Current preconception care practice in the Netherlands - An evaluation study among birth care professionals.

OBJECTIVE: To evaluate the current practice of preconception care in the Netherlands and the perceptions of birth care professionals concerning preconception care. METHODS: We have developed a digital questionnaire and conducted a cross-sectional study by distributing the questionnaire among 102 organisations: 90 primary care midwifery practices and obstetric departments of 12 hospitals in the Southwest region of the Netherlands between December 2020 and March 2021. One birth care professional per organization was asked to complete the questionnaire. Descriptive statistics were used to present the results. FINDINGS: Respondents of eighty-three organisations (81.4 %) filled in the questionnaire, of whom 74 respondents were independent primary care midwives and 9 respondents were obstetricians. Preconception care mostly consisted of an individual consultation in which personalized health and lifestyle advice was given. Among the respondents, 44.4 % reported that the organization had a preconception care protocol. The way in which the consultation was carried out, as well as the health and lifestyle related questions asked, differed between respondents. More than 85 % of the respondents inquire about the following possible risk factors for complications: maternal illnesses, obstetric history, folic acid supplement intake, alcohol intake, smoking, substance abuse, hereditary disease, prescription medication, dietary habits, overweight, and birth defects in the family. The respondents acknowledged that preconception care should be offered to all couples who wish to become pregnant, as opposed to offering preconception care only to those with an increased risk of complications. Still, respondents do not receive many questions regarding the preconception period or requests for preconception care consultations. KEY CONCLUSION: Birth care professionals acknowledge the need for preconception care for all couples. In the Netherlands, preconception care consists mostly of an individual consultation with recommendations for health and lifestyle advice. However, the identification of risk factors varies between birth care professionals and less than half of the respondents indicate that they have a protocol available in their practice. Furthermore, the demand of parents-to-be for preconception care is low. More research, that includes more obstetricians, is necessary to investigate if there is a difference between the care provided by primary care midwives and obstetricians. IMPLICATIONS FOR PRACTICE: To increase the awareness and uptake of preconception care, it would be prudent to emphasize its importance to parents-to-be and professionals, and actively promote the use of widespread, standardized protocols for birth care professionals.

A phase I trial assessing the safety, tolerability, pharmacokinetic and pharmacodynamic characteristics of single-dose Auron Misheil therapy in healthy male subjects.

BACKGROUND AND OBJECTIVE: Auron Misheil therapy (AMT) is a combination of widely used pharmaceuticals and herbal components that has been used since the 1980s as a supportive therapy, mainly in end-stage cancer patients on a compassionate basis. This phase I study was conducted to assess the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of AMT in a controlled trial environment. METHODS: The study was conducted in a single rising dose, double-blind, placebo-controlled design. Three groups of eight healthy male volunteers received one of three doses of AMT (0·011, 0·033 or 0·066 mL AMT/kg body weight intramuscularly; n = 6 per group) or placebo (n = 2 per group). RESULTS AND DISCUSSION: Auron Misheil therapy was shown to be well tolerated, revealing no severe or serious adverse events. There were no unexpected PK or PD results for any of the three components of AMT. CONCLUSIONS: These data provide important PK, PD and safety data for AMT, and support further controlled clinical investigation in patients with different types of cancer as an option for supportive care.

Pharmacokinetics of ertapenem in colorectal tissue.

BACKGROUND: There are only limited data on tissue kinetics of ertapenem in colorectal tissue more than 3 h after administration of the drug. The purpose of this study was to assess the pharmacokinetics (PK) of ertapenem in colorectal tissue via population PK modeling. PATIENTS AND METHODS: Patients ≥18 years requiring surgical intervention at the colon and/or rectum were eligible (ClinicalTrials.gov identifier: NCT 00535652). Tissue and blood samples were taken during surgery after a single dose of 1 g ertapenem. Ertapenem concentration was determined by high-performance liquid chromatography/mass spectrometry. Population PK modeling was performed in S-ADAPT. RESULTS: Twenty-three patients were enrolled. The highest tissue concentration was 6.4 ± 2.3 mg/kg, the highest total plasma concentration 51.34 ± 9.4 mg/l, the highest unbound plasma concentration 7.05 ± 1.1 mg/l, and the unbound fraction in plasma was 14-15% for total ertapenem concentrations below approximately 22 mg/l, 19% at 100 mg/l, and 25% at 250 mg/l. The estimated geometric mean terminal half-life was 2.5 h for plasma and tissue. In the Monte Carlo simulation, a single dose of 1,000 mg ertapenem achieved robust (≥90%) probabilities of target attainment up to a minimum inhibitory concentration (MIC) of approximately 2 mg/l for the bacteriostasis target (free time above MIC, fT(>)(MIC) = 20%) and up to 0.25-0.5 mg/l for the near-maximal killing target (40% fT(>)(MIC)). CONCLUSION: Our data indicate an adequate penetration of ertapenem into uninfected colorectal tissue up to 8.5 h (35% of the dosing interval) after administration of 1 g intravenously.

Determination of Ras-GTP and Ras-GDP in patients with acute myelogenous leukemia (AML), myeloproliferative syndrome (MPS), juvenile myelomonocytic leukemia (JMML), acute lymphocytic leukemia (ALL), and malignant lymphoma: assessment of mutational and indirect activation.

The 21-kD protein Ras of the low-molecular-weight GTP-binding (LMWG) family plays an important role in transduction of extracellular signals. Ras functions as a 'molecular switch' in transduction of signals from the membrane receptors of many growth factors, cytokines, and other second messengers to the cell nucleus. Numerous studies have shown that in multiple malignant tumors and hematopoietic malignancies, faulty signal transduction via the Ras pathway plays a key role in tumorigenesis. In this work, a non-radioactive assay was used to quantify Ras activity in hematologic malignancies. Ras activation was measured in six different cell lines and 24 patient samples, and sequence analysis of N- and K-ras was performed. The 24 patient samples comprised of seven acute myelogenous leukemia (AML) samples, five acute lymphocytic leukemia (ALL) samples, four myeloproliferative disease (MPD) samples, four lymphoma samples, four juvenile myelomonocytic leukemia (JMML) samples, and WBC from a healthy donor. The purpose of this study was to compare Ras activity determined by percentage of Ras-GTP with the mutational status of the Ras gene in the hematopoietic cells of the patients. Mutation analysis revealed ras mutations in two of the seven AML samples, one in codon 12 and one in codon 61; ras mutations were also found in two of the four JMML samples, and in one of the four lymphoma samples (codon 12). We found a mean Ras activation of 23.1% in cell lines with known constitutively activating ras mutations, which was significantly different from cell lines with ras wildtype sequence (Ras activation of 4.8%). Two of the five activating ras mutations in the patient samples correlated with increased Ras activation. In the other three samples, Ras was probably activated through "upstream" or "downstream" mechanisms.

[Current perioperative antibiotic prophylaxis]. / Neues in der perioperativen antibiotischen Prophylaxe.

Perioperative antimicrobial prophylaxis (PAP) leads to a reduction in surgical site infections. The aim of PAP is adequate serum and tissue concentrations of the antimicrobial drug in the field of operation. The antibiotic must be effective against the expected pathogens during the operation, safe, and have the fewest possible side effects. The indication for PAP should take into account the risks of the operative procedure and especially the individual risk factors of the patient. Depending on pharmacokinetics, the antibiotic should be administered within 60 min before incision. After closure of the wound, further applications of the antibiotic drug have no influence on the infection rate of the wound but do increase the side effects (resistance, CDT colitis, allergy). Operation-specific recommendations according to guidelines of the Paul Ehrlich Society are given.

[Therapy of intraabdominal fungal infections]. / Therapie der intraabdominellen Pilzinfektionen.

Candida albicans is the fourth most germ that can be identified on surgical intensive care unit (SICU). During the course of severe peritonitis recognition of Candida is crucial for physicians but interpretation of Candida-positive microbiologic samples is difficult. The indication for antimycotic therapy requires differentiation between harmless contamination or severe invasive mycosis associated with high mortality. Therefore, we propose a four-stage classification. Stage I is the initial contamination of the abdominal cavity by Candida spp. Stage IIa is characterized by persistence of fungi in patients without risk factors, IIb with risk factors respectively. Stage III means histological evidence of Candida invasion into the peritoneal layer. Stage IV is a generalized infection with fungemia/fungal sepsis. We recommend antimycotic therapy in stage IIb or higher.

Palliative portal vein stent placement for lymphatic recurrence of gastric cancer.

INTRODUCTION: Percutaneous transhepatic stenting of the main portal vein is a rare intervention. CASE REPORT: In the current patient, percutaneous angioplasty and stenting of a main portal vein stenosis due to lymphatic recurrence of gastric cancer ameliorated the progressing therapeutic restriction. The wall stent achieved portal venous patency that enabled ongoing chemotherapy. The stent remained patent for the entire subsequent survival period.

Rectal prolapse: which surgical option is appropriate?

Numerous surgical procedures have been suggested to treat rectal prolapse. In elderly and high-risk patients, perineal approaches such as Delorme's procedure and perineal rectosigmoidectomy (Altemeier's procedure) have been preferred, although the incidence of recurrence and the rate of persistent incontinence seem to be high when compared with transabdominal procedures. Functional results of transabdominal procedures, including mesh or suture rectopexy and resection-rectopexy, are thought to be associated with low recurrence rates and improved continence. Transabdominal procedures, however, usually imply rectal mobilization and fixation, colonic resection, or both, and some concern is voiced that morbidity, in terms of infection or leakage, and mortality could be increased. If we focus on surgical outcome, our own experience of laparoscopic resection-rectopexy for rectal prolapse shows that the laparoscopic approach is safe and effective, and functional results with respect to recurrence are favorable. However, the controversy "which operation is appropriate?" cannot be answered definitely, as a clear definition of rectal prolapse, the extent of a standardized diagnostic assessment, and the type of surgical procedure have not been identified in published series. Randomized trials are needed to improve the evidence with which the optimal surgical treatment of rectal prolapse can be defined.

Effect of inappropriate initial empiric antibiotic therapy on outcome of patients with community-acquired intra-abdominal infections requiring surgery.

To assess the significance of initial empiric parenteral antibiotic therapy in patients requiring surgery for community-acquired secondary peritonitis, 425 patients hospitalized between January 1999 and September 2001 in 20 clinics across Germany were followed for a total of 6,521 patient days. Perforated appendix (38%), colon (27%), or gastroduodenum (22%) were the most common sites of infection. Escherichia coli was the most common pathogen. A total of 54 (13%) patients received inappropriate initial parenteral therapy not covering all bacteria isolated, or not covering both aerobes and anaerobes in the absence of culture results. Clinical success, predefined as the infection resolving with initial or step-down therapy after primary surgery, was achieved in 322 patients (75.7%; 95% confidence interval (CI), 70.6-81.2). Patients were more likely to have clinical success if initial antibiotic therapy was appropriate (78.6%; 95% CI, 73.6-83.9) rather than inappropriate (53.4%; 95% CI, 41.1-69.3). Patients having clinical success were estimated to stay 13.9 days in hospital (95% CI, 13.1-14.7), while those who had clinical failure stayed 19.8 days (95% CI, 17.3-22.3). In conclusion, appropriateness of initial parenteral antibiotic therapy was a predictor of clinical success, which in turn was associated with length of stay.

Impact of positron emission tomography on strategy in liver resection for primary and secondary liver tumors.

PURPOSE: Outcome of patients with metastatic disease mainly depends on accurate preoperative tumor staging. 18[F]fluorodeoxyglucose positron emission tomography (18F-PET) has been proven to be a valuable diagnostic tool in a number of different tumors but its direct influence on liver surgery has not been thoroughly investigated. MATERIALS AND METHODS: Between July 1999 and March 2000, 50 consecutive patients with 174 suspected liver lesions were admitted to the University Hospital Jena. All 50 patients underwent abdominal ultrasound, CT-scan, and 18-FDG positron emission tomography scanning. In 23 patients the diagnostic work-up was completed by MRI scan. RESULTS: Altogether there were a total of 174 histologically proven intrahepatic lesions, nine of which were benign. The sensitivity, specificity, and positive predictive value of PET for all hepatic lesions was 82%, 25%, and 96% compared with 63%, 50%, and 96% for abdominal ultrasound, 71%, 50%, and 97% for CT-scan, and 83%, 57%, and 97% for MRI-scan. In 23 of 50 patients 24 extrahepatic lesions were identified. In these patients the sensitivity and specificity of PET-compared to abdominal ultrasound, CT-scan, and MRI-scan for all extrahepatic lesions-was 63% and 60%, 29% and 25%, 47% and 50% and 40% and 50%, respectively. The findings on PET scan had a direct impact on operative management in nine patients (18%). CONCLUSIONS: Our series demonstrates good sensitivity and specificity for the detection of primary and secondary liver lesions which is superior to ultrasound and CT scan but not to MRI scan. The main value of PET scan consists in the detection of extrahepatic tumor (64%). Due to better detection of extrahepatic tumor, FDG-PET is a very useful addition to the currently used anatomically-based images in all cases of advanced tumor spread with high risk of extrahepatic tumor.

[Importance of rectal extirpation for the therapy concept of low rectal cancers]. / Stellenwert der Rektumexstirpation im Therapiekonzept des tief sitzenden Rektumkarzinoms.

INTRODUCTION: The main objective of surgery of rectal carcinomas is to avoid a permanent colostomy by sphincter-sparing surgical procedures. A variety of different abdominoperineal resection rates is described in the literature. MATERIAL/METHOD: The study was performed in 2000 within the framework of a multicentric study including 282 hospitals. The purpose of the study was to document the quality of diagnosis and therapy for colorectal carcinomas.A total of 9477 patients were included in this study: 3402 suffering from a rectal carcinoma and 6075 suffering from a colon carcinoma. RESULTS: A total of 866 abdominoperineal resections was performed. This corresponds to an abdominoperineal resection rate of 27.4%. In 30.4% of all men and in 23.0% of all women an abdominoperineal resection was performed. Of all tumor patients who underwent abdominoperineal resection, 8.3% had a pT4 carcinoma and 57.5% a pT3 carcinoma. Adapted to the localization of the tumor in the rectum, i.e., the distance of the aboral tumor margin to the anal verge, the following abdominoperineal resection rates were found: <4 cm from the anal verge 84.6%, 4-7.9 cm 43.9%, 8-11.9 cm 5.8%, and 12-16 cm 0.5%.Intraoperative complications occurred in 11.8%, specific postoperative complications in 33.1%, and general postoperative complications in 27.4% of the patients. The postoperative lethality was 2.8%. The mean postoperative hospital stay was 21.7 days. Logistic regression identified the body mass index, gender, the distance of the carcinoma from the anal verge, and the T category as independent factors influencing the abdominoperineal resection rate. DISCUSSION: Despite an overall decrease in use, abdominoperineal resection will continue to play an important role for the surgical treatment of low rectal cancers in routine clinical practice in Germany. It will remain an individual decision for each patient whether the tumor and the patient allow sphincter preservation or whether abdominoperineal resection seems to be necessary. According to the results of the present study,a general definition of an abdominoperineal resection rate in an unselected group of patients should be viewed critically.

[Interdisciplinary cooperation as a prerequisite for precise tumor documentation. Illustrated by an example of surgery for colorectal carcinoma]. / Interdisziplinäre Zusammenarbeit als Voraussetzung einer exakten Tumordokumentation. Gezeigt am Beispiel der kolorektalen Karzinomchirurgie.

Current tumor management is increasingly founded on interdisciplinary cooperation. The main partners in cases of solid tumors are oncologic surgery, medical oncology,and radiotherapy, guided by pathology. The cooperative concept, particularly the individual strategy and selection of the most adequate approach, oriented on guidelines and therapeutic standards, depends on the quality of the involved components as well as personal abilities of the "actors." In addition to the personal qualification, decision making depends on both tumor stage and completeness of tumor removal. In this point, the overall quality of the therapeutic concept is based on an interaction between the operating surgeon and clinical pathologist that had seldom been taken into consideration. The basic rules of their cooperation and quality-focused implementation regarding tumor dignity, stage, and R classification are discussed based on the example of colorectal carcinoma. In particular, those pitfalls in tumor documentation are emphasized,which may appear less relevant for each partner individually, but bear the risk of misinterpretation and therefore misleading conclusions.

Putative colon cancer risk factors damage global DNA and TP53 in primary human colon cells isolated from surgical samples.

This study describes a novel in vitro method in genetic toxicology that is based on detection of chemical-induced DNA damage connected with altered migration of TP53 in primary human colonocytes. Techniques were developed to isolate high numbers of human epithelial colon cells from surgical tissues. High quantities of viable cells were obtained per donor. The primary cells were treated with the endogenous risk factors trans-2-hexenal, and hydrogen peroxide. Global DNA damage and repair were measured by single-cell gel electrophoresis (Comet assay). We compared responses of primary colon cells to HT29clone19A, a differentiated human colon tumour cell line, for which the karyotype was analysed with 24-colour FISH. Both compounds were genotoxic in both cell types and most of the induced DNA damage was repaired after 30 min. Specific migration of TP53 was determined by fluorescence in situ hybridization (Comet FISH). Using primary colon cells, we quantified the migration of TP53 signals into the comet tails. In these cells TP53 was more sensitive than global DNA for genotoxicity induced by trans-2-hexenal and H(2)O(2). HT29clone19A cells cannot be used for Comet FISH because of their aberrant karyotype. The approach described allows us to obtain more knowledge of putative risk factors in colon carcinogenesis.

Meizothrombin, an intermediate of prothrombin cleavage potently activates renal carcinoma cells by interaction with PAR-type thrombin receptors.

Recently, meizothrombin (MT), an intermediate enzyme in the prothrombin cleavage cascade has been shown to activate cells of a brain tumor cell line by interaction with PAR-1-type thrombin receptors with a potency comparable to that of thrombin. In this study, we investigated the effect of recombinant human MT (rMT) on calcium mobilization in primary cultures established from surgically resected human renal cell carcinomas. Meizothrombin induced very rapidly transient calcium mobilization in RCC cells comparable to that observed with thrombin. RCC cells stimulated with thrombin after rMT challenge were unable to elicit a new calcium response and vice versa. Therefore, rMT and thrombin seem to activate calcium signaling in primary RCC cultures by similar mechanisms including PAR-1- and PAR-3-type thrombin receptors as shown by using PAR-type specific antibodies. Our results demonstrate rMT as a potent activator of human RCC cells suggesting a function of not only thrombin but also of this catalytically active thrombin precursor enzyme in human renal cell carcinoma.

Application of MARS artificial liver support as bridging therapy before split liver retransplantation in a 15-month-old child.

Molecular Adsorbent Recirculating System (MARS) is a blood-filtering system designed to provide biological artificial liver support. We describe its use in a small child to illustrate its effectiveness and practicality in this age group. A 15-month-old male underwent split liver transplantation for acute liver failure following bone marrow transplantation. After development of graft dysfunction we instituted MARS-dialysis. MARS therapy led to a dramatic fall in serum bilirubin and transaminases. Liver synthetic function was not affected. This was accompanied by a stabilization of the patients clinical condition until repeat split liver transplantation was performed 2 weeks after the first graft. MARS-dialysis is practical in the small child. In this case, it did not provide definitive treatment but was an excellent bridging therapy before retransplantation.

The serine proteinase thrombin promotes migration of human renal carcinoma cells by a PKA-dependent mechanism.

In this study, we demonstrated that thrombin activates protein kinase C (PKC), mitogen activated protein kinases (MAP kinases), transcription factor nuclear factor-kappa B (NF-kappa B), and cAMP-dependent protein kinase (PKA) in the human renal carcinoma cell line A-498. In addition, it enhanced the migratory capacity, but had no effect on the proliferation of A-498 cells. The effect of thrombin on migration could be blocked by the PKA inhibitor H-89 but was not influenced by inhibition of PKC, MAP kinases or NF-kappa B. We concluded, that thrombin acts as a regulator on human A-498 renal carcinoma cell migration including PKA.

Association of p53 mutations, microvessel density and neoangiogenesis in pairs of colorectal cancers and corresponding liver metastases.

p53 suppressor gene mutations are a well known step which occurs in the late stages of the complex tumourigenesis of colorectal cancer. A deregulation of p53 protein function may be associated with increased neovascularization and aggressive tumour growth. In vitro studies have shown that these genetic alterations cause a loss of wild-type p53-induced anti-angiogenetic control and could possibly induce expression of the neoangiogenic vascular endothelial growth factor (VEGF). Therefore, this in vivo study was performed to assess p53 mutations, i.e. hot spots in exons 4-9, in primary colorectal cancers and in corresponding liver metastases in order to test whether there is an association between p53 mutated tumours with increased microvessel density (MVD) and VEGF overexpression. Twenty-two tissue samples taken from primary colorectal cancers and the corresponding liver metastases were immediately snap-frozen in liquid nitrogen and fixed in formaldehyde. After DNA extraction exons 4-9 were amplified and directly sequenced. Cryostat sections were stained immunohistochemically using antibodies against VEGF, CD34, and p53 protein. A modified semiquantitative Weidner score and interactive computerized image analysis was used to assess MVD. Overexpression of immunohistochemically detected p53 protein was found in 7 of the 11 primary tumours and liver metastases (64%). Sequencing showed 3 out of 11 primary tumours (27%) and 5 out of 11 liver metastases (46%) to have p53 point or frameshift mutations; these samples tested immunohistochemically positive for p53 protein. Two p53 mutations in samples of liver metastases were not detectable in the corresponding primaries. We detected one frameshift mutation in exon 4 that has not yet been described in the literature. Tumour samples with p53 mutations and increased VEGF immunoreactivity were associated with higher MVD (p<0.01 and p<0.05, respectively). However, there was no association detected immunohistochemically between p53 and MVD as well as p53 mutations and VEGF overexpression. Our data demonstrate specific genetic alterations in the coding regions of p53 suppressor gene in both primary colorectal cancers and corresponding liver metastases, these alterations are associated with an increase in MVD, but not in VEGF overexpression. In addition, a novel frameshift mutation in both colorectal cancer and metastasis is described.