The Effects of Prenatal Exposure to Altered Melatonin Levels on Hippocampal Gene Expression in the Male Rat

The stability of the circadian rhythm for mammals depends on the levels of serotonin and melatonin, neurohormones that signal for lightness and darkness, respectively. Disruption in the stability of neurohormones has been shown to be a critical factor in psychopathological disorders in humans. For example, altering levels of melatonin in utero through administration of melatonin or the melatonin receptor antagonist, luzindole, has been shown to cause changes in developmental growth and adult behavior in the male rat. Analysis of relative adult hippocampal gene expression with RT-PCR revealed differences in ARNTL expression that suggested abnormality in clock gene expression of the rats that were prenatally exposed to altered levels of melatonin. Differences in the degree of plasticity as suggested by previous behavior testing did not result in differences in gene expression for GABA receptors or NMDA receptors. Morevoer, growth associated protein 43, GAP-43, a protein that is necessary for neuronal growth cones as well as long term learning has been found to be critical for axon and presynaptic terminal formation and retention in other studies, but hippocampal gene expression in our study showed no significant alteration after exposure to various maternal melatonin levels. However, ARNTL is a key regulatory component of clock genes and the circadian cycle so that alterations in the expression of thi critical gene may lead to critical changes in neuronal growth and plasticity. Our data support the conclusion that the manipulation of maternal melatonin levels alters the brain development and the circadian cycles that may lead to physiological and behavioral abnormalities in adult offspring.

EFFECTS OF PRENATAL DEXAMETHASONE ON HIPOPCAMPAL SEROTONIN 1A RECEPTORS IN ADULT MALE RATS

The main activation route for the stress response is the hypothalamo-pituitaryadrenal axis (HPA) and the sympatho-adrenomedullary system. The HPA axis is a neuroendocrine feedback loop mediated by an array of tissue specific hormones, receptors and neurotransmitters that regulate glucocorticoid (GC) release. GCs are steroidal hormones produced by the adrenal glands and are key players in a negativefeedback loop controlling HPA activity. They influence the HPA axis through glucocorticoid receptors in the hypothalamus and pituitary and through both glucocorticoid (GR) and mineralcorticoid receptors (MR) that are co-localized in the hippocampus. Repeated or chronic stress exerts a negative influence on these HPA axis regulatory sites and contributes to potentially pathological conditions, especially during early development. For example, chronic stress promotes increased maternal adrenal gland secretion of glucocortiocoid, leading to abnormally high concentrations of GC inthe fetal environment. The timing and maturation of the HPA axis relative to birth is highly species specific and is closely linked to landmarks in fetal development. In rats this development of the HPA axis takes place in utero and continues even shortly after birth. It is likely that the maternal endocrine environment will affect fetal development during this critical time point and may alter the overall set point for the expression ofgenes and their protein products that mediate fetal HPA axis function. Dexamethasone (DEX) is a synthetic glucocorticoid (sGC) and is a consensus treatment in preterm pregnancies used to expedite fetal lung development. However it has been shown that DEX causes long term physiological and behavioral disorders in prenatally-exposed laboratory animals. Previous studies have also shown that it alters the MR: GR receptor ratio in the hippocampus. Taking into consideration corticosteroid regulation of serotonin receptors, especially 5HT1A receptors and their putative interaction with glucocorticoid receptors in the hippocampus, we hypothesized that prenatal DEX exposure would lead to changes in the expression and function of 5HT1A receptors in the hippocampus. We administered DEX to rat dams during the last trimester of gestation and investigated the changes in these receptors in the adult rat offspring. Radioligand receptor binding assays were used to study hippocampal 5HT1A receptor binding affinity and number. Our results demonstrate that hippocampal 5HT1A receptors are increased in the DEX animalscompared with controls by 36%, with no change in binding affinity. The efficiency of ligand-induced receptor signal transduction via G-protein activation was also studied using [35S]GTPγS incorporation assay. Using this technique, we showed that there was no significant difference in the maximum ligand mediated stimulation (Emax) of 5HT1Areceptors between control and dex exposed animals. However, the intracellular signalling efficiency of hippocampal 5HT1A receptors was diminished, since a significant increase in EC50 values was obtained with the dex exposed group showing a value 51% higherEC50 than controls. Taken together these data illustrate a considerable change in the 5HT1A component of the serotonergic system following prenatal DEX exposure.

Social Cognition and Neural Substrates of Face Perception: Implications for Neurodevelopmental and Neuropsychiatric Disorders

BACKGROUND: Social cognition is an important aspect of social behavior in humans. Social cognitive deficits are associated with neurodevelopmental and neuropsychiatric disorders. In this study we examine the neural substrates of social cognition and face processing in a group of healthy young adults to examine the neural substrates of social cognition. METHODS: Fifty-seven undergraduates completed a battery of social cognition tasks and were assessed with electroencephalography (EEG) during a face-perception task. A subset (N=22) were administered a face-perception task during functional magnetic resonance imaging. RESULTS: Variance in the N170 EEG was predicted by social attribution performance and by a quantitative measure of empathy. Neurally, face processing was more bilateral in females than in males. Variance in fMRI voxel count in the face-sensitive fusiform gyrus was predicted by quantitative measures of social behavior, including the Social Responsiveness Scale (SRS) and the Empathizing Quotient. CONCLUSIONS: When measured as a quantitative trait, social behaviors in typical and pathological populations share common neural pathways. The results highlight the importance of viewing neurodevelopmental and neuropsychiatric disorders as spectrum phenomena that may be informed by studies of the normal distribution of relevant traits in the general population. Copyright 2014 Elsevier B.V. All rights reserved.

Rhinovirus infections in infancy and early childhood

Rhinovirus (RV) infections occur early and recurrently in life, imposing a significant burden of disease on infants and young children. They are the most frequent causative agents of both upper and lower respiratory tract infections in this age group and are associated with a broad variety of clinical outcomes, ranging from asymptomatic infections to severe respiratory disease requiring hospitalisation. In addition to their impact on short-term morbidity, RVs are also debated as important pathogens in the development of recurrent wheeze and/or asthma. Several studies in infants at high-risk for atopy and asthma and in hospitalised children have demonstrated that recurrent wheezing illnesses induced by RVs early in life are a risk factor for the development of asthma later in childhood. However, underlying mechanisms are poorly understood. The question whether RVs are directly involved in the development of childhood wheeze and asthma, or whether symptomatic RV infections only represent a proxy for infants prone to develop obstructive lung diseases, is still open. In this review we provide an overview on the role of RVs as important disease-causing agents from infancy to early childhood and discuss their contribution to the subsequent development of childhood wheeze and/or asthma.

The Influence of the Social and Cultural Environment on a Child's Playing in the First Three Years of Life

The research focused on children's behaviour in playing with objects both independently and in interaction with adults. It was based on studies of 40 Slovene children in 4 age groups (6,12,18 and 24 months) and of 23 Croatian children in 2 age groups (18 and 24 months). All the children were sampled proportionally by their gender and the educational level of their parents (middle and higher). Several coding check lists with satisfactory internal consistency were constructed during the study and used to analyse the video-recorded playing sessions with each child. The basic conclusion reached was that even in early childhood playing behaviour differs significantly between the infants from the two Central European countries. The difference lies not so much in the structure or the content of the playing actions, but in the way in which the infants deal playfully with the objects. This difference appears regardless of the type of object the infants are playing with and even regardless of the playing condition. It can best be described as the difference between the first significant discriminant function activity versus passivity. The Slovene infants were found to be on the active pole and the Croatians on the passive one. Social and gender differences were much less significant than cultural ones in determining the structure, the content and the way of playing. Significant age differences appeared in all three aspects, which was consistent with general trends in infants' psychological development. The group define the Slovene interactive playing style as object oriented, while the Croatian one was largely communicated oriented. Within the experimenter-infant dyads, children of both cultures played at a developmentally more advanced level than they did with their mothers, showing that the mothers were not as successful at reaching the ZPD as were the trained experimenters. In addition, the children of mothers who attributed more cognitive benefit to play played on a more advanced level than those whose mothers attributed more emotional benefit to play. The quality of the object the children were playing with was also significantly related to the structure, content and partly the way of dealing with the objects. Highly-structured objects stimulated complex play and low-structured ones stimulated simple play, regardless of playing conditions. The group concluded that both culture and the quality of the available object have an important impact on young children's play. Through the playing interaction, the infants internalise culturally specific patterns of behaviour and culturally specific meanings. These internalisations become apparent very early in their lives, even in non-social situations. On the other hand, the objects themselves have an impact on the level of infants' play. When they do not provide sufficient perceptive and functional support for a representational action, the infants' play will lag behind their actual developmental capacities.

Alteration of host cell phenotype by Theileria annulata and Theileria parva: mining for manipulators in the parasite genomes

The apicomplexan parasites Theileria annulata and Theileria parva cause severe lymphoproliferative disorders in cattle. Disease pathogenesis is linked to the ability of the parasite to transform the infected host cell (leukocyte) and induce uncontrolled proliferation. It is known that transformation involves parasite dependent perturbation of leukocyte signal transduction pathways that regulate apoptosis, division and gene expression, and there is evidence for the translocation of Theileria DNA binding proteins to the host cell nucleus. However, the parasite factors responsible for the inhibition of host cell apoptosis, or induction of host cell proliferation are unknown. The recent derivation of the complete genome sequence for both T. annulata and T. parva has provided a wealth of information that can be searched to identify molecules with the potential to subvert host cell regulatory pathways. This review summarizes current knowledge of the mechanisms used by Theileria parasites to transform the host cell, and highlights recent work that has mined the Theileria genomes to identify candidate manipulators of host cell phenotype.

TSE surveillance in small ruminants and pigs: a pilot study

Switzerland is controlling Transmissible Spongiform Encephalopathies (TSE) in cattle (BSE) and small ruminants (scrapie). Since BSE is potentially transmissible to sheep, goats or pigs through feeding of contaminated meat and bone meal, implementation of an active surveillance programme for TSE in these species is discussed. The aim of this pilot study was to obtain preliminary data on the prevalence ofTSE and other neurological disorders in these populations. For that purpose, a total of 398 perished and 825 slaughtered adult small ruminants and pigs was examined for the presence of neuropathological changes. None of these animals revealed positive for TSE. However, the investigations demonstrated that perished sheep and goats exhibited a higher prevalence of relevant neuropathological changes when compared with slaughtered animals. From these results, it is concluded that perished small ruminants are probably a risk population for TSE and should be considered as target populations for an active surveillance programme.

Neurodegenerative diseases in domestic animals: a comparative review

Neurodegenerative diseases are characterised by selective damage to specific neurons in the nervous system. Interest in such diseases in humans has resulted in considerable progress in the molecular understanding of these disorders in recent decades. Numerous neurodegenerative diseases have also been described in domestic animals but relatively little molecular work has been reported. In the present review, we have classified neurodegenerative disease according to neuroanatomical criteria. We have established two large groups, based on whether the neuronal cell body or its axon was primarily affected. Conditions such as motor neuron diseases, cerebellar degenerations and neuroaxonal dystrophies are discussed in terms of their clinical and neuropathological features. In the most studied disorders, we also present what is known about underlying pathomechanisms, and compare them with their human counterparts. The purpose of this review is to re-kindle interest in this group of diseases and to encourage veterinary researchers to investigate molecular mechanisms by taking advantage of current diagnostic tools.

Dystonic movement disorders and spinal degenerative disease

The occurrence of degenerative spinal disease subsequent to dystonic movement disorders has been neglected and has received more attention only recently. Spinal surgery is challenging with regard to continuous mechanical stress when treatment of the underlying movement disorder is insufficient. To characterize better the particular features of degenerative spinal disease in patients with dystonia and to analyze operative strategies, we reviewed the available published data. Epidemiologic studies reveal that degenerative spinal disorders in patients with dystonia and choreoathetosis occur much earlier than in the physiological aging process. Dystonic movement disorders more often affect the spine at higher cervical levels (C(2-5)), in contrast to spinal degeneration with age which manifests more frequently at the middle and lower cervical spine (C(5-7)). Degenerative changes of the cervical spine are more likely to occur on the side where the chin is rotated or tilted to. Various operative approaches for treatment of spinal pathologies have been advocated in patients with dystonic movement disorders. The available data do not allow making firm statements regarding the superiority of one approach over the other. Posterior approaches were first used for decompression, but additional anterior fusion became necessary in many instances. Anterior approaches with or without instrumented fusion yielded more favorable results, but drawbacks are pseudarthrosis and adjacent-level disease. Parallel to the development of posterior fusion techniques, circumferential surgery was suggested to provide a maximum degree of cord decompression and a higher fusion rate. Perioperative local injections of botulinum toxin were used initially to enhance patient comfort with halo immobilization, but they are also applied in patients without external fixation nowadays. Treatment algorithms directed at the underlying movement disorder itself, taking advantage of new techniques of functional neurosurgery, combined with spinal surgery have recently been introduced and show promising results.

Elevated exhaled nitric oxide in newborns of atopic mothers precedes respiratory symptoms

RATIONALE: Exhaled nitric oxide (NO) is a well-known marker of established airway inflammation in asthma. Its role in the disease process before the onset of respiratory symptoms remains unclear. Objectives: To examine whether elevated NO in newborns with clinically naive airways is associated with subsequent respiratory symptoms in infancy. METHODS: We measured exhaled NO concentration and output after birth and prospectively assessed respiratory symptoms during infancy in a birth cohort of 164 unselected healthy neonates. We examined a possible association between NO and respiratory symptoms using Poisson regression analysis. RESULTS: In infants of atopic mothers, elevated NO levels after birth were associated with increased risk of subsequent respiratory symptoms (risk ratio [RR], 7.5; 95% confidence interval [CI], 1.7-32.4 for each nl/s increase in NO output; p = 0.007). Similarly, a positive association between NO and symptoms was seen in infants of smoking mothers (RR, 6.6; 95% CI, 2.3-19.3; p = 0.001), with the strongest association in infants whose mothers had both risk factors (RR, 21.8; 95% CI, 5.8-81.3; p < 0.001). CONCLUSIONS: The interaction of NO with maternal atopy and smoking on subsequent respiratory symptoms is present early in life. Clinically, noninvasive NO measurements in newborns may prove useful as a new means to identify high-risk infants. Future confirmation of a role for NO metabolism in the evolution of respiratory disease may provide an avenue for preventative strategies.

Leydig-cell tumour in children: variable clinical presentation, diagnostic features, follow-up and genetic analysis of four cases

BACKGROUND: Testicular tumours are relatively uncommon in infants and children, accounting for only 1-2% of all paediatric solid tumours. Of these approximately 1.5% are Leydig-cell tumours. Further, activating mutations of the luteinizing hormone receptor gene (LHR), as well as of the G protein genes, such as Gsalpha (gsp) and Gialpha (gip2) subunits, and cyclin-dependent kinase gene 4(CDK4) have been associated with the development of several endocrine neoplasms. AIMS/METHODS: In this report, the clinical variability of Leydig-cell tumours in four children is described. The LHR-, gsp-, gip2- and CDK4 genes were investigated to establish the possible molecular pathogenesis of the variable phenotype of the Leydig-cell tumours. RESULTS: No activating mutations in these genes were found in the four Leydig-cell tumours studied. Therefore, the absence of activating mutations in LHR, as well as in both the 'hot spot' regions for activating mutations within the G-alpha subunits and in the regulatory 'hot spot' on the CDK4 genes in these tumours indicates molecular heterogeneity among Leydig-cell tumours. CONCLUSION: Four children with a variable phenotype caused by Leydig-cell tumours are described. A molecular analysis of all the 'activating' genes and mutational regions known so far was performed, but no abnormalities were found. The lessons learnt from these clinically variable cases are: perform ultrasound early and most importantly, consider discrepancies between testicular swelling, tumour size and androgen production.

[Examination of urine in the child]

The examination of urine in children can be very complex, due to the difficulty to obtain clean urine specimens in infants and toddlers. Clean catch is an easy system to obtain urine but patience is needed. Transurethral catheterization or suprapubic aspiration is useful in infants and toddlers with sign of pyelonephritis. Urine bag specimens are not useful in the diagnosis of urinary tract infection because of the high rate of false positive cultures. The 24 hours urine collection is frequently replaced by a spot urine and the ratio of the measured substances with the urine creatinine are calculated. Urine microscopy is needed for the evaluation of pathological results in the dipstick testing: confirm that red urine is due to haematuria by demonstration of red blood cells on urine microscopy, dysmorphic cells and red-cell casts are pathognomonic of glomerular bleeding, white-cell casts signify glomerular inflammation and bacteria are easily seen in unstained urine. A urine culture is pathologic if the colony count exceeds 10(4) in the transurethral catheterization or clean void. In the suprapubic aspiration is any number of colony pathologic. Urate crystals in the urine of infants may cause a pink discoloration to nappies. Urine screenings are not very useful and should be performed only at the age of 5 years or by sexual-active adolescents.

[Recurrent febrile episodes--normal, periodic fever syndrome or immunodeficiency?]

Fever is one of the main symptoms leading to medical evaluation. Not only infections cause fever but also inflammatory disorders. To distinguish one from another, a thorough medical history and clinical evaluation are needed. Sometimes, only the clinical course will reveal the diagnosis. PFAPA-Syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis) is the most frequent periodic fever syndrome in Switzerland. No diagnostic test is available to support the diagnosis. Some important diseases have to be ruled out, such as Immunodeficiency, cyclic neutropenia, chronic viral infections and rheumatologic disorders. To know the diagnosis of the PFAPA-Syndrome can help avoiding antibiotic courses for febrile episodes in infants. There is a clinical overlap to hereditary periodic fever syndromes as familial Mediterranean fever (FMF), Hyper-IgD and fever syndrome (HIDS), Tumor-necrosis factor receptor associated periodic syndrome (TRAPS) and others, in which a genetic basis for the disease has already been found.

A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans

BACKGROUND: High fructose consumption is suspected to be causally linked to the epidemics of obesity and metabolic disorders. In rodents, fructose leads to insulin resistance and ectopic lipid deposition. In humans, the effects of fructose on insulin sensitivity remain debated, whereas its effect on ectopic lipids has never been investigated. OBJECTIVE: We assessed the effect of moderate fructose supplementation on insulin sensitivity (IS) and ectopic lipids in healthy male volunteers (n = 7). DESIGN: IS, intrahepatocellular lipids (IHCL), and intramyocellular lipids (IMCL) were measured before and after 1 and 4 wk of a high-fructose diet containing 1.5 g fructose . kg body wt(-1) . d(-1). Adipose tissue IS was evaluated from nonesterified fatty acid suppression, hepatic IS from suppression of hepatic glucose output (6,6-2H2-glucose), and muscle IS from the whole-body glucose disposal rate during a 2-step hyperinsulinemic euglycemic clamp. IHCL and IMCL were measured by 1H magnetic resonance spectroscopy. RESULTS: Fructose caused significant (P < 0.05) increases in fasting plasma concentrations of triacylglycerol (36%), VLDL-triacylglycerol (72%), lactate (49%), glucose (5.5%), and leptin (48%) without any significant changes in body weight, IHCL, IMCL, or IS. IHCL were negatively correlated with triacylglycerol after 4 wk of the high-fructose diet (r = -0.78, P < 0.05). CONCLUSION: Moderate fructose supplementation over 4 wk increases plasma triacylglycerol and glucose concentrations without causing ectopic lipid deposition or insulin resistance in healthy humans.