin itself. The basin and its surroundings contain mainly two groups of rock units namely the paleotectonic units and the neotectonic units. Paleotectonic units, which are deposited or formed during different phase(s) of tectonic regimes, comprise several formations. The most important one of these formations is the Upper Miocene &ndash / Lower Pliocene Eskipazar formation which plays an important role in understanding the evolutionary history of the basin. Neotectonic unit deposited under the control of today&rsquo / s tectonic regime is the Plio-Quaternary Betem&uuml / rl&uuml / formation.v Betem&uuml / rl&uuml / formation unconformably overlies the paleotectonic Eskipazar formation throughout the study area and the unconformity separating these two units corresponds to the time interval during which the paleotectonic stress regime changed into the neotectonic stress regime. Thus, onset age of the strike-slip neotectonic regime in the study area is Late Pliocene (~ 2,6 My). Common basin margin-bounding faults of the Yeni&ccedil / aga Basin are, the ASagi Kuldan fault, the Aksu fault, the izmirli fault set, the Saray&ccedil / ali fault, the Degirmen fault set and the Hamzabey fault set. They display well-preserved fault scarps in places. Morphological expressions of these faults and their geometrical relationships with the local stress regime indicate that these faults are mainly strike-slip and oblique-slip faults. Morphotectonic expressions of the faults exposing within the study area indicate that these faults are active. Most of the settlements within the study area are located on water-saturated loose basin fill nearby the active faults. Hence, these are open to future earthquake hazards. Therefore, structures and settlements have to be constructed on strong grounds away from the active faults.

Background: Community acquired pneumonia (CAP) is a high incidence disease resulting in about 260,000 hospital admissions per year in Germany, more than myocardial infarction or stroke. Worldwide, CAP is the most frequent infectious disease with high lethality ranging from 1.2 % in those 20–29 years old to over 10 % in patients older than 70 years, even in industrial nations. CAP poses numerous medical challenges, which the PROGRESS (Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) network aims to tackle: Operationalization of disease severity throughout the course of disease, outcome prediction for hospitalized patients and prediction of transitions from uncomplicated CAP to severe CAP, and finally, to CAP with sepsis and organ failure as a life-threatening condition. It is a major aim of PROGRESS to understand and predict patient heterogeneity regarding outcome in the hospital and to develop novel treatment concepts. Methods: PROGRESS was designed as a clinical, observational, multi-center study of patients with CAP requiring hospitalization. More than 1600 patients selected for low burden of co-morbidities have been enrolled, aiming at a total of 3000. Course of disease, along with therapy, was closely monitored by daily assessments and long-term follow-up. Daily blood samples allow in depth molecular-genetic characterization of patients. We established a well-organized workflow for sample logistics and a comprehensive data management system to collect and manage data from more than 50 study centers in Germany and Austria. Samples are stored in a central biobank and clinical data are stored in a central data base which also integrates all data from molecular assessments. Discussion: With the PROGRESS study, we established a comprehensive data base of high quality clinical and molecular data allowing investigation of pressing research questions regarding CAP. In-depth molecular characterization will contribute to the discovery of disease mechanisms and establishment of diagnostic and predictive biomarkers. A strength of PROGRESS is the focus on younger patients with low burden of co-morbidities, allowing a more direct look at host biology with less confounding. As a resulting limitation, insights from PROGRESS will require validation in representative patient cohorts to assess clinical utility. Trial registration: The PROGRESS study was retrospectively registered on May 24th, 2016 with ClinicalTrials.gov: NCT02782013

Purpose: To investigate if apparent diffusion coefficient (ADC) values within primary central nervous system lymphoma correlate with cellularity and proliferative activity in corresponding histological samples. Materials and Methods: Echo-planar diffusion-weighted magnetic resonance images obtained from 21 patients with primary central nervous system lymphoma were reviewed retrospectively. Regions of interest were drawn on ADC maps corresponding to the contrast enhancing parts of the tumors. Biopsies from all 21 patients were histologically analyzed. Nuclei count, total nuclei area and average nuclei area were measured. The proliferation index was estimated as Ki-67 positive nuclei divided by total number of nuclei. Correlations of ADC values and histopathologic parameters were determined statistically. Results: Ki-67 staining revealed a statistically significant correlation with ADCmin (r = -0.454, p = 0.038), ADCmean (r = -0.546, p = 0.010) and ADCmax (r = -0.515, p = 0.017). Furthermore, ADCmean correlated in a statistically significant manner with total nucleic area (r = -0.500, p = 0.021). Conclusion: Low ADCmin, ADCmean and ADCmax values reflect a high proliferative activity of primary cental nervous system lymphoma. Low ADCmean values—in concordance with several previously published studies—indicate an increased cellularity within the tumor.

Background: Lysosomal storage diseases (LSD) often manifest with cherry red macular spots. Diagnosis is based on clinical features and specific biochemical and enzymatic patterns. In uncertain cases, genetic testing with next generation sequencing can establish a diagnosis, especially in milder or atypical phenotypes. We report on the diagnostic work-up in a boy with sialidosis type I, presenting initially with marked cherry red macular spots but non-specific urinary oligosaccharide patterns and unusually mild excretion of bound sialic acid. Methods: Biochemical, enzymatic and genetic tests were performed in the patient. The clinical and electrophysiological data was reviewed and a genotype-phenotype analysis was performed. In addition a systematic literature review was carried out. Case report and results: Cherry red macular spotswere first noted at 6 years of age after routine screening myopia. Physical examination, psychometric testing, laboratory investigations aswell as cerebralMRIwere unremarkable at 9 years of age. So far no clinical myoclonic seizures occurred, but EEG displays generalized epileptic discharges and visual evoked potentials are prolonged bilaterally. Urine thin layer chromatography showed an oligosaccharide pattern compatible with different LSD including sialidosis, galactosialidosis, GM1 gangliosidosis or mucopolysaccharidosis type IV B. Urinary bound sialic acid excretion was mildly elevated in spontaneous and 24 h urine samples. In cultured fibroblasts, α-sialidase activity was markedly decreased to b1%; however, bound and free sialic acid were within normal range. Diagnosis was eventually established by multigene panel next generation sequencing of genes associated to LSD, identifying two novel, compound heterozygous variants in NEU1 gene (c.699CNA, p.S233R in exon 4 and c.803ANG; p.Y268C in Exon 5 in NEU1 transcriptNM_000434.3), leading to amino acid changes predicted to impair protein function. Discussion: Sialidosis should be suspected in patients with cherry red macular spots, even with non-significant urinary sialic acid excretion. Multigene panel next generation sequencing can establish a definite diagnosis, allowing for counseling of the patient and family.