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Background: Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system, believed to be triggered by an autoimmune reaction to myelin. Recently, a fundamentally different pathomechanism termed ‘chronic cerebrospinal venous insufficiency’ (CCSVI) was proposed, provoking significant attention in the media and scientific community.
Methods: Twenty MS patients (mean age 42.2±13.3 years; median Extended Disability Status Scale 3.0, range 0–6.5) were compared with 20 healthy controls. Extra- and intracranial venous flow direction was assessed by colour-coded duplex sonography, and extracranial venous cross-sectional area (VCSA) of the internal jugular and vertebral veins (IJV/VV) was measured in B-mode to assess the five previously proposed CCSVI criteria. IJV-VCSA≤0.3 cm2 indicated ‘stenosis,’ and IJV-VCSA decrease from supine to upright position ‘reverted postural control.’ The sonographer, data analyser and statistician were blinded to the patient/control status of the participants.
Results: No participant showed retrograde flow of cervical or intracranial veins. IJV-VCSA≤0.3 cm2 was found in 13 MS patients versus 16 controls (p=0.48). A decrease in IJV-VCSA from supine to upright position was observed in all participants, but this denotes a physiological finding. No MS patient and one control had undetectable IJV flow despite deep inspiration (p=0.49). Only one healthy control and no MS patients fulfilled at least two criteria for CCSVI.
Conclusions: This triple-blinded extra- and transcranial duplex sonographic assessment of cervical and cerebral veins does not provide supportive evidence for the presence of CCSVI in MS patients. The findings cast serious doubt on the concept of CCSVI in MS.
Acupuncture is a therapy based on sensory stimulation of the human
body by means of metal needles. The exact underlying mechanisms of
acupuncture have not been clarified so far. Functional magnetic
resonance imaging (fMRI) has become an important tool in
acupuncture research. Standard acupuncture needles, which are made
of ferromagnetic steel, however, are problematic in
acupuncture-fMRI studies for several reasons, such as attraction
by the scanner's magnetic field, significant image distortions and
signal-dropouts, when positioned close to the head or even heating
due to absorption of radio frequency (RF). The aim of this study
was to compare two novel types of acupuncture needles with a
standard needle for their effect on MRI image quality. The
standard needle severely reduced image quality, when located
inside the RF coil. The nonferromagnetic metal needle may pose a
risk due to RF heating, while the plastic needle has a
significantly larger diameter. In conclusion, our recommendations
are: (1) standard needles should not be used in MRI; (2)
Nonferromagnetic metal needles seem to be the best choice for
acupoints outside of the transmitter coil; and (3) only plastic
needles are suited for points inside the coil. Laser acupuncture
may be a safe alternative, too.
The role of peroxisome proliferator-activated receptor gamma during sepsis-induced lymphopenia
(2011)
Sepsis is one of the most common diseases on intensive care units all over the world and accounts there for the highest mortality rate. One of the hallmarks of sepsis is an accelerated T-cell apoptosis, resulting in a compromised immune state with the inability to eradicate pathogens. This promotes organ damage or even organ failure. A multiple organ dysfunction evolves, which often ends up in septic shock and death. Recently, it was shown that severe T-cell depletion correlates with sepsis mortality. When inhibiting T-cell apoptosis, an increased mouse survival was observed in experimental sepsis. ...
The E3 ubiquitin ligase MYCBP2 negatively regulates neuronal growth, synaptogenesis, and synaptic strength. More recently it was shown that MYCBP2 is also involved in receptor and ion channel internalization. We found that mice with a MYCBP2-deficiency in peripheral sensory neurons show prolonged thermal hyperalgesia. Loss of MYCBP2 constitutively activated p38 MAPK and increased expression of several proteins involved in receptor trafficking. Surprisingly, loss of MYCBP2 inhibited internalization of transient receptor potential vanilloid receptor 1 (TRPV1) and prevented desensitization of capsaicin-induced calcium increases. Lack of desensitization, TRPV internalization and prolonged hyperalgesia were reversed by inhibition of p38 MAPK. The effects were TRPV-specific, since neither mustard oil-induced desensitization nor behavioral responses to mechanical stimuli were affected. In summary, we show here for the first time that p38 MAPK activation can inhibit activity-induced ion channel internalization and that MYCBP2 regulates internalization of TRPV1 in peripheral sensory neurons as well as duration of thermal hyperalgesia through p38 MAPK.
Background: Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats.
Methods: Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed.
Results: The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling.
Conclusion: The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension.
Endovaskuläres Stenting der thorakalen Aorta- halten die Langzeitergebnisse was die frühen Ergebnisse erwarten ließen? Hintergrund: Die frühen Ergebnisse des Endovaskulären Stentings sind in der Literatur gut dokumentiert. Das Anliegen dieser Studie ist es Langzeitergebnisse der Patienten die sich endovaskulärem Stenting der thorakalen Aorta unterzogen zu ermitteln. Methode: Insgesamt 92 Patienten unterzogen sich endovaskulärem Stenting, als Erkrankungen wurden hierbei Läsionen der thorakalen Aorta (thorakales Aortenaneuysma n=45, Typ B Dissektion n=31, traumatische Ruptur n=16) behandelt. Insgesamt waren es 62 männliche und 30 weibliche Patienten. Der Follow-up Zeitraum betrug zwischen 1-7 Jahren, der mittlere Follow-up Zeitraum lag bei 4,05 Jahren. Die Patienten wurden in jährlichen Intervallen nachuntersucht. Ergebnisse: Insgesamt belief sich die Mortalität auf 27.2% (n=25). Unterteilt in 30 Tage-Mortalität, die sich auf 9.8% (n=9) belief und die Spätmortalität mit 17.4% (n=16). 5 (5.4%) Patienten erlitten einen Schlaganfall , 3 Fälle von Paraplegie (3.2%). 7 Patienten (7.6%) entwickelten Endoleaks, 5 von ihnen starben während des Follow-up Zeitraums und 3 benötigten chirurgische Reoperation wegen persistierender Perfusion und Vergrößerung des Aneurysmasacks. Zusammenfassung: Langzeitergebnisse zeigen eine Stentgraft assoziierte Morbidität und Sterblichkeit. Deshalb ist eine regelmäßige Kontrolle unerlässlich.
TIM23-mediated insertion of transmembrane alpha-helices into the mitochondrial inner membrane
(2011)
While overall hydrophobicity is generally recognized as the main characteristic of transmembrane (TM) alpha-helices, the only membrane system for which there are detailed quantitative data on how different amino acids contribute to the overall efficiency of membrane insertion is the endoplasmic reticulum (ER) of eukaryotic cells. Here, we provide comparable data for TIM23-mediated membrane protein insertion into the inner mitochondrial membrane of yeast cells. We find that hydrophobicity and the location of polar and aromatic residues are strong determinants of membrane insertion. These results parallel what has been found previously for the ER. However, we see striking differences between the effects elicited by charged residues flanking the TM segments when comparing the mitochondrial inner membrane and the ER, pointing to an unanticipated difference between the two insertion systems. Keywords: CoxVa , membrane protein , Mgm1p , mitochondria , TIM23
Environmental tobacco smoke (ETS) is a major contributor to indoor air pollution. Since decades it is well documented that ETS can be harmful to human health and cause premature death and disease. In comparison to the huge research on toxicological substances of ETS, less attention was paid on the concentration of indoor ETS-dependent particulate matter (PM). Especially, investigation that focuses on different tobacco products and their concentration of deeply into the airways depositing PM-fractions (PM10, PM2.5 and PM1) must be stated. The tobacco smoke particles and indoor air quality study (ToPIQS) will approach this issue by device supported generation of indoor ETS and simultaneously measurements of PM concentration by laser aerosol spectrometry. Primarily, the ToPIQ study will conduct a field research with focus on PM concentration of different tobacco products and within various microenvironments. It is planned to extend the analysis to basic research on influencing factors of ETS-dependent PM concentration.
High attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drug development, the role of Plk1 in primary cells remains widely unexplored. Therefore, we evaluated the utility of an RNA interference-based model to assess responses to an inducible knockdown (iKD) of Plk1 in adult mice. Here we show that Plk1 silencing can be achieved in several organs, although adverse events are rare. We compared responses in Plk1-iKD mice with those in primary cells kept under controlled culture conditions. In contrast to the addiction of many cancer cell lines to the non-oncogene Plk1, the primary cells' proliferation, spindle assembly and apoptosis exhibit only a low dependency on Plk1. Responses to Plk1-depletion, both in cultured primary cells and in our iKD-mouse model, correspond well and thus provide the basis for using validated iKD mice in predicting responses to therapeutic interventions.