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Schulterschmerzen gehören zu den häufigsten Gelenkbeschwerden. Da in der Schulter auf engstem Raum viele Muskeln, Bänder, Sehnen, Schleimbeutel und Knochen zusammenarbeiten, können die Beschwerden verschiedene Gründe haben. Die genaue Ursache herauszufinden, gelingt nicht immer. Die Dauer der Erkrankung liegt zwischen 3 Monaten und 1 Jahr. Die Ursachen für das Auftreten und die Dauer der Erkrankung sind vielfältig und mithilfe der ganzheitlichen Sichtweise der osteopathischen Medizin gut zu erfassen und zu behandeln. Der Erfolg ist abhängig von der Schwere der Schädigung, der Auswahl von adäquaten Behandlungsmethoden und von der Compliance des Patienten.

Forest landowners are an important target audience for many state Extension programs. Acknowledging the differences and associations between landownership values, characteristics, and educational preferences of forest landowners should lead to improvement of educational programs and ensuring that educational needs are being met. Through an internet-based survey of forest landowners four distinct landowner typologies were identified based on respondents’ reason for owning forestland. Results also identified the educational needs and barriers to meeting these needs for the landowners. Creating typologies based on attitudinal responses will allow for a more focused approach to developing educational products and services to meet landowner needs.

Analysis of CD4+CD25+ cells in immune cell populations isolated from primary tumors after neoadjuvant treatment.

Figure Legends for Figure S1-S5

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and natural killier (NK) cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells. Local T-cell activation was confirmed by increased tumor infiltration with CD103+CD8+ T cells and neoantigen-specific CD8 T lymphocytes against the marker neoepitope LAMA4-G1254V. To achieve effective prevention of distant metastases in a complementary approach, we blocked the NK-cell checkpoint CD96, an inhibitory NK-cell receptor that binds CD155, which was abundantly expressed in primary PDAC and metastases of human patients. In gemcitabine-treated mice, neoadjuvant PD-1 blockade followed by adjuvant inhibition of CD96 significantly prevented relapse of PDAC, allowing for long-term survival. In summary, our results show in an aggressively growing transgenic mouse model of PDAC that the coordinated activation of both innate and adaptive immunity can effectively reduce the risk of tumor recurrence after surgery, facilitating long-term remission of this lethal disease.Significance: Coordinated neoadjuvant and adjuvant immunotherapies reduce the risk of disease relapse after resection of murine PDAC, suggesting this concept for future clinical trials. Cancer Res; 78(2); 475–88. ©2017 AACR.

In COVID-19 neurological alterations are noticed during the systemic viral infection. Various pathophysiological mechanisms on the central nervous system (CNS) have been suggested in the past two years, including the viral neurotropism hypothesis. Nevertheless, neurological complications can also occur independent of neurotropism and at different stages of the disease and may be persistent.Previous autopsy studies of the CNS from patients with severe COVID-19 show infiltration of macrophages and T lymphocytes, especially in the perivascular regions as well as pronounced microglial activation, but without signs of viral encephalitis.However, there is an ongoing debate about long-term changes and cytotoxic effects in the CNS due to the systemic inflammation.Here, we show the brain-specific host response during and after COVID-19. We profile single-nucleus transcriptomes and proteomes of brainstem tissue from deceased COVID-19 patients who underwent rapid autopsy. We detect a disease phase-dependent inflammatory type-I interferon response in acute COVID-19 cases. Integrating single-nucleus RNA sequencing and spatial transcriptomics, we could localize two patterns of reaction to severe systemic inflammation. One neuronal with direct focus on cranial nerve nuclei and one diffusely affecting the whole brainstem, the latter reflecting a bystander effect that spreads throughout the vascular unit and alters the transcriptional state of oligodendrocytes, microglia and astrocytes.Our results indicate that even without persistence of SARS-CoV-2 in the CNS, the tissue activates highly protective mechanisms, which also cause functional disturbances that may explain the neurological symptoms of COVID-19, triggered by strong systemic type-I IFN signatures in the periphery.

Stream ecosystems are impacted by multiple stressors in complex spatio-temporal interactions. The lack of understanding of these interactions and impacts hampers the successful restoration of streams and rivers. The German Research Foundation-funded collaborative research centre RESIST (https://sfb-resist.de/index.html) aims to disentangle these complex dependencies applying a novel theoretical framework: the ‘Asymmetric Response Concept’. The concept hypothesizes that degradation and recovery processes depend on different, non-linear biotic and abiotic interactions between stressors, environmental variables, and organisms. Therefore, unprecedented data and information are required which are collected through lab and field experiments, species sampling, observations of environmental variables and modelling.High-resolution ecohydrological modelling is a core component in this process to provide historic information on water quality in two mesoscale catchments (Boye with 124km² and Kinzig with 1065km²) in Germany. Due to history, storage- and hysteresis effects in the hydrologic system, the spatio-temporal dynamics of in-stream environmental variables follow an asymmetric function to degradation and recovery. The model SWAT+ (Soil and Water Assessment Tool) is therefore applied to simulate streamflow as well as the water quality components temperature, oxygen, nitrogen components and salinity (TONS) at more than 20 sites in each catchment.We present the conceptual framework of the approach, including data sources and data collection, model parameterization, required code adaptations, calibration techniques and expected results.

Freshwater resources as a key aspect of socio-economic development, provide a large number of services in human and environmental systems. Nevertheless, human appropriation of these water resources and the modification of landscapes lead to potential threats on water availability and quality from local to global scales. The Inle Lake in Myanmar is an economically, traditionally, and ecologically important freshwater ecosystem that faced severe degradation from the 2000s. In its catchment area, a Driver-Pressure-State-Impact-Response (DPSIR) framework is applied for an assessment period of 30 years from 1990 to 2020. The analysis results are complemented with a socio-hydrological survey, water quality assessment, a land use classification based on ground truth and satellite data, and hydrologic models. The resulting land use changes, − 13% forest, + 13% agriculture, and + 5% urban areas, lead to increased water yield, decreased evapotranspiration, and increased sediment yield. Together with other drivers and pressures such as climate change and anthropogenic pollution, these human activities are major threats for freshwater resources and the ecosystem. However, the existing awareness of the local population for the environmental degradation is obstructed by national and international crises and responses to negative developments can accelerate degradation if they are unplanned and short-term solutions. Our study shows that environmental degradation processes have a complex nature and can only be tackled in a coordinated way with a long-term perspective. DPSIR is a suitable approach to assess human-water dynamics and disentangle the complex interconnectedness of social and environmental systems in freshwater ecosystems, even in data-scarce regions.

Clear cell foci (CCF) of the liver are considered to be pre-neoplastic lesions of hepatocellular adenomas and carcinomas. They are hallmarked by glycogen overload and activation of AKT (v-akt murine thymoma viral oncogene homolog)/mTOR (mammalian target of rapamycin)-signaling. Here, we report the transcriptome and proteome of CCF extracted from human liver biopsies by laser capture microdissection. We found 14 genes and 22 proteins differentially expressed in CCF and the majority of these were expressed at lower levels in CCF. Using immunohistochemistry, the reduced expressions of STBD1 (starch-binding domain-containing protein 1), USP28 (ubiquitin-specific peptidase 28), monad/WDR92 (WD repeat domain 92), CYB5B (Cytochrome b5 type B), and HSPE1 (10 kDa heat shock protein, mitochondrial) were validated in CCF in independent specimens. Knockout of Stbd1, the gene coding for Starch-binding domain-containing protein 1, in mice did not have a significant effect on liver glycogen levels, indicating that additional factors are required for glycogen overload in CCF. Usp28 knockout mice did not show changes in glycogen storage in diethylnitrosamine-induced liver carcinoma, demonstrating that CCF are distinct from this type of cancer model, despite the decreased USP28 expression. Moreover, our data indicates that decreased USP28 expression is a novel factor contributing to the pre-neoplastic character of CCF. In summary, our work identifies several novel and unexpected candidates that are differentially expressed in CCF and that have functions in glycogen metabolism and tumorigenesis.

// Silvia Ribback 1 , Jenny Sonke 1 , Andrea Lohr 1 , Josephine Frohme 1 , Kristin Peters 1 , Johannes Holm 1 , Michele Peters 1 , Antonio Cigliano 1 , Diego F. Calvisi 1 and Frank Dombrowski 1 1 Institut fur Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany Correspondence to: Silvia Ribback, email: silvia.ribback@uni-greifswald.de Keywords: preneoplastic foci; hepatocarcinogenesis; intraportal pancreatic islet transplantation; clear cell foci of altered hepatocytes; AKT/mTOR Received: July 06, 2017 Accepted: October 05, 2017 Published: November 01, 2017 ABSTRACT Aims: The intraportal pancreatic islet transplantation (IPIT) model of diabetic rats is an insulin mediated model of hepatocarcinogenesis characterized by the induction of clear cell foci (CCF) of altered hepatocytes, which are pre-neoplastic lesions excessively storing glycogen (glycogenosis) and exhibiting activation of the AKT/mTOR protooncogenic pathway. In this study, we transferred the IPIT model to the mouse and combined it with the knockout of the transcription factor carbohydrate responsive element binding protein (chREBP). Methods : C57BL/6J Wild-type (WT) and chREBP-knockout (chREBP-KO) mice (n = 297) were matched to 16 groups (WT/ chREBP-KO, experimental/control, streptozotocine-induced diabetic/not diabetic, one/four weeks). Experimental groups received the intraportal transplantation of 70 pancreatic islets. Liver and pancreatic tissue was examined using histology, morphometry, enzyme- and immunohistochemistry and electron microscopy. Results : CCF emerged in the liver acini downstream of the transplanted islets. In comparison to WT lesions, CCF of chREBP-KO mice displayed more glycogen accumulation, reduced activity of the gluconeogenic enzyme glucose-6-phosphatase, decreased glycolysis, lipogenesis and reduced levels of the AKT/mTOR cascade members. Proliferative activity of CCF was ~two folds higher in WT mice than in chREBP-KO mice. Conclusions : The IPIT model is applicable to mice, as murine CCF resemble preneoplastic liver lesions from this hepatocarcinogenesis model in the rat in terms of morphological, metabolic and molecular alterations and proliferative activity, which is diminished after chREBP knockout. chREBP appears to be an essential component of AKT/mTOR mediated cell proliferation and the metabolic switch from a glycogenotic to lipogenic phenotype in precursor lesions of hepatocarcinogenesis.

ZusammenfassungPatienten mit Morbus Parkinson können mit regelmäßigem Laufbandtraining Ganggeschwindigkeit und Schrittlänge verbessern und damit dem typischen krankheitsbedingten Gangbild entgegenwirken. Aber auch die dynamische Gleichgewichtskontrolle während des Gehens ist gestört und das Sturzrisiko erhöht, was besonders bei der Fortbewegung in natürlicher Umgebung relevant ist. Die Gangtherapie auf dem Laufband spiegelt diese Anforderungen an das Gleichgewichtssystem jedoch nicht wider. Deshalb haben die Autoren ein neues sensomotorisches Laufband evaluiert, das durch kleine, ständig wechselnde Kippbewegungen der Lauffläche, das Gehen auf unebenen Untergründen simuliert und die dynamische Gleichgewichtsfähigkeit trainiert. Der Artikel stellt das sensomotorische Laufbandtraining vor und stellt die Ergebnisse einer ersten Pilotstudie vor.

ZusammenfassungUnstillbar und exzessiv schreiende Säuglinge werden als Schreikinder bezeichnet. Die Ursachen des Schreiens sind weitgehend ungeklärt. In der Osteopathie geht man von der Hypothese aus, dass unter der Geburt entstandene emotionale Belastungen in den Faszien und dem limbischen System gespeichert werden. Auf bestimmte Sinneseindrücke, die der Säugling unter der Geburt erfahren und die Panik ausgelöst haben, reagiert er mit panikartigem unstillbaren Schreien. Die erlebte lebensbedrohliche Situation, Schmerzen und eventuelle Bewegungseinschränkungen sind ein Ansatz, um die Ursachen für das exzessive nicht stillbare Schreien zu verstehen. Die osteopathische Behandlung der Schreikinder setzt in der Behandlung der durch die Geburt ausgelösten Dysfunktion an.

ZusammenfassungMiktionsstörungen sind die zweithäufigste chronische Erkrankung des Kindes. Zu unterscheiden sind 2 verschiedene Typen. Die Enuresis ist durch ein nächtliches Überfluten des Bettes bei verminderter Erweckbarkeit gekennzeichnet und auf eine Reifungsverzögerung des Nervensystems zurückzuführen. Die Inkontinenz tagsüber entspricht der Dranginkontinenz des Erwachsenen. Es besteht ein imperativer, häufiger Harndrang mit einer geringen Miktionsmenge. Bewusste oder unbewusste Haltemanöver sollen den Toilettengang hinauszögern. Veränderte Druckverhältnisse im Abdomen reizen die Blase und bedingen eine viel zu frühe Kontraktion.Bei der Enuresis und der Inkontinenz liegen komplett unterschiedliche Entstehungsmechanismen vor. Daher ist deren Behandlung individuell je nach entsprechender Form durchzuführen.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and natural killier (NK) cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells. Local T-cell activation was confirmed by increased tumor infiltration with CD103+CD8+ T cells and neoantigen-specific CD8 T lymphocytes against the marker neoepitope LAMA4-G1254V. To achieve effective prevention of distant metastases in a complementary approach, we blocked the NK-cell checkpoint CD96, an inhibitory NK-cell receptor that binds CD155, which was abundantly expressed in primary PDAC and metastases of human patients. In gemcitabine-treated mice, neoadjuvant PD-1 blockade followed by adjuvant inhibition of CD96 significantly prevented relapse of PDAC, allowing for long-term survival. In summary, our results show in an aggressively growing transgenic mouse model of PDAC that the coordinated activation of both innate and adaptive immunity can effectively reduce the risk of tumor recurrence after surgery, facilitating long-term remission of this lethal disease. Significance: Coordinated neoadjuvant and adjuvant immunotherapies reduce the risk of disease relapse after resection of murine PDAC, suggesting this concept for future clinical trials. Cancer Res; 78(2); 475–88. ©2017 AACR.

SummaryRhizarthrose

Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions to HCC. In short- and long-term experiments, administration of N-Nitrosomorpholine (NNM) or intrahepatic transplantation of pancreatic islets in diabetic (PTx), thyroid follicles in thyroidectomized (TTx) and ovarian fragments in ovariectomized (OTx) rats was conducted for the induction of foci of altered hepatocytes (FAH). Gefitinib was administered for two weeks (20 mg/kg) or three and nine months (10 mg/kg). In NNM-treated rats, Gefitinib administration decreased the amount of FAH when compared to controls. The amount of HCA and HCC was decreased, but development was not prevented. Upon all transplantation models, proliferative activity of FAH was lower after administration of Gefitinib in short-term experiments. Nevertheless, the burden of HCA and HCC was not changed in later stages. Thus, EGFR inhibition by Gefitinib diminishes chemical and hormonal also induced hepatocarcinogenesis in the initiation stage in the non-cirrhotic liver. However, progression to malignant hepatocellular tumors was not prevented, indicating only a limited relevance of the EGFR signaling cascade in later stages of hepatocarcinogenesis.