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Here we extend the understanding of how chemical inhibition of SHIP paralogs controls obesity. We compare different classes of SHIP inhibitors and find that selective inhibitors of SHIP1 or SHIP2 are unable to prevent weight gain and body fat accumulation during increased caloric intake. Surprisingly, only pan-SHIP1/2 inhibitors (pan-SHIPi) prevent diet-induced obesity. We confirm that pan-SHIPi is essential by showing that dual treatment with SHIP1 and SHIP2 selective inhibitors reduced adiposity during excess caloric intake. Consistent with this, genetic inactivation of both SHIP paralogs in eosinophils or myeloid cells also reduces obesity and adiposity. In fact, pan-SHIPi requires an eosinophil compartment to prevent diet-induced adiposity, demonstrating that pan-SHIPi acts via an immune mechanism. We also find that pan-SHIPi increases ILC2 cell function in aged, obese mice to reduce their obesity. Finally, we show that pan-SHIPi also reduces hyperglycemia, but not via eosinophils, indicating a separate mechanism for glucose control., Competing Interests: W.G.K, S.F., C.P. and J.D.C have patents, pending and issued, concerning the analysis and targeting of SHIP1 and SHIP2 in disease. The other authors have no interests to declare., (© 2023 The Author(s).)

AQX-1125 is an indane based SHIP1 agonist that has been evaluated in the clinic for the treatment of bladder pain syndrome/interstitial cystitis. To support our own studies on SHIP1 agonists as potential treatments for IBD and Crohn's disease, a new synthetic route to the SHIP1 agonist AQX-1125 has been developed. This sequence utilizes a hydroxy-acid intermediate which allows for ready differentiation of the C6 and C7 positions. The role of the C17 alkene in the biological activity of the system is also investigated, and this functional group is not required for SHIP1 agonist activity. While AQX-1125 shows SHIP1 agonist activity in enzyme assays, it does not show activity in cell based assays similar to other SHIP1 agonists, which limits the utility of this molecule.

Modulating the activity of the Src Homology 2 (SH2) - containing Inositol 5'-Phosphatase (SHIP) enzyme family with small molecule inhibitors provides a useful and unconventional method of influencing cell signaling in the PI3K pathway. The development of small molecules that selectively target one of the SHIP paralogs (SHIP1 or SHIP2) as well as inhibitors that simultaneously target both enzymes have provided promising data linking the phosphatase activity of the SHIP enzymes to disorders and disease states that are in dire need of new therapeutic targets. These include cancer, immunotherapy, diabetes, obesity, and Alzheimer's disease. In this mini-review, we will provide a brief overview of research in these areas that support targeting SHIP1, SHIP2 or both enzymes for therapeutic purposes., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Sexuality is excluded in house regulations, guidelines, instructions and regulations in German hospitals. The English literature does not show much more, but more often the wish for clear guidelines is formulated. Under the guidance of the clinical Ethics Committee a paper with recommendations was prepared, which comprises regulations for responsible handling of sexuality in the Pfalzklinikum. This includes sexuality of acute patients in psychiatry, nursing home inhabitants, forensic patients and above all patients in the department of child and youth psychiatry. The right of self-realization on the one hand, the staff's responsibility for patients with limitations in the determination of one's intent on the other hand and the rules for staff members define the range of the paper.

A new small animal model of bone atrophic nonunion was established for investigating the process of bone regeneration by performing cauterization of the periosteum, removal of the local bone marrow, and stabilization with external fixation. The model allows the creation of an atrophic nonunion without the need for a critical size defect. Furthermore, it provides reproducible, well-defined mechanical conditions and minimized physical interference of the implant with the biological processes in the healing zone. Eighty adult Sprague-Dawley rats received an osteotomy of the left femur, stabilized with an external fixator. In half of the animals, the periosteum proximal and distal to the osteotomy was destroyed by cauterization and the adjacent bone marrow was removed (nonunion group). At 2 and 8 weeks after surgery, radiological, biomechanical, histological, and histomorphometrical analyses showed a typical physiological healing in the control group, while the nonunion group was characterized by resorption of the bone ends with some callus formation distant to the osteotomy. At both time points, the callus was composed of significantly less bone and significantly more connective tissue (p < 0.001). In addition, the torsional strength of the osteotomized femur was significantly less in the nonunion group than in the control group, which was comparable to that of the intact femur (p < 0.001). In conclusion, the present model allows the induction of an atrophic nonunion without the need of a critical size defect. It is reproducible, provides standardized biomechanical conditions, and allows minimized interaction of the implant with the healing zone.

Post-transplantation lymphoproliferative disorder is an infrequent complication after hematopoietic stem cell transplantation. It is hypothesized that lack of T-cell surveillance following transplantation permits reactivation of latent EBV leading to polyclonal B-cell expansion and finally outgrowth of a predominant clone. Most cases are of donor origin. Here, we describe an 8-year old boy with early onset post-transplantation lymphoproliferative disorder following matched-unrelated stem cell transplantation for high-risk T-cell leukemia whose disease was unusual for two reasons. First, his B-cell clone was of host origin and, in contrast to the few PTLD of host origin described so far, not associated with autologous reconstitution. Secondly, using clonal analysis, we could retrospectively show that the B-cell clone emerged during consolidation chemotherapy for T-cell leukemia, 3 months before stem cell transplantation.

Unlabelled: Neonates with Down syndrome can present with a haematological disorder called transient abnormal myelopoiesis (TAM). While TAM is usually a self-limiting disease, patients with severe complications such as hydrops fetalis, cardiorespiratory failure and liver fibrosis have been described. Here, we present five consecutive neonates with trisomy 21 and TAM, four of whom were critically ill and were therefore treated with cytosine-arabinoside. All five patients survived., Conclusion: severely affected neonates with Down syndrome and transient abnormal myelopoiesis might benefit from early cytostatic treatment with cytosine-arabinoside., (Copyright 2004 Springer-Verlag)

Pattern formation in multicellular spheroids is addressed with a hybrid lattice-gas cellular automaton model. Multicellular spheroids serve as experimental model system for the study of avascular tumor growth. Typically, multicellular spheroids consist of a necrotic core surrounded by rings of quiescent and proliferating tumor cells, respectively. Furthermore, after an initial exponential growth phase further spheroid growth is significantly slowed down even if further nutrient is supplied. The cellular automaton model explicitly takes into account mitosis, apoptosis and necrosis as well as nutrient consumption and a diffusible signal that is emitted by cells becoming necrotic. All cells follow identical interaction rules. The necrotic signal induces a chemotactic migration of tumor cells towards maximal signal concentrations. Starting from a small number of tumor cells automaton simulations exhibit the self-organized formation of a layered structure consisting of a necrotic core, a ring of quiescent tumor cells and a thin outer ring of proliferating tumor cells.

During intercellular induction of apoptosis, transformed fibroblasts are eliminated through the action of neighbouring nontransformed cells. TGF-beta thereby plays three distinct and central roles. a) TGF-beta released by transformed cells or added exogenously to the assay system triggers nontransformed cells to release a shortlived apoptosis inducing factor, which is specifically directed against transformed cells. b) TGF-beta is involved in the maintenance of the transformed state, which is required for expression of sensitivity for intercellular induction of apoptosis. c) TGF-beta further sensitizes transformed cells through downmodulation of their endogenous survival factors, which control a constitutively expressed apoptosis machinery. These data demonstrate that TGF-beta which is utilized by transformed fibroblasts for the maintenance of their transformed state, causes recognition of transformed cells by their nontransformed neighbours and triggers and enhances an apoptosis-inducing response which finally causes elimination of potential tumor cells.

Fibroblasts constitutively express a functional apoptosis machinery which is under negative control by operationally defined endogenous survival factors. Oncogenic transformation causes a marked downmodulation of endogenous survival factor concentration which renders transformed cells more sensitive to various apoptosis stimuli compared to their nontransformed counterparts. Endogenous survival factors can be inactivated by reactive oxygen species (ROS). Endogenous survival factors are the ultimate targets for apoptosis-inducing factors derived from TGF-beta-triggered nontransformed cells during intercellular induction of apoptosis. During this control step of oncogenesis, endogenous survival factors in transformed cells are inactivated by ROS and the apoptosis machinery is released from negative control. This mechanism leads to the specific elimination of transformed cells. Our data show that the transformed state causes both the ability of the cells to perceive the apoptosis-inducing signal and a decrease in the concentration of endogenous survival factors. These two mechanisms are of central importance for the regulation of intercellular induction of apoptosis.

Polygraphic sleep recordings were performed in 12 sober alcoholic patients, 8 young normals and 12 healthy elderly subjects. An automatic sleep analysis including two different methods (standard and adaptive) of SWS scoring was used. The standard method is based on amplitude dependent rules according to Rechtschaffen and Kales. The basis for classification of SWS in the adaptive method is the relative increase of the integrated delta-activity during NREM sleep. Whereas in young and elderly normal subjects the method used has no influence on the duration of SWS during the night, the amount of SWS in alcoholic patients is significantly higher when applying the adaptive sleep analysis compared with the results of the standard method. Alcoholics show the lowest level of integrated delta activity during NREM and also the shortest duration of SWS resulting from the standard sleep analysis. On the contrary the relative dynamic of EEG synchronization and the duration of SWS measured by the adaptive sleep analysis are comparable with the values of normal subjects. The general decrease of the delta activity during sleep in sober alcoholics is assumed to be not a reflection of the reduction of SWS.

Our investigation deals with high interindividual variability of Event-Related-Potentials (ERP). We tried to find out systematic causes of these variability. In a performance situation 36 Ss were asked to solve arithmetical tasks. They got a weak electric shock applied at one finger when the result was wrong (negative feedback), at another finger when it was correct (positive feedback). The electrical stimulus triggered the ERPs. Special personality characteristics related to "need-achievement" (processing of success and failure) "and anxiety" had influence upon ERPs. We found various differences between ERPs following positive as well as negative feedback (success and failure) that point to the suggestion that there exist differences in processing feedback information in persons with different personality traits mentioned above.