Angiogenic imbalance in pre-eclampsia and fetal growth restriction: enhanced soluble fms-like tyrosine kinase-1 binding or diminished production of placental growth factor?

OBJECTIVES: To assess levels of total placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and free PlGF in women with pre-eclampsia (PE) with or without a small-for-gestational-age (SGA) neonate in order to establish whether low free PlGF levels associated with PE and SGA are due to enhanced sFlt-1 binding or decreased PlGF production. METHODS: This was a secondary analysis of a prospective multicenter cohort study involving 407 pregnancies with suspected or confirmed PE, in which total PlGF levels were calculated from measured sFlt-1 and free PlGF levels. The control group included women who were suspected to have PE at a certain point in pregnancy but did not develop PE. The analysis was stratified according to whether PE was early- or late-onset (gestational age < 34 weeks vs ≥ 34 weeks) and according to the presence of SGA at birth, which was used as a proxy of fetal growth restriction in the absence of Doppler ultrasound and biometric data. RESULTS: In early-onset PE, both women with and those without SGA had lower free (19 and 45 pg/mL) and total (44 and 100 pg/mL) PlGF levels compared with women without PE (free and total PlGF, 300 and 381 pg/mL, respectively). SGA alone did not affect free and total PlGF in this condition (free and total PlGF, 264 and 352 pg/mL, respectively). Observations in women with late-onset PE were similar, although the changes were more modest. Both SGA (gestational age < 34 weeks) and PE were individually associated with increased sFlt-1 and, in women with both PE and SGA, the upregulation of sFlt-1 occurred in a synergistic manner, thus resulting in the highest sFlt-1/free PlGF ratio in this group. This occurred in both early- and late-onset PE. CONCLUSIONS: Particularly in pregnancies with early-onset PE and SGA, diminished PlGF production is an important cause of low free PlGF levels. Under such conditions, sFlt-1 lowering is unlikely to restore the angiogenic balance. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of pre-eclampsia-related complications in women with suspected or confirmed pre-eclampsia: development and internal validation of clinical prediction model.

OBJECTIVE: A model that can predict reliably the risk of pre-eclampsia (PE)-related pregnancy complications does not exist. The aim of this study was to develop and validate internally a clinical prediction model to predict the risk of a composite outcome of PE-related maternal and fetal complications within 7, 14 and 30 days of testing in women with suspected or confirmed PE. METHODS: The data for this study were derived from a prospective, multicenter, observational cohort study on women with a singleton pregnancy and suspected or confirmed PE at 20 to < 37 weeks' gestation. For the development of the prediction model, the possible contribution of clinical and standard laboratory variables, as well as the biomarkers soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and their ratio, in the prediction of a composite outcome of PE-related complications, consisting of maternal and fetal adverse events within 7, 14 and 30 days, was explored using multivariable competing-risks regression analysis. The discriminative ability of the model was assessed using the concordance (c-) statistic. A bootstrap validation procedure with 500 replications was used to correct the estimate of the prediction model performance for optimism and to compute a shrinkage factor for the regression coefficients to correct for overfitting. RESULTS: Among 384 women with suspected or confirmed PE, 96 (25%) had an adverse PE-related outcome at any time after hospital admission. Important predictors of adverse PE-related outcome included sFlt-1/PlGF ratio, gestational age at the time of biomarker measurement and protein-to-creatinine ratio as continuous variables. The c-statistics (corrected for optimism) for developing a PE-related complication within 7, 14 and 30 days were 0.89, 0.88 and 0.87, respectively. There was limited overfitting, as indicated by a shrinkage factor of 0.91. CONCLUSIONS: We propose a simple clinical prediction model with good discriminative performance to predict PE-related complications. Determination of its usefulness in clinical practice awaits further investigation and external validation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Copeptin and mid-regional pro-atrial natriuretic peptide in women with suspected or confirmed pre-eclampsia: comparison with sFlt-1/PlGF ratio.

OBJECTIVES: Arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) may contribute to the pathogenesis of pre-eclampsia (PE), but their role remains to be elucidated. Our aims were to evaluate the surrogates of AVP and ANP, C-terminal pro-AVP (copeptin) and mid-regional pro-ANP (MR-proANP), as biomarkers for the prediction of PE-related pregnancy complications and whether they are associated with angiogenic markers and/or clinical manifestations of PE. METHODS: This was a retrospective analysis of a prospective cohort study that enrolled pregnant women with suspected or confirmed PE, between December 2013 and April 2016. From each patient, a blood sample was obtained at study entry and serum levels of copeptin, MR-proANP, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured. We evaluated the ability of sFlt-1, PlGF, sFlt-1/PlGF ratio, copeptin and MR-proANP, assessed either alone or combined with traditional predictors (gestational age, parity, diastolic blood pressure and proteinuria), to predict maternal complications and fetal/neonatal complications. Models were compared using concordance statistic (C-index). RESULTS: A total of 526 women were evaluated in the study. Women with confirmed PE displayed elevated serum copeptin and MR-proANP levels in comparison to those with suspected PE but no hypertensive disease of pregnancy. When combined with traditional predictors, the sFlt-1/PlGF ratio displayed a higher C-index than copeptin and MR-proANP (0.76, 0.63 and 0.67, respectively, vs 0.60 for the traditional predictors alone) for the prediction of maternal complications. Similarly, for the prediction of fetal/neonatal complications, the sFlt-1/PlGF ratio displayed a higher C-index than copeptin and MR-proANP when added to the traditional model (0.83, 0.79 and 0.80, respectively, vs 0.79 for the traditional predictors alone). When subdividing women according to sFlt-1/PlGF ratio (≥ 85 vs < 85), no differences in copeptin levels were observed, while MR-proANP level was elevated in women with sFlt-1/PlGF ratio ≥ 85. Multiple regression analysis revealed that copeptin and MR-proANP were independent determinants of proteinuria. CONCLUSIONS: Copeptin and MR-proANP have limited value in predicting PE-related complications when compared with the sFlt-1/PlGF ratio. However, both copeptin and MR-proANP were associated with proteinuria, with copeptin exerting this effect independently of the sFlt-1/PlGF ratio. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Strontium hexaferrite nanomagnets suspended in a cosmetic preparation: a convenient tool to evaluate the biological effects of surface magnetism on human skin.

BACKGROUND/PURPOSE: Magnetic therapy has been popular for ages, but its therapeutic abilities remain to be demonstrated. We aimed to develop a homogeneous, stable dispersion of magnetic nanoparticles in a skin-care preparation, as a tool to analyze the biological and physiological effects of superficial magnetism in skin. METHODS: SrFe(12)O(19) nanoparticles were generated by ultrasound, dispersed in glycerol, stabilized in Dermud cream and permanently magnetized. The magnetic cream was applied on the epidermis of human skin organ cultures. The effects on UV-induced cell toxicity, apoptosis and inflammatory cytokine expression were analyzed. A clinical test was performed to check skin moisturization. RESULTS: Nanomagnets were found to be homogenously and stably dispersed. After magnetization, the preparation generated a magnetic field of 1-2 G. Upon cream application, no cytotoxicity and no impairment of cellular vitality were found after 24 and 48 h, respectively. The anti-apoptotic and anti-inflammatory properties of Dermud were not modified, but its long-term effect on moisturization in vivo was slightly increased. CONCLUSION: Nanomagnetic Dermud cream can be used as a tool to analyze the biological effects of nanomagnets dispersed on the skin surface at the cellular and molecular levels, thus allowing to explore the possible therapeutic uses of superficial magnetism for skin care.

Interaction of alcohols with [val5]angiotensin in alcohol-water mixtures.

Intermolecular solvent-solute NOE experiments have been used to probe interactions of various alcohols with the peptide hormone [val(5)]angiotensin II at 0 degrees C. It is found that these NOEs are detectable but dependent on the kind of alcohol present and the conformation of the peptide. Solvent-solute NOEs in 100% methanol and 89% methanol-water are basically those predicted by a hard sphere model for intermolecular spin dipole interactions. NOEs at the peptide backbone (N-H, C alpha-H) protons in 25% methanol-water and 36% ethylene glycol-water mixtures indicate that alcohol interactions near these groups are also adequately described by this model. However, in 35% ethanol-water, interactions of alcohol methyl protons with the peptide result in unexpectedly negative NOEs, probably signaling that peptide-alcohol interactions in this solvent take place on a significantly slower time scale than that defined by mutual diffusion of these species. Some side chain-alcohol interactions result in NOEs up to 8 times larger than expected. Possible reasons for these enhanced effects are discussed.

Transport distraction osteogenesis for closing full-thickness calvarial defects in sheep.

OBJECTIVE: To prove the hypothesis that transport distraction osteogenesis can be applied to the skull to close critical-size calvarial defects. DESIGN: A sheep model was developed to investigate this hypothesis. In four sheep, bilateral parietal bone windows were created and adjacent osteotomies performed. On the tested side, an adjacent bone segment was transported into the defect. The contralateral side was left untreated as a control. MAIN OUTCOME MEASURES: After completion of the distraction and consolidation period, a computed tomography study was performed, and the animals were sacrificed. The newly formed bone was examined macroscopically and histologically. RESULTS: A successful closure of the defect with transport distraction was achieved in all of the animals. The control side healed spontaneously in one (younger) sheep but did not heal in the other three animals. The closure of the bony defect with transport distraction was evident macroscopically as well as on the computerized tomography. Microscopic examination showed new healthy bone formation on the treated side. CONCLUSION: We conclude that transport distraction is an effective tool in closing full-thickness calvarial defects in adult sheep. Further investigation is needed before applying this promising technique in humans.

Breast reconstruction: complication rate and tissue expander type.

BACKGROUND: Limited literature exists regarding complication rates among women undergoing breast reconstruction and the association of these rates with tissue expander types (anatomic, round and Becker). METHODS: A historical cohort study investigated all breast reconstructions performed at Hadassah Medical Center for 140 consecutive women. Analyses were performed using both logistic and Poisson regression multivariate methods. RESULTS: At least one major complication occurred in each of the following groups: anatomic (41%), round (20%), and Becker (11.7%) (p = 0.015). Women reconstructed with anatomic expanders were at increased risk for at least one complication (odds ratio [OR], 3.96; 95% confidence interval [CI], 1.18-13.3; p = 0.026) and an average increase of 331% (95% CI, 102-817%; p = 0.0002) in the number of major complications. CONCLUSION: The results of this study suggest that integrated-valve expanders are associated with more complications than the distant inflation port. The benefits of an anatomic shape may perhaps be better exploited using devices with a distant port.

Family factors and sampling approach differentially influence attention deficit/hyperactivity disorder subtypes.

A widely used statistical method to test for genetic association is the transmission disequilibrium test (TDT) using two parent-proband trios. West et al(1) have presented evidence from clinically ascertained ADHD families that children from trios were less likely to have DSM-IV combined subtype ADHD and conduct disorder. They suggest that the exclusion of parent-proband duos could reduce the power of the TDT and similar tests to detect susceptibility genes for this subtype of ADHD. We sought to test this hypothesis in a population-based sample of twin families, while controlling for the effects of other proband and family characteristics in a multivariant logistic regression framework using both latent class and DSM-IV ADHD subtype definitions. For both latent class and DSM-IV defined combined and inattentive ADHD, sex of the proband and comorbid conduct disorder or oppositional defiant disorder, significantly predicted diagnosis. For latent class and DSM-IV defined combined subtype, younger age also significantly predicted ADHD subtype. Latent class and DSM-IV defined combined subtype ADHD with comorbid conduct disorder was significantly less common in children from trios while conduct disorder without ADHD did not differ in frequency between families with zero, one or two participating parents.

Mutational analysis of the nicotinic acetylcholine receptor alpha 4 subunit gene in attention deficit/hyperactivity disorder: evidence for association of an intronic polymorphism with attention problems.

Recent studies suggest the presence of genetically distinct subtypes of attention deficit/hyperactivity disorder (ADHD) and that attention problems can be treated with receptor subtype selective nicotine agonists. In this study, individuals with two independent familial subtypes of ADHD defined by latent class analysis were systematically screened for sequence variations in the coding regions and intron/exon junctions of the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4). Common polymorphisms were used for transmission disequilibrium test (TDT) analyses. A significant association was found for a 5' intron 2 single nucleotide polymorphism and severe inattention problems (P = 0.007, effect size = 4, 95% CI 1.3-14.1). The location of the polymorphism is compatible with it affecting pre-mRNA stability or splicing.

Familiality and heritability of subtypes of attention deficit hyperactivity disorder in a population sample of adolescent female twins.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly heritable but clinically heterogeneous syndrome. The study examined the familiality and heritability of ADHD subtypes as defined by DSM-IV and by latent-class analysis in a population sample of adolescent female twins. METHOD: To determine which elements of ADHD cluster together, latent-class analysis was applied to data obtained from parents on the 18 DSM-IV ADHD symptoms in 4,036 female twins age 13-23 years in a population sample identified from the registry of all births in Missouri for the years 1968-1996. Relative risk and odds ratios were used to assess within-subtype and between-subtype familiality and heritability of both DSM-IV and latent-class ADHD subtypes. RESULTS: Latent-class analysis was most compatible with the existence of three mild and three severe classes of ADHD symptoms in the general population. The three severe classes showed moderate overlap with DSM-IV ADHD subtypes. The primarily inattentive and combined subtypes of DSM-IV ADHD co-clustered within families. The primarily hyperactive/impulsive DSM-IV subtype and the individual latent-class analysis subtypes did not co-cluster. Subtypes defined by both approaches were highly heritable. CONCLUSIONS: Unlike DSM-IV subtypes of ADHD, latent-class ADHD subtypes appear to be independently transmitted in families. These classes may be more appropriate targets for molecular genetic studies of ADHD.

Latent class analysis of ADHD and comorbid symptoms in a population sample of adolescent female twins.

Attention-deficit/hyperactivity disorder (ADHD) is a phenotypically heterogeneous and highly heritable syndrome. which commonly co-occurs with other psychiatry disorders. To assess the role of genetic influences in ADHD, we used latent class analysis (LCA) to identify subtypes of ADHD taking into account its comorbidity with separation anxiety, oppositional defiant disorder (ODD), and three major depression symptoms. A structured interview was used to collect diagnostic data from a population sample of 2,904 adolescent female twins and their parents. LCA was applied to ADHD. separation anxiety. ODD symptom profiles obtained from the twins' parents, and major depression symptom profiles obtained from the twins' self-report. Odds ratios were used to test for familiality of class membership by examining the effect of zygosity on twin concordance within and between latent classes. Structural equation modeling was used to compute heritabilities for latent class membership. LCA revealed three ADHD categories of clinical interest: an inattentive subtype without comorbidity, a second inattentive subtype with increased number of ODD symptoms. and a combined inattentive/hyperactive-impulsive type with elevated levels of ODD, separation anxiety, and depressive symptoms. LCA also distinguished an ODD class and a separation anxiety class, each without increased levels of other comorbid symptoms; a second ODD class co-occurring with increased separation anxiety and depression symptoms; and a pure depression class. Odds ratios for MZ contrasted with DZ twin concordance for individual latent class membership ranged from 2.5 to 19.4. Overall, 66% of MZ pairs, but only 36% of DZ pairs, were assigned to the same latent class, consistent with a genetic hypothesis for latent class membership. Individual class membership was shown to have high heritability ranging from .34-.85. The pattern of latent classes suggested that in the general female adolescent population, there are three highly heritable ADHD subtypes, two of which are comorbid with other disorders. These classes were consistent with a genetic hypothesis for ADHD, with each class potentially reflecting a unique genetic subtype.

An integrative approach for studying the etiology of alcoholism and other addictions.

Studies of alcoholism etiology often focus on genetic or psychosocial approaches, but not both. Greater understanding of the etiology of alcohol, tobacco and other addictions will come from integration of these research traditions. A research approach is outlined to test three models for the etiology of addictions--behavioral undercontrol, pharmacologic vulnerability, negative affect regulation--addressing key questions including (i) mediators of genetic effects, (ii) genotype-environment correlation effects, (iii) genotype x environment interaction effects, (iv) the developmental unfolding of genetic and environmental effects, (v) subtyping including identification of distinct trajectories of substance involvement, (vi) identification of individual genes that contribute to risk, and (vii) the consequences of excessive use. By using coordinated research designs, including prospective assessment of adolescent twins and their siblings and parents; of adult substance dependent and control twins and their MZ and DZ cotwins, the spouses of these pairs, and their adolescent offspring; and of regular families; by selecting for gene-mapping approaches sibships screened for extreme concordance or discordance on quantitative indices of substance use; and by using experimental (drug challenge) as well as survey approaches, a number of key questions concerning addiction etiology can be addressed. We discuss complementary strengths and weaknesses of different sampling strategies, as well as methods to implement such an integrated approach illustrated for the study of alcoholism etiology. A coordinated program of twin and family studies will allow a comprehensive dissection of the interplay of genetic and environmental risk-factors in the etiology of alcoholism and other addictions.

Lack of association of dopamine D4 receptor gene polymorphisms with ADHD subtypes in a population sample of twins.

Attention-deficit hyperactivity disorder (ADHD) is a common, highly heritable syndrome of childhood characterized by problems with inattention, hyperactivity, and impulsivity. A variety of case control and family-based transmission distortion genetic studies of ADHD have focused on the possible involvement of polymorphisms of the DRD4 receptor gene. The majority of studies have examined the association of variously defined ADHD with an exon 3 polymorphism containing a variable number of imperfect 48 base pair repeats. Recently, McCracken et al. [2000: Mol Psych 5:531-536] reported an association of the DSM-IV primarily inattentive ADHD subtype with a 5' 120 base pair repeat polymorphism in the DRD4 gene. In this report, we test for the possible association of these two polymorphisms with population-derived samples of DSM-IV ADHD subtypes. Furthermore, we extend previous studies by testing for associations with ADHD subtypes derived from latent-class analysis of interview responses. In contrast to most, but not all, previous studies, we failed to demonstrate any significant association of the exon 3 7-repeat allele with ADHD. Nor did we replicate the association of the 5'120 base pair repeat polymorphism. We do find a significant association of the exon 3 3-repeat allele with a novel talkative/impulsive latent-class-defined subtype of ADHD.

Factor and latent class analysis of DSM-IVADHD symptoms in a school sample of Brazilian adolescents.

OBJECTIVE: To evaluate the validity of the multidimensional construct proposed by DSM-IV for the diagnosis of attention-deficit/hyperactivity disorder (ADHD) in a school sample of young Brazilian adolescents. METHOD: An instrument including all 18 DSM-IVADHD symptoms was administered to 1,013 students aged 12 to 14 years at 64 state schools by trained research assistants. Each symptom was rated on a Likert scale with five levels of severity (never, almost never, sometimes, frequently, and always). RESULTS: Using an exploratory factor analytic approach (principal components analysis), two factors were extracted. Factor I (hyperactivity-impulsivity) comprised eight DSM-IV hyperactive-impulsive symptoms with loadings > or =0.40. Factor II (inattention) included also eight DSM-IV symptoms of inattention. The two factors explained 34% of the total variance and had an interfactor correlation of 0.45. Latent class analysis demonstrated similar classes in males and females, but class structures were markedly different from previous analyses of parent report data. CONCLUSION: The findings support the appropriateness of the multidimensional construct introduced by DSM-IV in the diagnosis of ADHD in a different culture but emphasize the possible impact of different reporters on the results of structural model-testing.

No association of the dopamine transporter gene 3' VNTR polymorphism with ADHD subtypes in a population sample of twins.

Dopamine pathway genes have been the subject of a variety of studies testing the association of candidate genes and liability for attention-deficit hyperactivity disorder (ADHD). Due to the known effects of stimulant medications such as methylphenidate on the dopamine transporter, a variety of case control and family-based transmission distortion genetic studies of ADHD have focused on DAT1 polymorphisms. The most widely reported positive finding has been with a variable number of tandem repeats (VNTR) polymorphism of unknown function in the 3' untranslated region of the DAT1 gene. In this report, we test for association of alleles of this polymorphism with ADHD using population-derived samples of twins. We use the transmission disequilibrium test and ADHD subtypes defined by both DSM-IV and latent class criteria. We fail to demonstrate any significant association or trend for association of any of the VNTR alleles with any of the variously defined ADHD subtypes.

A clustering approach for localizing disease susceptibility loci.

Latent class (LCA) and cluster analysis (CLA) were utilized to identify trait loci for the Genetic Analysis Workshop 12 simulated disease. These techniques create non-overlapping subsets of concordant and discordant affected relative pairs based upon identity-by-descent (IBD) allele sharing at sequences of markers. Subgroups with a large proportion of affected pairs are used to identify markers in proximity to disease susceptibility loci. Both methods are model-free and make use of information from affected and unaffected subjects. In analyses performed without knowledge of the true disease model, LCA and CLA identified regions containing five of the seven trait loci.

Covariates in linkage analysis using sibling and cousin pairs.

Using simulated data from GAW 12, problem 2, we further develop a novel technique to detect and use significant covariates in linkage analysis. The method, first introduced by Rice et al. [Genet Epidemiol 17(Suppl. 1):S691-5, 1999], uses logistic regression to model perturbation in sharing as a function of covariate levels. The original method allows use of all sib pairs (concordant affected, concordant unaffected, and discordant). Here we extend this method to include cousin pairs in analysis.

Clustering methods applied to allele sharing data.

Here we focus on using clustering methods to disentangle the interacting factors that lead to the presentation of complex diseases. Relative pairs are placed in discrete subgroups, or classes, based upon their pattern of allele sharing at a sequence of markers and on concomitant risk factors. The relationship between the locus information and the affectation status of the relative pairs within each subgroup then can be assessed. Cluster analysis (CLA) and latent class analysis (LCA) were applied to sibling allele sharing data from GAW11 simulated data, and to an existing Alzheimer's disease (AD) dataset. Both methods were able to identify markers linked to all 3 disease loci in the GAW11 data. LCA and CLA also replicated regions of chromosomes identified in an analysis of the AD data using affected-sib-pair methods. These analyses indicate that classification tools may be useful for detecting susceptibility genes for complex traits.