Markers of gut mucosal inflammation and cow's milk specific immunoglobulins in non-IgE cow's milk allergy

Peer reviewe

Sleep Physiology, Circadian Rhythms, Waking Performance and the Development of Sleep-Wake Therapeutics

Disturbances of the sleep-wake cycle are highly prevalent and diverse. The aetiology of some sleep disorders, such as circadian rhythm sleep-wake disorders, is understood at the conceptual level of the circadian and homeostatic regulation of sleep and in part at a mechanistic level. Other disorders such as insomnia are more difficult to relate to sleep regulatory mechanisms or sleep physiology. To further our understanding of sleep-wake disorders and the potential of novel therapeutics, we discuss recent findings on the neurobiology of sleep regulation and circadian rhythmicity and its relation with the subjective experience of sleep and the quality of wakefulness. Sleep continuity and to some extent REM sleep emerge as determinants of subjective sleep quality and waking performance. The effects of insufficient sleep primarily concern subjective and objective sleepiness as well as vigilant attention, whereas performance on higher cognitive functions appears to be better preserved albeit at the cost of increased effort. We discuss age-related, sex and other trait-like differences in sleep physiology and sleep need and compare the effects of existing pharmacological and non-pharmacological sleep- and wake-promoting treatments. Successful non-pharmacological approaches such as sleep restriction for insomnia and light and melatonin treatment for circadian rhythm sleep disorders target processes such as sleep homeostasis or circadian rhythmicity. Most pharmacological treatments of sleep disorders target specific signalling pathways with no well-established role in either sleep homeostasis or circadian rhythmicity. Pharmacological sleep therapeutics induce changes in sleep structure and the sleep EEG which are specific to the mechanism of action of the drug. Sleep- and wake-promoting therapeutics often induce residual effects on waking performance and sleep, respectively. The need for novel therapeutic approaches continues not at least because of the societal demand to sleep and be awake out of synchrony with the natural light-dark cycle, the high prevalence of sleep-wake disturbances in mental health disorders and in neurodegeneration. Novel approaches, which will provide a more comprehensive description of sleep and allow for large-scale sleep and circadian physiology studies in the home environment, hold promise for continued improvement of therapeutics for disturbances of sleep, circadian rhythms and waking performance

Separation of the PROX1 gene from upstream conserved elements in a complex inversion/translocation patient with hypoplastic left heart

Hypoplastic left heart (HLH) occurs in at least 1 in 10 000 live births but may be more common in utero. Its causes are poorly understood but a number of affected cases are associated with chromosomal abnormalities. We set out to localize the breakpoints in a patient with sporadic HLH and a de novo translocation. Initial studies showed that the apparently simple 1q41;3q27.1 translocation was actually combined with a 4-Mb inversion, also de novo, of material within 1q41. We therefore localized all four breakpoints and found that no known transcription units were disrupted. However we present a case, based on functional considerations, synteny and position of highly conserved non-coding sequence elements, and the heterozygous Prox1(+/-) mouse phenotype (ventricular hypoplasia), for the involvement of dysregulation of the PROX1 gene in the aetiology of HLH in this case. Accordingly, we show that the spatial expression pattern of PROX1 in the developing human heart is consistent with a role in cardiac development. We suggest that dysregulation of PROX1 gene expression due to separation from its conserved upstream elements is likely to have caused the heart defects observed in this patient, and that PROX1 should be considered as a potential candidate gene for other cases of HLH. The relevance of another breakpoint separating the cardiac gene ESRRG from a conserved downstream element is also discusse

Second premolar agenesis is associated with mandibular form : a geometric morphometric analysis of mandibular cross-sections

The aim of this study was to compare mandibular form (i.e., size and shape) between patients with agenesis of the lower second premolar (P2) and a control group with no agenesis. Three hypotheses were tested: (H1) agenesis causes a change in mandibular morphology because of inadequate alveolar ridge development in the area of the missing tooth (mandibular plasticity); (H2) agenesis is caused by spatial limitations within the mandible (dental plasticity); and (H3) common genetic/ epigenetic factors cause agenesis and affect mandibular form (pleiotropy). A geometric morphometric analysis was applied to cross-sectional images of computed tomography (CT) scans of three matched groups (n = 50 each): (1) regularly erupted P2; (2) agenesis of P2 and the primary second molar in situ; and (3) agenesis of P2 and the primary second molar missing for 43 months. Cross-sections of the three areas of interest (first premolar, P2, first molar) were digitized with 23 landmarks and superimposed by a generalized Procrustes analysis. On average, the mandibular cross-sections were narrower and shorter in patients with P2 agenesis compared with that in the control group. Both agenesis groups featured a pronounced submandibular fossa. These differences extended at least one tooth beyond the agenesis-affected region. Taken together with the large interindividual variation that resulted in massively overlapping group distributions, these findings support genetic and/or epigenetic pleiotropy (H3) as the most likely origin of the observed covariation between mandibular form and odontogenesis. Clinically, reduced dimensions and greater variability of mandibular form, as well as a pronounced submandibular fossa, should be expected during the treatment planning of patients with P2 agenesis