EAU Guidelines on vesicoureteral reflux in children

Context

Primary vesicoureteral reflux (VUR) is a common congenital urinary tract abnormality in children. There is considerable controversy regarding its management. Preservation of kidney function is the main goal of treatment, which necessitates identification of patients requiring early intervention.

Objective

To present a management approach for VUR based on early risk assessment.

Evidence acquisition

A literature search was performed and the data reviewed. From selected papers, data were extracted and analyzed with a focus on risk stratification. The authors recognize that there are limited high-level data on which to base unequivocal recommendations, necessitating a revisiting of this topic in the years to come.

Evidence synthesis

There is no consensus on the optimal management of VUR or on its diagnostic procedures, treatment options, or most effective timing of treatment. By defining risk factors (family history, gender, laterality, age at presentation, presenting symptoms, VUR grade, duplication, and other voiding dysfunctions), early stratification should allow identification of patients at high potential risk of renal scarring and urinary tract infections (UTIs). Imaging is the basis for diagnosis and further management. Standard imaging tests comprise renal and bladder ultrasonography, voiding cystourethrography, and nuclear renal scanning. There is a well-documented link with lower urinary tract dysfunction (LUTD); patients with LUTD and febrile UTI are likely to present with VUR. Diagnosis can be confirmed through a video urodynamic study combined with a urodynamic investigation. Early screening of the siblings and offspring of reflux patients seems indicated.Conservative therapy includes watchful waiting, intermittent or continuous antibiotic prophylaxis, and bladder rehabilitation in patients with LUTD. The goal of the conservative approach is prevention of febrile UTI, since VUR will not damage the kidney when it is free of infection. Interventional therapies include injection of bulking agents and ureteral reimplantation. Reimplantation can be performed using a number of different surgical approaches, with a recent focus on minimally invasive techniques.

Conclusions

While it is important to avoid overtreatment, finding a balance between cases with clinically insignificant VUR and cases that require immediate intervention should be the guiding principle in the management of children presenting with VUR.     

Biophysical characterization of recombinant human ameloblastin

Ameloblastin (AMBN) is a protein expressed mainly during dental hard tissue development. Biochemically, it is classified as an intrinsically disordered protein (IDP). Its biological role remains largely unknown; however, the question of AMBN function will undoubtedly be connected to its structural properties and its potential for protein-protein and protein-cell interactions. A basic biophysical characterization of human recombinant ameloblastin (hrAMBN) and its N- and C-terminal domains by means of circular dichroism spectroscopy and dynamic light scattering showed that under physiological conditions ameloblastin is an IDP with a prevalent polyproline-II (PPII) conformation. Both the N- and C-terminal polypeptides, when expressed independently, showed different structural preferences upon heating as well as different behaviour in the presence of trifluoroethanol and CaCl(2) salt. The N-terminal peptide showed a more ordered structure with a strong tendency to adopt a helical conformation upon the addition of trifluorethanol, whereas the C-terminal domain seemed to be primarily responsible for the structural disorder of the entire AMBN molecule.     

Baseline chromosome aberrations in children

Field studies conducted in children exposed to ionizing radiation and industrial chemicals have consistently reported increased frequencies of chromosome aberrations in those environmentally exposed than in referent subjects. Exposure(s) occurring during childhood--as well as in utero--may continue for several years, become chronic, and eventually play a relevant role in the etiology of childhood as well as adulthood cancers. Indeed the statistical association between CA frequency in peripheral blood lymphocytes and cancer risk detected in occupationally exposed adults supports the hypothesis that CA is a predictor of cancer. These facts suggest the usefulness of including CA as biomarkers of genetic damage in epidemiologic studies of children exposed to environmental pollutants. As reported for other cytogenetic biomarkers, CA frequency may vary with gender and age in children as well as in adults. Estimates of the baseline frequency of CA in a pediatric population is a prerequisite in planning epidemiologic investigations of children exposed to low level of environmental genotoxic agents. The CA baseline levels were estimated from 16 published epidemiologic studies and from a large sample of Czech children aged 7-16 years (n=1214) and 206 newborns, all serving as referents (not exposed individuals). For the whole referent population (age range 0-19 years) the mean CA frequency estimated from the published findings was 1.24% (95%CI=1.05-1.47). Similar baseline levels were found for chromosome breaks frequency in boys and girls: 1.22% (95%CI=1.12-1.32) and 1.21% (95%CI=1.10-1.31), respectively. Among newborns CA baseline frequency was 1.14% (95%CI=0.96-1.32). Based on the reviewed studies and the reanalysed data, CA baseline levels were similar in boys and girls and failed to show any increase with age.     

Relationship between rank and plasma testosterone and cortisol in red deer males (Cervus elaphus)

The objective of this study was to assess the effect of a change in the social composition in a group of red deer males on the relationship between their rank and testosterone. A group of twelve adult red deer males (Cervus elaphus) was tested in two social settings. From April 15 to June 9 (Period 1) this group was kept separately in an enclosure. On June 10, nine 3-year-old males were added to that group of adult males. They were kept together until August 31. We performed 10 observations of the group when the agonistic interactions of the males were recorded and we took 9 blood samples per male in Period 1; 11 observations were made and 10 samples were taken in Period 2. Concentrations of testosterone and cortisol were later determined in plasma. Adding much younger and smaller sparring partners into the experimental group of adult males in Period 2 altered the agonistic behaviour of the adults even though this did not trigger any change in rank position of the experimental males except one. Adult males targeted preferentially their attacks on individuals much lower in the hierarchy. Experimental male deer with higher social rank had lower levels of testosterone in Period 1; in Period 2 it was just the opposite. In Period 1 the animals had higher cortisol levels than in Period 2. As controls we used four adult (5 years old) males sharing the enclosure with four 3-year-old males. No changes in hormone concentrations were observed in the control group. Thus, changing the social environment of adult red deer males resulted in change of the relationship between rank and testosterone and cortisol concentrations.     

An overview of the <Emphasis Type="Italic">Gyrodactylus</Emphasis> (Monogenea: Gyrodactylidae) species parasitizing African catfishes,and their morphological and molecular diversity

An overview of Gyrodactylus infecting catfishes from the African continent is provided, including new data from Sudan, Senegal, Kenya and Mozambique. Haptoral sclerite morphometry and nuclear ribosomal DNA sequences revealed the presence of eight Gyrodactylus species. On Senegalese Synodontis nigrita, Gyrodactylus synodonti n. sp. and Gyrodactylus nigritae n. sp. are described. These are the first reports of gyrodactylid parasites from mochokid hosts. From the fins of North African catfish Clarias gariepinus collected in Mozambique, Gyrodactylus alekosi n. sp. and Gyrodactylus rysavyi were identified. G. rysavyi was also reported from Kenyan C. gariepinus and Senegalese Clarias anguillaris. From the fins of C. anguillaris studied in Senegal, two more species, Gyrodactylus transvaalensis and Gyrodactylus gelnari n. sp. were recognised. In addition, Gyrodactylus turkanaensis n. sp. from the gills of Kenyan C. gariepinus was described and an undescribed Gyrodactylus sp. was recorded from Sudanese representatives of the same host. Detailed morphometrical and molecular comparisons of the species are presented and discussed. The study highlights the hitherto understudied diversity of viviparous monogenean parasites throughout Africa.     

Charcot-Marie-Tooth neuropathy due to a novel EGR2 gene mutation with mild phenotype--usefulness of human mapping chip linkage analysis in a Czech family

Charcot-Marie-Tooth neuropathies (CMT) are a group of clinically and genetically heterogeneous disorders of the peripheral nervous system. Selection of candidate disease genes for mutation analysis is sometimes difficult since more than 40 genes and loci are known to be associated with CMT neuropathies. Hence a Czech family Cz-CMT with demyelinating type of autosomal dominant CMT disease was investigated by genome-wide linkage analysis by means of single-nucleotide polymorphism (SNP) arrays. Among 35 regions with linkage, five carried known CMT genes. In the final result a novel early growth response 2 - missense mutation c.1235 A>G, p.Glu412Gly was found. Surprisingly, the more severely affected proband carried an additional heterozygous myelin protein zero variant p.Asp246Asn detected previously, which may modify the phenotype. However, this MPZ variant is benign in heterozygous state alone, because it is also carried by the patient's healthy father.     

Schizophrenia symptoms and functioning in patients receiving long-term treatment with olanzapine long-acting injection formulation: a pooled analysis

ABSTRACT: BACKGROUND: This analysis of pooled data evaluates maintenance treatment outcomes of patients with schizophrenia receiving maintenance treatment with olanzapine long-acting injection (OLAI) by means of a categorical approach addressing the symptomatic and functional status of patients at different times. METHODS: Patients were grouped into 5 categories at baseline, 6 months, and 12 months. Shifts between categories were assessed for individual patients and factors associated with improvement were analyzed. 1182 patients from 3 clinical trials were included in the current analysis. RESULTS: At baseline, 434 (36.8%) patients had minimal Positive and Negative Syndrome Scale (PANSS) symptoms but seriously impaired Heinrich Carpenter's Quality of Life Scale (QLS) functioning; 303 (25.6%) had moderate to severe symptoms and seriously impaired function; 208 (17.6%) had mild to moderate symptoms but good functioning, and 162 (13.7%) had minimal symptoms and good functioning. Baseline category was significantly associated with Clinical Global Impression - Severity (CGI-S), extrapyramidal symptoms, working status, age, and number of previous episodes. The majority of all patients starting OLAI treatment maintained or improved (62% 6 months and 52% 12 months) their symptom and functioning levels on OLAI maintenance treatment. Less than 8% of the patients showed worsening of symptoms or functioning. An improvement in category was associated with high PANSS positive and low CGI-S scores at baseline. CONCLUSIONS: We present evidence that a composite assessment of schizophrenic patients including symptom severity and functioning is helpful in the evaluation of maintenance treatment outcomes. This approach could also be useful for the assessment of treatment options in clinical practice. The trials from which data are reported here were registered on clinicaltrials.gov as NCT00088491, NCT00088465, and NCT00320489.     

JNK inhibitor SP600125 is a partial agonist of human aryl hydrocarbon receptor and induces CYP1A1 and CYP1A2 genes in primary human hepatocytes

SP600125, a specific inhibitor of c-Jun-N-Terminal kinase (JNK), was reported as a ligand and antagonist of aryl hydrocarbon receptor (AhR) [Joiakim A, Mathieu PA, Palermo C, Gasiewicz TA, Reiners Jr JJ. The Jun N terminal kinase inhibitor SP600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug Metab Dispos 2003;31(11):1279-82]. Here we show that SP600125 is not an antagonist but a partial agonist of human AhR. SP600125 significantly induced CYP1A1 and CYP1A2 mRNAs in primary human hepatocytes and CYP1A1 mRNA in human hepatoma cells HepG2. This effect was abolished by resveratrol, an antagonist of AhR. Consistent with the recent report, SP600125 dose-dependently inhibited CYP1A1 and CYP1A2 genes induction by a prototype AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in human hepatocytes. Moreover, SP600125 displayed typical behavior of a partial agonist in HepG2 cells transiently transfected with a reporter plasmid containing two inverted repeats of the dioxin responsive element or with a plasmid containing 5'-flanking region of human CYP1A1 gene. SP600125 transactivated the reporter plasmids with EC(50) of 0.005 and 1.89 microM, respectively. On the other hand, TCDD-dependent transactivation of the reporter plasmids was inhibited by SP600125 with IC(50) values of 1.54 and 2.63 microM, respectively. We also tested, whether the effects of SP600125 are due to metabolism. Using liquid chromatography/mass spectrometry approach, we observed formation of two minor monohydroxylated metabolites of SP600125 in human hepatocytes, human liver microsomes but not in HepG2 cells. These data imply that biotransformation is not responsible for the effects of SP600125 on AhR signaling. In conclusion, we demonstrate that SP600125 is a partial agonist of human AhR, which induces CYP1A genes.     

Prenatal exposures to persistent and non-persistent organic compounds and effects on immune system development

Immune system development, particularly in the prenatal period, has far-reaching consequences for health during early childhood, as well as throughout life. Environmental disturbance of the complex balances of Th1 and Th2 response mechanisms can alter that normal development. Dysregulation of this process or an aberrant trajectory or timing of events can result in atopy, asthma, a compromised ability to ward off infection, or other auto-immune disease. A wide range of chemical, physical and biological agents appear to be capable of disrupting immune development. This MiniReview briefly reviews developmental milestones of the immune system in the prenatal period and early life, and then presents examples of environmentally induced alterations in immune markers. The first example involves a birth cohort study linked to an extensive programme of air pollution monitoring; the analysis shows prenatal ambient polycyclic aromatic hydrocarbons (PAH) and fine particle (PM2.5) exposures to be associated with altered lymphocyte immunophenotypic distributions in cord blood and possible changes in cord serum immunoglobulin E levels. The second example is a study of prenatal-polychlorinated biphenyl (PCB) exposures and the foetal development of the thymus, the organ responsible for lymphocyte maturation. Mothers with higher serum concentrations of PCBs gave birth to neonates having smaller indices of thymus size. Finally, this report underscores the tight connection between development of the immune system and that of the central nervous system, and the plausibility that disruption of critical events in immune development may play a role in neurobehavioural disorders.     

Placental passage of olomoucine II,but not purvalanol A,is affected by p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-associated proteins (ABCCs)

1.?Purine cyclin-dependent kinase inhibitors have recently been recognised as promising candidates for the treatment of various cancers. While pharmacodynamic properties of these compounds are relatively well understood, their pharmacokinetics including possible interactions with placental transport systems have not been characterised to date.

2.?In this study, we investigated transplacental passage of olomoucine II and purvalanol A in rat focusing on possible role of p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and/or multidrug resistance-associated proteins (ABCCs). Employing the in situ method of dually perfused rat term placenta, we demonstrate transplacental passage of both olomoucine II and purvalanol A against the concentration gradient in foetus-to-mother direction. Using several ATP-binding cassette (ABC) drug transporter inhibitors, we confirm the participation of ABCB1, ABCG2 and ABCCs transporters in the placental passage of olomoucine II, but not purvalanol A.

3.?Transplacental passage of olomoucine II and purvalanol A from mother to foetus is significantly reduced by active transporters, restricting thereby foetal exposure and providing protection against harmful effects of these xenobiotics. Importantly, we demonstrate that in spite of their considerable structural similarity, the two molecules utilise distinct placental transport systems. These facts should be kept in mind when introducing these prospective anticancer candidates and/or their analogues into the clinical area.