Non-invasive fetal electrocardiography, electrohysterography and speckle-tracking echocardiography in the second trimester: study protocol of a longitudinal prospective cohort study (BEATS-study).

BACKGROUND: Worldwide, hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR) and preterm birth remain the leading causes of maternal and fetal pregnancy-related mortality and (long-term) morbidity. Fetal cardiac deformation changes can be the first sign of placental dysfunction, which is associated with HDP, FGR and preterm birth. In addition, preterm birth is likely associated with changes in electrical activity across the uterine muscle. Therefore, fetal cardiac function and uterine activity can be used for the early detection of these complications in pregnancy. Fetal cardiac function and uterine activity can be assessed by two-dimensional speckle-tracking echocardiography (2D-STE), non-invasive fetal electrocardiography (NI-fECG), and electrohysterography (EHG). This study aims to generate reference values for 2D-STE, NI-fECG and EHG parameters during the second trimester of pregnancy and to investigate the diagnostic potential of these parameters in the early detection of HDP, FGR and preterm birth. METHODS: In this longitudinal prospective cohort study, eligible women will be recruited from a tertiary care hospital and a primary midwifery practice. In total, 594 initially healthy pregnant women with an uncomplicated singleton pregnancy will be included. Recordings of NI-fECG and EHG will be made weekly from 22 until 28 weeks of gestation and 2D-STE measurements will be performed 4-weekly at 16, 20, 24 and 28 weeks gestational age. Retrospectively, pregnancies complicated with pregnancy-related diseases will be excluded from the cohort. Reference values for 2D-STE, NI-fECG and EHG parameters will be assessed in uncomplicated pregnancies. After, 2D-STE, NI-fCG and EHG parameters measured during gestation in complicated pregnancies will be compared with these reference values. DISCUSSION: This will be the a large prospective study investigating new technologies that could potentially have a high impact on antepartum fetal monitoring. TRIAL REGISTRATION: Registered on 26 March 2020 in the Dutch Trial Register (NL8769) via https://www.trialregister.nl/trials and registered on 21 October 2020 to the Central Committee on Research Involving Human Subjects (NL73607.015.20) via https://www.toetsingonline.nl/to/ccmo_search.nsf/Searchform?OpenForm .

COVID-19 during pregnancy: non-reassuring fetal heart rate, placental pathology and coagulopathy.

We report a case of a pregnant woman with COVID-19 who developed coagulopathy in the absence of severe clinical symptoms. A polymerase chain reaction test of a vaginal swab was positive for SARS-CoV-2 RNA, suggesting a possibility of perinatal transmission. Cesarean delivery was performed because of a non-reassuring fetal heart rate; the placenta showed increased perivillous fibrin deposition and intervillositis. Moreover, placental infection with SARS-CoV-2 was demonstrated by placental immunostaining. The findings suggest a possible relationship between placental fibrin deposition and chronic and acute intervillositis, non-reassuring fetal heart rate and coagulopathy in pregnant women with COVID-19. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Cemented versus uncemented hemiarthroplasty of the hip in patients with a femoral neck fracture: a comparison of two modern stem design implants.

PURPOSE: We wished to compare the outcome of two types of cemented and uncemented modern stem design implants after hemiarthroplasty, with both an Orthopaedic Data Evaluation Panel rating of 10A. METHODS: This retrospective study compares data obtained from two centres, with a total study population of 655 (n = 393 cemented, n = 262 uncemented). Patients were matched at baseline for gender, age, surgery side, American Society of Anesthesiologists score, body mass index and pre-operative haemoglobin level. Outcome measurements were prosthesis-related complications, pre- and post-operative, with reoperation rate and mortality and other complications after 1 year, surgery time, blood loss and immobility at discharge. RESULTS: There were no significant differences in mortality after 1 year, total other complications, immobility at the time of discharge and total prosthesis-related complications between both groups. Significantly more periprosthetic fractures and post-operative infections were seen in the uncemented group with significantly more reoperations compared to the cemented group. Significant differences were seen in cardiovascular complications, blood loss and surgery time in favour of the uncemented group. CONCLUSIONS: In consequence of the significant higher prosthesis-related complications (e.g. infections, periprosthetic fractures and reoperations) in the uncemented group in this study, we recommend cemented hemiarthroplasty in patients with a femoral neck fracture. LEVEL OF EVIDENCE: Level III, Case Controlled Study.

Accidental rupture of membranes and neonatal infection after labor induction with silicone or latex balloon catheters: A retrospective cohort study.

OBJECTIVE(S): Accidental rupture of membranes (acROM), an insertion-related complication of the balloon catheter for labor induction, may prolong the duration of ruptured membranes. Prolonged rupture of membranes is associated with an increased risk of intra-uterine infection with possibly neonatal infection as result. Little is known about safety profiles of different catheters regarding the occurrence of these complications. This study compares the incidence of neonatal early-onset sepsis (EOS) and acROM in women receiving either silicone or latex balloon catheters. STUDY DESIGN: A retrospective cohort study was performed including 2200 women (silicone balloon catheter, n = 1100 vs. latex balloon catheter, n = 1100). The primary outcomes were the incidence of acROM, and suspected and proven neonatal EOS. Secondary outcomes were: prolonged rupture of membranes, intrapartum fever, pre- or postnatal neonatal exposure to antibiotics, and perinatal outcomes. A subgroup analysis was performed between women with and without acROM. RESULTS: No statistically significant difference with regard to suspected or proven EOS was seen between the silicone and latex groups. The acROM rate was significantly higher in the silicone group compared to the latex group (2.9 % and 0.3 %, p < 0.01). Prolonged rupture of membranes was significantly more common in the silicone group compared to the latex group (5.0 % and 2.4 %, p < 0.01), as was the use of intrapartum antibiotics (12.7 % and 9.6 %, p = 0.02). Neonates were significantly more often exposed to pre- or postnatal antibiotics in the silicone group compared to the latex group (17.6 % and 13.6 %, p = 0.01). Subgroup analysis showed significantly more suspected and proven neonatal EOS when catheter-insertion was complicated with acROM (11.4 % and 20.0 %), compared to cases without acROM (3.8 % and 2.5 %), irrespective of the type of catheter used. CONCLUSION(S): The use of silicone balloon catheters for labor induction results in higher rates of acROM, prolonged rupture of membranes and use of intrapartum antibiotics, compared to latex balloon catheters. No statistically significant differences were found in the occurrence of suspected or proven neonatal EOS, however neonates from the silicone group were more often exposed to pre- or postnatal antibiotics. When acROM occurs, irrespective of type of catheter used, suspected and proven neonatal EOS was seen more often.

The association between uterine contraction frequency and fetal scalp pH in women with suspicious or pathological fetal heart rate tracings: A retrospective study.

OBJECTIVE: Current guidelines provide little supporting literature for the definition of uterine tachysystole during labour and no distinction is made for optimal contraction frequency depending on the clinical situation. We hypothesize that fetal hypoxia is frequently caused by uterine tachysystole and that high uterine contraction frequencies are especially harmful when fetal heart rate (FHR) abnormalities are present. We studied the association between contraction frequency and fetal scalp pH values in women with an indication for fetal blood sampling (FBS) based on FHR abnormalities. STUDY DESIGN: A retrospective study including 762 women was performed in a tertiary teaching hospital in the Netherlands from January 2015 until January 2020. Women with a singleton pregnancy with a gestational age ≥ 34+0 weeks were included when FBS was performed because of suspicious or pathological FHR tracings. Exclusion criteria were maternal age < 18 years, failed fetal scalp pH values, lack of thirty minute registration by tocodynamometry prior to FBS, poor quality of uterine monitoring, intrauterine resuscitation in the thirty minutes prior to FBS, maternal body mass index ≥ 30 kg/m2 and neonatal birth weight < 10th percentile. Uterine contractions in the thirty minutes prior to FBS were manually annotated by a researcher who was blinded to FBS values, FHR and other obstetrical data. Linear and logistic analysis were used to explore the association between uterine contraction frequency and FBS results. RESULTS: Low fetal scalp pH values were significantly associated with contraction frequency prior to FBS. Fetuses of women with four to five contractions per ten minutes prior to FBS were 2.4 times more likely to have hypoxia as compared to fetuses of women with two to three contractions per ten minutes (aOR 2.4, 95% CI 1.1-5.4). With increasing contraction frequency, the risk of fetal hypoxia further increased. CONCLUSIONS: Contraction frequency above four per ten minutes prior to FBS is significantly associated with fetal hypoxia in women with FHR abnormalities. We suggest to aim for a maximum contraction frequency of four per ten minutes in these women.

Imaging of exercise-induced spinal remodeling in elite rowers.

OBJECTIVES: As in-vivo knowledge of training-induced remodeling of intervertebral discs (IVD) is scarce, this study assessed how lumbar IVDs change as a function of long-term training in elite athletes and age-matched controls using compositional Magnetic Resonance Imaging (MRI). DESIGN: Prospective case-control study. METHODS: Prospectively, lumbar spines of 17 elite rowers (ERs) of the German national rowing team (mean age: 23.9 ±â€¯3.3 years) were imaged on a clinical 3.0 T MRI scanner. ERs were imaged twice during the annual training cycle, i.e., at training intensive preseason preparations (t0) and 6 months later during post-competition recovery (t1). Controls (n = 22, mean age: 26.3 ±â€¯1.9 years) were imaged once at corresponding time points (t0: n = 11; t1: n = 11). Segment-wise, the glycosaminoglycan (GAG) content of lumbar IVDs (n = 195) was determined using glycosaminoglycan chemical exchange saturation transfer (gagCEST). Linear mixed models were set up to assess the influence of cohort and other variables on GAG content. RESULTS: During preseason, IVD GAG values of ERs were significantly higher than those of controls (ERs(t0): 2.58 ±â€¯0.27% (mean ±â€¯standard deviations); controls(t0): 1.43 ±â€¯0.36%; p ≤ 0.001), while during post-competition recovery, such differences were not present anymore (ERs(t1): 2.11 ±â€¯0.18%; controls(t1): 1.89 ±â€¯0.24%; p = 0.362). CONCLUSIONS: Professional elite-level rowing is transiently associated with significantly higher gagCEST values, which indicate increased lumbar IVD-GAG content and strong remodeling effects in response to training. Beyond professional rowing, core-strengthening full-body exercise may help to enhance the resilience of the lumbar spine as a potential therapeutic target in treating back pain.

A nationwide survey on bariatric surgery in Germany--results 2005-2007.

BACKGROUND: Most studies on bariatric surgery outcomes are performed as clinical trials or reflect the clinical experience in single centers. The status of bariatric surgery in Germany has been examined since January 1st, 2005 with the cooperation of clinics and hospitals at the Institute of Quality Assurance in Surgery at the Otto-von-Guericke University of Magdeburg (Germany). METHODS: In this prospective multicenter observational study, the data obtained for all primary bariatric procedures, including all repeated operations, performed on consecutive patients with morbid obesity at participating hospitals from 2005 to 2007 were prospectively collected using an Internet online data registry. In particular, perioperative characteristics, such as the spectrum of diagnostic measurements, type of surgical procedures, and short- and long-term outcomes, were investigated. RESULTS: During the study period, 629 surgical procedures were performed at 21 hospitals in 2005, 828 procedures at 32 hospitals in 2006, and 1,666 procedures at 35 hospitals in 2007. In 2005 and 2006, gastric banding was the most frequently performed operation, followed by the Roux-en-Y gastric bypass (RYGBP). In 2007, a RYGBP was carried out in 42.1% of all bariatric procedures. Among all patients, 74.4% were female. The mean body mass index (BMI) was 48.5 kg/m(2) in 2005, 48.4 kg/m(2) in 2006, and 48.0 kg/m(2) in 2007. Follow-up data after 12 months were available for 63.8% of the patients in 2005 and 2006; these data showed greater reduction of BMI after malabsorptive rather than restrictive bariatric procedures. The mortality was 0.1% (30 days) and 0.16% (overall). CONCLUSION: As indicated by the worldwide trend, there is an ongoing change from restrictive bariatric procedures to malabsorptive procedures and sleeve gastrectomy. Although the BMIs of German patients undergoing bariatric surgery appear to be substantially higher than those of patients from most other countries, there were no differences in intraoperative and short-term complications or in overall outcomes during follow-up when compared with published studies.

Results of sleeve gastrectomy-data from a nationwide survey on bariatric surgery in Germany.

BACKGROUND: Beginning January 1, 2005, the status and outcomes of bariatric surgery were examined in Germany. Data are registered in cooperation with the An-Institute of quality assurance in surgery at the Otto-von-Guericke-University Magdeburg. The objective of this study was to examine the morbidity and mortality rates secondary to sleeve gastrectomy (SG) in Germany since 2006. METHODS: Data collection occurred prospectively in an online data bank. All primary bariatric procedures performed were recorded as were all re-operations in patients that had already undergone a primary operation. Specific data compiled on the sleeve gastrectomy procedure were evaluated with a focus on operative details and complication rates. RESULTS: The total study cohort contains 3,122 patients. From January 2006 to December 2007, 144 sleeve gastrectomy procedures were performed in the 17 hospitals participating in the study. The mean body mass index (BMI) of all patients was 48.8 kg/m(2). The BMI of patients undergoing SG was 54.5 kg/m(2). In total, 73.8% of the patients were female and 26.2% of the patients were male. There were no significant differences between patients undergoing SG. The general complication rate after SG was 14.1%, and the surgical complication rate was 9.4%. The postoperative mortality rate was 1.4%. CONCLUSIONS: The complication rate during the first 2 years after SG in Germany is similar to that published in the literature. In order to improve the quality of bariatric surgery, an evaluation of data from a German multicenter trial is necessary to evaluate the position of SG in the bariatric algorithm.

Evidence of thromboembolism prophylaxis in bariatric surgery-results of a quality assurance trial in bariatric surgery in Germany from 2005 to 2007 and review of the literature.

BACKGROUND: Since January 1st, 2005, the current situation for bariatric surgery has been examined by means of a voluntary quality assurance study in Germany with a multicenter design in which 38 hospitals and surgical departments participated. The data are registered in cooperation with the Institute of Quality Assurance in Surgery at the Otto-von-Guericke University of Magdeburg (Germany). METHODS: Data describing peri-interventional characteristics were prospectively documented in an internet online data registry. All primary bariatric procedures performed since January 1st, 2005, were registered. In addition, reoperations in patients who had previously undergone primary surgical intervention were included. As a representative excerpt from the overall prospective multicenter observational study on obesity surgery, data on the type, regimen, and time course of deep venous thrombosis (DVT) prophylaxis were documented. From the number and spectrum of complications, the incidences of clinically manifest DVT or pulmonary embolism (PE) were derived during the in-hospital course and follow-up in conjunction with the type of surgical procedure and body mass index (BMI). RESULTS: Overall, 3,122 bariatric procedures were performed at 38 German hospitals between January 2005 and December 2007. These procedures were subdivided into 2,869 primary operations and 253 revisions (sex ratio, male to female = 25.6:74.4%). The average BMI of all patients was 48.5 kg/m(2) in 2005, 48.4 kg/m(2) in 2006, and 48.0 kg/m(2) in 2007. In 2005 and 2006, gastric banding (GB) was the most commonly performed operation, followed by Roux-en-Y gastric bypass (RYGBP). In 2007, RYGBP was carried out in 42.1% of all bariatric procedures. Interestingly, the incidence of deep venous thrombosis (DVT) was only 0.06%, whereas PE occurred in 0.06% of patients only after hospital discharge. The DVT prophylaxis protocol used has been changed for the last 2 years: the majority of patients with a BMI above 50 kg/m(2) received low-molecular-weight heparin twice a day. CONCLUSION: In Germany, a trend from GB to sleeve gastrectomy (SG) and malabsorptive approach has been evaluated. This trend is associated with differences of the DVT prophylaxis regimen in the profile of bariatric surgical patients depending on BMI and the type of bariatric procedure. Despite the low incidence of DVT and pulmonary embolism (PE) detected, there is a lack of evidence on a reasonable regimen for sufficient DVT prophylaxis in bariatric surgery; instead, there are only recommendations from the guidelines and statements of a specific medical society. Therefore, prospective studies are necessary to determine the optimal DVT prophylaxis for bariatric surgical patients as well as obese patients undergoing surgery.

[Surgical anatomy of the abdominal wall]. / Chirurgische Anatomie der Bauchdecke.

Knowledge of the anterolateral abdominal wall anatomy is crucial for a surgical approach to the abdominal cavity and for reconstructive surgery of abdominal wall defects. Furthermore it can help the surgeon ensure optimal surgical results by avoiding anatomical complications. This overview presents the surgical relevant anatomy and emphasizes surgical principles and pitfalls in abdominal wall surgery.

[Management of complications in bariatric surgery]. / Management von Frühkomplikationen in der Adipositaschirurgie.

Bariatric surgery is known to be the most effective and long-lasting treatment for morbid obesity and associated comorbidities. These comorbidities together with cardiopulmonary decompensation make morbidly obese patients a high risk group for operative interventions. Early detection of postoperative complications is a challenging task in these patients and requires accurate and timely interpretation of any alarm signals. Symptoms, such as tachycardia and abdominal pain are highly suspicious. The same applies to elevated inflammatory parameters and fever. Early diagnostic laparoscopy is mandatory once cardiopulmonary complications have been excluded. Moreover, it has a higher sensitivity and specificity than other radiological modalities and is a minimally invasive procedure with a highly satisfactory outcome.

Cardiovascular operations in patients with dialysis-dependent renal failure.

BACKGROUND: Cardiac operations in patients with end-stage renal disease carry a significantly increased perioperative risk, and long-term functional results and survival are still purely defined. METHODS: Therefore, we performed a retrospective analysis of 45 consecutive patients with dialysis-dependent renal failure who underwent either coronary artery bypass grafting (n = 30), valve replacement or combined procedures (n = 13), or pericardiotomy (n = 2). Mean age of the patients was 59+/-10 years. RESULTS: There were two perioperative deaths (30-day mortality, 4.4%). Actuarial survival rates at 1, 2, 3, and 5 years were 0.90, 0.73, 0.67, and 0.67, respectively, after bypass operation and 0.77, 0.77, 0.77, and 0.39, respectively, after valvular or combined operation. Late deaths (n = 13) occurred 2 to 60 months after operation and were attributable to cardiac events in 7 patients. Of the long-term survivors after either bypass grafting (n = 20) or a valvular or combined procedure (n = 8), 15 and 7 patients had improved anginal status and New York Heart Association functional status, respectively, after 36+/-4 months (range, 21 to 66 months). Five patients underwent renal transplantation 32+/-9 months after cardiac operation. CONCLUSIONS: Cardiac operations in patients with endstage renal disease may be performed with a fairly low perioperative risk and the perspective of long-term functional improvement and acceptable long-term survival.

Sensory gating in rats: lack of correlation between auditory evoked potential gating and prepulse inhibition.

This study was designed to evaluate the possible similarities between two paradigms designed to measure sensory gating: (1) an auditory evoked potential (AEP), called the P50 gating paradigm; and (2) an acoustic startle (ASR), called the prepulse inhibition paradigm. These paradigms show a number of methodological, pharmacological, and neurobiological similarities, and they are both disturbed in patients with schizophrenia. In the first of three experiments, the AEP gating and the ASR gating were measured in rats. Although both AEP and ASR gating could readily be obtained, there appeared to be no correlation between the performance in these two paradigms. This lack of correlation was confirmed using a factor analytical approach, where the AEP gating and the ASR gating parameters were found to load on different factors. In the second experiment, the interstimulus interval in the ASR paradigm was increased to 500 ms (identical to the interstimulus interval of the AEP gating paradigm). This increase reduced the degree of ASR gating, although some gating could still be obtained. Again no correlation was found between AEP and ASR gating, and this was again confirmed by the factorial analysis. In the final experiment, the effects of the dopamine D2/3 agonist 7-OHDPAT were evaluated in both paradigms. This selective agonist dose dependently reduced ASR gating but had no effect on AEP gating. Together, these data strongly suggest that AEP and ASR gating measure two different aspects of information processing and indicate that both paradigms may be important for investigating the neurobiological disturbances observed in patients with psychoses.

Interconversion into a low active state protects vascular 5-HT2-receptors against irreversible antagonism by phenoxybenzamine.

Recently, Kaumann and Frenken (1985) proposed an allosteric model of vascular 5-HT2-receptors. We now present experiments in both bovine coronary and pulmonary artery, using the method of irreversible receptor occlusion, that support and extend the model. 1) Phenoxybenzamine was found to cause irreversible antagonism of the effects of 5-hydroxytryptamine (5-HT). Maximal contractile effects induced by 5-HT were depressed and, with further receptor occlusion, concentration-effect curves for 5-HT became biphasic. The high-sensitivity and the low-sensitivity component of the curve for 5-HT consisted of quickly and slowly developing contractions, respectively. 2) Biphasic concentration-effect curves for 5-HT after receptor occlusion were shifted to the right in non-parallel manner by ketanserin and became monophasic with an unexpected partial restoration of maximal responses to 5-HT. The magnitude of the shift of the partially restored concentration-effect curve for 5-HT by ketanserin after receptor occlusion by phenoxybenzamine is consistent with an interaction of ketanserin with 5-HT2-receptors. 3) Preincubation with methysergide before phenoxybenzamine-treatment followed by washout of both drugs, and subsequent incubation with ketanserin completely prevented a depression of 5-HT-induced effects by phenoxybenzamine. 4) Estimates for the equilibrium dissociation constant of 5-HT for the 5-HT2-receptor derived from fast developing contractions range from 0.1 mumol/l to 0.4 mumol/l. 5) The results are consistent with a model of two interconvertible states of the 5-HT2-receptor. Phenoxybenzamine occludes the 5-HT2-receptor in the R-state but not in the R'-state. The low active R'-state of the 5-HT2-receptor appears to pre-exist in the absence of drugs and is not affected by phenoxybenzamine. By converting R' into R ketanserin restores partially the response to 5-HT after occlusion of the R-state by phenoxybenzamine. Methysergide prevents the 5-HT2-receptor occlusion induced by phenoxybenzamine indirectly by favouring isomerisation into the R'-state.

Effects of tryptamine mediated through 2 states of the 5-HT2 receptor in calf coronary artery.

The mode of action of tryptamine was investigated on strips of left circumflex coronary artery of calf. 1) Exposure to (-)-deprenyl, an irreversible inhibitor of monoamine oxidase B, markedly potentiated the contractions caused by tryptamine but not those by 5-hydroxy-tryptamine (5-HT). Experiments were therefore carried out on arteries treated with (-)-deprenyl. 2) Tryptamine, administered non-cumulatively, elicited fast developing contractions, which partially faded. The intrinsic activity for the peak response to tryptamine was 0.8 compared to 5-HT. Ketanserin competitively antagonized the tryptamine-induced contractions with a KB of (-log mol/l) 9.9. Methysergide antagonized the effects of tryptamine in a noncompetitive manner by depressing the maximum response with an IC50 (-log mol/l) greater than 9.0. 3) Tryptamine caused unsurmountable depression of 5-HT-induced contractions with an IC50 (-log mol/l) of 6.4. Ketanserin also competitively antagonized the depressant effects of tryptamine on 5-HT-induced contractions with a KB of (-log mol/l) 9.9. 4) At high concentrations of tryptamine (0.2-1 mmol/l), the fast developing contractions were followed by slowly developing contractions. Methysergide 1 nmol/l enhanced maximally the slow developing contractions. 5) These findings are consistent with an interaction of tryptamine at different sites of the allosteric 5-HT2-receptor system: (I) Tryptamine competes with ketanserin for the 5-HT2-receptor in the highly active R state. Binding of tryptamine to the R state would cause the fast contraction. (II) Tryptamine competes with ketanserin for the allosteric sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric properties of the 5-HT2 receptor system of the rat tail artery. Ritanserin and methysergide are not competitive 5-HT2 receptor antagonists but allosteric modulators.

We present an analysis of the interactions of 5-hydroxytryptamine (5-HT) and antagonists (methysergide, ketanserin, ritanserin) with the 5-HT2 receptor system of strips of rat tail artery. The mode of action of ritanserin was also studied on strips of calf coronary arteries. 1. Ketanserin competitively antagonized 5-HT-induced effects in rat tail artery with an affinity (pKB = 9.4 nmol/l) consistent with the assumption of an interaction of 5-HT and ketanserin at 5-HT2-receptors. 2. Methysergide reduced to 50-60% the maximum response to 5-HT in rat tail artery. Concentration-effect curves for 5-HT became biphasic in the presence of methysergide with quickly and slowly developing contractions at low and high concentrations of 5-HT, respectively. 100 nmol/l ketanserin completely restored effects of 5-HT depressed by low concentrations of methysergide (less than 10 nmol/l). Higher concentrations of methysergide in the presence of 100 nmol/l ketanserin again depressed the effects of 5-HT. 3. Ritanserin resembles methysergide by causing insurmountable antagonism of 5-HT-induced contractions which can be prevented by ketanserin in both rat tail artery and calf coronary artery. These results are inconsistent with competition between ritanserin and 5-HT for the 5-HT2 receptor. 4. The findings are consistent with the assumption of an interaction of ketanserin and methysergide or ritanserin with an allosteric site near the 5-HT2-receptor. Both methysergide and ritanserin appear to antagonize the effects of 5-HT through an allosteric site which is distinct from the 5-HT2 receptor.

Interaction of ketanserin and its metabolite ketanserinol with 5HT2 receptors in pulmonary and coronary arteries of calf.

A comparison of 5-hydroxytryptamine (5HT)-induced contractions was made on cocaine-treated strips of bovine pulmonary arteries and large coronary arteries. The affinities of the 5HT2 antagonist ketanserin, its metabolite ketanserinol, yohimbine and rauwolscine were estimated for both arteries. Ketanserin was a competitive antagonist of the effects of 5HT in both arteries. The KB values (-log mol/l) were 9.5 for large coronary arteries and 9.4 for pulmonary arteries. Ketanserinol was also a competitive antagonist of the effects of 5HT in both arteries. The KB values (-log mol/l) were 6.5 for large coronary arteries and 6.4 for pulmonary arteries. A combination of ketanserin with ketanserinol antagonized the 5HT effects as expected from competition of the 3 drugs for a single class of receptor in both arteries. Yohimbine and rauwolscine were competitive antagonists of the effects of 5HT in pulmonary artery. The KB-values (-log mol/l) were 6.8 for yohimbine and 6.5 for rauwolscine. A combination of ketanserin with either yohimbine or rauwolscine antagonized the 5HT effects as expected from competition of all 4 drugs for a single class of receptors in pulmonary arteries. The evidence is consistent with the assumption that smooth muscle 5HT receptors of both pulmonary artery and large coronary artery are of the 5HT2 class. The reduction of the ketone of ketanserin to alcohol (i.e. ketanserinol) causes an approximately 1000-fold decrease in affinity for arterial 5HT2 receptors. Reported peak plasma levels of ketanserinol are too low (less than or equal to 10(-7) mol/l) in humans to account for a contribution of the metabolite to the blockade of 5HT effects by ketanserin.

A paradox: the 5-HT2-receptor antagonist ketanserin restores the 5-HT-induced contraction depressed by methysergide in large coronary arteries of calf. Allosteric regulation of 5-HT2-receptors.

Methysergide depresses the contractile effects of 5-hydroxytryptamine (5-HT) in bovine large coronary arteries devoid of endothelium. The IC50 of methysergide for depression of the response to 5-HT was (-log mol/l) 9.8. A low sensitivity contractile effect of 5-HT was not influenced by 1-1,000 nmol/l methysergide. The maximum force of this residual response is approximately 1/3 of the maximum force elicited by 5-HT in the absence of methysergide. Ketanserin restored the 5-HT-induced contraction depressed by methysergide. In the presence of 0.1 mumol/l ketanserin, methysergide caused depression of the 5-HT-induced effects with an IC50 (-log mol/l) of 6.5 without affecting the residual response. We propose that methysergide depresses 5-HT-induced contractions by acting on an allosteric site. The effect of binding of methysergide to the allosteric site would lead to a conformational change of the 5-HT2-receptor, thereby only allowing the production of a residual 5-HT-induced contraction. Ketanserin competes with high affinity not only with 5-HT for the 5-HT2-receptor but also with methysergide for the allosteric site, thus shifting the receptor back into its original conformation. The affinity estimate of ketanserin for the allosteric site yielded a KB (-log mol/l) of 10.3. Ketanserin (1-1,000 nmol/l) antagonized the contractile effects of 5-HT with a potency expected from its affinity for 5-HT2-receptors (-log KB, mol/l 9.4). However, micromolar concentrations of ketanserin antagonized the effects of 5-HT less than expected from its affinity for 5-HT2-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Ketanserin causes surmountable antagonism of 5-hydroxytryptamine-induced contractions of large coronary arteries of dog.

Large coronary arteries of the dog were contracted with 5-hydroxytryptamine (5-HT). The 5-HT2-receptor antagonist ketanserin antagonized the 5-HT-induced effects. Unlike Brazenor and Angus (Europ J Pharmacol 81:569-576, 1982) who reported insurmountable antagonism of the effects of 5-HT in dog coronaries, we found that the antagonism by ketanserin can be surmounted, provided the concentrations of 5-HT are high enough. Ketanserin also unmasked a saturable component of the 5-HT-induced contractions. Although ketanserin (0.1-1 mumol/l) depressed the maximal force of the saturable component, it did not change its EC50 (-log mol/l 8.0). We conclude that large coronary arteries of dog are contracted by 5-HT mainly through 5-HT2-receptors and to a smaller extent through receptors different from 5-HT2.

TNF-alpha and serum induce SKALP/elafin gene expression in human keratinocytes by a p38 MAP kinase-dependent pathway.

Keratinocytes of inflamed epidermis (psoriasis, wound healing) are hyperproliferative and display an abnormal differentiation programme. This regenerative differentiation pathway is characterized by the induction of genes that are not expressed by keratinocytes in normal skin, such as the cytokeratins CK6, CK16, CK17, and the proteinase inhibitor SKALP/elafin. In the study reported here we investigated the induction and regulation of SKALP expression as a marker for regenerative differentiation in epidermal keratinocytes. Various cytokines and growth factors known to be present in psoriatic epidermis were examined for their ability to induce SKALP gene expression in cultured human keratinocytes. Tumour necrosis factor-alpha (TNF-alpha) and serum were found to be potent inducers of SKALP expression at both the mRNA and the protein levels. SB202190 or SB203580, two specific p38 MAP kinase inhibitors almost completely blocked the induction of SKALP expression by TNF-alpha and serum. These results suggest that in keratinocytes, p38 activity is crucial for the induction of SKALP gene expression. These findings could be relevant for the elucidation of the mechanisms involved in normal and disturbed epidermal differentiation.