Longitudinal follow-up of bladder function in children who participated in the Swedish Reflux Trial.

BACKGROUND: Several publications have reported the coexistence of vesicoureteral reflux (VUR) and bladder dysfunction in children. Whether this dysfunction remains in the longer term is not yet known. OBJECTIVE: This study revisited children who participated in the Swedish Reflux Trial (SRT) with the primary aim of evaluating whether bladder and bowel dysfunction (BBD) in these patients persisted until adolescence. The secondary aim was to evaluate two BBD subgroups, and relations to recurrent urinary tract infections (UTI). STUDY DESIGN: Of the 161 eligible children at SRT study-end, 73 children participated. Their bladder function was evaluated longitudinally using a validated BBD questionnaire with symptom score (cut-off ≥7) and uroflowmetry, at five (T2) and ten years (T3) after study-end. T1 was the SRT study-end. Besides BBD, the sub-diagnoses overactive bladder (OAB) and dysfunctional voiding symptoms (DVS) were calculated from symptom scores. RESULTS: BBD was diagnosed in 37% of children at mean age 3.7 years, which decreased with age to 23% of adolescents (mean age 15.7). DVS and OAB subgroups were equally common at T1, but only DVS was identified at the last follow-up (T3) (p = 0.0008). Recurrent UTIs were seen in 17% at T3 and were more common in patients with BBD (p = 0.038). The gender distribution of BBD also changed, from being equally common at the end of the SRT to affecting mainly adolescent girls at the last follow-up (p = 0.022). Information was available regarding VUR status after repeat VCUGs during follow-up in 22 patients, 12 of them after endoscopic treatment. An improvement in VUR grade was found in the 22, but during follow-up numbers with BBD or UTI did not differ between treated and non-treated groups. DISCUSSION: The prevalence of BBD decreased from 37% at 3-4 years of age to 23% in adolescence, when it was almost exclusively seen in girls. BBD and the subgroup DVS were associated with UTI. Even if epidemiological studies have established a predisposition to bladder symptoms and UTI in girls, little is known about bladder function in adolescents with a history of VUR during the first years of life. One limitation of the study was the number of patients participating. Also, the number of patients with kidney damage was more common in the cohort. CONCLUSION: In this longitudinal follow-up of BBD in children with VUR, the number of children with BBD decreased with age. In adolescence, both BBD and recurrent UTIs mainly affected girls.

Diffusion weighted imaging is a promising method to detect acute pyelonephritis in non-sedated free breathing infants.

INTRODUCTION: Urinary tract infection (UTI) is a common disease in infants. The initial evaluation includes imaging to identify risk factors for permanent renal damage, such as malformation and renal parenchymal involvement of the infection i.e. pyelonephritis. 99mTc-Dimercaptosuccinic acid (DMSA) scintigraphy is a well-established method for detection of pyelonephritis and renal damage, but has limitations in availability, spatial resolution, and detection of congenital malformations. Diffusion weighted magnetic resonance imaging (DWI) has been shown to have a high sensitivity for detection of pyelonephritis in children without the use of invasive procedures, contrast agents or ionizing radiation. How this method performs in young infants during non-sedated free breathing remains, however, to be investigated. OBJECTIVE: To prospectively assess the feasibility and performance of DWI for detection of pyelonephritis in non-sedated free breathing infants. METHODS: 32 children <6 months of age with first-time symptomatic UTI were examined with DWI and DMSA scintigraphy. The DWI examination was performed using a free breathing protocol without the use of sedation. Pyelonephritic lesions were registered for both methods by independent observers. Agreement between DWI and DMSA was evaluated. Consensus diagnosis was determined and compared to the DWI findings. RESULTS: The MRI and DMSA examinations were completed in 25 infants, with a median age of 1.7 (0.7-5.5) months. Focal uptake reductions were detected on the DMSA images in 12 (24%) of the 50 kidneys. The DWI method demonstrated a fair to good agreement with DMSA, k = 0.50 (p < 0.0001). The consensus diagnosis was pyelonephritis in eight (16%) of the 50 kidneys. DWI detected seven of the eight kidneys with pyelonephritis. No false positive findings were detected with DWI compared to consensus diagnosis. DISCUSSION: This study has shown an agreement between DWI and DMSA scintigraphy in the detection of pyelonephritis. Further validation of the performance of DWI, using a consensus diagnosis as a reference, confirmed the potential of the method. This feasibility study included a limited number of patients and the results need to be confirmed in a prospective study of a larger cohort. CONCLUSION: Free breathing DWI is a promising method for detection of pyelonephritic lesions in non-sedated infants.

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe.

OBJECTIVE: To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10 000 European Union (EU) population as part of an application for European Medicines Agency (EMA) orphan designation. DESIGN: Incidence estimation based on literature review and published national and EU statistics. SETTING AND POPULATION: European Union. METHODS: Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched. RESULTS: The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93-3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10 000 EU population (95% CI 3.07-3.60 per 10 000 EU population). This fell below the EMA threshold of 5 per 10 000 EU population. CONCLUSIONS: Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life-threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits. TWEETABLE ABSTRACT: Placental insufficiency meets the European Medicines Agency requirements for orphan disease designation.

Renal swelling indicates renal damage in infants with their first urinary tract infection.

AIM: We used ultrasound to evaluate renal swelling as a predictor of acute and permanent renal damage in infants with their first urinary tract infection (UTI). METHODS: The cohort at the Queen Silvia Children's Hospital, Gothenburg, Sweden, comprised 101 infants with their first UTI at a mean age of 3.9 ± 3.0 months. Acute and follow-up ultrasounds were carried out a few days and one month after treatment started, and a 99m technetium dimercaptosuccinic acid (DMSA) scan was carried out after one month and after a year if the first scan was abnormal. RESULTS: The acute ultrasounds showed that renal length and volume, calculated as standard deviation scores (SDS), were 1.39 ± 1.43 SDS and 1.30 ± 1.08 SDS. We found that 52% of the one-month DMSA scans and 25% of the one-year DMSA scans were abnormal. Renal length (p = 0.0026) and initial volume (p = 0.0005) on the ultrasound predicted acute renal damage at the one-month DMSA scan and initial renal length (p = 0.030) predicted permanent renal damage at the one-year DMSA scan. CONCLUSION: Renal swelling was associated with renal damage. Although the diagnostic performance compared with the DMSA scan was weak, renal swelling may help clinicians to make decisions about further investigations and follow-ups of infants with UTIs.

Ultrasound is an effective and noninvasive method of evaluating renal swelling in infants with their first urinary tract infection.

AIM: This study evaluated renal swelling in infants with a first urinary tract infection (UTI) by correlating renal length and volume with C-reactive protein (CRP) and body temperature. METHODS: Ultrasounds were carried out on 104 infants at The Queen Silvia Children's Hospital, Gothenburg, Sweden - 58 boys (mean age 3.3 months) and 46 girls (mean age 4.8 months) - during the acute phase of their UTI. A second scan was performed on 94 of them 4 weeks later. Renal length and volume were computed to standard deviation scores (SDS). RESULTS: The mean renal length and volume at the first ultrasound were 1.90 SDS (±1.54) and 1.67 SDS (±1.13) for the larger kidney and 0.86 SDS (±1.01) and 0.84 SDS (±0.90) for the smaller kidney. There was a significant decrease in renal length and volume between the two ultrasounds, with a mean difference of 0.96 SDS (±1.24) and 1.07 SDS (±1.10) for the larger kidney (p < 0.0001). The length and volume of the larger kidney correlated with CRP (p < 0.001), but only the renal length correlated with fever (p < 0.001). CONCLUSION: Early ultrasound determined renal swelling in infants with a UTI and may be a valuable noninvasive way of identifying infants with renal parenchymal involvement.

Feeding range of age 1+ year Eurasian perch Perca fluviatilis in the Baltic Sea.

Using the widespread Eurasian perch Perca fluviatilis as a model organism, feeding ranges were investigated using stable-isotope ratios (δ15 N and δ13 C) and body condition. Differences were found between closely located sampling sites in a littoral area without obvious migration barriers, indicating that individual fish had small feeding ranges. Body condition differences between sampled stations were consistent over 4 years. Such sedentary behaviour is important to consider in, e.g. fisheries management and environmental monitoring, as local catch regulations may be meaningful or geographic stability in sampling locations may reduce noise in data.

Large difference in carbon emission ­ burial balances between boreal and arctic lakes.

Lakes play an important role in the global carbon (C) cycle by burying C in sediments and emitting CO2 and CH4 to the atmosphere. The strengths and control of these fundamentally different pathways are therefore of interest when assessing the continental C balance and its response to environmental change. In this study, based on new high-resolution estimates in combination with literature data, we show that annual emission:burial ratios are generally ten times higher in boreal compared to subarctic - arctic lakes. These results suggest major differences in lake C cycling between biomes, as lakes in warmer boreal regions emit more and store relatively less C than lakes in colder arctic regions. Such effects are of major importance for understanding climatic feedbacks on the continental C sink - source function at high latitudes. If predictions of global warming and northward expansion of the boreal biome are correct, it is likely that increasing C emissions from high latitude lakes will partly counteract the presumed increasing terrestrial C sink capacity at high latitudes.

IFPA Meeting 2013 Workshop Report III: maternal placental immunological interactions, novel determinants of trophoblast cell fate, dual ex vivo perfusion of the human placenta.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialised topics. At IFPA meeting 2013 there were twelve themed workshops, three of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of placental function, cell turnover and immunology: 1) immunology; 2) novel determinants of placental cell fate; 3) dual perfusion of human placental tissue.

Successful treatment of severe ABO antibody-mediated rejection using bortezomib: a case report.

BACKGROUND: Our program for ABO-incompatible renal transplantation includes antigen-specific immunoadsorption (extracorporeal columns with the A or B trisaccharides), rituximab, and standard maintenance immunosuppression. Anti-A or -B titers ≤ 8 in the indirect antiglobulin test (IAT) against panel A1 or B RBC are acceptable for transplantation. CASE REPORT: A previously healthy, 15-month-old girl was diagnosed with Wilms' tumor and proteinuria. Denys-Drash syndrome was confirmed. Bilateral nephrectomy was performed. At 3.5 years of age she received an ABO-incompatible renal transplant from her father (A1 to O). The anti-A titers before transplantation were low. She was treated preoperatively with rituximab, immunoadsorption, immunoglobulin and mycophenolate mofetil (MMF). The maintenance immunosuppression protocol included basiliximab, tacrolimus, MMF, and prednisolone. The initial postoperative course was uncomplicated with rapid normalization of serum creatinine. The anti-A titers started to increase on postoperative day 5 (8 NaCl/16 IAT). Despite daily immunoadsorptions the titers rose to 1024 NaCl/1024 IAT on day 9. Renal function deteriorated and hemodialysis was started. A renal biopsy on day 9 showed acute severe antibody-mediated rejection. Additional treatment with bortezomib was given and after 2 doses the titers started to decline, renal allograft function improved and hemodialysis was stopped. On day 21 posttransplant the titers went down, creatinine was 28 µmol/L, and no more immunoadsorptions were performed. CONCLUSION: By using bortezomib, we were able to successfully reverse a severe ABO antibody-mediated rejection.

Gene expression profiling of placentae from women with early- and late-onset pre-eclampsia: down-regulation of the angiogenesis-related genes ACVRL1 and EGFL7 in early-onset disease.

The underlying mechanisms behind the obstetric condition pre-eclampsia (PE) are still unclear. Manifestation of PE is heterogeneous and it has therefore been proposed to be a syndrome with different causes rather than one disease with a specific aetiology. Recently, we showed differences in circulating angiogenic factors between two subgroups-early- and late-onset PE. To further elucidate the differences between the two, we investigated placental gene expression profiles. Whole genome microarray technology and bioinformatic analysis were used to evaluate gene expression profiles in placentae from early- (24-32 gestational weeks, n = 8) and late-onset (36-41 gestational weeks, n = 7) PE. The results were verified by using quantitative real-time (qRT)-PCR. We found significant differences in the expression of 196 genes in early- compared with late-onset PE, 45 of these genes showing a fold change above 2. Bioinformatic analysis revealed alterations in angiogenesis and regulation of cell motility. Two angiogenesis-associated transcripts (Egfl7 and Acvrl1) showed lower expression in early-onset PE versus late-onset PE (P = 0.037 and P = 0.003) and versus gestational age-matched controls (P = 0.007 and P = 0.011). We conclude that angiogenesis-associated genes are regulated in a different manner in the two subgroups, and that the gene expression profiles of early- and late-onset PE diverge, supporting the hypothesis of early- and late-onset PE being at least partly two separate entities.

Review: Biochemical markers to predict preeclampsia.

Worldwide the prevalence of preeclampsia (PE) ranges from 3 to 8% of pregnancies. 8.5 million cases are reported yearly, but this is probably an underestimate due to the lack of proper diagnosis. PE is the most common cause of fetal and maternal death and yet no specific treatment is available. Reliable biochemical markers for prediction and diagnosis of PE would have a great impact on maternal health and several have been suggested. This review describes PE biochemical markers in general and first trimester PE biochemical markers specifically. The main categories described are angiogenic/anti-angiogenic factors, placental proteins, free fetal hemoglobin (HbF), kidney markers, ultrasound and maternal risk factors. The specific biochemical markers discussed are: PAPP-A, s-Flt-1/PlGF, s-Endoglin, PP13, cystatin-C, HbF, and α1-microglobulin (A1M). PAPP-A and HbF both show potential as predictive biochemical markers in the first trimester with 70% sensitivity at 95% specificity. However, PAPP-A is not PE-specific and needs to be combined with Doppler ultrasound to obtain the same sensitivity as HbF/A1M. Soluble Flt -1 and PlGF are promising biochemical markers that together show high sensitivity from the mid-second trimester. PlGF is somewhat useful from the end of the first trimester. Screening pregnant women with biochemical markers for PE can reduce unnecessary suffering and health care costs by early detection of mothers at increased risk for PE, thus avoiding unnecessary hospitalization of pregnant women with suspect or mild PE and enabling monitoring of the progression of the disease thereby optimizing time for delivery and hopefully reducing the number of premature births.

OS089. Elevated levels of the heme scavenger alpha-1-microglobulin in maternal plasma at the end of first trimester in patients who subsequently develop preeclampsia.

INTRODUCTION: Resent research has revealed an increased concentration of free fetal hemoglobin (HbF) in maternal serum from patients who subsequently develops preeclampsia (PE). In a previous study of 96 patients we have shown that HbF in combination with the heme-scavenger alpha-1-microglobulin (A1M) are potential predictive biomarkers of PE. OBJECTIVES: In this validating case-control study we aimed to confirm the previous findings, that A1M is elevated in the maternal circulation at the end of first trimester in patients who subsequently develops PE. In this study A1M was measured in plasma instead of serum. METHODS: Patients were recruited from an ongoing prospective study of new biomarkers to predict and diagnose PE. In total we included 84 patients. 8 patients subsequently developed PE, 4 developed pregnancy induced hypertension (PIH) and 72 were controls with uncomplicated pregnancies. The plasma samples were all taken at 7+0-18+0 weeks of gestation (mean 12+1) and analyzed for concentrations of A1M with Radioimmuno Assay (RIA). This method has been previously described in details. Statistics was performed using one-way ANOVA. RESULTS: The mean plasma concentration of A1M in the PE group was 8.6mg/ml, 6.0 in the PIH group and 7.1mg/ml in the controls group. The PE group differed significantly from the controls group (p=0.004), whereas the PIH group did not differ significantly from the controls. CONCLUSION: Our findings in plasma confirm previous findings described for serum, i.e. A1M is significantly increased in in first trimester maternal plasma in patients who subsequently develops PE. Since A1M is the most efficient heme scavenger we suggest that A1M may be a physiological defense mechanism against the elevated levels of free HbF found in patients who subsequently develops PE or in patients with manifest PE. Furthermore, A1M did not increase in patients who develops PIH later in their pregnancies indicating its specificity for PE.

Differential gene expression analysis of placentas with increased vascular resistance and pre-eclampsia using whole-genome microarrays.

Pre-eclampsia is a pregnancy complication characterized by hypertension and proteinuria. There are several factors associated with an increased risk of developing pre-eclampsia, one of which is increased uterine artery resistance, referred to as "notching". However, some women do not progress into pre-eclampsia whereas others may have a higher risk of doing so. The placenta, central in pre-eclampsia pathology, may express genes associated with either protection or progression into pre-eclampsia. In order to search for genes associated with protection or progression, whole-genome profiling was performed. Placental tissue from 15 controls, 10 pre-eclamptic, 5 pre-eclampsia with notching, and 5 with notching only were analyzed using microarray and antibody microarrays to study some of the same gene product and functionally related ones. The microarray showed 148 genes to be significantly altered between the four groups. In the preeclamptic group compared to notch only, there was increased expression of genes related to chemotaxis and the NF-kappa B pathway and decreased expression of genes related to antigen processing and presentation, such as human leukocyte antigen B. Our results indicate that progression of pre-eclampsia from notching may involve the development of inflammation. Increased expression of antigen-presenting genes, as seen in the notch-only placenta, may prevent this inflammatory response and, thereby, protect the patient from developing pre-eclampsia.

Perfusion of human placenta with hemoglobin introduces preeclampsia-like injuries that are prevented by α1-microglobulin.

BACKGROUND: Preeclamptic women have increased plasma levels of free fetal hemoglobin (HbF), increased gene expression of placental HbF and accumulation of free HbF in the placental vascular lumen. Free hemoglobin (Hb) is pro-inflammatory, and causes oxidative stress and tissue damage. METHODOLOGY: To show the impact of free Hb in PE, we used the dual ex vivo placental perfusion model. Placentas were perfused with Hb and investigated for physical parameters, Hb leakage, gene expression and morphology. The protective effects of α(1)-microglobulin (A1M), a heme- and radical-scavenger and antioxidant, was investigated. RESULTS: Hb-addition into the fetal circulation led to a significant increase of the perfusion pressure and the feto-maternal leakage of free Hb. Morphological damages similar to the PE placentas were observed. Gene array showed up-regulation of genes related to immune response, apoptosis, and oxidative stress. Simultaneous addition of A1M to the maternal circulation inhibited the Hb leakage, morphological damage and gene up-regulation. Furthermore, perfusion with Hb and A1M induced a significant up-regulation of extracellular matrix genes. SIGNIFICANCE: The ex vivo Hb-perfusion of human placenta resulted in physiological and morphological changes and a gene expression profile similar to what is observed in PE placentas. These results underline the potentially important role of free Hb in PE etiology. The damaging effects were counteracted by A1M, suggesting a role of this protein as a new potential PE therapeutic agent.

Foraging, bioenergetic and predation constraints on diel vertical migration: field observations and modelling of reverse migration by young-of-the-year herring Clupea harengus.

Diel vertical migration (DVM) of young-of-the-year (YOY) herring Clupea harengus and one of their major predators, pikeperch Sander lucioperca, was examined using bottom-mounted hydroacoustics in Himmerfjärden, a brackish bay of the Baltic Sea, in summer. In contrast to previous studies on DVM of C. harengus aggregated across size and age classes, YOY C. harengus showed a reverse DVM trajectory, deeper at night and, on average, shallower during the day. This pattern was observed consistently on five acoustic sampling occasions in 3 years and was corroborated by two out of three trawl surveys. Large acoustic targets (target strength >-33 dB, probably piscivorous S. lucioperca >45 cm) showed a classic DVM trajectory, shallow at night and deeper during the day. Variability in YOY C. harengus vertical distribution peaked at dawn and dusk, and their vertical distribution at midday was distinctly bimodal. This reverse DVM pattern was consistent with bioenergetic model predictions for YOY C. harengus which have rapid gut evacuation rates and do not feed at night. Reverse DVM also resulted in low spatial overlap with predators.

IFPA Meeting 2010 Workshops Report II: Placental pathology; trophoblast invasion; fetal sex; parasites and the placenta; decidua and embryonic or fetal loss; trophoblast differentiation and syncytialisation.

Workshops are an important part of the IFPA annual meeting. At IFPA Meeting 2010 diverse topics were discussed in twelve themed workshops, six of which are summarized in this report. 1. The placental pathology workshop focused on clinical correlates of placenta accreta/percreta. 2. Mechanisms of regulation of trophoblast invasion and spiral artery remodeling were discussed in the trophoblast invasion workshop. 3. The fetal sex and intrauterine stress workshop explored recent work on placental sex differences and discussed them in the context of whether boys live dangerously in the womb.4. The workshop on parasites addressed inflammatory responses as a sign of interaction between placental tissue and parasites. 5. The decidua and embryonic/fetal loss workshop focused on key regulatory mediators in the decidua, embryo and fetus and how alterations in expression may contribute to different diseases and adverse conditions of pregnancy. 6. The trophoblast differentiation and syncytialisation workshop addressed the regulation of villous cytotrophoblast differentiation and how variations may lead to placental dysfunction and pregnancy complications.

Kidney transplantation--a 46-year experience from the Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.

The limiting factor in organ transplantation is the availability of organs. Ongoing work to improve donation rates both at the public and the organizational level in donating hospitals is essential. We also think that encouragement of live donation is important, and the possibility of ABO incompatible transplantation has increased the number of LD transplantations. The one-year graft survival rate is excellent and focus has shifted towards achieving long-term results to reduce the attrition rate. There is also an increasing interest in studying and working to reduce comorbidities on a long-term basis and thus, improve survival rates and recipient quality of life.