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Decompression sickness and arterial gas embolism, collectively known as decompression illness (DCI), are serious medical conditions that can result from compressed gas diving. DCI can present with a wide range of physiologic and neurologic symptoms. In diving medicine, skin manifestations are usually described in general as cutis marmorata (CM). Mainly in the Anglo-American literature the terms cutis marmorata, livedo reticularis (LR), and livedo racemosa (LRC) are used interchangeably but actually describe pathophysiologically different phenomena. CM is a synonym for LR, which is a physiological and benign, livid circular discoloration with a net-like, symmetric, reversible, and uniform pattern. The decompression-associated skin discolorations, however, correspond to the pathological, irregular, broken netlike pattern of LRC. Unlike in diving medicine, in clinical medicine/dermatology the pathology of livedo racemosa is well described as a thrombotic/embolic occlusion of arteries. This concept of arterial occlusion suggests that the decompression-associated livedo racemosa may be also caused by arterial gas embolism. Recent studies have shown a high correlation of cardiac right/left (R/L) shunts with arterial gas embolism and skin bends in divers with unexplained DCI. To further investigate this hypothesis, a retrospective analysis was undertaken in a population of Austrian, Swiss, and German divers. The R/L shunt screening results of 18 divers who suffered from an unexplained decompression illness (DCI) and presented with livedo racemosa were retrospectively analyzed. All of the divers were diagnosed with a R/L shunt, 83% with a cardiac shunt [patent foramen ovale (PFO)/atrium septum defect (ASD)], and 17% with a non-cardiac shunt. We therefore not only confirm this hypothesis but when using appropriate echocardiographic techniques even found a 100% match between skin lesions and R/L shunt. In conclusion, in diving medicine the term cutis marmorata/livedo reticularis is used incorrectly for describing the actual pathology of livedo racemosa. Moreover, this pathology could be a good explanation for the high correlation of livedo racemosa with cardiac and non-cardiac right/left shunts in divers without omission of decompression procedures.

Background Carotid sinus syndrome (CSS) is an exaggerated response to carotid sinus baroreceptor stimulation, which may result in hypotension, prolonged asystole, and subsequently transient loss of consciousness due to cerebral hypoperfusion. However, this commonly benign syndrome may have lethal consequences under certain circumstances such as scuba diving. Case summary We report the case of a trained 73-year-old male diver, who survived an almost fatal diving accident without any neurological deficits due to cardiac arrest under water. After recovery and intensive diagnostics in the local hospital, the origin of cardiac arrest remained unclear. However, after referral to our tertiary care centre CSS could be diagnosed by provoking syncope and asystole with carotid sinus massage (CSM). Consequently, a leadless pacing system was implanted and his medical diving fitness could then be recertified. Discussion In conclusion, CSS may be an underdiagnosed cause of loss of consciousness. Thus, screening for CSS by CSM should be included in medical exams in senior athletes and specifically in senior divers.

Sonic Hedgehog (SHH)-GLI signalling plays an important role during embryogenesis and in tumorigenesis. The survival and growth of several types of cancer depend on autonomously activated SHH-GLI signalling. A protein complex containing the ubiquitin-ligase MID1 and protein phosphatase 2A (PP2A) regulates the nuclear localization and transcriptional activity of GLI3, a transcriptional effector molecule of SHH, in cancer cell lines with autonomously activated SHH signalling. However, the exact molecular mechanisms that mediate the interaction between MID1 and GLI3 remained unknown. Here, we show that MID1 catalyses the ubiquitination and proteasomal cleavage of the GLI3-regulator Fu. Our data suggest that Fu ubiquitination and cleavage is one of the key elements connecting the MID1/PP2A protein complex with GLI3 activity control.

We have shown previously that the ubiquitin ligase MID1, mutations of which cause the midline malformation Opitz BBB/G syndrome (OS), serves as scaffold for a microtubule-associated protein complex that regulates protein phosphatase 2A (PP2A) activity in a ubiquitin-dependent manner. Here, we show that the MID1 protein complex associates with mRNAs via a purine-rich sequence motif called MIDAS (MID1 association sequence) and thereby increases stability and translational efficiency of these mRNAs. Strikingly, inclusion of multiple copies of the MIDAS motif into mammalian mRNAs increases production of the encoded proteins up to 20-fold. Mutated MID1, as found in OS patients, loses its influence on MIDAS-containing mRNAs, suggesting that the malformations in OS patients could be caused by failures in the regulation of cytoskeleton-bound protein translation. This is supported by the observation that the majority of mRNAs that carry MIDAS motifs is involved in developmental processes and/or energy homeostasis. Further analysis of one of the proteins encoded by a MIDAS-containing mRNA, namely PDPK-1 (3-phosphoinositide dependent protein kinase-1), which is an important regulator of mammalian target of rapamycin/PP2A signaling, showed that PDPK-1 protein synthesis is significantly reduced in cells from an OS patient compared with an age-matched control and can be rescued by functional MID1. Together, our data uncover a novel messenger ribonucleoprotein complex that regulates microtubule-associated protein translation. They suggest a novel mechanism underlying OS and point at an enormous potential of the MIDAS motif to increase the efficiency of biotechnological protein production in mammalian cells.

We report a 67 years old female patient out of a multigenerational family with spinocerebellar ataxia type 2 (SCA2) with an unusually benign course of disease. Although all SCA2 gene carriers have by now developed the predominant gait ataxia and brainstem oculomotor dysfunction, the index patient presented with a very mild course of disease, scoring only six points on the Scale for the Assessment and Rating of Ataxia after a disease duration of 13 years. Otherwise, intragenerational variability within family members such as the age at onset of disease and the course of disease was low. Reinvestigation of the genetic background variables in the SCA2 gene carrier reported here showed 27 repeats in the normal allele and 37 noninterrupted repeats in the abnormal allele. Interestingly, this patient has been taking lithium-carbonate over more than 30 years because of psychotic depression. Although anecdotic, this SCA2 case may provide promising insights into possible disease modifying mechanisms in SCA2.

Opitz BBB/G syndrome (OS) is a heterogenous malformation syndrome mainly characterised by hypertelorism and hypospadias. In addition, patients may present with several other defects of the ventral midline such as cleft lip and palate and congenital heart defects. The syndrome-causing gene encodes the X-linked E3 ubiquitin ligase MID1 that mediates ubiquitin-specific modification and degradation of the catalytic subunit of the translation regulator protein phosphatase 2A (PP2A). Here, we show that the MID1 protein also associates with elongation factor 1α (EF-1α) and several other proteins involved in mRNA transport and translation, including RACK1, Annexin A2, Nucleophosmin and proteins of the small ribosomal subunits. Mutant MID1 proteins as found in OS patients lose the ability to interact with EF-1α. The composition of the MID1 protein complex was determined by several independent methods: (1) yeast two-hybrid screening and (2) immunofluorescence, (3) a biochemical approach involving affinity purification of the complex, (4) co-fractionation in a microtubule assembly assay and (5) immunoprecipitation. Moreover, we show that the cytoskeleton-bound MID1/translation factor complex specifically associates with G- and U-rich RNAs and incorporates MID1 mRNA, thus forming a microtubule-associated ribonucleoprotein (RNP) complex. Our data suggest a novel function of the OS gene product in directing translational control to the cytoskeleton. The dysfunction of this mechanism would lead to malfunction of microtubule-associated protein translation and to the development of OS. Electronic supplementary material The online version of this article (doi:10.1007/s00439-007-0456-6) contains supplementary material, which is available to authorized users.

Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauopathies and is a crucial factor in the pathogenesis of these disorders. Though diverse kinases have been implicated in tau phosphorylation, protein phosphatase 2A (PP2A) seems to be the major tau phosphatase. Using murine primary neurons from wild-type and human tau transgenic mice, we show that the antidiabetic drug metformin induces PP2A activity and reduces tau phosphorylation at PP2A-dependent epitopes in vitro and in vivo. This tau dephosphorylating potency can be blocked entirely by the PP2A inhibitors okadaic acid and fostriecin, confirming that PP2A is an important mediator of the observed effects. Surprisingly, metformin effects on PP2A activity and tau phosphorylation seem to be independent of AMPK activation, because in our experiments ( i ) metformin induces PP2A activity before and at lower levels than AMPK activity and ( ii ) the AMPK activator AICAR does not influence the phosphorylation of tau at the sites analyzed. Affinity chromatography and immunoprecipitation experiments together with PP2A activity assays indicate that metformin interferes with the association of the catalytic subunit of PP2A (PP2Ac) to the so-called MID1-α4 protein complex, which regulates the degradation of PP2Ac and thereby influences PP2A activity. In summary, our data suggest a potential beneficial role of biguanides such as metformin in the prophylaxis and/or therapy of AD.

Nicht nur die Klimakrise und die Begrenztheit fossiler Rohstoffe stellt Energieversorgungsunternehmen vor erhebliche Herausforderungen. Um zu einer nachhaltigen Energieversorgung beizutragen, sind verschiedene Ansätze notwendig.

In this study we present a quick and easy method for counting trinucleotide repeats by de-oxyadenosine overhang (A-overhang)–dependent repeat expansion determination (ADRED). During standard Taq DNA polymerase–based sequencing reactions, the unterminated sequencing products of short PCR fragments are tagged with a 3′-end A-overhang that is visible as an intense peak in an electropherogram; this allows for easy and precise determination of the fragment length and thus the extent of repeat expansions. ADRED has clear advantages over existing methods, because repeat numbers of both normal and pathogenic (expanded) alleles can be analyzed without using labeled primers or labeled DNA standards. Because ADRED includes a sequencing step, disease-relevant polymorphisms (e.g., CAA interruptions in spinocerebellar ataxia type 2) can simultaneously be detected.

The TerraSAR-X earth-observing radar mission, scheduled for launch in October 2006, has been set up as a public private partnership (PPP) to serve both scientific and commercial needs. The TerraSAR-X ground segment has to deal with the scientific community on the one hand and a commercial exploiter on the other hand. The mission planning system has been designed to satisfy the scientific and commercial partners, having own structures and motivations and sometimes-diverging interests, in the frame of a common mission. Both partners are interested in a schedule that is stable with respect to the time. Also the commercial exploiter has the strong interest to provide his final customers with reliable information. For a stable schedule, order behaviour is crucial: the more orders are known in advance, the more steady the execution timeline will behave in time. On the science side, the science coordinator will guide the individual scientists and their orders in a review process. As a result, the typical science order will be set up and fed into the system well in advance of the envisaged execution time. On the other side, the nature of the commercial market will lead to orders that come in just-i n-time and have to be scheduled and produced as fast as possible. In addition, there will be short-time high-priority orders from both sides as well as the need to schedule data-takes in respond to emergency tasks. As a consequence, the task of establishing an optimising planning process is demanding: The high-priority orders, with execution times in the very near future, will conflict with the already established schedule. Even during the design and implementation phase, the mission planning system had to be adapted to the changing needs of the commercial market leading to new requirements. On such a basis, the optimisation criteria for the planning process are hard to quantify. As a solution, the TerraSAR-X planning system implements a priority concept, agreed by the science and commercial part. A quota concept wi ll make sure that both sides will get, on time average, a fair share of the satellite resources. Periodical strategic planning meetings, with members from the science and commercial side as well as from mission management, will be supported by experienced mission planning engineers with statistical information regarding the past mission as well as the order situation in the future. The paper will outline the experiences as by shortly before the launch. It will describe how initial concepts had to be modified and where add-ons emerging from the starting commercialisation affected the system design.