Presence of Ralstonia pseudosolanacearum (Phylotype I) in Aquatic Environments in the Netherlands.

Ralstonia pseudosolanacearum, a European Union quarantine organism, was until recently absent in the aquatic environments and outdoor cultivation systems of the region. This bacterium was only sporadically reported in restricted greenhouse cultivation systems in some EU countries. In this paper, we report the first findings of R. pseudosolanacearum (phylotype I) in surface water in two distinct geographic locations in the Netherlands in 2020. In 2021, the population of R. pseudosolanacearum in surface water ranged from 104 to 106 CFU/liter. An inoculum reservoir for R. pseudosolanacearum in these aquatic environments was the wild bittersweet plant where population densities ranged from 105 to 107 CFU/ml concentrated bittersweet extract. The virulence of the R. pseudosolanacearum isolates from surface water and bittersweet was confirmed by a pathogenicity test on Solanum lycopersicum cv. Moneymaker plants, resulting in wilting and necrosis of the plants. Sequence analysis of the egl locus of R. pseudosolanacearum isolates from surface water and bittersweet revealed that these isolates are closely related to R. pseudosolanacearum (phylotype I) isolates found previously in the Netherlands on rose. R. pseudosolanacearum (phylotype I) has a very broad host plant range, including potato, many ornamentals, and other economically important crops. This highlights the risk for various host plants grown in the vicinity of the geographic locations where R. pseudosolanacearum has been found and shows the importance of unraveling the epidemiological parameters of the survival, establishment, and spread of R. pseudosolanacearum in temperate climates.

Despite differential gene expression profiles pediatric MDS derived mesenchymal stromal cells display functionality in vitro.

Pediatric myelodysplastic syndrome (MDS) is a heterogeneous disease covering a spectrum ranging from aplasia (RCC) to myeloproliferation (RAEB(t)). In adult-type MDS there is increasing evidence for abnormal function of the bone-marrow microenvironment. Here, we extensively studied the mesenchymal stromal cells (MSCs) derived from children with MDS. MSCs were expanded from the bone-marrow of 17 MDS patients (RCC: n=10 and advanced MDS: n=7) and pediatric controls (n=10). No differences were observed with respect to phenotype, differentiation capacity, immunomodulatory capacity or hematopoietic support. mRNA expression analysis by Deep-SAGE revealed increased IL-6 expression in RCC- and RAEB(t)-MDS. RCC-MDS MSC expressed increased levels of DKK3, a protein associated with decreased apoptosis. RAEB(t)-MDS revealed increased CRLF1 and decreased DAPK1 expressions. This pattern has been associated with transformation in hematopoietic malignancies. Genes reported to be differentially expressed in adult MDS-MSC did not differ between MSC of pediatric MDS and controls. An altered mRNA expression profile, associated with cell survival and malignant transformation, of MSC derived from children with MDS strengthens the hypothesis that the micro-environment is of importance in this disease. Our data support the understanding that pediatric and adult MDS are two different diseases. Further evaluation of the pathways involved might reveal additional therapy targets.

Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is recalcitrant to treatment and new approaches to therapy are needed. Reduced expression of miR-15/16 in a range of cancer types has suggested a tumour suppressor function for these microRNAs, and re-expression has been shown to inhibit tumour cell proliferation. The miR-15/16 status in MPM is largely unknown. MATERIALS AND METHODS: MicroRNA expression was analysed by TaqMan-based RT-qPCR in MPM tumour specimens and cell lines. MicroRNA expression was restored in vitro using microRNA mimics, and effects on proliferation, drug sensitivity and target gene expression were assessed. Xenograft-bearing mice were treated with miR-16 mimic packaged in minicells targeted with epidermal growth factor receptor (EGFR)-specific antibodies. RESULTS: Expression of the miR-15 family was consistently downregulated in MPM tumour specimens and cell lines. A decrease of 4- to 22-fold was found when tumour specimens were compared with normal pleura. When MPM cell lines were compared with the normal mesothelial cell line MeT-5A, the downregulation of miR-15/16 was 2- to 10-fold. Using synthetic mimics to restore miR-15/16 expression led to growth inhibition in MPM cell lines but not in MeT-5A cells. Growth inhibition caused by miR-16 correlated with downregulation of target genes including Bcl-2 and CCND1, and miR-16 re-expression sensitised MPM cells to pemetrexed and gemcitabine. In xenograft-bearing nude mice, intravenous administration of miR-16 mimics packaged in minicells led to consistent and dose-dependent inhibition of MPM tumour growth. CONCLUSIONS: The miR-15/16 family is downregulated and has tumour suppressor function in MPM. Restoring miR-16 expression represents a novel therapeutic approach for MPM.

Stem cell self-renewal: lessons from bone marrow, gut and iPS toward clinical applications.

The hematopoietic stem cell (HSC) is the prototype organ-regenerating stem cell (SC), and by far the most studied type of SC in the body. Currently, HSC-based therapy is the only routinely used SC therapy; however, advances in the field of embryonic SCs and induced pluripotent SCs may change this situation. Interest into in vitro generation of HSCs, including signals for HSC expansion and differentiation from these more primitive SCs, as well as advances in other organ-specific SCs, in particular the intestine, provide promising new applications for SC therapies. Here, we review the basic principles of different SC systems, and on the basis of the experience with HSC-based SC therapy, provide recommendations for clinical application of emerging SC technologies.

Rise in maternal mortality in the Netherlands.

OBJECTIVE: To assess causes, trends and substandard care factors in maternal mortality in the Netherlands. Design Confidential enquiry into the causes of maternal mortality. SETTING: Nationwide in the Netherlands. POPULATION: 2,557,208 live births. METHODS: Data analysis of all maternal deaths in the period 1993-2005. MAIN OUTCOME MEASURES: Maternal mortality. RESULTS: The overall maternal mortality ratio was 12.1 per 100 000 live births, which was a statistically significant rise compared with the maternal mortality ratio of 9.7 in the period 1983-1992 (OR 1.2, 95% CI 1.0-1.5). The most frequent direct causes were (pre-)eclampsia, thromboembolism, sudden death in pregnancy, sepsis, obstetric haemorrhage and amniotic fluid embolism. The number of indirect deaths also increased, mainly caused by an increase in cardiovascular disorders (OR 2.5, 95% CI 1.4-4.6). Women younger than 20 years and older than 45 years, those with high parity or from nonwestern immigrant populations were at higher risk. Most substandard care was found in women with pre-eclampsia (91%) and in immigrant populations (62%). CONCLUSIONS: Maternal mortality in the Netherlands has increased since 1983-1992. Pre-eclampsia remains the number one cause. Groups at higher risk for complications during pregnancy should be better identified early in pregnancy or before conception, in order to receive preconception advice and more frequent antenatal visits. There is an urgent need for the better education of women and professionals concerning the danger signs, and for the training of professionals in order to improve maternal health care.

Maternal mortality and serious maternal morbidity in Jehovah's witnesses in The Netherlands.

OBJECTIVE: To determine the risk of maternal mortality and serious maternal morbidity because of major obstetric haemorrhage in Jehovah's witnesses in The Netherlands. DESIGN: A retrospective study of case notes. SETTING: All tertiary care centres, general teaching hospitals and other general hospitals in The Netherlands. SAMPLE: All cases of maternal mortality in The Netherlands between 1983 and 2006 and all cases of serious maternal morbidity in The Netherlands between 2004 and 2006. METHODS: Study of case notes using two different nationwide enquiries over two different time periods. MAIN OUTCOME MEASURES: Maternal mortality ratio (MMR) and risk of serious maternal mortality. RESULTS: The MMR for Jehovah's witnesses was 68 per 100,000 live births. We found a risk of 14 per 1000 for Jehovah's witnesses to experience serious maternal morbidity because of obstetric haemorrhage while the risk for the total pregnant population was 4.5 per 1000. CONCLUSIONS: Women who are Jehovah's witnesses are at a six times increased risk for maternal death, at a 130 times increased risk for maternal death because of major obstetric haemorrhage and at a 3.1 times increased risk for serious maternal morbidity because of obstetric haemorrhage, compared to the general Dutch population.

Start of induction of labour with oxytocin in the morning or in the evening. A randomised controlled trial.

OBJECTIVE: The objective of this study was to compare outcomes of induced labour with intravenous oxytocin with a start in the evening versus in the morning. DESIGN: Randomised controlled trial. SETTING: Labour wards of three hospitals in Amsterdam, the Netherlands. PARTICIPANTS: Women with an indication for induction of labour with intravenous oxytocin. METHODS: Included women were randomized to either the evening group with a start of induction of labour at 21:00 hours, or the morning group with a start at 07:00 hours. MAIN OUTCOME MEASURES: Primary outcome was duration of labour. Secondary outcomes were instrumental delivery rate, adverse neonatal outcome defined as an Apgar score below 7 after 5 minutes, number and indications of paediatric consults and neonatal admissions, duration of second stage, number of intrapartum infections and necessity of pain relief. RESULTS: We randomised 371 women. Mean duration of labour was not significantly different (primiparae: morning 12 hours and 8 minutes versus evening 11 hours and 22 minutes, P value 0.29; multiparae: morning 7 hours and 34 minutes versus evening 7 hours and 46 minutes, P value 0.70). There were no significant differences in instrumental deliveries rates, number of infections or patient satisfaction. Unexpectedly, neonatal outcome was better in women induced in the evening. CONCLUSION: Induction of labour with intravenous oxytocin in the evening is equally effective as induction in the morning.

Toward a myeloablative regimen with clinical potential: II. Treosulfan induces specific skin graft tolerance across haploidentical MHC barriers.

Treosulfan is a water-soluble structural analog of busulfan, acting as a prodrug of alkylating epoxide species. It does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has a limited organ toxicity. It is mainly indicated for the treatment of patients with ovarian cancer. In the present study, we report that permanent donor-specific tolerance and stable mixed multilineage chimerism can successfully be achieved across haploidentical MHC barriers when Treosulfan is administered in combination with anti-T-cell mAb and T-cell-depleted donor bone marrow cells. Furthermore, we show that less T-cell suppression is required when Treosulfan is included in the conditioning regimen. In conclusion, Treosulfan is a well-tolerated myeloablative agent with a low toxicity, and is a promising candidate drug for conditioning prior to bone marrow transplantation.

Towards a myeloablative regimen with clinical potential: I. Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers.

To investigate whether we could create a radiation-free conditioning regimen to induce permanent mixed and multilineage chimerism and donor-specific tolerance, we treated recipient mice with anti-T-cell antibodies, varying and fractionated doses of Treosulfan and fully MHC disparate bone marrow cells. Treosulfan is mainly used in the treatment of ovarian cancer. It is a structural analog of busulfan, but it does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has limited organ toxicity. We report here the successful induction of permanent mixed multilineage chimerism and donor-specific tolerance as was proven by skin transplantation and IFN-gamma ELISPOT. In conclusion, because of its lower nonhematological toxicity, compared with other myeloablative regimens (eg irradiation or busulfan admin- istration), Treosulfan could be a better candidate for conditioning to induce donor-specific allograft tolerance.

Vaginal birth after caesarean section in a population with a low overall caesarean section rate.

OBJECTIVE: To determine the clinical outcome of vaginal birth after caesarean section (VBAC) in a Dutch population with a low overall caesarean section (CS) rate of 6.5%. STUDY DESIGN: Prospective population based cohort study of 252 patients with a previous caesarean section (CS). Outcome parameters were trial of labour (TOL), success rate and VBAC rate. RESULTS: The TOL rate in the study cohort was 73%, success rate 77%, VBAC rate 56%. The reason for the previous CS influenced success rate. Complications, morbidity and mortality were not different between elective, emergency CS and TOL group, except for a higher incidence of haemorrhage more than 500 ml in the elective CS compared to the TOL group (29% versus 17%, relative risk (RR) 1.74 (1.15--2.34)). CONCLUSIONS: In this Dutch study the success rate is comparable to rate in US study reports. Increase of the VBAC rate can mainly be achieved by increasing the number of women attempting TOL.

The hour of birth: comparisons of circadian pattern between women cared for by midwives and obstetricians.

OBJECTIVE: To examine the difference, if any, between midwives' care and obstetricians' care in the circadian pattern of the hour of birth in spontaneous labour and delivery. DESIGN: A descriptive study comparing the circadian pattern of the hour of birth between women cared for by a midwife or an obstetrician. SETTING: Data were derived from the Perinatal Database of the Netherlands (LVR), comprising 83% of all births under midwives' care and 75% of all births under obstetricians' care. SUBJECTS: 57,871 women receiving midwives' care and 31,999 women receiving obstetricians' care with spontaneous labour and spontaneous delivery. MAIN OUTCOME MEASURES: Differences in the circadian rhythms between women receiving midwives' care and obstetricians' care. FINDINGS: There was a difference in the circadian pattern of the hour of birth between midwives' and obstetricians' care. Peak times differed 5.43 hours (CI 4.23-7.03) for primiparous and 3.34 hours (CI 3.00-4.08) for multiparous women between the midwives' group and the obstetricians' group. CONCLUSION: This study demonstrates a remarkable difference in circadian pattern of the hour of birth between midwives' care and obstetricians' care. In obstetricians' care the duration of normal labour appears to be prolonged, presumably by an increased level of stress. In normal birth the care of midwives is preferable.

Primary amenorrhea caused by crushing trauma of the pelvis.

An 18-year-old woman sought treatment for primary amenorrhea. Crushing trauma of the pelvis in her childhood had caused separation between the uterine corpus and the cervix. Through a combined abdominal and vaginal approach the continuity of the uterine outflow tract was restored. Years later, after in vitro fertilization, the patient was delivered of a healthy term baby in an elective cesarean procedure.

Semmelweis: the combat against puerperal fever.

Groups A and B streptococci are of great significance in the history of obstetrics. Group A streptococci were a great threat to the puerperium, especially in the 19th century, when homebirth was replaced by institutional birth in lying-in hospitals. The history of the rise and fall of puerperal fever is indeed a tragedy. Some people, like Semmelweis, who brought new and important evidence based findings were not believed by their fellow obstetricians, an attitude that spoiled thousands of innocent lives. Even today group A streptococci, though seldom, may be the cause of puerperal sepsis. Group B streptococci are widespread and may cause sepsis and important lifelong morbidity or mortality of the newborn. Obstetricians today try to establish cost-effective prophylactic measures during labor to prevent these neonatal infections.

Fibroblast-like synoviocytes from rheumatoid arthritis patients have intrinsic properties of follicular dendritic cells.

The production of IgG rheumatoid factors in the inflamed synovium of many patients with rheumatoid arthritis (RA) implies that local sites exist where plasma cell precursors undergo isotype switching and affinity maturation by somatic mutation and selection. Lymphonodular infiltrates of the synovium-containing germinal centers (GCs), are candidates to fulfill such function in the rheumatoid patient. It has been suggested that these GCs are organized around, obviously ectopic, follicular dendritic cells (FDCs). The present study attempts to find out whether these putative FDCs 1) are specific for RA, 2) have the same phenotype and functional capacity as FDCs in lymphoid organs, and 3) may locally differentiate from fibroblast-like synoviocytes (FLS). Synovial biopsies from patients with RA versus non-RA, yet arthritic backgrounds, were compared. Cells with the FDC phenotype were found in both RA and non-RA tissues as well as in single cell suspensions thereof. When FLS were cultured in vitro, part of these cell lines could be induced with IL-1beta and TNF-alpha to express the FDC phenotype, irrespective of their RA or non-RA background. By contrast, the FDC function, i.e., stable binding of GC B cells and switching off the apoptotic machinery in B cells, appeared to be the prerogative of RA-derived FLS only. The present data indicate that FDC function of FLS in RA patients is intrinsic and support the idea that synovial fibroblast-like cells have undergone some differentiation process that is unique for this disease.

Provider-associated factors in obstetric interventions.

OBJECTIVE: To assess which factors influence provider-associated differences in obstetric interventions. STUDY DESIGN: A survey of obstetricians and co-workers in a sample consisting of 38 Dutch hospitals was taken, using a questionnaire that contained questions about personal and hospital-policy data, and 19 clinical problems with a choice between intervention and non-intervention. From the clinical problems an Intervention Score was assembled. The influence of the personal and hospital-policy items on this Intervention Score was studied by analysis of variance. RESULTS: Overall the Intervention Score was low, with considerable interindividual variation. Four personal/hospital items influenced the Intervention Score: the teacher could affect the score in either direction; the increasing age of the obstetrician and routine electronic fetal monitoring had an increasing effect; employment of midwives had a decreasing effect. Other factors, including litigation, had no effect. CONCLUSION: Supplier-induced differences do exist in obstetric interventions and are influenced by personal and hospital-policy factors.

The Dutch obstetric intervention study--variations in practice patterns.

OBJECTIVE: To compare obstetric intervention rates between Dutch hospitals. METHODS: A total of 28,934 hospital births under secondary care (specialist care for medium-/high-risk pregnancies) in 1990 were analyzed in a stratified, random sample of Dutch hospitals based on the records of the Dutch Netherlands perinatal database. Comparisons were made of the intervention rates between hospitals. RESULTS: The intervention rates of the various hospitals differed widely. The most striking difference was in the cesarean section (CS) rate for non-vertex first twins, with a range of 0-100% and a mean rate of 47.6%. On average a CS for a term breech was performed in 30.8% of cases and sedation or analgesics were administered in 16.2% of cases. The mean rate of episiotomy for a term breech was 71.5%, the lowest rate being 18.8%. CONCLUSION: Our results show relatively low intervention rates with considerable interhospital variation.