Fetal hemodynamic response to aortic valvuloplasty and postnatal outcome: a European multicenter study.

OBJECTIVE: Fetal aortic stenosis may progress to hypoplastic left heart syndrome. Fetal valvuloplasty (FV) has been proposed to improve left heart hemodynamics and maintain biventricular (BV) circulation. The aim of this study was to assess FV efficacy by comparing survival and postnatal circulation between fetuses that underwent FV and those that did not. METHODS: This was a retrospective multicenter study of fetuses with aortic stenosis that underwent FV between 2005 and 2012, compared with contemporaneously enrolled natural history (NH) cases sharing similar characteristics at presentation but not undergoing FV. Main outcome measures were overall survival, BV-circulation survival and survival after birth. Secondary outcomes were hemodynamic change and left heart growth. A propensity score model was created including 54/67 FV and 60/147 NH fetuses. Analyses were performed using logistic, Cox or linear regression models with inverse probability of treatment weighting (IPTW) restricted to fetuses with a propensity score of 0.14-0.9, to create a final cohort for analysis of 42 FV and 29 NH cases. RESULTS: FV was technically successful in 59/67 fetuses at a median age of 26 (21-34) weeks. There were 7/72 (10%) procedure-related losses, and 22/53 (42%) FV babies were delivered at < 37 weeks. IPTW demonstrated improved survival of liveborn infants following FV (hazard ratio, 0.38; 95% CI, 0.23-0.64; P = 0.0001), after adjusting for circulation and postnatal surgical center. Similar proportions had BV circulation (36% for the FV cohort and 38% for the NH cohort) and survival was similar between final circulations. Successful FV cases showed improved hemodynamic response and less deterioration of left heart growth compared with NH cases (P ≤ 0.01). CONCLUSIONS: We report improvements in fetal hemodynamics and preservation of left heart growth following successful FV compared with NH. While the proportion of those achieving a BV circulation outcome was similar in both cohorts, FV survivors showed improved survival independent of final circulation to 10 years' follow-up. However, FV is associated with a 10% procedure-related loss and increased prematurity compared with the NH cohort, and therefore the risk-to-benefit ratio remains uncertain. We recommend a carefully designed trial incorporating appropriate and integrated fetal and postnatal management strategies to account for center-specific practices, so that the benefits achieved by fetal therapy vs surgical strategy can be demonstrated clearly. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Natural history of 107 cases of fetal aortic stenosis from a European multicenter retrospective study.

OBJECTIVES: Fetal aortic valvuloplasty (FV) aims to prevent fetal aortic valve stenosis progressing into hypoplastic left heart syndrome (HLHS), which results in postnatal univentricular (UV) circulation. Despite increasing numbers of FVs performed worldwide, the natural history of the disease in fetal life remains poorly defined. The primary aim of this study was to describe the natural history of fetal aortic stenosis, and a secondary aim was to test previously published criteria designed to identify cases of emerging HLHS with the potential for a biventricular (BV) outcome after FV. METHODS: From a European multicenter retrospective study of 214 fetuses with aortic stenosis (2005-2012), 107 fetuses in ongoing pregnancies that did not undergo FV were included in this study and their natural history was reported. We examined longitudinal changes in Z-scores of aortic and mitral valve and left ventricular dimensions and documented direction of flow across the foramen ovale and aortic arch, and mitral valve inflow pattern and any gestational changes. Data were used to identify fetuses satisfying the Boston criteria for emerging HLHS and estimate the proportion of these that would have been ideal FV candidates. We applied the threshold score whereby a score of 1 was assigned to fetuses for each Z-score meeting the following criteria: left ventricular length and width > 0; mitral valve diameter > -2; aortic valve diameter > -3.5; and pressure gradient across either the mitral or aortic valve > 20 mmHg. We compared the predicted circulation with known survival and final postnatal circulation (BV, UV or conversion from BV to UV). RESULTS: Among the 107 ongoing pregnancies there were eight spontaneous fetal deaths and 99 livebirths. Five were lost to follow-up, five had comfort care and four had mild aortic stenosis not requiring intervention. There was intention-to-treat in these 85 newborns but five died prior to surgery, before circulation could be determined, and thus 80 underwent postnatal procedures with 44 BV, 29 UV and seven BV-to-UV circulatory outcomes. Of newborns with intention-to-treat, 69/85 (81%) survived ≥ 30 days. Survival at median 6 years was superior in cases with BV circulation (P = 0.041). Those with a postnatal UV circulation showed a trend towards smaller aortic valve diameters at first scan than did the BV cohort (P = 0.076), but aortic valve growth velocities were similar in both cohorts to term. In contrast, the mitral valve diameter was significantly smaller at first scan in those with postnatal UV outcomes (P = 0.004) and its growth velocity (P = 0.008), in common with the left ventricular inlet length (P = 0.004) and width (P = 0.002), were reduced significantly by term in fetuses with UV compared with BV outcome. Fetal data, recorded before 30 completed gestational weeks, from 70 treated neonates were evaluated to identify emerging HLHS. Forty-four had moderate or severe left ventricular depression and 38 of these had retrograde flow in the aortic arch and two had left-to-right flow at atrial level and reversed a-waves in the pulmonary veins. Thus 40 neonates met the criteria for emerging HLHS and BV circulation was documented in 13 (33%). Of these 40 cases, 12 (30%) had a threshold score of 4 or 5, of which five (42%) had BV circulation without fetal intervention. CONCLUSIONS: The natural history in our cohort of fetuses with aortic stenosis and known outcomes shows that a substantial proportion of fetuses meeting the criteria for emerging HLHS, with or without favorable selection criteria for FV, had a sustained BV circulation without fetal intervention. This indicates that further work is needed to refine the selection criteria to offer appropriate therapy to fetuses with aortic stenosis. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Hypermobility among school children aged five to eight years: the Hospital del Mar Criteria gives higher prevalence for hypermobility than the Beighton score.

OBJECTIVES: The purpose was to investigate the distribution of hypermobility among school children aged five to eight years. METHODS: One hundred and twenty-eight participants were assessed using the Beighton score and the Hospital del Mar criteria. RESULTS: With the Beighton score using the cut-off ≥4, the prevalence was 12%, and with the Hospital del Mar criteria the prevalence was 34%. There were significantly higher scores for females on both the Beighton (p=0.01) and Hospital del Mar criteria (p<0.0001). The youngest children aged five to six years scored higher compared with the seven- and eight-year-olds (p=0.016). The knee flexion was most likely to be hypermobile (97%), followed by shoulder rotation (80%), thumb (31%), elbow (27%), metatarsal-phalangeal (16%), hip (15.5%), fingers (10%) or knee (10%), ankle (6%), trunk (4%) and patella (2%). CONCLUSIONS: Gender and probably age must be taken into account when children are assessed for hypermobility. The Hospital del Mar criteria need to be modified for some of the motions.

Fetal aortic valvuloplasty: investigating institutional bias in surgical decision-making.

OBJECTIVES: Fetal aortic valvuloplasty may prevent the progression of aortic stenosis to hypoplastic left heart syndrome and allow biventricular rather than univentricular postnatal treatment. This study aimed to investigate whether blinded simulation of a multidisciplinary team approach aids interpretation of multicenter data to uncover institutional bias in postnatal decision-making following fetal cardiac intervention for aortic stenosis. METHODS: The study included 109 cases of prenatally diagnosed aortic stenosis from 13 European countries, of which 32 had undergone fetal cardiac intervention. The multidisciplinary team, blinded to fetal cardiac intervention, institutional location and postnatal treatment, retrospectively assigned a surgical pathway (biventricular or univentricular) based on a review of recorded postnatal imaging and clinical characteristics. The team's decisions were the numerical consensus of silent voting, with case review when a decision was split. Funnel plots showing concordance between the multidisciplinary team and the local team's surgical choice (first pathway) and with outcome (final pathway) were created. RESULTS: In 105 cases the multidisciplinary team reached a consensus decision regarding the surgical pathway, with no decision in four cases because the available imaging records were inadequate. Blinded multidisciplinary team consensus for the first pathway matched the decision of the surgical center in 93/105 (89%) cases, with no difference in agreement between those that had undergone successful fetal cardiac intervention (n = 32) and no (n = 74) or unsuccessful (n = 3) valvuloplasty (no fetal cardiac intervention) (κ = 0.73 (95% CI, 0.38-1.00) vs 0.74 (95% CI, 0.51-0.96)). However, funnel plots comparing multidisciplinary team individual decisions with those of the local teams displayed more discordance (meaning biventricular-univentricular conversion) for the final surgical pathway following fetal cardiac intervention than they did for cases without such intervention (36/74 vs 34/130; P = 0.002), and identified one outlying center. CONCLUSIONS: The use of a blinded multidisciplinary team to simulate decision-making and presentation of data in funnel plots may assist in the interpretation of data submitted to multicenter studies and permit the identification of outliers for further investigation. In the case of aortic stenosis, a high level of agreement was observed between the multidisciplinary team and the surgical centers, but one outlying center was identified.

A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.

The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.

Solvent stabilized solution structures of galanin and galanin analogs, studied by circular dichroism spectroscopy.

Circular dichroism spectroscopy has been used to study how different solvents stabilize secondary structure in the neuropeptide galanin (rat), two N-terminal fragments of galanin, galanin(1-12) and galanin(1-16), and six other differently charged analogs. Among these analogs, the peptide M40, galanin(1-13)-Pro-Pro-Ala-Leu-Ala-Leu-Ala amide, is a high affinity, receptor subtype specific galanin receptor antagonist. The different solvents include sodium dodecyl sulfate (SDS) micelle solutions, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3-phosphoglycerol (DOPG) vesicle solutions. 100% 1,1,1,3,3,3-hexafluoro-2-propanol (HFP) and 100% 2,2,2-trifluoroethanol (TFE). DOPC vesicles did not change the structure of the peptides as compared to aqueous solvent. The negatively charged DOPG vesicles and SDS micelles induced similar changes towards alpha-helical structures in all peptides. The HFP and TFE solvents have an even stronger tendency to stabilize alpha-helical conformations in these peptides. Since DOPG vesicles can be considered as a model system for negatively charged biological membranes, the solution structures observed in the presence of DOPG or SDS may be the most relevant for the in vivo situation. Correlations between the binding affinity of the peptides to hippocampal galanin receptors and their observed structures in the DOPG solvent were investigated.

High-potential states of blue and purple copper proteins.

Electrochemical measurements show that there are high-potential states of two copper proteins, Pseudomonas aeruginosa azurin and Thermus thermophilus CuA domain; these perturbed states are formed in guanidine hydrochloride (GuHCl) solution in which the proteins are still blue (azurin) and purple (CuA). In each case, the high-potential state forms reversibly. Absorption (azurin, CuA), visible circular dichroism (azurin, CuA), resonance-Raman (CuA), and EPR (CuA) spectra indicate that the structure of the oxidized copper site of each high-potential form is very similar to that of the native protein. It is proposed that GuHCl perturbs one or more H-bonds in the blue or purple copper active site, thereby allowing Cu(I) to adopt a more favorable coordination structure than that in the rigid cavity of the native protein.

Season of birth and electrodermal unresponsiveness in male schizophrenics.

The present study was designed to examine differences in the electrodermal activity of schizophrenics born in the season of excessive risk (January-April), and those born in the season of nonexcessive risk (May-December). Thirty-two male schizophrenics were presented with a series of orienting tones (1000 Hz, 80dB, 2 sec duration) while electrodermal activity was monitored. They were subdivided according to season of birth and compared in three electrodermal variables, and also in some background and clinical parameters. We found that schizophrenics born in the season of excessive risk were characterized by significantly lower electrodermal activity and more negative symptoms than those born in the season of nonexcessive risk.

Fears, phobias, and preparedness: toward an evolved module of fear and fear learning.

An evolved module for fear elicitation and fear learning with 4 characteristics is proposed. (a) The fear module is preferentially activated in aversive contexts by stimuli that are fear relevant in an evolutionary perspective. (b) Its activation to such stimuli is automatic. (c) It is relatively impenetrable to cognitive control. (d) It originates in a dedicated neural circuitry, centered on the amygdala. Evidence supporting these propositions is reviewed from conditioning studies, both in humans and in monkeys; illusory correlation studies; studies using unreportable stimuli; and studies from animal neuroscience. The fear module is assumed to mediate an emotional level of fear learning that is relatively independent and dissociable from cognitive learning of stimulus relationships.

Emotional conditioning to masked stimuli: expectancies for aversive outcomes following nonrecognized fear-relevant stimuli.

The role of conscious awareness in human Pavlovian conditioning was examined in 2 experiments using masked fear-relevant (snakes and spiders; Experiments 1 and 2) and fear-irrelevant (flowers and mushrooms; Experiment 1) pictures as conditioned stimuli, a mild electric shock as the unconditioned stimulus, and skin conductance responses as the primary dependent variable. The conditioned stimuli were presented briefly (30 ms) and were effectively masked by an immediately following masking stimulus. Experiment 1 demonstrated nonconscious conditioning to fear-relevant but not to fear-irrelevant stimuli. Even though the participants could not recognize the stimuli in Experiment 2, they differentiated between masked stimuli predicting and not predicting shocks in expectancy ratings. However, expectancy ratings were not related to the conditioned autonomic response.

Emotion drives attention: detecting the snake in the grass.

Participants searched for discrepant fear-relevant pictures (snakes or spiders) in grid-pattern arrays of fear-irrelevant pictures belonging to the same category (flowers or mushrooms) and vice versa. Fear-relevant pictures were found more quickly than fear-irrelevant ones. Fear-relevant, but not fear-irrelevant, search was unaffected by the location of the target in the display and by the number of distractors, which suggests parallel search for fear-relevant targets and serial search for fear-irrelevant targets. Participants specifically fearful of snakes but not spiders (or vice versa) showed facilitated search for the feared objects but did not differ from controls in search for nonfeared fear-relevant or fear-irrelevant, targets. Thus, evolutionary relevant threatening stimuli were effective in capturing attention, and this effect was further facilitated if the stimulus was emotionally provocative.

The premise of equipotentiality in human classical conditioning: conditioned electrodermal responses to potentially phobic stimuli.

The premise of equipotentiality, which has been widely adhered to among learning theorists, states that the laws of learning should not vary with the use of particular stimuli, responses, or reinforcements. This premise has recently been challenged by some data originating within the learning tradition itself, for example, studies on the effects of verbal stimuli in eye-lid conditioning. More importantly, however, the premise of equipotentiality is incompatible with data from experiments carried out within a biological-ethological framework. The results of such studies indicate that a given species is prepared to associate certain stimuli, responses, and reinforcers but not others. In an attempt to examine the validity of this premise in human classical conditioning, we investigated the effect of pictures of potentially phobic objects as conditioned stimuli (CSs) for electrodermal responses, since it has been suggested that phobias may be instances of biologically prepared learning. Three experiments are reported, all of them involving a long interstimulus interval differential conditioning paradigm with different pictures as CSs and electric shock as the unconditioned stimulus (UCS). In Experiment 1 we established that different pictures are differentially effective as CSs. A groupconditioned to potentially phobic stimuli, snakes or spiders, showed greater resistance to extinction than a group conditioned to fear-irrelevant pictorial stimuli, that is, flowers or mushrooms. A third group conditioned to "representative laboratory stimuli," circles or triangles, fell in between thses two groups. Experuce similar effects to those observed with phobic and fear-irrelevant stimuli in Experiment 1. In Experiment 3 superior resistance to extinction for phobic stimuli was demonstrated when the UCS was an electric shock, but not when it was a tone to which the subject produced reaction times. Thus, the effect appears specific for aversive UCSs, and CS-UCS "belongingness" has been demonstrated. It was concluded that our data do challenge the premise of equipotentiality in human conditioning. There are several learning-theory accounts that could accommodate at least some aspects of the data, but they seem to be best explained in terms of biologically orsiented constructs, such as preparedness.

Effects of perphenazine enanthate injections on prolactin levels in plasma from schizophrenic women and men.

Levels of prolactin (PRL) in plasma were determined in schizophrenic women and men after i.m. injections of 50-150 mg perphenazine enanthate (PE). In both sexes PRL levels increased dose-dependently. In men the effect was significant for 2 and in women for 9 days. Biperiden treatment did not influence the effect of PE on the PRL levels. The data support the view that clinically used doses of PE induce a small but significant blockade of central dopamine receptors.

Perinatal characteristics and schizophrenia: electrodermal activity as a mediating link in a vulnerability-stress perspective.

Vulnerability-stress models of schizophrenia assert that the disorder results from an interaction between genetic or biologically acquired vulnerability and unfavourable environmental conditions. As our knowledge of early environmental factors for schizophrenia evolves, the question of links between early factors and a development of schizophrenia becomes more important. In this article, we analyse the relationship between obstetrical complications (OCs) and adult schizophrenia and methodological concerns in the search for pre- and perinatal risk factors. We review findings of aberrant electrodermal activity in schizophrenic patients and suggest that OCs may induce insults to cerebral structures that are critically involved in the control of orienting and of autonomic responses.

"Unconscious anxiety": phobic responses to masked stimuli.

We tested the hypothesis that an unconscious preattentive perceptual analysis of phobic stimuli is sufficient to elicit human fear responses. Selected snake- and spider-fearful Ss, as well as normal controls, were exposed to pictures of snakes, spiders, flowers, and mushrooms. A separate forced-choice recognition experiment established backward masking conditions that effectively precluded recognition of experimental stimuli both for fearful and nonfearful Ss. In the main experiment, these conditions were used to compare skin conductance responses (SCRs) to masked and nonmasked phobic and control pictures among fearful and nonfearful Ss. In support of the hypotheses, snake- and spider-fearful Ss showed elevated SCRs to snake and spider pictures as compared with neutral pictures and with responses of the nonfearful Ss under both masking conditions. Ratings of valence, arousal, and dominance indicated that the fearful Ss felt more negative, more aroused, and less dominant in relation to both masked and nonmasked phobic stimuli.

On the automatic nature of phobic fear: conditioned electrodermal responses to masked fear-relevant stimuli.

Normal subjects (n = 64) were exposed either to pictures of snakes and spiders or to pictures of flowers and mushrooms in a differential conditioning paradigm in which one of the pictures signaled an electric shock. In a subsequent extinction series, these stimuli were presented backwardly masked by another stimulus for half of the subjects, whereas the other half received non-masked extinction. In support of a hypothesis that suggests that nonconscious information-processing mechanisms are sufficient to activate responses to fear-relevant stimuli, differential skin conductance response to masked conditioning and control stimuli was obvious only for subjects conditioned to fear-relevant stimuli. These results were replicated in a second experiment (n = 32), which also demonstrated that the effect was unaffected by which visual half-field was used for stimulus presentation.

Electrodermal activity and obstetric complications in schizophrenia.

The pregnancy and birth records of 79 schizophrenic patients, from whom adult electrodermal data were available, were systematically evaluated for obstetric complications using 34 criteria of nonoptimality in pregnancy, delivery, and postpartum periods. Patients with many obstetric complications had lower levels of electrodermal activity. For frequency of skin conductance responses and spontaneous fluctuations in skin conductance, the association was more evident for women than for men. However, the ratio of stimulus-elicited to spontaneous skin conductance responses showed a reliable association with obstetric complications without any gender differences. The relationship between obstetric complications and electrodermal activity was interpreted in terms of neurodevelopmental insults resulting in structural brain abnormalities interfering with orienting and electrodermal activity.

Electrodermal activity as a predictor of social functioning in female schizophrenics.

Twenty-nine female schizophrenics and 20 female controls were presented with a series of moderately intense tones in a standard orienting habituation paradigm while skin conductance was monitored. Premorbid adjustment and symptoms were also rated, and the schizophrenics were observed 2 years later. The total schizophrenic group was divided into a good-outcome group and a poor-outcome group. Good social functioning outcome required both self-supporting ability in the job market and at least a minimal social life. The poor-outcome group had a significantly higher skin-conductance level and frequency of spontaneous skin-conductance fluctuations than the control group, whereas the few patients with good outcome did not differ from controls. These results are contrary to previous findings with a group of schizophrenic men in which poor social functioning was associated with low electrodermal activity. This discrepancy is discussed in terms of sex differences in schizophrenic disorder.

Electrodermal nonresponding, premorbid adjustment, and symptomatology as predictors of long-term social functioning in schizophrenics.

The hypothesis that electrodermal nonresponsiveness to orienting stimuli delineates a core group of "Kraepelinian" type schizophrenics was tested by following up social functioning outcome over a 2-year period in 37 schizophrenics. Good social functioning outcome required both some self-supporting ability in the job market and a minimal social life. The prior assessments included monitoring of electrodermal responses to a series of moderately intense tones, ratings of reported and observed symptoms during an interview, and ratings of premorbid adjustment on the basis of an interview with a close relative. Electrodermal nonresponding, poor premorbid adjustment, and negative symptomatology predicted poor social functioning during the second follow-up year, but the relationship to nonresponding pertained exclusively to a group of 15 first-episode patients. Discriminant analysis showed that electrodermal nonresponding and symptoms were the only independent predictors of outcome.

Electrodermal activity and social network as predictors of outcome of episodes in schizophrenia.

The predictive value of electrodermal activity and social network was examined among 48 consecutively admitted schizophrenic patients. The patients were followed from an initial admission, through hospital stay, discharge, follow-up (M = 31 months), and possible relapse. Outcome variables were the length of stay in the hospital at the key episode and time to relapse, defined as a marked exacerbation or return of schizophrenic symptoms requiring inpatient or expansion of outpatient treatment. Multivariate analyses showed that a psychosocial variable, the availability of attachment, was the only independent predictor of length of stay in the hospital. Age at admission was a strong predictor of time to relapse. Age interacted with both outcome and electrodermal activity, and young electrodermal nonresponders were found to have the shortest time to relapse. At the 1-year follow-up, a main relapse effect was found for patients with a low skin conductance level.