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Biomedical subjects

Andreas Herbst

Publications and source records attributed to Andreas Herbst.

At least 19 recordsLinked to original sources
PubMed2007

Sonographic characteristics of rectal sensations in healthy females.

PURPOSE: This study was designed to characterize rectal sensations by visualizing the internal and external anal sphincter and intra-anal transport of bolus during elicited rectal sensations. METHODS: The anal canal was visualized with real-time transperineal ultrasonography in 13 healthy female volunteers. Rectal sensations were elicited by injecting water into the rectum. The ultrasound images were recorded on a videotape and analyzed offline. RESULTS: The median time between an injection of water and the events studied was calculated in 105 rectal sensations. A relaxation in the internal anal sphincter (4 seconds after the injection of water), an antegrade transport of bolus (4 seconds) into the anal canal, and a contraction in the external anal sphincter (5 seconds) were observed before a sensation (6 seconds) was reported. The antegrade flow continued until the distal internal anal sphincter contracted (18 seconds) and the bolus moved in a retrograde transport direction (17 seconds) thereafter the sensation disappeared (18 seconds) and the external anal sphincter relaxed (22 seconds). A significant correlation in time between the end of the sensation, contraction in the internal anal sphincter, reversed flow of anal contents, and relaxation of the external anal sphincter was found (Pearson, P<0.01). CONCLUSIONS: The results verified that the internal anal sphincter contributes to the perception of rectal sensations by a relaxation allowing intra-anal bolus to increase the pressure on the anoderm during rectal contraction. A new observation is presented on the time relation between contraction in the distal internal anal sphincter, reversed flow in the anal canal, and the end of rectal sensations.

Adult↗
PubMed2007

Human meconium contains significant amounts of alkaline sphingomyelinase, neutral ceramidase, and sphingolipid metabolites.

Intestinal alkaline sphingomyelinase (Alk-SMase) and neutral ceramidase may catalyze the hydrolysis of endogenous sphingomyelin (SM) and milk SM in human-milk fed infants. The enzymes generate sphingolipid metabolites that may influence gut maturation. Alk-SMase also inactivates platelet-activating factor (PAF) that is involved in the pathogenesis of necrotizing enterocolitis (NEC). We examined whether the two enzymes are expressed in both preterm and term infants and analyzed Alk-SMase, neutral ceramidase, SM, and sphingolipid metabolites in meconium. Meconium was collected from 46 preterm (gestational ages 23-36 wk) and 38 term infants (gestational ages 37-42 wk) and analyzed for Alk-SMase using C-choline-labeled SM and for neutral ceramidase using C-octanoyl-sphingosine as substrates. Molecular species of SM, ceramide, and sphingosine were analyzed by high-performance liquid chromatography mass spectroscopy. Meconium contained significant levels of Alk-SMase and ceramidase at all gestational ages. It also contained 16-24 carbon molecular species of SM, palmitoyl- and stearoyl-sphingosine, and sphingosine. There were positive correlations between levels of SM and ceramide and between ceramide and sphingosine levels. In conclusion, Alk-SMase and ceramidase are expressed in the gut of both preterm and term newborn infants and may generate bioactive sphingolipid messengers.

Amidohydrolases↗
PubMed2007

Wnt signaling as a therapeutic target for cancer.

The Wnt/beta-catenin signaling pathway is tightly regulated and has important functions in development, tissue homeostasis, and regeneration. Deregulation of Wnt/beta-catenin signaling is frequently found in various human cancers. Eighty percent of colorectal cancers alone reveal activation of this pathway by either inactivation of the tumor-suppressor gene adenomatous polyposis coli or mutation of the proto-oncogene beta-catenin. Activation of Wnt/beta-catenin signaling has been found to be important for both initiation and progression of cancers of different tissues. Therefore, targeted inhibition of Wnt/beta-catenin signaling is a rational and promising new approach for the therapy of cancers of various origins.

Adenomatous Polyposis Coli↗
PubMed2006

Methylation of serum DNA is an independent prognostic marker in colorectal cancer.

PURPOSE: Aberrant CpG island hypermethylation is a feature of a subgroup of colorectal cancers, which can be detected in the serum of affected patients. This study was designed to identify methylation targets with prognostic significance in the serum of patients with colorectal cancer. EXPERIMENTAL DESIGN: In a gene evaluation set consisting of sera from 24 patients with local colorectal cancers, 14 with metastasized disease, and 20 healthy controls, the genes HPP1/TPEF, HLTF, and hMLH1 were identified as potential serum DNA methylation markers. These genes were further analyzed in a test set of sera of 104 patients with colorectal cancer. RESULTS: Methylation of HLTF, HPP1/TPEF, and hMLH1 was found to be significantly correlated with tumor size, and methylation of HLTF and HPP1/TPEF was significantly associated with metastatic disease and tumor stage. Moreover, methylation of HPP1/TPEF was also associated with serum carcinoembryonic antigen. The prognostic relevance of methylation of these genes was tested in pretherapeutic sera of 77 patients with known follow-up. Patients with methylation of HPP1/TPEF or HLTF were found to have unfavorable prognosis (P = 0.001 and 0.008). In contrast, serum methylation of hMLH1 was not associated with a higher risk of death. Multivariate analysis showed methylated HPP1 and/or HLTF serum DNA to be independently associated with poor outcome and a relative risk of death of 3.4 (95% confidence interval, 1.4-8.1; P = 0.007). CONCLUSIONS: These data show that the methylation status of specific genes in the serum of patients with colorectal cancer has the potential to become a pretherapeutic predictor of outcome.

Adult↗
PubMed2006

Influence of mode of delivery on neonatal mortality and morbidity in spontaneous preterm breech delivery.

OBJECTIVE: To study the association between mode of delivery and neonatal outcome in singleton pregnancy with breech presentation and preterm birth, due to premature labour (PTL) and/or preterm premature rupture of the membranes (pPROM). DESIGN AND METHODS: Information on preterm (gestational week 25-36) singleton births in breech presentation in Sweden during 1990-2002 was obtained from the Swedish Medical Birth Registry and the Swedish Hospital Discharge Registry. The study groups included 1975 caesarean and 699 vaginal deliveries with a diagnosis of PTL or pPROM, without pregnancy complications implying a high risk of fetal compromise. The rates of infant respiratory distress syndrome (IRDS), intraventricular haemorrhage (IVH), low Apgar scores, and neonatal deaths were compared between infants delivered vaginally and by caesarean section. Odds ratios were calculated with adjustment for gestational age, year of birth, maternal age and parity. RESULTS: The risk of neonatal death and the risk of an Apgar score below 5 min postnatally were both lower after caesarean delivery (OR 0.4; 95% CI 0.2-0.7, and OR 0.4; 95% CI 0.3-0.7, respectively), whereas the risk of IRDS was increased (OR 2.1; 95% CI 1.4-3.2). A diagnosis of IRDS was not associated with mortality (OR 0.8; 95% CI 0.5-1.5). IVH was not associated with mode of delivery (OR 1.2; 95% CI 0.5-2.8). CONCLUSION: The lower neonatal mortality after CS supports a policy of caesarean delivery of the preterm breech.

Apgar Score↗
PubMed2006

How often is a low 5-min Apgar score in term newborns due to asphyxia?

OBJECTIVE: To evaluate how often low 5-min Apgar scores (AS(5-min)) at term are associated with asphyxia. STUDY DESIGN: A cohort- and case-control study, including all 183 term infants with AS(5-min) below 7 born at Lund University Hospital during 1993-2002, antepartum deaths excluded. The control group included 183 randomly selected term newborns with AS(5-min) 9-10. Cardiotocography (CTG) traces were assessed blinded to group and outcome. Obstetric and pediatric files were reviewed. RESULTS: After excluding infants with severe malformations, indications of hypoxia were found at the following rates in cases with AS(5-min) below 4 (N = 30), scores 4-6 (N = 143), and controls (N = 182)-abnormal admission CTG: 38%, 8% and 0.6%; abnormal CTG before birth: 88%, 69% and 18%; obstetrical catastrophe: 28%, 6% and 0.6%; interventions for fetal distress: 83%, 48% and 9%; cord artery pH below 7.15: 69%, 54% and 7%; hypoxic ischemic encephalopathy or hypoxic death: 70%, 14% and none. All differences between each case group and controls were statistically significant (p < 0.0001). CONCLUSIONS: In the absence of severe malformations, the vast majority of AS(5-min) below 4, and at least half of scores 4-6 could be attributed to birth asphyxia. Signs of hypoxia usually appeared during labor, but were present at admission in 38% of cases with AS(5-min) below 4.

Acidosis↗
PubMed2006

Gene deletion of MK2 inhibits TNF-alpha and IL-6 and protects against cerulein-induced pancreatitis.

Inflammatory effects contribute to the pathogenesis of pancreatitis. Clearly, proinflammatory cytokines like TNF-alpha and IL-6 are involved in this process and the associated systemic complications. The MAPKAPK-2 (MK2) signaling pathway is involved in cytokine gene expression. Therefore, we hypothesized that blockade of this pathway inhibits the expression of proinflammatory cytokines and thereby protects against pancreatitis. To investigate this, we used an in vivo mouse model with a homozygous deletion of the MK2 gene. Pancreatitis was induced by injection of cerulein. The severity was determined by measuring serum lipase, pancreatic trypsin activation, pancreatic edema, and morphological changes by quantitative scoring of histological sections. Systemic inflammation was evaluated by measuring myeloperoxidase activity in lung tissue. Serum levels of TNF-alpha and IL-6 were measured using an ELISA, and mRNA levels were identified using RT-PCR and subsequent quantitative PCR analysis. Pancreatitis in animals with deletion of the MK2 gene is less severe and accompanied with reduced serum levels of TNF-alpha and IL-6. Pancreatic mRNA levels revealed a fourfold reduction of IL-6 mRNA expression in MK2 -/- mice. Effects were associated with suppression of pancreatic trypsin activity and reduced acinar cell injury. In summary, these data show that gene deletion of MK2 ameliorates cerulein-induced pancreatitis. TNF-alpha and IL-6 signaling is mediated by the MK2 pathway and therefore crucial for the regulatory inflammatory processes. TNF-alpha expression is supposably regulated by a posttranscriptional mechanism, whereas IL-6 expression is most likely regulated by transcriptional effects.

Animals↗
PubMed2006

Eclampsia in Scandinavia: incidence, substandard care, and potentially preventable cases.

BACKGROUND: Description of incidence, clinical signs, symptoms, and consequences of eclampsia in Scandinavia, and assessment of substandard care and potential preventability. METHODS: A descriptive cohort study including all women giving birth in a 2-year period (mid-1998-mid-2000) in Scandinavia. Notifications of eclampsia cases were obtained from all obstetric units at 3-monthly intervals. All patient files were reviewed, and systematic audit was performed to identify potentially preventable cases by using predefined criteria. MAIN OUTCOME MEASURES: Signs and symptoms preceding the eclamptic seizure, the standard of medical care, maternal and perinatal morbidity, and mortality were all recorded. Potentially preventable cases through improved care and cases eligible for primary prophylactic magnesium sulfate (MgSO4) were estimated. RESULTS: The incidence of eclampsia was 5.0/10,000 maternities (CI = 4.3-5.7/10,000). Eighty-six percent had a diagnosis of pre-eclampsia before the seizure. Nine of 10 had at least one physical complaint before the first seizure, severe headache being the most common symptom, occurring in two-thirds. Most seizures (90%) occurred after admission to hospital. By audit, 89 cases (42%) were classified as having received substandard care. Prophylactic use of magnesium sulfate might have reduced the number of eclampsia cases by 35 (17%). CONCLUSIONS: Eclampsia occurred mainly in hospital and the majority of women had symptoms heralding the seizure. In retrospect, nearly half of the cases were found potentially preventable by timely intervention, improved medical care, and systematic use of prophylactic treatment with MgSO4.

Cohort Studies↗
PubMed2006

Perinatal factors associated with cerebral palsy in children born in Sweden.

OBJECTIVE: To identify perinatal factors associated with cerebral palsy (CP). METHODS: This was a case-control study based on the Swedish Medical Birth Registry and the Swedish Hospital Discharge Registry, including 2,303 infants born in Sweden 1984-1998 with a diagnosis of CP and 1.6 million infants without this diagnosis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Infants born preterm had a highly increased risk for CP, and constituted 35% of all cases; OR 34 (95% CI 29-39) in weeks 23-27, OR 37 (95% CI 32-42) in weeks 28-29, OR 26 (95% CI 23-30) in weeks 30-31, and OR 3.9 (95% CI 3.4-4.4) in weeks 32-36. Boys had a higher risk (sex ratio 1.36:1), particularly before term (sex ratio 1.55:1). Other factors associated with CP were being small or large for gestational age at birth, abruptio placentae (OR 8.6, 95% CI 5.6-13.3), maternal insulin-dependent diabetes mellitus type 1 (OR 2.1, 95% CI 1.4-3.1), preeclampsia (OR 1.5, 95% CI 1.3-2.4), being a twin (OR 1.4, 95% CI 1.1-1.6), maternal age older than 40 years (OR 1.4, 95% CI 1.1-1.8) or 35-39 years (OR 1.2, 95% CI 1.1-1.4), primiparity (OR 1.2, 95% CI 1.1-1.3), and smoking (OR 1.2, 95% CI 1.1-1.3). In term infants, low Apgar scores were associated with a high risk for CP; OR 62 (95% CI 52-74) at score 6 at 5 minutes, OR 498 (95% CI 458-542) at score 3. Other factors associated with CP in term infants were breech presentation at vaginal birth (OR 3.0, 95% CI 2.4-3.7), instrumental delivery (OR 1.9, 95% CI 1.6-2.3), and emergency cesarean delivery (OR 1.8, 95% CI 1.6-2.0). CONCLUSION: Preterm birth entails a high risk for CP, but 65% of these children are born at term. Several obstetric factors and low Apgar scores are associated with CP. LEVEL OF EVIDENCE: II-2.

Abruptio Placentae↗
PubMed2005

Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants.

The c-Myc oncoprotein promotes proliferation and apoptosis, such that mutations that disable apoptotic programmes often cooperate with MYC during tumorigenesis. Here we report that two common mutant MYC alleles derived from human Burkitt's lymphoma uncouple proliferation from apoptosis and, as a result, are more effective than wild-type MYC at promoting B cell lymphomagenesis in mice. Mutant MYC proteins retain their ability to stimulate proliferation and activate p53, but are defective at promoting apoptosis due to a failure to induce the BH3-only protein Bim (a member of the B cell lymphoma 2 (Bcl2) family) and effectively inhibit Bcl2. Disruption of apoptosis through enforced expression of Bcl2, or loss of either Bim or p53 function, enables wild-type MYC to produce lymphomas as efficiently as mutant MYC. These data show how parallel apoptotic pathways act together to suppress MYC-induced transformation, and how mutant MYC proteins, by selectively disabling a p53-independent pathway, enable tumour cells to evade p53 action during lymphomagenesis.

Adoptive Transfer↗
PubMed2005

A conserved element in Myc that negatively regulates its proapoptotic activity.

Myc is an oncoprotein transcription factor that promotes cell proliferation and apoptosis. Analysis of highly conserved elements within vertebrate Myc proteins has been instrumental in defining the functions of the Myc protein. Here, we probe the role of a highly conserved, but little studied, element within the central region of c-Myc, termed 'Myc box III' (MbIII). We show that MbIII is important for transcriptional repression by Myc, and for transformation both in vitro and in a mouse model of lymphomagenesis. Curiously, disruption of MbIII decreases transformation activity by increasing the efficiency with which Myc can induce apoptosis, suggesting that MbIII is a negative regulator of programmed cell death. These findings reveal a role for MbIII in Myc biology, and establish that the oncogenic capacity of Myc is linked directly to its ability to temper the apoptotic response.

Animals↗
PubMed2005

Fetal heart rate patterns and ECG ST segment changes preceding metabolic acidaemia at birth.

OBJECTIVES: To compare the rates of abnormal ST segment patterns of the ECG and cardiotocographic (CTG) abnormalities in fetuses with metabolic acidaemia at birth and controls. To evaluate the inter-observer agreement in interpretation of ST analysis and CTG. DESIGN: Case-control study. SETTING: Three University hospitals in southern Sweden. POPULATION: Cases and controls were selected from the Swedish randomised controlled trial on intrapartum monitoring, including 4966 fetuses monitored with a scalp electrode. METHODS: Two obstetricians independently assessed the CTG and ST traces of 41 fetuses with metabolic acidaemia at birth and 101 controls, blinded to group, outcome and all clinical data. They classified each CTG trace and ST analysis as abnormal or not abnormal, and whether there was indication to intervene according to the CTG or to the CTG + ST guidelines. If their classification differed, assessment by a third obstetrician determined the final classification. MAIN OUTCOME MEASURES: Rates of CTG and ST abnormalities and decisions to intervene. Rates of inter-observer agreement. RESULTS: CTG was classified as abnormal in 50% and ST in 63% of cases with acidaemia, and in 20% and 34% of controls, respectively. CTG abnormalities were judged to be indication for intervention in 45% and CTG + ST abnormalities in 56% of cases with acidaemia, and in 15% and 8% of controls, respectively. The proportion of agreement between the two initial observers was significantly higher for ST abnormalities (94%) than for CTG abnormalities (73%), and for indication to intervene according to CTG + ST (89%) than according to CTG alone (76%). CONCLUSIONS: The inter-observer agreement rate was higher for a decision to intervene based on CTG + ST than on CTG alone.

Acidosis↗
PubMed2004

Trans-splicing of the mod(mdg4) complex locus is conserved between the distantly related species Drosophila melanogaster and D. virilis.

The modifier of mdg4, mod(mdg4), locus in Drosophila melanogaster represents a new type of complex gene in which functional diversity is resolved by mRNA trans-splicing. A protein family of >30 transcriptional regulators, which are supposed to be involved in higher-order chromatin structure, is encoded by both DNA strands of this locus. Mutations in mod(mdg4) have been identified independently in a number of genetic screens involving position-effect variegation, modulation of chromatin insulators, apoptosis, pathfinding of nerve cells, and chromosome pairing, indicating pleiotropic effects. The unusual gene structure and mRNA trans-splicing are evolutionary conserved in the distantly related species Drosophila virilis. Chimeric mod(mdg4) transcripts encoded from nonhomologous chromosomes containing the splice donor from D. virilis and the acceptor from D. melanogaster are produced in transgenic flies. We demonstrate that a significant amount of protein can be produced from these chimeric mRNAs. The evolutionary and functional conservation of mod(mdg4) and mRNA trans-splicing in both Drosophila species is furthermore demonstrated by the ability of D. virilis mod(mdg4) transgenes to rescue recessive lethality of mod(mdg4) mutant alleles in D. melanogaster.

Alleles↗
PubMed2004

Multiple cell-type-specific elements regulate Myc protein stability.

Myc is a highly unstable transcription factor that is destroyed by ubiquitin (Ub)-mediated proteolysis. We have previously identified an amino-terminal 'degron' within Myc that signals its destruction; this degron spans the transcriptional activation domain of Myc, and includes two highly conserved regions called Myc boxes I and II. We now report the identification of a second element--the D-element--which is also required for Myc proteolysis. The centrally located D-element is distinct from the PEST domain in Myc, but includes Myc box III, a third highly conserved region with no previously known function. We show that deletion of the D-element stabilizes the Myc protein without affecting its ubiquitylation, and report that the D-element and the degron act in a cell-type-specific manner to direct Myc proteolysis. These data thus demonstrate that Myc stability is regulated at both the ubiquitylation and postubiquitylation levels, and reveal that substrates of the Ub-proteasome system can be targeted for destruction differently in different cell types.

Amino Acid Sequence↗
PubMed2003

S100 protein in serum as a prognostic marker for cerebral injury in term newborn infants with hypoxic ischemic encephalopathy.

The astroglial protein S100 is an established biochemical marker for CNS injury in the adult. The aim was to investigate whether S100 in serum is a prognostic marker of cerebral injury in term newborn infants with hypoxic ischemic encephalopathy (HIE) after perinatal asphyxia. Serum S100 was measured on postnatal days 1-4 in 62 term infants with birth asphyxia. The infants were classified for HIE and had follow-up for at least 18 mo. Infants with moderate and severe HIE had significantly higher S100 levels on postnatal day 1 (p = 0.031) and day 2 (p = 0.008) than infants with mild or no HIE. The levels of S100 decreased on days 2 and 3 in all infants with HIE. The median S100 level on postnatal day 1 was higher in nine infants who died neonatally and in 10 infants who developed cerebral palsy (CP), compared with 43 infants with no signs of impairment at follow up, 14.0 (0.5-60.0) microg/L, 20.7 (0.2-64.0) microg/L and 5.5 (0.7-120.0) microg/L, respectively. A level of S100 above 12 microg/L the first day of life was significantly more frequent in infants who died or developed CP than in infants with no impairment at follow up (p = 0.02). Increased S100 levels were significantly inversely correlated with perinatal pH in the infants and associated with abnormal CTG at admission to the labor ward. Early determination of serum S100 may reflect the extent of brain damage in infants with HIE after asphyxia.

Biomarkers↗
PubMed2003

Significant delay of birth in advanced preterm labour at 23 gestational weeks with an oxytocin antagonist.

CASE: A 27-year-old primigravid woman with advanced preterm labour at 23 weeks and 5 days gestation received tocolytic therapy with a continuous infusion of the oxytocin antagonist, atosiban, during 154 h. The delivery was postponed for 12 days. The baby was discharged after 3 months of neonatal care and at 6 months of age is healthy. The prolonged treatment was not associated with maternal or fetal side effects.

Adult↗
PubMed2003

Skp2 regulates Myc protein stability and activity.

Myc is an oncoprotein transcription factor that plays a prominent role in cancer. Like many transcription factors, Myc is an unstable protein that is destroyed by ubiquitin (Ub)-mediated proteolysis. Here, we report that the oncoprotein and Ub ligase Skp2 regulates Myc ubiquitylation and stability. Because of the growing number of Ub ligases that function as transcriptional coactivators, we speculated that Skp2 might also regulate Myc's transcriptional activity. Consistent with this model, we also show that Skp2 is a transcriptional coactivator for Myc, recognizing an essential element within the Myc activation domain and activating Myc target genes. These data suggest that Skp2 functions to connect Myc activity and destruction, and reveal an unexpected oncoprotein connection that may play an important role in controlling cell growth in normal and cancer cells.

Animals↗