Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects.

BACKGROUND: Darier disease (DD) is a rare genodermatosis caused by heterozygous mutations in the ATP2A2 gene. It has been associated with neuropsychiatric manifestations. OBJECTIVES: To investigate the genetic basis of Israeli patients with DD, and its association with the neuropsychiatric phenotype. METHODS: A cohort of 32 families comprising 74 affected individuals and 13 unaffected family members was recruited from the Haemek Dermatology Department and other dermatology clinics in Israel. The individuals were evaluated by detailed questionnaires, physical examination and genetic analysis. The main outcome measures were genetic mutations, psychiatric profile and their association. RESULTS: Twenty-three mutations in ATP2A2 were scattered over the entire gene, 14 of them novel. Two families shared the same mutation. Twenty-one patients (28%) had a history of psychiatric disorders, most of them mood disorders. Another seven patients (9%) were highly suspected of having a psychiatric disorder; 21 (28%) reported suicidal thoughts and five (7%) had attempted suicide. The psychiatric phenotype demonstrated inter- and intrafamilial variability, and was not associated with disease severity, family history of psychiatric disease or mutation location. CONCLUSIONS: The cohort demonstrated genetic heterogeneity with no mutation cluster along the gene, and a high prevalence of psychiatric disorders. Although no clear genotype-phenotype correlation was found, the results point to a major effect of genetic background on psychiatric phenotype, together with other modifiers.

Impact of antipsoriatic therapy on endothelial function.

BACKGROUND: Endothelial function (EF) impairment is one of the first events in the process of atherosclerosis, which is known to be associated with psoriasis. Nevertheless, the effect of antipsoriatic treatments, some of them with atherogenic risks, on cardiovascular morbidity and EF is still unclear. OBJECTIVES: To investigate the effect of short-term antipsoriatic treatments on EF values as a potential marker of their effect on cardiovascular morbidity. METHODS: EF was evaluated in 26 patients with moderate-to-severe psoriasis by measuring microvascular blood flow, expressed as the reactive hyperaemia index (RHI), before and after phototherapy (8 weeks) or systemic antipsoriatic treatment (12 weeks). RESULTS: Antipsoriatic intervention was effective (46% achieving ≥ 75% improvement in Psoriasis Area and Severity Index), while the average RHI did not improve during the study (1·73 ± 0·48. vs. 1·66 ± 0·35, average difference -0·12 ± 0·43, not significant). Patients with baseline preserved EF exhibited a decline in RHI (difference -0·2 ± 0·4, P = 0·053), while patients with abnormal baseline RHI presented nonsignificant RHI improvement (RHI difference 0·1 ± 0·2). CONCLUSIONS: There was no positive effect on EF of short-term antipsoriatic treatment. It is possible that a longer period of treatment and EF evaluation would uncover a positive endothelial effect, especially in patients with baseline abnormal EF.

Learning disabilities in Darier's disease patients.

BACKGROUND: Neuropsychiatric features and intellectual difficulties have been reported in studies of Darier's disease. Learning disabilities have never been reported or evaluated systematically in these patients. OBJECTIVE: To assess the prevalence of learning disabilities in 76 patients with Darier's disease, and cognitive functioning in 19 of them. METHODS: The data were collected by two methods: a questionnaire, as part of a larger study on the clinical characteristics of 76 patients; and neuropsychological measures for the assessment of learning disabilities in 19 of them. RESULTS: Thirty-one of the 76 patients reported learning disabilities (41%) and 56 (74%) reported a family history of learning disabilities. Significant differences were found between the 19 patients evaluated on cognitive tasks and a control group of 42 skilled learners on subtraction and multiplication tasks. Six (32%) of the 19 were identified as having reading difficulties and five (26%) exhibited low performance on the Concentration Performance Test. All patients had general cognitive ability in the average range. CONCLUSIONS: Findings suggest an association between Darier's disease and learning disabilities, a heretofore unreported association, pointing to the need to obtain personal and family history of such disabilities in order to refer cases of clinical concern for further study.

Bacteriological aspects of Darier's disease.

BACKGROUND: There are no established data on the prevalence of bacterial colonization of lesional skin, nares and perineum in Darier's disease (DD), or its contribution to the clinical manifestations of the disease. OBJECTIVE: To determine the prevalence of bacterial colonization of lesional skin and Staphylococcus aureus (S. aureus) in nares and perineum in 75 patients with DD, the association of these parameters with disease and patient characteristics, and the features of the bacterial skin infection in this group. METHODS: Medical interviews and physical examinations were performed. Bacteria were isolated from swabs taken from lesional skin, nares and perineum. RESULTS: S. aureus was isolated in 68%, 47% and 22% of lesional skin, nares and perineum cultures respectively. Subjects with positive S. aureus culture from lesional skin and/or nares had a statistically significant higher percentage of skin area affected and a more severe disease than patients with negative culture. Thirty of the 75 patients (40%) recalled bacterial skin infection, most often on the chest. CONCLUSIONS: Patients with DD have high prevalence of S. aureus colonization in lesional skin and nares, with a correlation between disease severity and extent of the colonization. Further studies examining the consequences of S. aureus eradication in those sites may establish the need for S. aureus lesional skin and nares colonization screening and eradication as part of the treatment of DD exacerbations.

Health-related quality of life among Darier's disease patients.

BACKGROUND: Darier's disease (DD) is an autosomal dominant skin disorder characterized by persistent eruption of hyperkeratotic papules. The effect of DD on quality of life (QOL) has been assessed in only one study, which found no correlation between the Dermatology Life Quality Index (DLQI) score and clinical severity of the disease. The correlation between health-related quality of life (HRQL) and other diseases and patient characteristics has not been studied. OBJECTIVES: To examine the HRQL of patients with DD and to evaluate the association between HRQL scores and disease and patient characteristics. METHODS: A total of 74 DD patients completed three QOL questionnaires: DLQI, EQ-5D, and one specially designed for the study. The data reported in this study were collected as part of a larger study on the clinical characteristics of DD; the socio-demographic and clinical data were used in the statistical analysis of the current study. RESULTS: Mean DLQI was 5.41 ± 5.57 and the mean EQ-Visual Analogue Scale (VAS), was 70.84 ± 19.25. DLQI and EQ-VAS were significantly associated with skin area affected, disease severity, age at onset of DD and a seborrhoeic distribution pattern of DD. Stepwise linear regression showed skin area affected to be the most significant variable in the predication of DLQI (beta = 0.183; SE = 0.04; P < 0.001), and disease severity the most significant variable in the predication of EQ-VAS (beta = -9.15; SE = 3.21; P < 0.006). CONCLUSIONS: Darier's disease has a negative impact on HRQL of patients and the HRQL is associated with various disease characteristics, mainly skin area affected and clinical severity.

Should neonates sleep alone?

BACKGROUND: Maternal-neonate separation (MNS) in mammals is a model for studying the effects of stress on the development and function of physiological systems. In contrast, for humans, MNS is a Western norm and standard medical practice. However, the physiological impact of this is unknown. The physiological stress-response is orchestrated by the autonomic nervous system and heart rate variability (HRV) is a means of quantifying autonomic nervous system activity. Heart rate variability is influenced by level of arousal, which can be accurately quantified during sleep. Sleep is also essential for optimal early brain development. METHODS: To investigate the impact of MNS in humans, we measured HRV in 16 2-day-old full-term neonates sleeping in skin-to-skin contact with their mothers and sleeping alone, for 1 hour in each place, before discharge from hospital. Infant behavior was observed continuously and manually recorded according to a validated scale. Cardiac interbeat intervals and continuous electrocardiogram were recorded using two independent devices. Heart rate variability (taken only from sleep states to control for level of arousal) was analyzed in the frequency domain using a wavelet method. RESULTS: Results show a 176% increase in autonomic activity and an 86% decrease in quiet sleep duration during MNS compared with skin-to-skin contact. CONCLUSIONS: Maternal-neonate separation is associated with a dramatic increase in HRV power, possibly indicative of central anxious autonomic arousal. Maternal-neonate separation also had a profoundly negative impact on quiet sleep duration. Maternal separation may be a stressor the human neonate is not well-evolved to cope with and may not be benign.

Guilt and pride are heartfelt, but not equally so.

We examined the cardiovascular physiology of guilt and pride to elucidate physiological substrates underpinning the behavioral motivations of these moral emotions. Although both emotions motivate prosocial behavior, guilt typically inhibits ongoing behavior, whereas pride reinforces current behavior. To succeed in eliciting real emotions, we used a novel social interaction task. We found dissociable sympathetic activation during guilt and pride; specifically, Guilt participants experienced prolonged cardiac sympathetic arousal as measured by preejection period (PEP), whereas Pride participants experienced transient non-cardiac somatic arousal and a shift to low frequency (LF) power in the cardiac spectrogram. This dissociation supports their distinctive motivational functions. Higher self-reported Behavioral Inhibition System (BIS) sensitivity was furthermore uniquely associated with guilt, supporting its function as a punishment cue.

Pregnancy outcomes in women with moderate-to-severe psoriasis.

BACKGROUND: The association between psoriasis and pregnancy outcomes has not been adequately examined, although psoriasis onset is common in the reproductive period. OBJECTIVE: To evaluate the association between moderate-to-severe psoriasis and pregnancy complications. METHODS: A retrospective, matched cohort study of 68 deliveries in 35 women with moderate-to-severe psoriasis compared to 237 deliveries in 236 women without psoriasis randomly selected after matching for age, parity and gestational age. RESULTS: The psoriasis patients had higher mean of past spontaneous (0.42±0.58 vs. 0.26±0.63, P=0.002) and induced (0.32±0.60 vs. 0.06±0.25, P=0.001) abortions than controls. They had a higher percentage of pregnancy-induced hypertensive diseases (7.4% vs. 2.1%, P<0.05) and premature rupture of membranes (16% vs. 5.5%, P<0.008). Newborns to women with psoriasis had higher birth weight (3375±543 g vs. 3247±460 g, P=0.03), increased percentage of large-for-gestational age (24% vs. 12%, P=0.02), and macrosomia (13% vs. 4.2%P=0.02). In multivariate analysis, moderate-to-severe psoriasis was an independent risk factor for previous spontaneous abortions, induced abortions, premature rupture of membranes (PROM), and newborn macrosomia. CONCLUSION: Moderate-to-severe psoriasis is associated with spontaneous and induced abortions, pregnancy-induced hypertensive diseases, premature rupture of membranes, large-for-gestational age newborns, and macrosomia.

Socially explosive minds: the triple imbalance hypothesis of reactive aggression.

The psychobiological basis of reactive aggression, a condition characterized by uncontrolled outbursts of socially violent behavior, is unclear. Nonetheless, several theoretical models have been proposed that may have complementary views about the psychobiological mechanisms involved. In this review, we attempt to unite these models and theorize further on the basis of recent data from psychological and neuroscientific research to propose a comprehensive neuro-evolutionary framework: The Triple Imbalance Hypothesis (TIH) of reactive aggression. According to this model, reactive aggression is essentially subcortically motivated by an imbalance in the levels of the steroid hormones cortisol and testosterone (Subcortical Imbalance Hypothesis). This imbalance not only sets a primal predisposition for social aggression, but also down-regulates cortical-subcortical communication (Cortical-Subcortical Imbalance Hypothesis), hence diminishing control by cortical regions that regulate socially aggressive inclinations. However, these bottom-up hormonally mediated imbalances can drive both instrumental and reactive social aggression. The TIH suggests that reactive aggression is differentiated from proactive aggression by low brain serotonergic function and that reactive aggression is associated with left-sided frontal brain asymmetry (Cortical Imbalance Hypothesis), especially observed when the individual is socially threatened or provoked. This triple biobehavioral imbalance mirrors an evolutionary relapse into violently aggressive motivational drives that are adaptive among many reptilian and mammalian species, but may have become socially maladaptive in modern humans.

Gray's BIS/BAS dimensions in non-comorbid, non-medicated social anxiety disorder.

Gray's behavioural inhibition and behavioural activation (BIS/BAS) neural systems model has led to research on approach and withdrawal as the two most fundamental dimensions of affective behaviour, and their role in psychopathology. Although Gray proposed the BIS as the neurological basis of anxiety, there are no reports examining approach and withdrawal predispositions in social anxiety disorder. Here we report approach and withdrawal predispositions in a group of 23 non-medicated individuals with social anxiety disorder (SAD) without co-morbid depression and in 48 normal controls. Results show increased BIS and decreased BAS fun-seeking in SAD subjects thereby underscoring Gray's dimensional model.

Intestinal immunity following a combined enhanced inactivated polio vaccine/oral polio vaccine programme in Israel.

Intestinal immunity was studied in a polio-free community immunised with a combined enhanced inactivated/oral polio vaccine (EIPV/OPV) vaccination programme. Poliovirus excretion was evaluated in three groups of infants primed with a partial (2 EIPV+2 OPV) or complete (3 EIPV+3 OPV) dose schedule. Poliovirus replicated in the gut of 59.8-55.8% of infants in the three groups 7 days after administration of an additional OPV dose. Significant decreases in the percent of type-specific-virus excreters appeared after 14 and 21 days for serotypes 1 and 2, and after 21 and 28 days for serotype 3. The percent of excreters was inversely correlated with pre-challenge neutralising antibody (NA) titers (p<0.05). Intrafamilial virus transmission to mothers and siblings was minimal. The principal factor for interruption of disease and virus transmission in the community was a strong and persistent humoral immunity with immunological memory. A satisfactory level of family hygiene contributed towards breaking the chain of transmission of poliovirus to contacts.

Behavioral inhibition: a neurobiological perspective.

Behavioral inhibition (BI) during early childhood has been associated with subsequent development of anxiety disorders. However, understanding of the neuroanatomical substrates of BI in humans generally has not kept pace with that of anxiety disorders. Recent interpretations and implementations of Gray's and Kagan's concepts of BI are examined from the perspective of current neurobiological models. Particular attention is given to evidence pointing to conceptual and operational limitations of self-report scales purported to measure trait BI in adults, and especially to inconsistent correlations between such behavioral inhibition system (BIS) scores and amygdala and autonomic responses to fear- or startle-inducing stimuli. Evidence showing a dissociation of both BI and trait anxiety from the amygdala is considered. Possible reasons for the poor association between BIS and trait anxiety self-report scale scores and predicted physiological outputs of the BIS are identified. Reasons to distinguish between the neural bases of BI as against trait anxiety also are discussed. The need to critically examine the role of the amygdala in BI and trait anxiety, as well as to consider other brain areas that appear to be involved in subserving these emotional traits, is emphasized.

Rapid, simple, and accurate method for measurement of VFA and carbonate alkalinity in anaerobic reactors.

This paper presents a new simple, rapid, and accurate method suitable for on-site measurement of volatile fatty acids (VFA) and carbonate alkalinity in anaerobic reactors. This titrimetric method involves eight pH observations, and typically, the full procedure takes approximately 15 min. An important feature of the method is a built-in quality control mechanism allowing the user a rapid means of assessing the reliability of the experimental procedure. To evaluate the accuracy of the method, both laboratory-made waters and industrial UASB effluent were tested. High accuracy for both VFA and carbonate alkalinity measurements (error within 2% and 1%, respectively) plus good repetition (average standard deviation of 6.7% and 1.45%, respectively) was obtained. The method takes into account the effects of the phosphate, ammonium, and sulfide weak acid subsystems. Appraisal of the effect of an input error in these subsystems revealed that VFA measurement is fairly insensitive to phosphate and ammonium concentrations. It is, however, sensitive to H2S loss during titration where the sulfide concentration is higher than approximately 10 mg/Las S. With regard to the carbonate alkalinity measurement, error in concentration of either phosphate or sulfide or H2S loss might result in a significant error. Short guidelines for correct execution of the method are given in an appendix.