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Gautier T.,French Institute of Health and Medical Research | Becker S.,Universitaetsklinikum Schleswig Holstein | Drouineaud V.,University of Burgundy | Menetrier F.,Service de Microscopie Electronique | And 7 more authors.
Journal of Lipid Research | Year: 2010

Thus far, liver, intestine, heart, and placenta have been shown to secrete apolipoprotein (apo)B-containing lipoproteins. In the present study, we first investigated lipoproteins in human follicular fluid (FF), surrounding developing oocytes within the ovary, as well as in corresponding plasma samples (n = 12). HDL cholesterol within FF correlated well with plasma HDL cholesterol (r = 0.80, P < 0.01), whereas VLDL cholesterol did not, indicating that VLDL in FF might originate directly from the granulosa cells producing FF. Primary human granulosa cells expressed apoB, microsomal triglyceride transfer protein, and apoE, but not the apoB-editing enzyme apobec-1. Using 3H-leucine, we show that granulosa cells secrete apoB100-containing lipoproteins and that secretion can be stimulated by adding oleate to the medium (+83%). With electron microscopy, apoB-containing lipoproteins within the secretory pathway of human granulosa cells were directly visualized. Finally, we found a positive relationship between apoB levels in FF and improved fertility parameters in a population of 27 women undergoing in vitro fertilization. This study demonstrates that human granulosa cells assemble and secrete apoB100-containing lipoproteins, thereby identifying a novel cell type equipped with these properties. These results might have important implications for female infertility phenotypes as well as for the development of drugs targeting the VLDL production pathway. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.


Bruix J.,University of Barcelona | Poynard T.,University Pierre and Marie Curie | Colombo M.,University of Milan | Schiff E.,University of Miami | And 14 more authors.
Gastroenterology | Year: 2011

Background & Aims: Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC)3 program. Methods: Data were analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n = 311) or no treatment (controls, n = 315) for a maximum period of 5 years or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event. Results: There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI]: 0.8802.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b compared with controls (HR, 1.564; 95% CI: 1.1302.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event compared with controls (P = .016). There were no new safety observations. Conclusions: Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension. © 2011 AGA Institute.


Stockburger M.,Charité - Medical University of Berlin | Gomez-Doblas J.J.,Campus Universitario Teatinos | Lamas G.,Columbia University | Alzueta J.,Campus Universitario Teatinos | And 7 more authors.
European Journal of Heart Failure | Year: 2011

AimsPrevious experimental and clinical studies have consistently suggested that right ventricular (RV) apical pacing has important adverse effects. Ventricular pacing (VP), however, is required, and cannot be reduced in many patients with atrioventricular (AV) block. The PREVENT-HF study was an international randomized trial that explored differences in left ventricular (LV) remodelling during RV apical vs. biventricular (BIV) pacing in patients with AV block.Methods and ResultsPatients with an expected VP prevalence <80 were assigned to RV apical or BIV pacing. The primary endpoint was the change in LV end-diastolic volume (EDV) >12 months. Secondary endpoints were LV end-systolic volume (ESV), LV ejection fraction (EF), mitral regurgitation (MR), and a combination of heart failure (HF) events and cardiovascular hospitalizations. Overall, 108 patients were randomized (RV: 58; BIV: 50). Intention to treat and on-treatment analyses revealed no significant differences in any of the outcomes. Analysis of covariance (ANCOVA) difference for treatment according to randomization (in mL): LVEDV -3.92 (-18.71 to 10.85), P 0.6; LVESV -1.38 (-12.07 to 9.31), P 0.80; LVEF 2.47 (-3.00 to 7.94), P 0.37. Analysis of covariance difference for the on-treatment analysis: LVEDV -4.90 (-20.02 to 10.22, PP 0.52; LVESV -6.45 (-17.28 to 4.38), P 0.24, LVEF 2.18 (-3.37 to 7.73), P 0.44. Furthermore, secondary endpoints did not differ significantly.ConclusionThis study did not demonstrate significant LV volume differences >12 months between RV apical and BIV pacing for AV block. Thus, BIV pacing cannot be recommended as a routine treatment for AV block in these patients. However, the results encourage and inform the design of subsequent larger trials with higher power for detecting small volume changes. © 2011 The Author.


Lange B.,Medizinisches Laserzentrum Luebeck GmbH | Jocham D.,Universitaetsklinikum Schleswig Holstein | Brinkmann R.,Medizinisches Laserzentrum Luebeck GmbH | Cordes J.,Universitaetsklinikum Schleswig Holstein
Lasers in Surgery and Medicine | Year: 2014

Study Design/Materials and Methods: Firstly, in vitro reflectance spectra (Xenon light source, wavelength range λ=350-850 nm) of 38 human kidney stones, porcine renal calix and ureter tissue were collected. Secondly, in an in vivo study with 8 patients, 72 ureter and 49 stone reflectance signals were recorded during endourological interventions. The spectra were analyzed to discriminate between stone and tissue by the absence or presence of minima due to hemoglobin absorption at λ1=542nm and λ3=576nm.Results: In vitro, all stone and tissue signals could correctly be identified by calculating the ratio R=I (λ1=542nm)/I (λ2=475 nm): Because of the hemoglobin absorption at λ1, R is smaller for tissue than for calculi. In vivo, only 75% tissue spots could correctly be identified utilizing this method. Using the more sophisticated evaluation of looking for minima in the diffuse reflectance spectra at λ1=542nm and λ3=576nm, 62 out of 64 tissue spots were correctly identified (sensitivity 96.9%). This was also the case for 39 out of 43 stone spots. Taking into account the number of measured spectra, a tissue detection probability of 91% and a stone detection probability of 77% was achieved (significance level 5%).Conclusion: White light diffusely reflected off the treatment zone into the fiber can be used to strongly improve the safety of Holmium laser lithotripsy by implementing an automatic feedback control algorithm that averts mispositioning the fiber. Lasers Surg. Med. 46:614-619, 2014.Background and Objective: Holmium laser lithotripsy is the 'gold standard' for intracorporeal fragmentation of stones. However, there is a risk of damaging and perforating the ureter wall when the laser is accidentally fired while the fiber is in contact with tissue. The aim of this study was to evaluate if white illumination light, diffusely reflected back into the treatment fiber and spectrally analyzed, can be used for differentiating between stone and tissue. © 2014 Wiley Periodicals, Inc.


PubMed | Universitaetsklinikum Schleswig Holstein and Medizinisches Laserzentrum Luebeck GmbH
Type: | Journal: Lasers in surgery and medicine | Year: 2016

Holmium laser lithotripsy is the gold standard for intracorporeal fragmentation of urinary calculi. Usually, a visible beam is superimposed on the IR treatment laser as an aiming beam to guide the surgeon. In vitro tests showed that this aiming beam (532nm, power <1mW) excites strong fluorescence on human calculi. Tissue, in contrast, emitted much weaker fluorescence. If this is verified in vivo, the fluorescence signal induced by the aiming beam could be used to implement a feedback loop, preventing the Holmium laser being fired on tissue.Fluorescence signals of 67 tissue and 68 stone spots were measured in a clinical proof of concept study with eight patients. For this, a modulated excitation/detection scheme (lock-in technique) was implemented. A frequency-doubled, diode-pumped solid-state laser module (532nm, modulation frequency 66Hz, average power 0.3mW) was coupled via a dichroic mirror with the Holmium lithotripsy laser into the treatment fiber. The fluorescence signal entering the treatment fiber was detected via another dichroic mirror with a photodiode and a lock-in amplifier.In most instances (94%), the calculus of a patient gave a signal which was at least twice the maximum signal of ureteral tissue.The results of our proof of concept study indicate that measuring the fluorescence signal of a green aiming beam could be used to implement a feedback loop for Holmium laser lithotripsy. Preventing the laser being fired on tissue, this would increase the safety of the procedure. Lasers Surg. Med. 2016 Wiley Periodicals, Inc.


Pfau D.B.,University of Heidelberg | Krumova E.K.,Ruhr University Bochum | Treede R.-D.,University of Heidelberg | Baron R.,Universitaetsklinikum Schleswig Holstein | And 8 more authors.
Pain | Year: 2014

Age- and gender-matched reference values are essential for the clinical use of quantitative sensory testing (QST). To extend the standard test sites for QST - according to the German Research Network on Neuropathic Pain - to the trunk, we collected QST profiles on the back in 162 healthy subjects. Sensory profiles for standard test sites were within normal interlaboratory differences. QST revealed lower sensitivity on the upper back than the hand, and higher sensitivity on the lower back than the foot, but no systematic differences between these trunk sites. Age effects were significant for most parameters. Females exhibited lower pressure pain thresholds (PPT) than males, which was the only significant gender difference. Values outside the 95% confidence interval of healthy subjects (considered abnormal) required temperature changes of >3.3-8.2 °C for thermal detection. For cold pain thresholds, confidence intervals extended mostly beyond safety cutoffs, hence only relative reference data (left-right differences, hand-trunk differences) were sufficiently sensitive. For mechanical detection and pain thresholds, left-right differences were 1.5-2.3 times more sensitive than absolute reference data. The most sensitive parameter was PPT, where already side-to-side differences >35% were abnormal. Compared to trunk reference data, patients with postherpetic neuralgia exhibited thermal and tactile deficits and dynamic mechanical allodynia, mostly without reduced mechanical pain thresholds. This pattern deviates from other types of neuropathic pain. QST reference data for the trunk will also be useful for patients with postthoracotomy pain or chronic back pain. © 2014 Published by Elsevier B.V. on behalf of International Association for the Study ofPain. All rights reserved.


Chen P.,University of Utah | Dendorfer A.,Universitaetsklinikum Schleswig Holstein | Finol-Urdaneta R.K.,University of Calgary | Finol-Urdaneta R.K.,University of Kiel | And 3 more authors.
Journal of Biological Chemistry | Year: 2010

Conus snail (Conus) venoms are a valuable source of pharmacologically active compounds; some of the peptide toxin families from the snail venoms are known to interact with potassium channels. We report the purification, synthesis, and characterization of κM-conotoxin RIIIJ from the venom of a fish-hunting species, Conus radiatus. This conopeptide, like a previously characterized peptide in the same family, κM-RIIIK, inhibits the homotetrameric human Kv1.2 channels. When tested in Xenopus oocytes, κM-RIIIJ has an order of magnitude higher affinity (IC50=33 nM) to Kv1.2 than κM-RIIIK (IC50=352 nM). Chimeras of RIIIK and RIIIJ tested on the human Kv1.2 channels revealed that Lys-9 from κM-RIIIJ is a determinant of its higher potency against hKv1.2. However, when compared in a model of ischemia/reperfusion, κM-RIIIK (100 μg/kg of body weight), administered just before reperfusion, significantly reduces the infarct size in rat hearts in vivo without influencing hemodynamics, providing a potential compound for cardioprotective therapeutics. In contrast, κM-RIIIJ does not exert any detectable cardioprotective effect. κM-RIIIJ shows more potency for Kv1.2-Kv1.5 and Kv1.2-Kv1.6 heterodimers than κM-RIIIK, whereas the affinity of κM-RIIIK to Kv1.2-Kv1.7 heterodimeric channels is higher (IC50=680 nM) than that of κM-RIIIJ (IC50=3.15 μM). Thus, the cardioprotection seems to correlate to antagonism to heteromultimeric channels, involving the Kv1.2 α-subunit rather than antagonism to Kv1.2 homotetramers. Furthermore, κM-RIIIK and κM-RIIIJ provide a valuable set of probes for understanding the underlying mechanism of cardioprotection. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Baron R.,Universitaetsklinikum Schleswig Holstein | Hans G.,University of Antwerp | Dickenson A.H.,University College London
Annals of Neurology | Year: 2013

Many pain states begin with damage to tissue and/or nerves in the periphery, leading to enhanced transmitter release within the spinal cord and central sensitization. Manifestations of this central sensitization are windup and long-term potentiation. Hyperexcitable spinal neurons show reduced thresholds, greater evoked responses, increased receptive field sizes, and ongoing stimulus-independent activity; these changes probably underlie the allodynia, hyperalgesia, and spontaneous pain seen in patients. Central sensitization is maintained by continuing input from the periphery, but also modulated by descending controls, both inhibitory and facilitatory, from the midbrain and brainstem. The projections of sensitized spinal neurons to the brain, in turn, alter the processing of painful messages by higher centers. Several mechanisms contribute to central sensitization. Repetitive activation of primary afferent C fibers leads to a synaptic strengthening of nociceptive transmission. It may also induce facilitation of non-nociceptive Aβ fibers and nociceptive Aδ fibers, giving rise to dynamic mechanical allodynia and mechanical hyperalgesia. In postherpetic neuralgia and complex regional pain syndrome, for example, these symptoms are maintained and modulated by peripheral nociceptive input. Diagnosing central sensitization can be particularly difficult. In addition to the medical history, quantitative sensory testing and functional magnetic resonance imaging may be useful, but diagnostic criteria that include both subjective and objective measures of central augmentation are needed. Mounting evidence indicates that treatment strategies that desensitize the peripheral and central nervous systems are required. These should generally involve a multimodal approach, so that therapies may target the peripheral drivers of central sensitization and/or the central consequences. © 2013 American Neurological Association.


Lange B.,Medical Laser Center Luebeck GmbH | Cordes J.,Universitaetsklinikum Schleswig Holstein | Brinkmann R.,Medical Laser Center Luebeck GmbH
Lasers in Surgery and Medicine | Year: 2015

Background and Objectives Holmium laser lithotripsy is a safe and effective method to disintegrate urinary stones of all compositions in an endoscopic procedure. However, handling and safety could be improved by a real-time feedback system permanently monitoring the position of the treatment fiber. The laser is fired only when the fiber is identified as being placed in front of stone. This work evaluates the potential of fluorescence detection with an excitation wavelength of 532 nm for this purpose. Materials and Methods A fiber-based fluorescence measurement was set-up to acquire autofluorescence signals from several human renal calculi, artificial stones, and porcine tissue samples (renal calix and ureter). Three different approaches were investigated. First, experiments were performed with a pulsed laser source with a wavelength of 532 nm, pulse energy 36.5 ± 1 μJ, pulse duration 1.2 ± 0.5 nanoseconds, and a repetition rate of 1 kHz with 15 urinary concretions. In the second step, a series of measurements on 42 human urinary calculi samples was carried out using low power continuous wave excitation of 0.4 ± 0.1 mW. Fluorescence was also measured simultaneously to stone fragmentation by holmium laser pulses (pulse energy 240 ± 50 mJ, repetition rate 10 Hz). Finally, a modulated excitation/detection scheme (lock-in technique) was implemented to render fluorescence detection insensitive to white background light. Results Unlike porcine renal calix, ureter, and artificial stone human urinary calculi show a strong fluorescence signal when excited with 532 nm. With pulsed excitation on urinary stone (20,000 ± 11,000) counts were registered at 587 nm with the CCD-array of a grating spectrometer in an integration time of 50 milliseconds. Tissue gave lower count rates of ≤(5,500 ± 1,100) even with longer integration times (500 milliseconds/1 second). With a cw excitation power of 0.4 mW (13,000 ± 11,000) counts were registered in an integration time of 200 milliseconds at 587 nm (porcine renal calix: (770 ± 340)). Modulated excitation (66 Hz) with an average power of 0.3 mW and detection with a photodiode resulted in a lock-in amplifier signal of 1.5-4.3V on stone (background and skin: <0.5V). Conclusion With the lock-in technique, autofluorescence from stones can be detected with only the average excitation power of a green aiming beam overlaid to the Ho:YAG-laser beam (power ≤ 1 mW). Since tissue shows very little autofluorescence when excited with 532 nm, this fluorescence signal enables monitoring of the correct position of the treatment fiber during ureteroscopic procedures. Lasers Surg. Med. 47:737-744, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.


PubMed | Universitaetsklinikum Schleswig Holstein
Type: Journal Article | Journal: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | Year: 2016

Electrical isolation of the pulmonary veins (PVs) has been established in clinical routine as a curative treatment for atrial fibrillation (AF). While catheter ablation carries procedural risks, radiosurgery might be able to non-invasively induce lesions at the PV ostia to block veno-atrial electrical conduction. This porcine feasibility and dose escalation study determined the effect of radiosurgery on electrophysiologic properties of the left atrial-PV junction.Eight adult Goettingen mini-pigs underwent electrophysiological voltage mapping in the left atrium and the upper right PV. Radiation was delivered with a conventional linear accelerator. A single homogeneous dose ranging from 22.5 to 40 Gy was applied circumferentially to the target vein antrum. Six months after radiosurgery, electrophysiological mapping was repeated and a histological examination performed. Voltage mapping consistently showed electrical potentials in the upper right PV at baseline. Pacing the target vein prompted atrial excitation, thus proving veno-atrial electrical conduction. After 6 months, radiation had reduced PV electrogram amplitudes. This was dose dependent with a mean interaction effect of -5.8%/Gy. Complete block of atrio-venous electrical conduction occurred after 40 Gy dose application. Histology revealed transmural scarring of the targeted PV musculature with doses >30 Gy. After 40 Gy, it spanned the entire circumference in accordance with pulmonary vein isolation.Pulmonary vein isolation to treat AF can be achieved by radiosurgery with a conventional linear accelerator. Yet, it requires a high radiation dose which might limit clinical applicability.

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