Publications by authors named "Sassen M"

43 Publications

Time to change the times? Time of recurrence of ventricular fibrillation during OHCA.

Resuscitation 2020 12 3;157:219-224. Epub 2020 Oct 3.

Center of Emergency Medicine, Philipps-University Marburg, Marburg, Germany. Electronic address:

Aim Of The Study: For out-of-hospital-cardiac-arrest (OHCA) due to ventricular fibrillation (VF) guidelines recommend early defibrillation followed by chest compressions for two minutes before analyzing shock success. If rhythm analysis reveals VF again, it is obscure whether VF persisted or reoccurred within the two-minutes-cycle of chest compressions after successful defibrillation. We investigated the time of VF-recurrence in OHCA.

Methods: We examined all cases of OHCA presenting with initial VF rhythm at arrival of ALS-ambulance (Marburg-Biedenkopf-County, 246.648 inhabitants) from January 2014 to March 2018. Three independent investigators analyzed corpuls3® ECG-recordings. We included ECG-data from CPR-beginning until four minutes after the third shock. VF termination was defined as the absence of a VF-waveform within 5 s of shock delivery. VF recurrence was defined as the presence of a VF-waveform in the interval 5 s post shock delivery.

Results: We included 185 shocks in 82 patients. 74.1% (n = 137) of all shocks terminated VF, but VF recurred in 81% (n = 111). The median (IQR) time of VF-recurrences was 27 s (13.5 s/80.5 s) after shock. 51.4% (n = 57) of VF-recurrence occurred 5-30 s after shock, 13.5% (n = 15) VF-recurrence occurred 31-60 s after shock, 21.6% (n = 24) of VF-recurrence occurred 61-120 s after shock, 13.5% (n = 15) of VF-recurrence occurred 121-240 s after shock.

Conclusions: Although VF was terminated by defibrillation in 74.1%, VF recurred in 81% subsequent to the chest compression interval. Thus, VF reappears frequently and early. It is unclear to which extend chest compressions influence VF-relapse. Further studies need to re-evaluate the algorithm, timing of antiarrhythmic therapy or novel defibrillation strategies to minimize refibrillation during shockable OHCA.
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http://dx.doi.org/10.1016/j.resuscitation.2020.09.029DOI Listing
December 2020

Hypothermia does not influence liver damage and function in a porcine polytrauma model.

Technol Health Care 2018 ;26(2):209-221

Center for Orthopedics and Trauma Surgery, University Hospital Giessen and Marburg, Marburg, Germany.

Background: Previous studies revealed evidence that induced hypothermia attenuates ischemic organ injuries after severe trauma. In the present study, the effect of hypothermia on liver damage was investigated in a porcine long term model of multi-system injury, consisting of blunt chest trauma, penetrating abdominal trauma, musculoskeletal injury, and hemorrhagic shockMETHODS: In 30 pigs, a standardized polytrauma including blunt chest trauma, penetrating abdominal trauma, musculoskeletal injury, and hemorrhagic shock of 45% of total blood volume was induced. Following trauma, hypothermia of 33∘C was induced for 12 h and intensive care treatment was evaluated for 48 h. As outcome parameters, we assessed liver function and serum transaminase levels as well as a histopathological analysis of tissue samples. A further 10 animals served as controls.

Results: Serum transaminase levels were increased at the end of the observation period following hypothermia without reaching statistical significance compared to normothermic groups. Liver function was preserved (p⩽ 0.05) after the rewarming period in hypothermic animals but showed no difference at the end of the observation period. In H&E staining, cell death was slightly increased hypothermic animals and caspase-3 staining displayed tendency towards more apoptosis in hypothermic group as well.

Conclusions: Induction of hypothermia could not significantly improve hepatic damage during the first 48 h following major trauma. Further studies focusing on multi-organ failure including a longer observation period are required to illuminate the impact of hypothermia on hepatic function in multiple trauma patients.
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http://dx.doi.org/10.3233/THC-171043DOI Listing
October 2018

Long-Term Effects of Induced Hypothermia on Local and Systemic Inflammation - Results from a Porcine Long-Term Trauma Model.

PLoS One 2016 4;11(5):e0154788. Epub 2016 May 4.

Department of Orthopedic Trauma and Harald Tscherne Research Laboratory, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.

Background: Hypothermia has been discussed as playing a role in improving the early phase of systemic inflammation. However, information on the impact of hypothermia on the local inflammatory response is sparse. We therefore investigated the kinetics of local and systemic inflammation in the late posttraumatic phase after induction of hypothermia in an established porcine long-term model of combined trauma.

Materials & Methods: Male pigs (35 ± 5kg) were mechanically ventilated and monitored over the study period of 48 h. Combined trauma included tibia fracture, lung contusion, liver laceration and pressure-controlled hemorrhagic shock (MAP < 30 ± 5 mmHg for 90 min). After resuscitation, hypothermia (33°C) was induced for a period of 12 h (HT-T group) with subsequent re-warming over a period of 10 h. The NT-T group was kept normothermic. Systemic and local (fracture hematoma) cytokine levels (IL-6, -8, -10) and alarmins (HMGB1, HSP70) were measured via ELISA.

Results: Severe signs of shock as well as systemic and local increases of pro-inflammatory mediators were observed in both trauma groups. In general the local increase of pro- and anti-inflammatory mediator levels was significantly higher and prolonged compared to systemic concentrations. Induction of hypothermia resulted in a significantly prolonged elevation of both systemic and local HMGB1 levels at 48 h compared to the NT-T group. Correspondingly, local IL-6 levels demonstrated a significantly prolonged increase in the HT-T group at 48 h.

Conclusion: A prolonged inflammatory response might reduce the well-described protective effects on organ and immune function observed in the early phase after hypothermia induction. Furthermore, local immune response also seems to be affected. Future studies should aim to investigate the use of therapeutic hypothermia at different degrees and duration of application.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154788PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856279PMC
July 2017

A porcine polytrauma model with two different degrees of hemorrhagic shock: outcome related to trauma within the first 48 h.

Eur J Med Res 2015 Sep 4;20:73. Epub 2015 Sep 4.

Trauma Department, University of Aachen, Aachen, Germany.

Background: An animal polytrauma model was developed, including trunk and extremity injuries combined with hemorrhagic shock and a prolonged post-traumatic phase. This could be useful for the assessment of different therapeutic approaches during intensive care therapy.

Methods: A standardized polytrauma including lung contusion, liver laceration and lower leg fracture was applied in 25 pigs. They underwent controlled haemorrhage either with a blood volume loss of 45 % and a median arterial pressure (MAP) <30 mmHg/90 min (group L, n = 15) or a 50 % blood loss of and an MAP <25 mmHg/120 min (group H, n = 10). Five non-traumatized pigs served as a control (group C). Subsequently, intensive care treatment was given for an observational period of 48 h.

Results: Both trauma groups showed signs of shock and organ injury (heart rate, MAP and lactate). The frequency of cardiopulmonary resuscitation (CPR) and lung injury was directly related to the severity of the haemorrhagic shock (CPR-group L: 4 of 15 pigs, group H: 4 of 10 pigs; Respiratory failure-group L: 3 of 13, group H: 3 of 9. There was no difference in mortality between trauma groups.

Conclusion: The present data suggest that our model reflects the mortality and organ failure of polytrauma in humans during shock and the intensive care period. This suggests that the experimental protocol could be useful for the assessment of therapeutic approaches during the post-traumatic period.
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http://dx.doi.org/10.1186/s40001-015-0162-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559152PMC
September 2015

Impact of haemorrhagic shock intensity on the dynamic of alarmins release in porcine poly-trauma animal model.

Eur J Trauma Emerg Surg 2016 Feb 28;42(1):67-75. Epub 2015 Feb 28.

Department of Hand, Traumatology and Reconstructive Surgery, University Hospital Marburg, Marburg, Germany.

Purpose: Traumatic insults result in an altered inflammatory response, in which alarmins release has a central role. The impact of haemorrhagic shock intensity on the long-term kinetics of alarmins is not yet fully elucidated. We investigated these aspects in a combined trauma (chest, abdominal, and extremities injury) porcine model with different severities and durations of haemorrhagic shock.

Methods: After induction of combined trauma (tibia fracture, lung contusion, and liver laceration), haemorrhagic shock was induced at different intensities: moderate haemorrhage (MH; n = 15): mean arterial pressure (MAP) <30 ± 5 mmHg [maximum loss of total blood volume (TBVmax): 45 %] for 90 min, and severe haemorrhage (SH; n = 10): MAP <25 ± 5 mmHg (TBVmax 50 %) for 120 min. Resuscitation was performed using a standardized crystalloid infusion protocol. Animals were mechanically ventilated and underwent ICU-monitoring for 48 h (MH) and 48.5 h (SH). Blood samples were collected over the clinical time course, and systemic levels of serum alarmins [High-Mobility Group Protein B-1 (HMGB-1) and Heat Shock Protein 70 (HSP70)] were measured using an ELISA kit.

Results: Heart rate, systemic blood pressure, lactate, and base excess were significantly altered as a function of haemorrhagic shock in both trauma groups (MH and SH). Systemic HMGB-1 levels were significantly elevated in both trauma groups when compared to the sham group. Haemorrhagic shock severity and duration were positively correlated with HMGB-1 levels and compared to baseline values, concentrations remained significantly increased in SH when compared to MH. On the other hand, we observed a significant decrease in the systemic HSP70 levels of trauma groups (MH, and SH) when compared to the sham group, which was significantly decreased compared to baseline values in SH over the entire time course.

Conclusion: Our data show that haemorrhagic shock duration and severity affect the systemic levels of HMGB-1 and HSP70. This early alarmins release after trauma can be used to guide the treatment strategies (e.g. surgical procedures) of polytrauma patients.
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http://dx.doi.org/10.1007/s00068-015-0504-1DOI Listing
February 2016

Local inflammation in fracture hematoma: results from a combined trauma model in pigs.

Mediators Inflamm 2015 28;2015:126060. Epub 2015 Jan 28.

Department of Orthopedic Trauma and Harald Tscherne Research Laboratory, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.

Background. Previous studies showed significant interaction between the local and systemic inflammatory response after severe trauma in small animal models. The purpose of this study was to establish a new combined trauma model in pigs to investigate fracture-associated local inflammation and gain information about the early inflammatory stages after polytrauma. Material and Methods. Combined trauma consisted of tibial fracture, lung contusion, liver laceration, and controlled hemorrhage. Animals were mechanically ventilated and under ICU-monitoring for 48 h. Blood and fracture hematoma samples were collected during the time course of the study. Local and systemic levels of serum cytokines and diverse alarmins were measured by ELISA kit. Results. A statistical significant difference in the systemic serum values of IL-6 and HMGB1 was observed when compared to the sham. Moreover, there was a statistical significant difference in the serum values of the fracture hematoma of IL-6, IL-8, IL-10, and HMGB1 when compared to the systemic inflammatory response. However a decrease of local proinflammatory concentrations was observed while anti-inflammatory mediators increased. Conclusion. Our data showed a time-dependent activation of the local and systemic inflammatory response. Indeed it is the first study focusing on the local and systemic inflammatory response to multiple-trauma in a large animal model.
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http://dx.doi.org/10.1155/2015/126060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324980PMC
January 2016

Synaptic proteome changes in a DNA repair deficient ercc1 mouse model of accelerated aging.

J Proteome Res 2012 Mar 13;11(3):1855-67. Epub 2012 Feb 13.

Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University , De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.

Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used Ercc1 mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged Ercc1 mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and Ercc1 mutant hippocampal neurons displayed normal outgrowth and synapse formation in vitro. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline.
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http://dx.doi.org/10.1021/pr201203mDOI Listing
March 2012

Differences in pathological gambling prevalence estimates: facts or artefacts?

Int J Methods Psychiatr Res 2011 Dec;20(4):e83-99

IFT Institut für Therapieforschung, Munich, Germany.

The paper aims at investigating whether survey methodology has recently converged to justify the common practice of comparing prevalence estimates and interpreting differences within and between countries. To this end, prevalence studies of problem (PrG) and pathological gambling (PG) published in peer-reviewed journals between 2000 and 2010 were critically reviewed. A systematic computer-based literature search was conducted within various databases and major gambling journals. In a two-step search process, a total of 39 studies reporting current prevalence data of non-clinical national samples from different countries were identified. Analyses revealed wide ranges in estimated PrG/PG rates for adults, adolescents, and college students, whereas similar estimates were reported in two studies on PrG/PG in seniors. Despite the discussion on methodological consistency in the field of gambling research, comparability of the reported estimates was found to be still highly limited by major variation between studies with regard to survey description, administration format, exclusion criteria, assessment instrument, cut-off scores, sample frame, and reference period. The interpretation of differences in PrG and PG prevalence estimates within and between countries may be improved by using valid and reliable instruments and by applying comparable survey methodology in well-defined populations.
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http://dx.doi.org/10.1002/mpr.354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878318PMC
December 2011

LLM3D: a log-linear modeling-based method to predict functional gene regulatory interactions from genome-wide expression data.

Nucleic Acids Res 2011 Jul 21;39(13):5313-27. Epub 2011 Mar 21.

Department of Mathematics, Faculty of Sciences, VU University, De Boelelaan 1081, 1081 HV Amsterdam, The Netherlands.

All cellular processes are regulated by condition-specific and time-dependent interactions between transcription factors and their target genes. While in simple organisms, e.g. bacteria and yeast, a large amount of experimental data is available to support functional transcription regulatory interactions, in mammalian systems reconstruction of gene regulatory networks still heavily depends on the accurate prediction of transcription factor binding sites. Here, we present a new method, log-linear modeling of 3D contingency tables (LLM3D), to predict functional transcription factor binding sites. LLM3D combines gene expression data, gene ontology annotation and computationally predicted transcription factor binding sites in a single statistical analysis, and offers a methodological improvement over existing enrichment-based methods. We show that LLM3D successfully identifies novel transcriptional regulators of the yeast metabolic cycle, and correctly predicts key regulators of mouse embryonic stem cell self-renewal more accurately than existing enrichment-based methods. Moreover, in a clinically relevant in vivo injury model of mammalian neurons, LLM3D identified peroxisome proliferator-activated receptor γ (PPARγ) as a neuron-intrinsic transcriptional regulator of regenerative axon growth. In conclusion, LLM3D provides a significant improvement over existing methods in predicting functional transcription regulatory interactions in the absence of experimental transcription factor binding data.
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http://dx.doi.org/10.1093/nar/gkr139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141251PMC
July 2011

Genome-wide gene expression and promoter binding analysis identifies NFIL3 as a repressor of C/EBP target genes in neuronal outgrowth.

Mol Cell Neurosci 2011 Feb 26;46(2):460-8. Epub 2010 Nov 26.

Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.

NFIL3 (nuclear factor IL-3 regulated) is a multifunctional transcription factor implicated in a wide range of physiological processes, including cellular survival, circadian gene expression and natural killer cell development. We recently demonstrated that NFIL3 acts as a repressor of CREB-induced gene expression underlying the regeneration of axotomized DRG sensory neurons. In this study we performed chromatin immunoprecipitation assays combined with microarray technology (ChIP-chip) to reveal direct NFIL3 and CREB target genes in an in vitro cell model for regenerating DRG neurons. We identified 505 promoter regions bound by NFIL3 and 924 promoter regions bound by CREB. Based on promoter analysis of NFIL3-bound genes, we were able to redefine the NFIL3 consensus-binding motif. Histone H3 acetylation profiling and gene expression microarray analysis subsequently indicated that a large fraction (>60%) of NFIL3 target genes were transcriptionally silent, whereas CREB target genes in general were transcriptionally active. Only a small subset of NFIL3 target genes also bound CREB. Computational analysis indicated that a substantial number of NFIL3 target genes share a C/EBP (CCAAT/Enhancer Binding Protein) DNA binding motif. ChIP analysis confirmed binding of C/EBPs to NFIL3 target genes, and knockdown of C/EBPα, C/EBPβ and C/EBPδ, but not C/EBPγ, significantly reduced neurite outgrowth in vitro. Together, our findings show that NFIL3 is a general feed-forward repressor of basic leucine zipper transcription factors that control neurite outgrowth.
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http://dx.doi.org/10.1016/j.mcn.2010.11.011DOI Listing
February 2011

NFIL3 and cAMP response element-binding protein form a transcriptional feedforward loop that controls neuronal regeneration-associated gene expression.

J Neurosci 2009 Dec;29(49):15542-50

Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands.

Successful regeneration of damaged neurons depends on the coordinated expression of neuron-intrinsic genes. At present however, there is no comprehensive view of the transcriptional regulatory mechanisms underlying neuronal regeneration. We used high-content cellular screening to investigate the functional contribution of 62 transcription factors to regenerative neuron outgrowth. Ten transcription factors are identified that either increase or decrease neurite outgrowth. One of these, NFIL3, is specifically upregulated during successful regeneration in vivo. Paradoxically however, knockdown of NFIL3 and overexpression of dominant-negative NFIL3 both increase neurite outgrowth. Our data show that NFIL3, together with CREB, forms an incoherent feedforward transcriptional regulatory loop in which NFIL3 acts as a negative regulator of CREB-induced regeneration-associated genes.
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http://dx.doi.org/10.1523/JNEUROSCI.3938-09.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666114PMC
December 2009

[Diagnostic image (347). A man with a swelling underneath his tongue].

Ned Tijdschr Geneeskd 2007 Oct;151(43):2381

Leids Universitair Medisch Centrum, afd. KNO, Leiden.

A 23-year-old man presented with a painless, growing swelling underneath his tongue due to a ranula, i.e. accumulation of saliva in the drainage canal of the sublingual salivary gland.
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October 2007

Can renal tubular hypokalemic disorders be accurately diagnosed on the basis of the diuretic response to thiazide?

Nat Clin Pract Nephrol 2007 Oct 14;3(10):528-9. Epub 2007 Aug 14.

Department of Pediatrics/Pediatric Nephrology, Philipps-University Children's Hospital, Marburg, Germany.

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http://dx.doi.org/10.1038/ncpneph0576DOI Listing
October 2007

Interaction of the Ca2+-sensing receptor with the inwardly rectifying potassium channels Kir4.1 and Kir4.2 results in inhibition of channel function.

Am J Physiol Renal Physiol 2007 Mar 22;292(3):F1073-81. Epub 2006 Nov 22.

Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.

The Ca(2+)-sensing receptor (CaR), a G protein-coupled receptor, is expressed in many epithelial tissues including the parathyroid glands, kidney, and GI tract. Although its role in regulating PTH levels and Ca(2+) metabolism are best characterized, it may also regulate salt and water transport in the kidney as demonstrated by recent reports showing association of potent gain-of-function mutations in the CaR with a Bartter-like, salt-wasting phenotype. To determine whether this receptor interacts with novel proteins that control ion transport, we screened a human adult kidney cDNA library with the COOH-terminal 219 amino acid cytoplasmic tail of the CaR as bait using the yeast two-hybrid system. We identified two independent clones coding for approximately 125 aa from the COOH terminus of the inwardly rectifying K(+) channel, Kir4.2. The CaR and Kir4.2 as well as Kir4.1 (another member of Kir4 subfamily) were reciprocally coimmunoprecipitated from HEK-293 cells in which they were expressed, but the receptor did not coimmunoprecipitate with Kir5.1 or Kir1.1. Both Kir4.1 and Kir4.2 were immunoprecipitated from rat kidney extracts with the CaR. In Xenopus laevis oocytes, expression of the CaR with either Kir4.1 or Kir4.2 channels resulted in inactivation of whole cell current as measured by two-electrode voltage clamp, but the nonfunctional CaR mutant CaR(R796W), and that does not coimmunoprecipitate with the channels, had no effect. Kir4.1 and the CaR were colocalized in the basolateral membrane of the distal nephron. The CaR interacts directly with Kir4.1 and Kir4.2 and can decrease their currents, which in turn could reduce recycling of K(+) for the basolateral Na(+)-K(+)-ATPase and thereby contribute to inhibition of Na(+) reabsorption.
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http://dx.doi.org/10.1152/ajprenal.00269.2006DOI Listing
March 2007

Dysregulation of renal sodium transporters in gentamicin-treated rats.

Kidney Int 2006 Sep 19;70(6):1026-37. Epub 2006 Jul 19.

The Water and Salt Research Center, University of Aarhus, Aarhus C, Denmark.

We aimed to investigate the molecular mechanisms underlying the renal wasting of Na(+), K(+), Ca(2+), and Mg(2+) in gentamicin (GM)-treated rats. Male Wistar rats were injected with GM (40 or 80 mg/kg/day for 7 days, respectively; GM-40 or GM-80). The expression of NHE3, Na-K-ATPase, NKCC2, ROMK, NCC, alpha-, beta- and gamma-ENaC, and CaSR was examined in the kidney by immunoblotting and immunohistochemistry. Urinary fractional excretion of Na(+), K(+), Ca(2+), and Mg(2+) was increased and urinary concentration was decreased in both GM-40 and GM-80 rats. In cortex and outer stripe of outer medulla (cortex) in GM-80 rats, the expression of NHE3, Na-K-ATPase, and NKCC2 was decreased; NCC expression was unchanged; and CaSR was upregulated compared to controls. In the inner stripe of outer medulla (ISOM) in GM-80 rats, NKCC2 and Na-K-ATPase expression was decreased, whereas CaSR was upregulated, and NHE3 and ROMK expression remained unchanged. In GM-40 rats, NKCC2 expression was decreased in the cortex and ISOM, whereas NHE3, Na-K-ATPase, CaSR, ROMK, and NCC abundance was unchanged in both cortex and ISOM. Immunoperoxidase labeling confirmed decreased expression of NKCC2 in the thick ascending limb (TAL) in both GM-80- and GM-40-treated rats. Immunoblotting and immunohistochemical analysis revealed increased expression of alpha-, beta-, and gamma-ENaC in cortex in GM-80 rats, but not in GM-40 rats. These findings suggest that the decrease in NKCC2 in TAL seen in response to low-dose (40 mg/kg/day) gentamicin treatment may play an essential role for the increased urinary excretion of Mg(2+) and Ca(2+), and play a significant role for the development of the urinary concentrating defect, and increased urinary excretion of Na(+) and K(+). At high-dose gentamicin, both proximal and TAL sodium transporter downregulation is likely to contribute to this.
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http://dx.doi.org/10.1038/sj.ki.5001654DOI Listing
September 2006

Biphasic changes of epithelial sodium channel abundance and trafficking in common bile duct ligation-induced liver cirrhosis.

Kidney Int 2006 Jan;69(1):89-98

The Water and Salt Research Center, University of Aarhus, Aarhus C, Denmark.

We hypothesize that dysregulation of the epithelial sodium channel (ENaC) may be responsible for the increased sodium retention in liver cirrhosis. Liver cirrhosis was induced by common bile duct ligation (CBDL). We examined the abundance of ENaC subunits and type 2 isoform of 11beta-hydroxysteroid dehydrogenase (11betaHSD2) in the kidney by immunoblotting and immunohistochemistry at 6 or 8 weeks after operation. At 6 weeks, cirrhotic rats had developed ascites and displayed a positive sodium balance. The urinary sodium excretion and fractional excretion of sodium were decreased, while plasma aldosterone was unchanged. The abundance of ENaC subunits was not changed in the cortex and outer stripe of the outer medulla (OSOM). In contrast, immunoperoxidase microscopy revealed an increased apical targeting of alpha-, beta- and gammaENaC in late distal convoluted tubule, connecting tubule and collecting duct. Moreover, 11betaHSD2 abundance was decreased in the cortex/OSOM and inner stripe of the outer medulla. At 8 weeks, urinary sodium excretion and fractional excretion of sodium were not changed, while the plasma aldosterone level was decreased. The expression of ENaC subunits was decreased in the cortex/OSOM. Immunoperoxidase microscopy confirmed decreased expression of ENaC subunits, whereas subcellular localization was not changed. These results suggest that increased apical targeting of ENaC subunits and diminished abundance of 11betaHSD2 may contribute to promote sodium retention in the sodium-retaining stage of liver cirrhosis (at 6 weeks). The subsequent decreased expression and reduced targeting of ENaC subunits may play a role in promoting sodium excretion in the later stage of liver cirrhosis (at 8 weeks).
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http://dx.doi.org/10.1038/sj.ki.5000018DOI Listing
January 2006

Increased apical targeting of renal ENaC subunits and decreased expression of 11betaHSD2 in HgCl2-induced nephrotic syndrome in rats.

Am J Physiol Renal Physiol 2006 Mar 27;290(3):F674-87. Epub 2005 Sep 27.

The Water and Salt Research Center, Bldg. 233/234, University of Aarhus, DK-8000 Aarhus C, Denmark.

Nephrotic syndrome is often accompanied by sodium retention and generalized edema. We hypothesize that dysregulation of the epithelial sodium channel (ENaC) and/or of sodium (co)transporters may be responsible for the increased sodium retention associated with HgCl(2)-induced nephropathy. In addition, we examined the hypothesis that the expression of type 2 11beta-hydroxysteroid dehydrogenase (11betaHSD2) is reduced, contributing to the enhanced mineralocorticoid activity. Membranous nephropathy was induced in Brown Norway rats by repeated injections of HgCl(2) (1 mg/kg sc), whereas the control group received only vehicle. After 13 days of treatment, the abundance of ENaC subunits, sodium (co)transporters, and 11betaHSD2 in the kidney was examined by immunoblotting and immunohistochemistry. HgCl(2) treatment induced marked proteinuria, hypoalbuminemia, decreased urinary sodium excretion, and ascites. The protein abundance of alpha-ENaC was increased in the cortex/outer stripe of outer medulla (OSOM) and inner stripe of the outer medulla (ISOM). The protein abundances of beta-ENaC and gamma-ENaC were decreased in the cortex/OSOM while increased in the ISOM. Immunoperoxidase microscopy demonstrated increased targeting of ENaC subunits to the apical plasma membrane in the distal convoluted tubule, connecting tubule, and cortical and medullary collecting duct segments. Moreover, 11betaHSD2 abundance was decreased in cortex/OSOM and ISOM. The protein abundances of type 3 Na/H exchanger (NHE3), Na-K-2Cl cotransporter (NKCC2), and thiazide-sensitive Na-Cl cotransporter (NCC) were decreased. Moreover, the abundance of the alpha-1 subunit of the Na-K-ATPase was decreased in the cortex/OSOM and ISOM but remained unchanged in the inner medulla. These results suggest that increased apical targeting of ENaC subunits combined with diminished abundance of 11betaHSD2 may contribute to sodium retention associated with HgCl(2)-induced nephrotic syndrome. The decreased abundance of NHE3, NKCC2, NCC, and Na-K-ATPase may play a compensatory role in promoting sodium excretion.
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http://dx.doi.org/10.1152/ajprenal.00084.2005DOI Listing
March 2006

Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia.

J Am Soc Nephrol 2005 Oct 17;16(10):3061-9. Epub 2005 Aug 17.

University Children's Hospital Marburg, Deutschhausstrasse 12, 35037 Marburg, Germany.

Primary hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder characterized by profound hypomagnesemia associated with hypocalcemia. Pathophysiology is related to impaired intestinal absorption of magnesium accompanied by renal magnesium wasting as a result of a reabsorption defect in the distal convoluted tubule. Recently, mutations in the TRPM6 gene coding for TRPM6, a member of the transient receptor potential (TRP) family of cation channels, were identified as the underlying genetic defect. Here, the results of a TRPM6 mutational analysis of 21 families with 28 affected individuals are presented. In this large patient cohort, a retrospective clinical evaluation based on a standardized questionnaire was also performed. Genotype analysis revealed TRPM6 mutations in 37 of 42 expected mutant alleles. Sixteen new TRPM6 mutations were identified, including stop mutations, frame-shift mutations, splice-site mutations, and deletions of exons. Electrophysiologic analysis of mutated ion channels after heterologous expression in Xenopus oocytes proved complete loss of function of TRPM6. Clinical evaluation revealed a homogeneous clinical picture at manifestation with onset in early infancy with generalized cerebral convulsions. Initial laboratory evaluation yielded extremely low serum magnesium levels, low serum calcium levels, and inadequately low parathyroid hormone levels. Treatment usually consisted of acute intravenous magnesium supplementation leading to relief of clinical symptoms and normocalcemia, followed by lifelong oral magnesium supplementation. Serum magnesium levels remained in the subnormal range despite adequate therapy. This is best explained by a disturbed magnesium conservation in the distal convoluted tubule, which emerged in all patients upon magnesium supplementation. Delay of diagnosis resulted in permanent neurologic damage in three patients.
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http://dx.doi.org/10.1681/ASN.2004110989DOI Listing
October 2005

Granularin, a novel molluscan opsonin comprising a single vWF type C domain is up-regulated during parasitation.

FASEB J 2004 May 19;18(7):845-7. Epub 2004 Mar 19.

Graduate School Neurosciences Amsterdam, Institute of Neuroscience, Department of Molecular and Cellular Neurobiology, Vrije Universiteit, Amsterdam, The Netherlands.

Snails are intermediate hosts to schistosome parasites, some of which are the main cause of human schistosomiasis (bilharzia), and have been used as models for parasite-host interactions for a long time. Here, we have characterized a novel internal defense peptide of the snail Lymnaea stagnalis, of which the relative abundance in brain tissue increases upon infection with the avian schistosome Trichobilharzia ocellata. This protein, named granularin, is secreted by granular cells, which are numerous in the connective tissue surrounding the brain. The protein is unique because it comprises only a single Von Willebrand factor type C domain that is normally found in large transmembrane and secreted extracellular matrix proteins. The granularin gene is twice up-regulated during parasitation. Purified granularin stimulates phagocytosis of foreign particles by blood hemocytes. Together, our data indicate that granularin represents a novel protein that acts as an opsonin in the molluscan internal defense response.
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http://dx.doi.org/10.1096/fj.03-0590fjeDOI Listing
May 2004

Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia.

Proc Natl Acad Sci U S A 2004 Mar 19;101(9):2894-9. Epub 2004 Feb 19.

Institute for Pharmacology and Toxicology, Philipps University Marburg, 35033 Marburg, Germany.

Impaired magnesium reabsorption in patients with TRPM6 gene mutations stresses an important role of TRPM6 (melastatin-related TRP cation channel) in epithelial magnesium transport. While attempting to isolate full-length TRPM6, we found that the human TRPM6 gene encodes multiple mRNA isoforms. Full-length TRPM6 variants failed to form functional channel complexes because they were retained intracellularly on heterologous expression in HEK 293 cells and Xenopus oocytes. However, TRPM6 specifically interacted with its closest homolog, the Mg(2+)-permeable cation channel TRPM7, resulting in the assembly of functional TRPM6/TRPM7 complexes at the cell surface. The naturally occurring S141L TRPM6 missense mutation abrogated the oligomeric assembly of TRPM6, thus providing a cell biological explanation for the human disease. Together, our data suggest an important contribution of TRPM6/TRPM7 heterooligomerization for the biological role of TRPM6 in epithelial magnesium absorption.
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http://dx.doi.org/10.1073/pnas.0305252101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC365716PMC
March 2004

Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family.

Nat Genet 2002 Jun 28;31(2):166-70. Epub 2002 May 28.

Department of Pediatrics, Philipps University of Marburg, Deutschhausstrasse 12, D-35037 Marburg, Germany.

Magnesium is an essential ion involved in many biochemical and physiological processes. Homeostasis of magnesium levels is tightly regulated and depends on the balance between intestinal absorption and renal excretion. However, little is known about specific proteins mediating transepithelial magnesium transport. Using a positional candidate gene approach, we identified mutations in TRPM6 (also known as CHAK2), encoding TRPM6, in autosomal-recessive hypomagnesemia with secondary hypocalcemia (HSH, OMIM 602014), previously mapped to chromosome 9q22 (ref. 3). The TRPM6 protein is a new member of the long transient receptor potential channel (TRPM) family and is highly similar to TRPM7 (also known as TRP-PLIK), a bifunctional protein that combines calcium- and magnesium-permeable cation channel properties with protein kinase activity. TRPM6 is expressed in intestinal epithelia and kidney tubules. These findings indicate that TRPM6 is crucial for magnesium homeostasis and implicate a TRPM family member in human disease.
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http://dx.doi.org/10.1038/ng889DOI Listing
June 2002

Risk factors for otitis media with effusion in children 0 to 2 years of age.

Am J Otolaryngol 1997 Sep-Oct;18(5):324-30

Department of Otorhinolaryngology, University Hospital Leiden, The Netherlands.

Purpose: To determine the possible risk factors associated with the occurrence of otitis media with effusion.

Patients And Methods: Two hundred eighty-nine children born between July 1987 and October 1988 were studied up to the age of 24 months. The enrollment of the children took place during their regular check-up visits at three different health-care centers.

Results: Having older sibling was the most important risk factor, for both the time elapsed until the first occurrence and for the probability of otitis media with effusion at each visit. Other significant risk factors for the probability at each visit were: having had acute otitis media before the visit or before the previous visit, age, a positive family history of otitis media, and upper respiratory tract infections (URTI).

Conclusion: Having older siblings is the most important risk factor for otitis media with effusion in this age group.
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http://dx.doi.org/10.1016/s0196-0709(97)90027-2DOI Listing
November 1997

Breast-feeding and acute otitis media.

Am J Otolaryngol 1994 Sep-Oct;15(5):351-7

Department of Otorhinolaryngology, University Hospital, Leiden, The Netherlands.

Introduction: The risk of acute otitis media (AOM) is estimated as a function of a number of covariates, with special emphasis on changes to this risk after breast-feeding is discontinued.

Materials And Methods: Two hundred eighty-nine children born between July 1987, and October 1988, were studied up to the age of 24 months. The enrollment of the children took place during their regular check-up visits at three different child health care centers.

Results: The risk of AOM was significantly decreased until 4 months after breast-feeding was discontinued; then, without the protective effect of breast-feeding, and with increasing months, the children approached the risk level estimated in the group of children who were never breast-fed. Approximately 12 months after breast-feeding was discontinued, the risk was virtually the same as if the child had never been breast-fed. The risk of AOM was also significantly dependent on the infant's number of siblings and socioeconomic status.

Conclusion: The risk of AOM depends on the number of months an infant is breast-fed and the number of months that pass after breast-feeding is discontinued.
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http://dx.doi.org/10.1016/0196-0709(94)90134-1DOI Listing
December 1994

Validity of tympanometry in the diagnosis of middle ear effusion.

Clin Otolaryngol Allied Sci 1994 Jun;19(3):185-9

Department of Otorinolaryngology, University Hospital Leiden, The Netherlands.

A group of 266 children (515 ears), ranging in age from 5 months to 11 years, was studied. These children were candidates for the insertion of ventilation tubes, or adenoidectomy and/or tonsillectomy with myringotomy. Before surgery, tympanometry was performed. The surgical and tympanometric findings were compared afterwards. Two different tympanometers were used (GSI-27A and TYMP-85TT). This study showed a comparable validity of these two tympanometers. The sensitivity and specificity of tympanometry in the age group of 5 months to 2 years did not show a significant difference from that in the age group of 2-12 years. Otoscopy has limited value for the diagnosis of middle ear effusion in this age group.
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http://dx.doi.org/10.1111/j.1365-2273.1994.tb01211.xDOI Listing
June 1994

Otitis media, respiratory tract infections and hearing loss in pre-term and low birthweight infants.

Clin Otolaryngol Allied Sci 1994 Jun;19(3):179-84

ENT Department, University Hospital Leiden, The Netherlands.

In 1983, 1338 liveborn infants with a gestational age of less than 32 weeks and/or a birthweight of less than 1500 g, were enrolled in a national follow-up study in The Netherlands. At the age of 5 years, 966 children were alive. Of these, 927 (96%) were assessed on a home visit 2-6 weeks after their fifth birthday by three specially trained paediatricians. An assessment of ENT morbidity was made and compared with ENT morbidity in full-term children of the same age group. Markedly preterm birth or very low birthweight does not seem to be a risk factor for developing middle ear disease in childhood, however, the rate of ENT problems seems to be higher than in the general population of Dutch pre-school children.
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http://dx.doi.org/10.1111/j.1365-2273.1994.tb01210.xDOI Listing
June 1994

Hearing loss in very preterm and very low birthweight infants at the age of 5 years in a nationwide cohort.

Int J Pediatr Otorhinolaryngol 1993 Feb;26(1):11-28

Department of Pediatrics, University Hospital Leiden, The Netherlands.

In a geographically defined population of very preterm and very low birthweight infants (gestational age < 32 weeks and/or birthweight < 1500 g) hearing was evaluated in 890 children by pure-tone audiometry at the age of 5 years. Hearing loss was conductive/unspecified in 123 (13.8%) and sensorineural in 13 (1.5%) children. The prevalence of sensorineural hearing loss was 15 times as high as in 5-7 year old children in the Dutch population at large. The sensorineural hearing loss prevalence in very low birthweight and extremely low birthweight infants was similar. On account of communication disorders 10 (1.1%) children were classified as disabled and 6 (0.7%) as handicapped, following the definitions of the International Classification of Impairments, Disabilities, and Handicaps of the World Health Organisation. Children with conductive hearing loss had a higher risk of impairments, disabilities and handicaps of language and speech development, than children with normal hearing, the difference being statistically significant. The same holds for children with sensorineural hearing loss; moreover they had a significantly higher risk of impairments, disabilities and handicaps of mental development. Overall comparison of children with and without sensorineural hearing loss proved that the children with sensorineural hearing loss had a significantly less favourable outcome, based on 15 perinatal factors simultaneously. The age at which sensorineural hearing loss in very preterm and/or very low birthweight infants is detected has to be improved.
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http://dx.doi.org/10.1016/0165-5876(93)90192-6DOI Listing
February 1993

In vitro release of the anti-gonadotropic hormone, schistosomin, from the central nervous system of Lymnaea stagnalis is induced with a methanolic extract of cercariae of Trichobilharzia ocellata.

Parasitology 1992 Apr;104 ( Pt 2):309-14

Faculty of Biology, Vrije Universiteit, Amsterdam, The Netherlands.

Infection with digenetic trematodes causes an inhibition or complete cessation of fecundity in their intermediate hosts, freshwater snails. It has been demonstrated in the host-parasite combination Lymnaea stagnalis-Trichobilharzia ocellata that the action of the female gonadotropic hormones upon their target organs is inhibited by the peptide schistosomin. Schistosomin is produced in the central nervous system of the snail and released upon parasitic infection. In order to study the in vitro release of schistosomin, a bioassay was developed. Central nervous systems were incubated with either an acetic acid or a methanolic extract of larval stages of Trichobilharzia ocellata (miracidia, mother sporocysts, cercariae). The incubation media were chromatographed using HPLC and released schistosomin (-like material) was tested for bioactivity in the calfluxin bioassay. The in vitro release of schistosomin was only induced with a methanolic extract of cercariae. The nature of the cercarial factor is discussed.
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http://dx.doi.org/10.1017/s0031182000061758DOI Listing
April 1992

Deposition and reorientation of cellulose microfibrils in elongating cells of Petunia stylar tissue.

Planta 1991 Sep;185(2):179-89

Department of Experimental Botany, University of Nijmegen, Toernooiveld, NL-6525, ED Nijmegen, The Netherlands.

According to Roelofsen and Houwink's (1953, Acta Bot. Neerl. 2, 218-225) multinet growth hypothesis, microfibrils originally deposited transversely in the cell wall become gradually reoriented towards more axial orientations during cell elongation. To establish the extent of reorientation, microfibrils were studied during their deposition and elongation, using stylar parenchyma and transmitting tissue cells of Petunia hybrida L. At the inner surface of very young cells, microfibrils were deposited in alternating Z- and S-helical orientations. The following sequence in deposition, from the exterior to the interior side of the wall, could be inferred: Axial: 150°-180° (Z-helical), 0°-30° (S-helical); oblique: 110°-150° (Z-helical), 30°-70° (S-helical); transverse: 90°-110° (Z-helical), 70°-90° (S-helical). With the increasing pitch, the density of the deposited microfibrils increased as well, giving rise to an alternating helical texture. During elongation, only transversely S- and Z-helically oriented microfibrils were deposited and all microfibrils underwent a certain reorientation as described in the multinet growth hypothesis. The texture resembled that of young cells and the wall maintained its thickness. The extent of passive reorientation was in agreement with the theoretical calculations made by Preston.
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http://dx.doi.org/10.1007/BF00194059DOI Listing
September 1991

Trichobilharzia ocellata: influence of infection on the fecundity of its intermediate snail host Lymnaea stagnalis and cercarial induction of the release of schistosomin, a snail neuropeptide antagonizing female gonadotropic hormones.

Parasitology 1991 Feb;102 Pt 1:85-91

Faculty of Biology, Vrije Universiteit, Amsterdam, The Netherlands.

Subadult and adult specimens of the pond snail Lymnaea stagnalis were infected with the schistosome Trichobilharzia ocellata. Egg production and growth of the snails were monitored over an 8-week period post-infection (p.i.). Snail haemolymph was collected and analysed for the presence of schistosomin, a neuropeptide which antagonizes the action of the snails' female gonadotropic hormones. Snails infected as subadults showed an increase in fecundity during the first 4 weeks p.i. compared with non-infected controls. The possibility is discussed that this increase is caused by an accelerated maturation of the female sex organs due to elevated levels of Dorsal Body Hormone, a female gonadotropic hormone. No difference in fecundity was found between snails infected as adults and control snails during the first 4 weeks p.i. Snails infected as subadults and as adults showed a decrease in fecundity from week 5 p.i. and onwards. This decrease coincided with the appearance of schistosomin in the haemolymph of the snails and with that of differentiating cercariae in the daughter sporocysts. Cercariae are probably involved in the induction of schistosomin release from the snails' CNS into the haemolymph. Snails infected as subadults or as adults grew at approximately the same rate as uninfected snails.
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http://dx.doi.org/10.1017/s0031182000060376DOI Listing
February 1991

ORIGIN AND DEVELOPMENT OF FLORAL BUDS IN TOBACCO EXPLANTS.

New Phytol 1987 Jan;105(1):57-65

Department of Botany, University of Nijmegen, Toernooiveld, 6525 ED Nijmegen, The Netherlands.

Initiation and formation of floral buds was studied on explants of Nicotiana tabacum. During the first stage of development (0 to 4 d), protrusions are formed at the basal side of the explant as a result of cell divisions in both sub-epidermal and epidermal cell layers. The second stage (4 to 7 d) is characterized by the formation of tracheary centres inside the protrusions followed by the formation of floral primordia at the surface of the protrusions. These primordia result from both epidermal and sub-epidermal cell divisions. In the final stage (7 to 15 d), flower primordia develop into flower buds and tracheary elements grow into the buds. Polarity present in cells of freshly cut explants is lost within a few days after the onset of the experiment. After 4 to 7 d, a new polarity axis has differentiated inside the protrusion. This axis runs from the tracheary structure inside the protrusion to the flower primordium at the periphery.
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http://dx.doi.org/10.1111/j.1469-8137.1987.tb00109.xDOI Listing
January 1987
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