Effect of COVID-19 lockdown on maternity care and maternal outcome in the Netherlands: a national quasi-experimental study.

OBJECTIVES: The COVID-19 pandemic and associated lockdowns disrupted health care worldwide. High-income countries observed a decrease in preterm births during lockdowns, but maternal pregnancy-related outcomes were also likely affected. This study investigates the effect of the first COVID-19 lockdown (March-June 2020) on provision of maternity care and maternal pregnancy-related outcomes in the Netherlands. STUDY DESIGN: National quasi-experimental study. METHODS: Multiple linked national registries were used, and all births from a gestational age of 24+0 weeks in 2010-2020 were included. In births starting in midwife-led primary care, we assessed the effect of lockdown on provision of care. In the general pregnant population, the impact on characteristics of labour and maternal morbidity was assessed. A difference-in-regression-discontinuity design was used to derive causal estimates for the year 2020. RESULTS: A total of 1,039,728 births were included. During the lockdown, births to women who started labour in midwife-led primary care (49%) more often ended at home (27% pre-lockdown, +10% [95% confidence interval: +7%, +13%]). A small decrease was seen in referrals towards obstetrician-led care during labour (46%, -3% [-5%,-0%]). In the overall group, no significant change was seen in induction of labour (27%, +1% [-1%, +3%]). We found no significant changes in the incidence of emergency caesarean section (9%, -1% [-2%, +0%]), obstetric anal sphincter injury (2%, +0% [-0%, +1%]), episiotomy (21%, -0% [-2%, +1%]), or post-partum haemorrhage: >1000 ml (6%, -0% [-1%, +1%]). CONCLUSIONS: During the first COVID-19 lockdown in the Netherlands, a substantial increase in homebirths was seen. There was no evidence for changed available maternal outcomes, suggesting that a maternity care system with a strong midwife-led primary care system may flexibly and safely adapt to external disruptions.

The barriers and needs of transgender men in pregnancy and childbirth: A qualitative interview study.

OBJECTIVE: Transgender and gender diverse individuals are individuals whose gender identity differs from their sex assigned at birth. The discordance between gender identity and sex assignment may cause significant psychological distress: gender dysphoria. Transgender individuals may choose to undergo gender-affirming hormone treatment or surgery, but some decide to (temporarily) refrain from surgery and gender affirming hormone treatment and hence retain the possibility to become pregnant. Pregnancy may enhance feelings of gender dysphoria and isolation. To improve perinatal care for transgender individuals and their health care providers, we conducted interviews to explore the needs and barriers of transgender men in family planning, pregnancy, childbirth, puerperium and perinatal care. DESIGN: In this qualitative study five in-depth semi-structured interviews were conducted with Dutch transgender men who had given birth while identifying on the transmasculine spectrum. The interviews were conducted online through a video remote-conferencing software program (n=4) or live (n=1). Interviews were transcribed verbatim. An inductive approach was used to find patterns and collect data from the participants' narratives and constant comparative method was adapted in analysing the interviews. MEASUREMENTS AND FINDINGS: The experiences of transgender men regarding the preconception period, pregnancy and puerperium and with perinatal care varied widely. Though all participants expressed overall positive experiences, their narratives emphasized they had to overcome substantial hurdles pursuing pregnancy. For instance the necessity to prioritise becoming pregnant over gender transitioning, lack of support by healthcare providers and increased gender dysphoria and isolation during pregnancy KEY CONCLUSIONS: Since pregnancy in transgender men enhances feelings of gender dysphoria, transgender men comprise a vulnerable group in perinatal care. Health care providers are perceived as feeling unaccustomed for the care of transgender patients, as they are perceived to often lack the right tools and knowledge to provide adequate care. Our findings help strengthen the foundation of insight in the needs and hurdles of transgender men pursuing pregnancy and therefore may guide health care providers to provide equitable perinatal care, and emphasize the necessity of patient-centred gender-inclusive perinatal care. A guideline including the option for consultation of an expertise center is advised to facilitate patient-centered gender-inclusive perinatal care.

Progesterone for prevention of preterm birth in women with short cervical length: 2-year infant outcomes.

OBJECTIVE: To evaluate the long-term outcomes of children born to women with a short cervix and otherwise low risk for preterm birth, after antenatal exposure to vaginal progesterone vs placebo. METHODS: This was a follow-up study of the Triple P trial, which randomized 80 low-risk women with a short cervix (≤ 30 mm) at 18-22 weeks' gestation to progesterone (n = 41) or placebo (n = 39). At 2 years of corrected age, children were invited for a neurodevelopmental assessment, using the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), and a neurological and physical examination by an assessor blinded to the allocated treatment. Parents filled out the Ages and Stages Questionnaire, the Child Behavior Checklist (CBCL) and a general-health questionnaire. The main outcome of interest was mean BSID-III cognitive and motor scores. Additionally, a composite score of mortality and abnormal developmental outcome, including BSID-III ≤-1 SD, CBCL score in the clinical range and/or parental reported physical problems (at least two operations or at least two hospital admissions in the previous 2 years), was evaluated. Our sample size, dictated by the original sample of the Triple P trial, provided 80% power to detect a mean difference (MD) of 15 points (1 SD) between groups for the BSID-III tests. RESULTS: Of the 80 children born to the randomized women, one in the progesterone group and two in the placebo group died in the neonatal period. Follow-up data were obtained for 59/77 (77%) children and BSID-III outcomes in 57 children (n = 28 in the progesterone group and n = 29 in the placebo group) born at a median gestational age of 38 + 6 weeks (interquartile range (IQR), 37 + 3 to 40 + 1 weeks) with a median birth weight of 3240 g (IQR, 2785-3620 g). In the progesterone vs placebo groups, mean BSID-III cognitive development scores were 101.6 vs 105.0 (MD, -3.4 (95% CI, -9.3 to 2.6); P = 0.29) while mean motor scores were 102.4 vs 107.3 (MD, -4.9 (95% CI, -11.2 to 1.4); P = 0.13). No differences were seen between the two groups in physical (including genital and neurological examination), behavioral and health-related outcomes. CONCLUSION: In this sample of children born to low-risk women with a short cervix at screening, no relevant differences in neurodevelopmental, behavioral, health-related and physical outcomes were found between offspring exposed to vaginal progesterone and those exposed to placebo. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Assessment of novel cardiovascular biomarkers in women with a history of recurrent miscarriage.

OBJECTIVES: A history of recurrent miscarriage is associated with future cardiovascular disease. The aim of this study was to determine novel cardiovascular biomarkers in women with a history of recurrent miscarriage as this might lead to a better understanding of the association. STUDY DESIGN: Women who visited the recurrent miscarriage clinic at Leiden University Medical Centre (between 2000 and 2010), and had three consecutive miscarriages ≤30 years were invited to participate in this follow-up study (between 2012 and 2014). The reference group consisted of women with at least one uncomplicated pregnancy and a history of no miscarriage, matched on zip code, age, and date of pregnancy. MAIN OUTCOME MEASURES: Cardiovascular biomarkers were determined, classified into; inflammation (HsCRP, lipoprotein-associated phospholipase A2), thrombosis (homocysteine, folate, anti-cardiolipin antibodies and anti-ß-2-glycoprotein antibodies), lipid metabolism (lipoprotein(a)), renal function (creatinine, microalbuminuria), myocardial damage (N-terminal pro-brain natriuretic peptide, high sensitive TroponineT) and multiple mechanisms (albumin, vitamin D). RESULTS: In both groups, 36 women were included. Women with recurrent miscarriage had a significantly higher median HsCRP (1.49 mg/L) compared to women with no miscarriage (1.01 mg/L, p = 0.03) and a significantly lower mean albumin (46.0 vs 47.6g/L, p = 0.004) and vitamin D (55.6 vs 75.4nmol/L, p = 0.007), respectively. Differences remained after adjustments for classic cardiovascular risk factors (BMI, smoking, diabetes mellitus, and hypertension). CONCLUSIONS: Our findings suggest a proinflammatory state in women with a history of recurrent miscarriage, which suggests a less optimal health, compared to women with no miscarriage. More research (observational and intervention) is warranted to investigate the association with vitamin D.

Maternal and neonatal outcomes in women with severe early onset pre-eclampsia before 26 weeks of gestation, a case series.

OBJECTIVE: To describe the maternal and neonatal outcomes and prolongation of pregnancies with severe early onset pre-eclampsia before 26 weeks of gestation. DESIGN: Nationwide case series. SETTING: All Dutch tertiary perinatal care centres. POPULATION: All women diagnosed with severe pre-eclampsia who delivered between 22 and 26 weeks of gestation in a tertiary perinatal care centre in the Netherlands, between 2008 and 2014. METHODS: Women were identified through computerised hospital databases. Data were collected from medical records. MAIN OUTCOME MEASURES: Maternal complications [HELLP (haemolysis, elevated liver enzyme levels, and low platelet levels) syndrome, eclampsia, pulmonary oedema, cerebrovascular incidents, hepatic capsular rupture, placenta abruption, renal failure, and maternal death], neonatal survival and complications (intraventricular haemorrhage, retinopathy of prematurity, necrotising enterocolitis, bronchopulmonary dysplasia, and sepsis), and outcome of subsequent pregnancies (recurrent pre-eclampsia, premature delivery, and neonatal survival). RESULTS: We studied 133 women, delivering 140 children. Maternal complications occurred frequently (54%). Deterioration of HELLP syndrome during expectant care occurred in 48%, after 4 days. Median prolongation was 5 days (range: 0-25 days). Neonatal survival was poor (19%), and was worse (6.6%) if the mother was admitted before 24 weeks of gestation. Complications occurred frequently among survivors (84%). After active support, neonatal survival was comparable with the survival of spontaneous premature neonates (54%). Pre-eclampsia recurred in 31%, at a mean gestational age of 32 weeks and 6 days. CONCLUSIONS: Considering the limits of prolongation, women need to be counselled carefully, weighing the high risk for maternal complications versus limited neonatal survival and/or extreme prematurity and its sequelae. The positive prospects regarding maternal and neonatal outcome in future pregnancies can supplement counselling. TWEETABLE ABSTRACT: Severe early onset pre-eclampsia comes with high maternal complication rates and poor neonatal survival.

Influence of cut-off value on prevalence of short cervical length.

OBJECTIVE: To assess the distribution of cervical length (CL) in a large cohort of asymptomatic low-risk women with singleton pregnancy and no previous preterm birth and to explain the low prevalence of short CL ≤ 30 mm in this cohort. METHODS: This was a secondary analysis of a multicenter cohort study with an embedded randomized controlled trial (Triple P trial; NTR-2078) on the prevention of preterm birth with progesterone. In the cohort study, CL was measured in asymptomatic low-risk women with singleton pregnancy to investigate its predictive capacity to identify those at increased risk for preterm birth. A short CL was defined by a cut-off value of ≤ 30 mm, based on existing literature. Women with a short CL were subsequently included in a randomized controlled trial evaluating the effect of progesterone, compared with placebo, on preterm birth. In total, 57 centers and 20 234 women participated in the study. Normal distributions for CL were simulated based on the mean and SD of the original data. The distribution of CL was assessed for each individual center and measurements were compared between levels of care: primary (29 ultrasound centers), secondary (21 general hospitals) and tertiary (seven university medical centers) care institutions. Comparison was also performed between centers with low, intermediate and high volume of CL measurements. CL distributions before (n = 12 284 women) and after (n = 7950 women) a national symposium, at which the prevalence of short CL measurements was addressed publicly, were analyzed. RESULTS: Between November 2009 and August 2013, 20 234 women had CL measurements, of whom 367 (1.8%) had a short CL. Mean ± SD CL was 44.2 ± 7.8 mm. A 'dip' in the distribution of CL measurements between 20 and 30 mm was observed, defined by a ratio of < 50% when comparing the number of measurements in observed and simulated normal distributions. The dip was present in 89% of participating centers. All centers showed a dip in the distribution of measurements ≤ 30 mm when analyzed according to the level of care and volume of measurements. A significant difference was found when comparing the distribution before and after publicly addressing the low prevalence of short CL (1.7% vs 2.0% of measurements were ≤ 30 mm, respectively; P < 0.001). CONCLUSIONS: A cut-off value of 30 mm for CL was used to include women in a randomized clinical trial that was embedded in a cohort study. We suggest that the use of a predefined cut-off value for a short cervix influences the distribution of the CL measurements. Since the measurement is not blinded, preference of assessors for the control or intervention arms may have introduced selection bias. This might have resulted in fewer measurements around the cut-off value. Other trials using similar designs could benefit from this observation and take precautions to avoid selection bias. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prenatal detection of congenital heart disease--results of a national screening programme.

OBJECTIVE: Congenital heart disease (CHD) is the most common congenital malformation and causes major morbidity and mortality. Prenatal detection improves the neonatal condition before surgery, resulting in less morbidity and mortality. In the Netherlands a national prenatal screening programme was introduced in 2007. This study evaluates the effects of this screening programme. DESIGN: Geographical cohort study. SETTING: Large referral region of three tertiary care centres. POPULATION: Fetuses and infants diagnosed with severe CHD born between 1 January 2002 and 1 January 2012. METHODS: Cases were divided into two groups: before and after the introduction of screening. MAIN OUTCOME MEASURES: Detection rates were calculated. RESULTS: The prenatal detection rate (n = 1912) increased with 23.9% (95% confidence interval [95% CI] 19.5-28.3) from 35.8 to 59.7% after the introduction of screening and of isolated CHD with 21.4% (95% CI 16.0-26.8) from 22.8 to 44.2%. The highest detection rates were found in the hypoplastic left heart syndrome, other univentricular defects and complex defects with atrial isomerism (>93%). Since the introduction of screening, the 'late' referrals (after 24 weeks of gestation) decreased by 24.3% (95% CI 19.3-29.3). CONCLUSIONS: This is the largest cohort study to investigate the prenatal detection rate of severe CHD in an unselected population. A nationally organised screening has resulted in a remarkably high detection rate of CHD (59.7%) compared with earlier literature.

Prenatal detection of transposition of the great arteries reduces mortality and morbidity.

OBJECTIVES: To evaluate the prenatal detection of transposition of the great arteries (TGA), after the introduction of a Dutch screening program in 2007, as well as the effect of prenatal detection on pre- and postsurgical mortality and morbidity. METHODS: In a geographical cohort study, all infants with TGA who were born between 1 January 2002 and 1 January 2012 were included. The cases were divided into two groups: those with and those without a prenatal diagnosis. Pre- and postsurgical mortality was assessed, with a follow-up of 1 year. Presurgical morbidity was assessed in terms of cardiovascular compromise, metabolic acidosis, renal and/or hepatic dysfunction and closure of the duct before initiation of therapy. RESULTS: Of all cases (n = 144), 26.4% were diagnosed prenatally, with detection rates of 15.7% and 41.0% in the first and last 5 years of the study period, respectively. First-year mortality was significantly lower in cases with a prenatal diagnosis of TGA than in those without (0.0% vs 11.4%, respectively). Presurgical mortality (4.9%) only occurred in undetected simple TGA cases. Closure of the duct before treatment, renal dysfunction and hypoxia occurred significantly more often in the group without a prenatal diagnosis. CONCLUSIONS: The prenatal detection rate of TGA has increased significantly since the introduction of the screening program in 2007. Prenatal diagnosis is an important factor that contributes to survival of the infant in the first postnatal year. Furthermore, some morbidity indicators were significantly higher in the group without a prenatal diagnosis. These results justify efforts to improve prenatal screening programs.

Association between weight gain during pregnancy and pregnancy outcomes after dietary and lifestyle interventions: a meta-analysis.

OBJECTIVES: Lifestyle interventions in obese pregnant women reduce adverse maternal outcomes of pregnancy. However, the association between weight change due to interventions and the actual reduction in complications is unknown. The objective of this study was to determine the association between gestational weight gain (GWG) and the rate of pregnancy complications. STUDY DESIGN: The authors included randomized controlled trials (RCTs) assessing the effect of lifestyle interventions during pregnancy on GWG and adverse maternal and fetal outcomes. For each outcome they assessed the association between GWG and the risk of adverse pregnancy outcomes. RESULTS: They analyzed data of 23 RCTs (4,990 women). Increased GWG was associated with a nonsignificant increase in the incidence of preeclampsia (PE) (0.2% per gained kg, 95% confidence interval [CI] 0.5 to 0.9%, p > 0.05), gestational diabetes (GDM) (0.3% per gained kg, 95% CI -0.5 to 1.0%, p > 0.05), and induction of labor (IOL) (1.5% per gained kg, 95% CI -0.9 to 3.9%, p > 0.05). CONCLUSIONS: Reduction in GWG due to lifestyle interventions in pregnancy had statistically nonsignificant effects on lowering the incidence of PE, GDM, and IOL. Possibly, the beneficial effect of lifestyle interventions on pregnancy outcomes is due to an effect independent of the reduction of GWG.

Risk factors for developmental dysplasia of the hip: a meta-analysis.

Early detection and subsequent treatment of developmental dysplasia of the hip (DDH) is thought to improve its prognosis. Frequently reported risk factors for DDH are a positive family history of DDH, female sex and breech presentation, but there is not a lot of systematic knowledge about DDH risk factors. We performed a systematic review and meta-analysis of the available evidence on DDH risk factors. We searched Medline, EMBASE and The Cochrane Library from conception up until October 2011 for primary articles on the subject. All studies reporting on potential risk factors for DDH that allowed construction of a two-by-two table were selected. Language restrictions were not applied. Two reviewers independently selected studies, extracted data and assessed study quality. The association between risk factors and DDH was expressed as a common odds ratio (OR) with a 95% confidence interval (CI). We identified 30 relevant studies reporting on 1,494,387 children; 26 studies were cohort studies and four studies used a case-control design. The risk of DDH was strongly increased in case of breech delivery (OR 5.7, 95% CI 4.4-7.4), female sex (OR 3.8, 95% CI 3.0-4.6) a positive family history of DDH (OR 4.8, 95% CI 2.8-8.2) and clicking hips at clinical examination (OR 8.6, 95% CI 4.5-16.6). This meta-analysis shows that infants born in breech presentation, female infants, infants with a positive family history and clicking hips at clinical examination have an increased risk for DDH. This knowledge can be helpful in the development of screening programs for DDH.

[Acute abdominal pain in the third trimester of pregnancy caused by adnexal torsion based on a small cystic adenoma]. / Acute buik in het derde trimester van de zwangerschap door torsie van het adnexum op basis van een klein cysteadenoom.

A 25-year-old woman presented in the third trimester of pregnancy with severe abdominal pain in the lower right abdominal quadrant. Differential diagnosis included urolithiasis, adnexal torsion and appendicitis. A definitive diagnosis could not be made based on clinical and laboratory examination. Ultrasonography revealed a 3-cm cyst in the lower right abdomen, which was considered unlikely to cause abdominal pain. During laparotomy, adnexal torsion was found, which was deemed to be the cause of the abdominal pain. The twisted portion was uncoiled and the dark-coloured cyst was extirpated. The cyst was determined to be a cystic adenoma. Adnexal torsion is rarely caused by cysts smaller than 5 cm, especially in the third trimester. Emergency laparoscopyllaparotomy should be performed if adnexal torsion is suspected to confirm the diagnosis and uncoil the twist to prevent ovarian damage. Adnexal torsion should be considered in the differential diagnosis of acute abdominal pain in the third trimester of pregnancy.

Recurrence rate of pre-eclampsia in women with thrombophilia influenced by low-molecular-weight heparin treatment?

OBJECTIVES: (1) To assess the recurrence rate of pre-eclampsia in women with this history before 34 weeks of pregnancy and thrombophilia. (2) To evaluate the effects of low-molecular-weight heparin (LMWH) on pregnancy outcome. METHODS: In a multicentre retrospective study subsequent pregnancies of women with a history of pre-eclampsia necessitating birth before 34 weeks and thrombophilia were analysed. Of 58 women, 26 received LMWH and aspirin (ASA) and 32 ASA (22) or no (10) medication in their subsequent pregnancies. RESULTS: In eight women treated with LMWH and ASA and in 16 women receiving ASA or no medication pre-eclampsia recurred in the subsequent pregnancy. (OR 0.55, 95% CI 0.15-1.31) There were no significant differences in birth weight or gestational age between both groups. CONCLUSIONS: The recurrence rate of pre-eclampsia in women with thrombophilic disorders is high in this small retrospective study. No positive effect was found for LMWH treatment. A multicentred randomised study has been started to reach an adequate number of patients to evaluate the influence of LMWH treatment.

New approach for the identification of folate-related pathways in human embryogenesis.

The role of natural folate intake and synthetic folic acid supplementation in the prevention of some congenital malformations is known, but on a molecular biological level poorly understood. In a first approach to identify folate-regulated pathways in human embryogenesis, tryptic digests of Epstein Barr Virus-immortalized B-lymphoblasts proteins from 6 cleft lip and/or palate patients and 2 controls were compared using matrix assisted laser desorption ionisation--time of flight (MALDI-TOF) mass spectrometry. After immortalisation, the lymphoblasts were cultured for 22 days in folate-rich, i.e. 5-methyltetrahydrofolate (5-mTHF), or folate-free medium. On day 22, 5-mTHF was added to the folate-free cultures and the profiles on day 22 and 23 were compared. After background correction for the peptide profiles of the folate-rich cultures, we found in the folate-free mediaseveral differentially expressed peptide peaks upon addition of 5-mTHF. These peptide peaks were mass annotated and matched withthe MSDB human database. The results suggest some folate-regulated protein candidates as Frizzled and the Rho GTP-ases WRCH and Chp that are known in human embryogenesis. Differential folate expressed proteins in patients and controls, however, have to be further investigated.

Novel monoclonal antibodies against proteolipid protein peptide 139-151 demonstrate demyelination and myelin uptake by macrophages in MS and marmoset EAE lesions.

Experimental autoimmune encephalomyelitis (EAE) induced by immunization of mice with epitopes of the proteolipid protein (PLP), a major myelin constituent, forms a useful model for the study of multiple sclerosis (MS). In addition, MS patients display PLP-specific T- and B-cell responses, suggesting that PLP reactivity is relevant to pathogenesis.Here, the generation and characterization of a panel of mouse monoclonal antibodies (Mab) against PLP139-151, the prominent encephalitogenic sequence in SJL/J mice is described. Five Mab were generated by conventional immunization of an SJL/J mouse and hybridoma generation. These Mab reacted well with the PLP139-151 peptide in ELISA and belonged to the IgG2a and IgG2b subclasses, consistent with CD4+ T helper 1-cell-supported antibody formation. The Mab also efficiently detected PLP peptide-BSA conjugates in Western blot, confirming their multi-assay applicability. The Mab were subsequently used to determine the occurrence of demyelination in brains of MS patients and marmoset monkeys with EAE. Immunohistochemistry on both paraffin and frozen sections demonstrated a homogeneous expression of PLP139-151 in normal myelin, and a complete absence in lesions containing demyelinated areas, confirming that the Mab can be used as a general myelin marker. In active demyelinating MS lesions, the Mab visualized the peptide in the cytoplasm of macrophages containing phagocytosed myelin. In conclusion, this panel of Mab against the encephalitogenic PLP139-151 epitope forms a useful tool for further study of autoantigen expression, demyelination/remyelination and the staging of lesional activity in MS patients, as well as in EAE models in distinct animal species.

The expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lesions and normal appearing white matter of multiple sclerosis.

In multiple sclerosis, matrix metalloproteinases (MMPs) are effectors of crucial pathogenetic steps, such as blood-brain barrier breakdown, invasion of brain parenchyma by immune cells and demyelination. However, only limited data are available on the types of MMPs induced in the course of multiple sclerosis, and on the role of their endogenous antagonists, the tissue inhibitors of metalloproteinases (TIMPs). We quantified the transcriptional expression of six MMPs and the four TIMPs in lesions and in normal appearing white matter (NAWM) from post-mortem multiple sclerosis brain tissue by real-time polymerase chain reaction, and compared levels with those in brain tissue from six control patients without neurological disease. The mRNA expression of MMP-7 and -9, but not of other metalloproteinases [MMP-2 and -3, and tumour necrosis factor (TNF)-alpha-converting-enzyme] was equally upregulated throughout all stages of lesion formation with active inflammation, and in most of matched NAWM tissue. The transcription of cytokines TNF-alpha/beta and IL (interleukin)-2, known modulators of MMPs, was upregulated only in distinct stages of lesion formation, while their receptors were not induced at all, which suggests that additional signalling molecules participate in the sustained upregulation of MMP-7 and -9 in multiple sclerosis. None of the TIMPs showed a significant induction over baseline expression of controls. We hypothesize that an imbalance between MMP and TIMP expression may cause a persistent proteolytic overactivity in multiple sclerosis, that may be a factor for continuous tissue destruction, and hence for secondary disease progression.

Cyclooxygenase expression in microglia and neurons in Alzheimer's disease and control brain.

Epidemiological studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) lower the risk of developing Alzheimer's disease (AD). Most NSAIDs act upon local inflammatory events by inhibiting the expression or activation of cylooxygenase (COX). In the present study the expression of COX-1 and COX-2 in AD and non-demented control temporal and frontal cortex was investigated using immunohistochemistry. COX-1 expression was detected in microglial cells, while COX-2 expression was found in neuronal cells. In AD brains, COX-1-positive microglial cells were primarily associated with amyloid beta plaques, while the number of COX-2-positive neurons was increased compared to that in control brains. No COX expression was detected in astrocytes. In vitro, primary human microglial and astrocyte cultures, and human neuroblastoma cells (SK-N-SH) were found to secrete prostaglandin E2 (PGE2), especially when stimulated. PGE2 synthesis by astrocytes and SK-N-SH cells was stimulated by interleukin-1beta. Microglial cell PGE2 synthesis was stimulated by lipopolysaccharide only. Although astrocytes are used in studies in vitro to investigate the role of COX in AD, there are no indications that these cells express COX-1 or COX-2 in vivo. The different distribution patterns of COX-1 and COX-2 in AD could implicate that these enzymes are involved in different cellular processes in the pathogenesis of AD.

Isolation and characterization of adult microglial cells and oligodendrocytes derived from postmortem human brain tissue.

The present study provides a detailed description of the simultaneous establishment and immunocytochemical characterization of highly enriched human adult microglial cell cultures as well as of oligodendrocyte cultures. For this study, brain tissue specimens were collected at autopsy with relatively short postmortem times (3-9 h) from various regions of the CNS of Alzheimer's disease, Pick's disease and non-demented control cases. Although methods to isolate viable glial cells from human adult brain tissue have been described, these human brain specimens were often derived from surgical resections, i.e., in order to treat intractable epilepsy, brain tumors or cardiovascular diseases involving the brain. However, for the study of many neurological disorders, surgical material is not available. Furthermore, for obvious reasons, there is a limit to the number of central nervous system (CNS) regions from which (enough) tissue can be obtained at surgery. The adherent primary microglial cells, isolated according to the here described procedures consisted of proliferating, phagocytotic cells that expressed various microglia/macrophage-specific markers as judged by immunocytochemical analysis. Non-adherent cells isolated from the same brain tissue samples expressed oligodendrocyte-specific markers. The current described culture system may provide a valuable tool in studying human CNS biology and disease.

Clinimetric evaluation of the pain observation scale for young children in children aged between 1 and 4 years after ear, nose, and throat surgery.

This study assessed the reliability, validity, and responsiveness of a new pain measure for children aged 1 to 4 years that was developed from the Children's Hospital of Ontario Pain Scale and its Neonatal Infant Pain Scale. Pain in 311 children, aged 1 to 4 years, was measured by two observers at fixed intervals after adenotonsillectomy (n = 114), adenotomy (n = 109), or insertion of ventilation tubes (grommets) (n = 88) until discharge using a dichotomous pain scale of 9 behavioral and physiological categories. The scale proved to be strongly homogeneous. The interobserver agreement was substantial for 7 items. On these final 7 items, the ability to distinguish between patients with differing degrees of pain and the sensitivity to detect changes over time within each patient were substantial. The resulting Pain Observation Scale for Young Children is reliable and easy to use for assessment of short- and longer-lasting pain after ear, nose, and throat surgery and may be used for assessing pain with other conditions.

Effective cancer therapy with a single injection of interleukin-2 at the site of the tumour.

Mice with a severe metastasized tumour burden can be cured with a single local injection of interleukin-2. Such a treatment can also be effective against ocular squamous cell carcinoma in cows and transmissible venereal tumours in dogs. We did not notice any toxic effects of this treatment.