Adverse outcome following selective termination of presenting twin vs non-presenting twin.

OBJECTIVE: Data are lacking on the impact on pregnancy outcome of the position of the abnormal fetus in a discordant twin pregnancy undergoing selective termination (ST). Tissue maceration post ST of the presenting twin may lead to early rupture of membranes, amnionitis and preterm labor. The aim of this study was to evaluate pregnancy complications and outcome following ST of the presenting vs non-presenting twin. METHODS: This was a multicenter retrospective cohort study of dichorionic diamniotic twin pregnancies that underwent ST due to a discordant fetal anomaly (structural or genetic) between 2007 and 2021. The study population was divided into two groups according to the position of the reduced twin (presenting or non-presenting) and outcomes were studied accordingly. The primary outcome was a composite of early complications following ST, including infection, preterm prelabor rupture of membranes and pregnancy loss. RESULTS: A total of 190 dichorionic twin pregnancies were included, of which 73 underwent ST of the presenting twin and 117 of the non-presenting twin. The groups did not differ in either baseline demographic characteristics or mean gestational age at the time of the procedure. ST of the presenting twin resulted in a significantly higher rate of early complications compared with the non-presenting twin (19.2% vs 7.7%; P = 0.018). Moreover, the rates of preterm delivery (75.3% vs 37.6%; P < 0.001) and neonatal intensive care unit admission (45.3% vs 17.1%; P < 0.001) were higher, and birth weight was lower (P < 0.001), in those pregnancies in which the presenting twin was reduced. CONCLUSIONS: ST of the presenting twin resulted in a higher rate of adverse pregnancy outcome compared with that of the non-presenting twin. These findings should be acknowledged during patient counseling and, if legislation permits, taken into consideration when planning ST. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Universal chromosomal microarray analysis reveals high proportion of copy-number variants in low-risk pregnancies.

OBJECTIVES: To evaluate the yield and utility of the routine use of chromosomal microarray analysis (CMA) for prenatal genetic diagnosis in a large cohort of pregnancies with normal ultrasound (US) at the time of genetic testing, compared with pregnancies with abnormal US findings. METHODS: We reviewed all prenatal CMA results in our center between November 2013 and December 2018. The prevalence of different CMA results in pregnancies with normal US at the time of genetic testing ('low-risk pregnancies'), was compared with that in pregnancies with abnormal US findings ('high-risk pregnancies'). Medical records were searched in order to evaluate subsequent US follow-up and the outcome of pregnancies with a clinically relevant copy-number variant (CNV), i.e. a pathogenic or likely pathogenic CNV or a susceptibility locus for disease with > 10% penetrance, related to early-onset disease in the low-risk group. RESULTS: In a cohort of 6431 low-risk pregnancies that underwent CMA, the prevalence of a clinically significant CNV related to early-onset disease was 1.1% (72/6431), which was significantly lower than the prevalence in high-risk pregnancies (4.9% (65/1326)). Of the low-risk pregnancies, 0.4% (27/6431) had a pathogenic or likely pathogenic CNV, and another 0.7% (45/6431) had a susceptibility locus with more than 10% penetrance. Follow-up of the low-risk pregnancies with a clinically significant early-onset CNV revealed that 31.9% (23/72) were terminated, while outcome data were missing in 26.4% (19/72). In 16.7% (12/72) of low-risk pregnancies, an US abnormality was discovered later on in gestation, after genetic testing had been performed. CONCLUSION: Although the background risk of identifying a clinically significant early-onset abnormal CMA result in pregnancies with a low a-priori risk is lower than that observed in high-risk pregnancies, the risk is substantial and should be conveyed to all pregnant women. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Placental hyperinflation and the risk of adverse perinatal outcome.

OBJECTIVES: To determine the pathological basis and clinical associations of excessively thick placentae observed at second-trimester ultrasound examination. METHODS: In a retrospective cohort of 19 singleton high-risk second-trimester pregnancies noted to have a placental length-to-maximum thickness ratio ≤ 2.0, maximum sonographic placental thickness was correlated with clinical outcome, maximum placental thickness after delivery and placental pathological findings. Results were compared with those of an intermediate group of 21 high-risk pregnancies with normal placental dimensions and a control group of 18 low-risk pregnancies also with normal placental dimensions. Increased maximum placental thickness (> 28 mm) and abnormal placental deflation following delivery (pathology - sonography difference in maximum placental thickness < -2 mm) were defined by the upper and lower quartile values, respectively, in the control group. RESULTS: The study group exhibited significantly more adverse outcomes and gross pathological placental features compared with both intermediate and control groups. Despite increased sonographic maximum placental thickness in the study group (median, 55 (range, 40-75) mm compared with both the intermediate group (median, 27 (range, 22-41) mm, P < 0.0001) and the control group (median 26 (range, 23-36) mm, P < 0.0001)), all three groups had similar maximal placental thickness following delivery (study group: median, 24 (range, 10-50) mm vs intermediate group: median, 27 (range, 15-40) mm, P = 0.82 and vs control group: median, 28.5 (range, 18-44), P = 0.42). Pathology-sonography difference in maximum placental thickness in the study group (median, -30 (range, -42 to 0) mm) was significantly greater than that in either the intermediate (median, -2 (range, -11 to 9) mm, P < 0.0001) or the control (median, 1.5 (range, -10 to 18) mm, P < 0.0001) group and was significantly associated with abnormal development of the gas-exchanging placental villi (distal villous hypoplasia) (P = 0.0001). CONCLUSIONS: Increased second-trimester sonographic maximum placental thickness represents a pathological finding associated with severe adverse perinatal outcome. This observation is due to overinflation of the intervillous space by maternal blood rather than to adaptive formation of functional placental tissue.

Glucose metabolism: key endogenous regulator of ß-cell replication and survival.

Recent studies in mice have shown that pancreatic ß-cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. Genetic lineage tracing studies indicate that ß-cell regeneration is based on the replication of fully differentiated, insulin-positive ß-cells. Thus, a major challenge for this field is to identify and enhance the molecular pathways that control ß-cell replication and mass. We review evidence, from human genetics and mouse models, that glucose is a major signal for ß-cell replication. The mitogenic effect of blood glucose is transmitted via glucose metabolism within ß-cells, and through a signalling cascade that resembles the pathway for glucose-stimulated insulin secretion. We introduce the concept that the individual ß-cell workload, defined as the amount of insulin that an individual ß-cell must secrete to maintain euglycaemia, is the primary determinant of replication, survival and mass. We also propose that a cell-autonomous pathway, similar to that regulating replication, appears to be responsible for at least some of the toxic effects of glucose on ß-cells. Understanding and uncoupling the mitogenic and toxic effects of glucose metabolism on ß-cells may allow for the development of effective regenerative therapies for diabetes.

Determinants of pancreatic beta-cell regeneration.

Recent studies have revealed a surprising plasticity of pancreatic beta-cell mass. beta-cell mass is now recognized to increase and decrease in response to physiological demand, for example during pregnancy and in insulin-resistant states. Moreover, we and others have shown that mice recover spontaneously from diabetes induced by killing of 70-80% of beta-cells, by beta-cell regeneration. The major cellular source for new beta-cells following specific ablation, as well as during normal homeostatic maintenance of adult beta-cells, is proliferation of differentiated beta-cells. More recently, it was shown that one form of severe pancreatic injury, ligation of the main pancreatic duct, activates a population of embryonic-type endocrine progenitor cells, which can differentiate into new beta-cells. The molecular triggers for enhanced beta-cell proliferation during recovery from diabetes and for activation of embryonic-type endocrine progenitors remain unknown and represent key challenges for future research. Taken together, recent data suggest that regenerative therapy for diabetes may be a realistic goal.

Correction of knee and ankle valgus in hereditary multiple exostoses using the Ilizarov apparatus.

BACKGROUND: Hereditary multiple exostoses (HME) is a genetic disorder that causes limb deformities due to disturbance at the growth plates. MATERIALS AND METHODS: Six adolescents, whith symptomatic valgus deformity at the ankle and knee (seven affected legs) underwent correction procedures using the Ilizarov apparatus. In 5 legs, a bifocal Ilizarov apparatus was used, whereas in 2 legs the use of a monofocal apparatus was sufficient. RESULTS: Correction of the mechanical axis was achieved in all cases, and limb length discrepancy was equalized in the 3 cases that underwent limb elogation. The average knee and ankle corrections were 15 degrees and 18 degrees , respectively. The average time from application to removal of the Ilizarove apparatus was 4.6 months. No major complication occurred. CONCLUSIONS: The use of the Ilizarov method in adolescents with HME enables successful simultaneous correction of multiplanar, multifocal complex limb deformities.

Mild tricuspid regurgitation: a benign fetal finding at various stages of pregnancy.

OBJECTIVE: Tricuspid regurgitation (TR) may accompany various anatomical malformations and/or dysfunction of the fetal right heart. It may also appear in an anatomically healthy heart. With improved ultrasound modalities, more cases than the previously estimated prevalence of fetal TR in the low-risk population are being diagnosed. The objective of this study was to determine the prevalence of mild fetal TR in a low-risk obstetric population. METHODS: In 157 low-risk pregnant women (age range, 18-42 years) undergoing both early second-trimester and mid-trimester targeted organ scanning, including complete fetal echocardiography according to the five transverse planes technique, the apical four-chamber view was visualized using gray-scale, color Doppler and spatiotemporal image correlation (STIC) ultrasound modalities, with optimal acquisition parameters. RESULTS: Mild-to-moderate TR was discovered in the early second-trimester scan in 131/157 (83.4%) fetuses. No cases of cardiac malformation were found. All fetuses showed normal flow in the ductus venosus, including in one case diagnosed with moderate TR. Only in 39 (24.8%) cases was mild TR still evident at the second, mid-trimester scan. Neonatal echocardiography revealed mild TR in eight (5.1%) cases. No cases of chromosomal anomalies were detected. CONCLUSION: Mild TR is a benign finding of a temporal nature in early pregnancy.

Fetal intracranial hemorrhage (fetal stroke): does grade matter?

OBJECTIVE: To determine if the severity of antenatally diagnosed hemorrhagic fetal brain insults and fetal stroke detected by ultrasound and magnetic resonance imaging (MRI) predicts postnatal neurodevelopmental prognosis. METHODS: The in-utero presentation and postnatal neurodevelopmental outcome of sonographically detected subdural hematoma or fetal stroke presenting as intraventricular hemorrhage (IVH) or intraparenchymal brain hemorrhage were investigated. RESULTS: Of 33 fetuses diagnosed with hemorrhagic brain lesions, 17 were electively terminated and two suffered intrauterine fetal demise. Thirteen were liveborn, seven by Cesarean delivery and six by spontaneous vaginal delivery. One case was lost to follow-up. Eight neonates had moderate to severe neurological deficit by a mean age of 35 (range, 6-96) months. One died at 2 months of age. These nine were diagnosed with Grade III-IV IVH in utero. Four neonates had normal neurological outcome by a mean age of 41 (range, 30-48) months; these four were diagnosed with subdural hematoma (n = 1) or Grade I-II IVH (n = 3) in utero. Fourteen cases were followed up with MRI, which confirmed ultrasound findings in 10 (71%) cases. In three (21%) cases MRI diagnosis was more accurate and the severity of grading was greater than that obtained on ultrasound imaging. Unilateral left hemispheric lesions were much more common than right-sided lesions (13 vs. 1, respectively). CONCLUSIONS: An antenatal sonographic diagnosis of fetal stroke with IVH Grade III-IV or with brain parenchymal involvement appears to be associated with poor neurological outcome. MRI may contribute to the accuracy of diagnosis, particularly in Grade II and III lesions. Left-sided unilateral lesions are more common than right-sided ones.

Adverse outcome of isolated fetal intra-abdominal umbilical vein varix despite close monitoring.

BACKGROUND AND OBJECTIVES: Fetal intra-abdominal umbilical vein (FIUV) varix-a focal dilatation of the umbilical vein-is an uncommon entity. Outcome varies from spontaneous resolution to fetal death. We describe here the experience of our center with this perplexing entity. METHODS: Case series review of seven cases of isolated FIUV treated in a tertiary care center from 2000 to 2003. RESULTS: We describe seven cases of isolated FIUV varix with varying natural history, follow-up strategies, and fetal outcome. In one of the cases, intrauterine fetal demise occurred despite close follow-up. CONCLUSIONS: We suggest that the course of FIUV is unpredictable, with a high fetal mortality rate. Close fetal monitoring with early delivery at 34 weeks' gestation should be advocated.

Fetal supraventricular tachycardia diagnosed and treated at 13 weeks of gestation: a case report.

Supraventricular tachycardia (SVT) is the most commonly encountered clinically significant tachycardia in the fetus. When SVT is sustained, congestive heart failure and fetal hydrops may ensue, due to both systolic and diastolic dysfunction. Sonographic diagnosis is usually incidental during the second or third trimester. Treatment goals are cardioversion to sinus rhythm and reversal of cardiac dysfunction. We describe a case of fetal SVT diagnosed at 13 weeks of gestation. Treatment with digoxin and flecainide was successful; the heart rate returned to sinus rhythm within one day, and fetal hydrops resolved within 8 days of treatment. We suspect that as more first-trimester examinations are performed, more cases with SVT will be diagnosed. We discuss the treatment protocol, and suggest that co-administration of two drugs that act synergistically may be more efficient than monotherapy, which is currently used as the first line of treatment. In addition, we discuss the potentially deleterious effect of heart failure encountered at an early developmental stage on the central nervous system. More data need to be collected in order to substantiate a clear recommendation regarding optimal management.

Fractures of the lateral process of the talus in children.

Fractures of the lateral process of the talus are an uncommon injury, which are often misdiagnosed as severe ankle sprain. This error may result in inappropriate treatment of an intraarticular fracture, with subsequent posttraumatic arthrosis. To date, only one fracture of a lateral talar process has been reported in a child, in whom delayed diagnosis and initial mismanagement led to a suboptimal result. The sport of 'snowboarding', which is gaining in popularity, has been significantly associated with fractures of the lateral talar process, leading some authors to dub this fracture 'Snowboarder's Fracture'. This and the ever-increasing incidence of major trauma lead us to believe that this fracture will be encountered more frequently, even in the pediatric population, as the two factors mentioned do not pass over this group. We report lateral talar process fractures in two children: one in a 9-year-old girl and one in an 11-year-old boy, the latter associated with talar neck and body fractures. Timely diagnosis enabled prompt open reduction and internal fixation, preventing subtalar arthrosis. We discuss the pertinent anatomy and mechanism, and present the clinical picture, imaging studies and treatment. Two important points are exemplified by these cases. First, this fracture, although rare, does occur in children, and should be sought in appropriate settings. Second, despite the severe talar injury in the 11 year old, early diagnosis and intervention conserved foot function.

Dopamine induces phenotypic differentiation or apoptosis in a dose-dependent fashion: involvement of the dopamine transporter and p53.

The effect of dopamine on the growth, phenotypes (morphological and biochemical) and programmed cell death (apoptosis) of the human neuronal NMB cell line was examined. Exposure to 20-50 microM of dopamine decreased cell growth, induced an apparent differentiated cell morphology and increased (3)H-dopamine uptake. At higher concentrations (100-300 microM) dopamine was neurotoxic and induced apoptosis, as reported previously. The observed effects of both low and high doses of dopamine were blocked by cocaine, which suggested involvement of dopamine transporters. Indeed, several experiments demonstrated the relationship between dopamine uptake of cells and their vulnerability to the toxic effect of dopamine. High concentrations of dopamine, which induced apoptosis, also increased p53 levels, detected by RT-PCR analysis and immunoblotting, whereas lower dopamine concentrations, which induced a differentiated phenotype, did not increase p53 immunoblotting. Dibutyryl-cAMP and dimethyl sulfoxide, which induced differentiation but not apoptosis of the NMB cells, did not increase p53 expression. These findings provide an insight into the role of dopamine, dopamine transporters and p53 in the differentiation and apoptosis of dopaminergic neurons, which will further our understanding of neuronal development and neurodegenerative diseases.

The "crushed open pelvis" in children.

A retrospective analysis was performed in order to review the outcome of open pelvic fractures in children. Medical records, radiographs and CT scans of 15 children with open pelvic fractures admitted to our trauma centre between 1983 and 1995 were reviewed. The minimal follow-up on the survivors was two years. Out of 15 open pelvic fractures ten were vertically unstable. The mechanism of injury was auto-pedestrian collision in 93% (n = 14) of the cases. 86% (n = 13) of the fractures were a result of a "run-over" mechanism, 40% (n = 6) were caused by heavy duty vehicles. All children had injuries in the proximity of the pelvis. Despite the severity of trauma, we found mortality to be 20% (n = 3). Sepsis and deep infection originating from anorectal and genitourinary excretions were found to be the most frequent complications. The improvement in surgical techniques of the pelvis influenced the orthopaedic treatment in these 15 children. External fixation of the pelvis is not always sufficient and to achieve better stabilization of the pelvis, open reduction and internal fixation should be considered. In order to minimize complications, aggressive intervention is needed including irrigation, debridement, intravenous antibiotics, diverging colostomies and cystostomies and fracture fixation. The coordination between trauma teams of different disciplines throughout all stages of the treatment is crucial to achieving better results.

Do axial dynamic fixators really produce axial dynamization?

The use of dynamic external fixators for the treatment of long bone fracture is widespread and well accepted. It is claimed that dynamization, i.e. small micromovements of compression/distraction at the fracture site, can be produced by allowing sliding of an inner rod within an outer housing. However, as the forces on the fixator are not direct but transferred from the bone via bone pins, there is a bending moment on the fixator. This produces "self-locking" and effectively prevents axial movements. We have studied the effect of this moment on the binding properties of the Orthofix system. The amount of movement at a simulated fracture site allowed before this locking occurs was measured and its implications discussed. It would appear that true axial dynamization does not take place using this system.

Effect of low-dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine-induced dopamine release in vivo.

1. Chronic treatment with low doses of the selective monoamine oxidase (MAO) type B inhibitors selegiline [(-)-deprenyl] and rasagiline, causes elevation in extracellular level of 3,4-dihydroxyphenylethylamine (dopamine) in the rat striatum in vivo (Lamensdorf et al., 1996). The present study was carried out to determine whether this effect of selegiline could be the result of an inhibition of the high-affinity dopamine neuronal transport process. 2. Changes in activity of the dopamine transporter (DAT) in vivo following selegiline treatment were evaluated indirectly by microdialysis technique in the rat, from the change in striatal dopamine extracellular concentration following systemic amphetamine administration (4 mg kg(-1), i.p.). Striatal levels of the DAT molecule were determined by immunoblotting. Uptake of [3H]-dopamine was determined in synaptosomes from selegiline-treated animals. 3. Amphetamine-induced increase in striatal extracellular dopamine level was attenuated by one day and by chronic (21 days) treatment with selegiline (0.25 mg kg(-1), s.c.). 4. Striatal levels of DAT were elevated after 1 and 21 days treatment with selegiline, but were not affected by clorgyline, rasagiline, nomifensine or amphetamine. 5. The increase in DAT expression, and attenuation of amphetamine-induced dopamine release, were not accompanied by a change in [3H]-dopamine uptake in synaptosomes of selegiline-treated animals. 6. The results suggest that a reversible inhibition of dopamine uptake occurs following chronic low dose selegiline treatment in vivo which may be mediated by an increase in endogenous MAO-B substrates such as 2-phenylethylamine, rather than by the inhibitor molecule or its metabolites. Increased DAT expression appears to be a special property of the selegiline molecule, since it occurs after one low dose of selegiline, and is not seen with other inhibitors of MAO-A or MAO-B. The new DAT molecules formed following selegiline treatment appear not to be functionally active.

Bcl-2 and p53: role in dopamine-induced apoptosis and differentiation.

The fate of a neuron in the developing brain to multiply, differentiate, or die in an apoptotic manner depends on the expression of genes that are involved in regulating the cell cycle. Recent studies determined the involvement of several genes, including cyclin A and B2, in dopamine-induced apoptosis in cultured chick sympathetic neurons. Another gene that plays a role in apoptosis and differentiation of neurons, oligodendrocytes and PC12 cells is p53. It is also known that DNA damage increases p53 levels, triggering repair or apoptosis in response to moderate or severe damage, respectively. NMB cells express active and inducible forms of p53, thus being particularly suitable to analyze the role of this gene in dopamine-induced apoptosis and differentiation. The main observation of this work is that low concentrations of dopamine induce differentiation while high concentrations induce apoptosis, and that concentrations of dopamine that induce apoptosis increased p53 levels. There peak increase in p53 was within 3-6 h, before cell death. Thus, treatment with a high dopamine concentration may result in oxidation products and/or free radicals that heavily damage DNA, thus increasing p53 levels and initiating a cascade of events leading to apoptosis. Lower concentrations of dopamine apparently have a milder damaging effect on the DNA and induce growth arrest and differentiation. In various systems Bcl-2 inhibits cell death, being apoptotic or necrotic. Bcl-2, and other members of the family, such as Bax, are located downstream to p53 in the apoptotic pathway, and they contain negative or positive p53 response elements. Bcl-2 also protects cells by acting as antioxidant. Neuronal differentiation may be accompanied with an increase in Bcl-2, though it was suggested that the role of Bcl-2 in differentiation is less critical than in apoptosis. Herein, Bcl-2 was found to inhibit dopamine neurotoxicity. Whether the expression of Bcl-2 is regulated by different dopamine concentrations, or by dibutyryl-cAMP and DMSO, remains to be determined.

[CT-guided excision of osteoid osteoma].

CT-guided excision of osteoid osteoma is a new surgical technique that enables accurate resection of the nidus during 1-day hospitalization. We present 5-year results in 42 patients (26 males and 16 females, mean age 18 years, range 3-46). In 40 out of 42, complaints disappeared immediately after the procedure. The recovery period was short and the return to normal activity was faster than in the open surgical approach. Complications were minimal and transient.