The sequelae of a missed Essex-Lopresti lesion

Radial head fractures are the most common type of elbow fracture in adults. Unrecognised disruption of the intraosseous membrane at the time of injury can lead to severe wrist pain from proximal radial migration especially if the radial head is excised. In this case, despite anatomical reduction and internal fixation of the radial head fracture, longitudinal forearm instability developed after delayed radial head resection was performed 7 months post-injury. A Suave-Kapandji procedure was performed due to ongoing wrist pain. Because of the previous radial head resection, this led to a floating forearm that could only be solved by creating a one-bone forearm, sacrificing all forearm rotation to achieve a stable lever arm between the elbow and wrist joint

Tambora 1815 as a test case for high impact volcanic eruptions: Earth system effects

The eruption of Tambora (Indonesia) in April 1815 had substantial effects on global climate and led to the ‘Year Without a Summer’ of 1816 in Europe and North America. Although a tragic event—tens of thousands of people lost their lives—the eruption also was an ‘experiment of nature’ from which science has learned until today. The aim of this study is to summarize our current understanding of the Tambora eruption and its effects on climate as expressed in early instrumental observations, climate proxies and geological evidence, climate reconstructions, and model simulations. Progress has been made with respect to our understanding of the eruption process and estimated amount of SO2 injected into the atmosphere, although large uncertainties still exist with respect to altitude and hemispheric distribution of Tambora aerosols. With respect to climate effects, the global and Northern Hemispheric cooling are well constrained by proxies whereas there is no strong signal in Southern Hemisphere proxies. Newly recovered early instrumental information for Western Europe and parts of North America, regions with particularly strong climate effects, allow Tambora's effect on the weather systems to be addressed. Climate models respond to prescribed Tambora-like forcing with a strengthening of the wintertime stratospheric polar vortex, global cooling and a slowdown of the water cycle, weakening of the summer monsoon circulations, a strengthening of the Atlantic Meridional Overturning Circulation, and a decrease of atmospheric CO2. Combining observations, climate proxies, and model simulations for the case of Tambora, a better understanding of climate processes has emerged

Propagation of tau pathology in Alzheimer’s disease: identification of novel therapeutic targets

Accumulation and aggregation of the microtubule-associated protein tau are a pathological hallmark of neurodegenerative disorders such as Alzheimer’s disease (AD). In AD, tau becomes abnormally phosphorylated and forms inclusions throughout the brain, starting in the entorhinal cortex and progressively affecting additional brain regions as the disease progresses. Formation of these inclusions is thought to lead to synapse loss and cell death. Tau is also found in the cerebrospinal fluid (CSF), and elevated levels are a biomarker for AD. Until recently, it was thought that the presence of tau in the CSF was due to the passive release of aggregated tau from dead or dying tangle-bearing neurons. However, accumulating evidence from different AD model systems suggests that tau is actively secreted and transferred between synaptically connected neurons. Transgenic mouse lines with localized expression of aggregating human tau in the entorhinal cortex have demonstrated that, as these animals age, tau becomes mislocalized from axons to cell bodies and dendrites and that human tau-positive aggregates form first in the entorhinal cortex and later in downstream projection targets. Numerous in vitro and in vivo studies have provided insight into the mechanisms by which tau may be released and internalized by neurons and have started to provide insight into how tau pathology may spread in AD. In this review, we discuss the evidence for regulated tau release and its specific uptake by neurons. Furthermore, we identify possible therapeutic targets for preventing the propagation of tau pathology, as inhibition of tau transfer may restrict development of tau tangles in a small subset of neurons affected in early stages of AD and therefore prevent widespread neuron loss and cognitive dysfunction associated with later stages of the disease

Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98

Tau is a neuronal protein that stabilizes axonal microtubules (MTs) in the central nervous system. In Alzheimer’s disease (AD) and other tauopathies, phosphorylated Tau accumulates in intracellular aggregates, a pathological hallmark of these diseases. However, the chronological order of pathological changes in Tau prior to its cytosolic aggregation remains unresolved. These include its phosphorylation and detachment from MTs, mislocalization into the somatodendritic compartment, and oligomerization in the cytosol. Recently, we showed that Tau can interact with phenylalanine-glycine (FG)-rich nucleoporins (Nups), including Nup98, that form a diffusion barrier inside nuclear pore complexes (NPCs), leading to defects in nucleocytoplasmic transport. Here, we used surface plasmon resonance (SPR) and bio-layer interferometry (BLI) to investigate the molecular details of Tau:Nup98 interactions and determined how Tau phosphorylation and oligomerization impact the interactions. Importantly, phosphorylation, but not acetylation, strongly facilitates the accumulation of Tau with Nup98. Oligomerization, however, seems to inhibit Tau:Nup98 interactions, suggesting that Tau-FG Nup interactions occur prior to oligomerization. Overall, these results provide fundamental insights into the molecular mechanisms of Tau-FG Nup interactions within NPCs, which might explain how stress-and disease-associated posttranslational modifications (PTMs) may lead to Tau-induced nucleocytoplasmic transport (NCT) failure. Intervention strategies that could rescue Tau-induced NCT failure in AD and tauopathies will be further discussed

Low Dose Rapamycin Exacerbates Autoimmune Experimental Uveitis

Rapamycin, a potent immune modulator, is used to treat transplant rejection and some autoimmune diseases. Uveitis is a potentially severe inflammatory eye disease, and 2 clinical trials of treating uveitis with rapamycin are under way. Unexpectedly, recent research has demonstrated that low dose rapamycin enhances the memory T cell population and function. However, it is unclear how low dose rapamycin influences the immune response in the setting of uveitis.B10.RIII mice were immunized to induce experimental autoimmune uveitis (EAU). Ocular inflammation of control and rapamycin-treated mice was compared based on histological change. ELISPOT and T cell proliferation assays were performed to assess splenocyte response to ocular antigen. In addition, we examined the effect of rapamycin on activation-induced cell death (AICD) using the MitoCapture assay and Annexin V staining.Administration of low dose rapamycin exacerbated EAU, whereas treating mice with high dose rapamycin attenuated ocular inflammation. The progression of EAU by low dose rapamycin coincided with the increased frequency of antigen-reactive lymphocytes. Lastly, fewer rapamycin-treated T cells underwent AICD, which might contribute to exaggerated ocular inflammation and the uveitogenic immune response.These data reveal a paradoxical role for rapamycin in uveitis in a dose-dependent manner. This study has a potentially important clinical implication as rapamycin might cause unwanted consequences dependent on dosing and pharmacokinetics. Thus, more research is needed to further define the mechanism by which low dose rapamycin augments the immune response

From Business to IT with SEAM: J2EE Pet Store Example

Business and IT alignment demands clear traceability between the applications to be developed and the business requirements. SEAM is a systemic visual approach for modeling systems, including information systems and organizations. This paper illustrates how we represent the business role of an IT application and its platform-specific realization in SEAM. We use the Java Pet Store sample application as an example

Seelische Belastung bei Menschen mit umweltbezogenen Störungen: Ein Vergleich zwischen Selbstbild und Fremdeinschätzung

Zusammenfassung: Umweltbezogene Gesundheitsstörungen stellen wissenschaftlich und klinisch ein diagnostisches und therapeutisches Konfliktfeld dar. Ein hoher subjektiver Leidensdruck, ein somatisches Krankheitsmodell sowie das Festhalten an einer Umweltursache gefährden die therapeutische Beziehung, wenn die Krankheitsmodelle von Arzt und Patient nicht übereinstimmen. Unsere Untersuchung greift diese empirisch noch kaum erforschte Diskrepanz auf, indem sie die Selbsteinschätzung von Patienten mit umweltbezogenen Krankheitsstörungen (n=61) systematisch der Fremdeinschätzung durch ein multidisziplinäres Expertenteam gegenüberstellt. Die Resultate weisen darauf hin, dass in Selbst- und Fremdeinschätzung psychisch unauffällige Probanden wenig psychiatrische Störungen zeigen, über stabile psychische Strukturen verfügen und v.a. unter umweltbedingten oder medizinischen Ursachen leiden. Wenn Selbst- und Fremdeinschätzung beide eine psychische Auffälligkeit beschreiben, sind entsprechend psychiatrische Störungen gehäuft, psychische Strukturen labil, und die Beschwerden werden psychiatrisch verursacht. Divergieren Selbst- und Fremdeinschätzung, erlaubt die Fremdeinschätzung akkuratere Aussagen bezüglich der psychiatrischen Diagnosen, der innerpsychischen Struktur und der Ursachenzuschreibun

High power arcjet

The activities on the development of the high power arc jet HIPARC, the thrust balance, and plasma diagnostic probes are discussed. Modifications of the HIPARC design and a synopsis of the materials used are given. Further experimental results with the TT30 thruster in the 50 kW range are presented. Some first calibration measurements of the thrust balance are also included. Progress concerning the development of plasma diagnostic devices is documented

Microtubules gate tau condensation to spatially regulate microtubule functions.

Tau is an abundant microtubule-associated protein in neurons. Tau aggregation into insoluble fibrils is a hallmark of Alzheimer's disease and other types of dementia1, yet the physiological state of tau molecules within cells remains unclear. Using single-molecule imaging, we directly observe that the microtubule lattice regulates reversible tau self-association, leading to localized, dynamic condensation of tau molecules on the microtubule surface. Tau condensates form selectively permissible barriers, spatially regulating the activity of microtubule-severing enzymes and the movement of molecular motors through their boundaries. We propose that reversible self-association of tau molecules, gated by the microtubule lattice, is an important mechanism of the biological functions of tau, and that oligomerization of tau is a common property shared between the physiological and disease-associated forms of the molecule

APOE isoform does not influence trans-synaptic spread of tau pathology in a mouse model

A key hallmark of Alzheimer’s disease (AD) is the accumulation of hyperphosphorylated tau in neurofibrillary tangles. This occurs alongsideneuroinflammation and neurodegeneration. Pathological tau propagates through the AD brain in a defined manner, which correlates withneuron and synapse loss and cognitive decline. One proposed mechanism of tau spread is through synaptically connected brain structures.Apolipoprotein E4 (APOE4) genotype is the strongest genetic risk factor for late-onset AD and is associated with increased tau burden. Whetherthe apolipoprotein E (APOE) genotype influences neurodegeneration via tau spread is currently unknown. Here, we demonstrate that virallyexpressed human tau (with the P301L mutation) injected into mouse entorhinal cortex at 5–6 months or 15–16 months of age spreads transsynaptically to the hippocampus by 14weeks post-injection. Injections of tau in mice expressing human APOE2, APOE3 or APOE4, as well as APOEknock-outs, showed that tau can spread trans-synaptically in all genotypes and that APOE genotype and age do not affect the spread of tau.These data suggest that APOE genotype is not directly linked to synaptic spread of tau in our model, but other mechanisms involving non-cellautonomous manners of tau spread are still possible