Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia

The atypical antipsychotic clozapine is one of the most potent drugs of its class, yet its precise mechanisms of action remain insufficiently understood. Recent evidence points toward the involvement of endogenous retinoic acid (RA) signaling in the pathophysiology of schizophrenia. Here we investigated whether clozapine may modulate RA-signaling. Effects of clozapine on the catabolism of all-trans RA (at-RA), the biologically most active metabolite of Vitamin A, were assessed in murine and human brain tissue and peripheral blood-derived mononuclear cells (PBMC). In patients with schizophrenia with and without clozapine treatment and matched healthy controls, at-RA serum levels and blood mRNA expression of retinoid-related genes in PBMCs were quantified. Clozapine and its metabolites potently inhibited RA catabolism at clinically relevant concentrations. In PBMC-derived microsomes, we found a large interindividual variability of the sensitivity toward the effects of clozapine. Furthermore, at-RA and retinol serum levels were significantly lower in patients with schizophrenia compared with matched healthy controls. Patients treated with clozapine exhibited significantly higher at-RA serum levels compared with patients treated with other antipsychotics, while retinol levels did not differ between treatment groups. Similarly, in patients without clozapine treatment, mRNA expression of RA-inducible targets CYP26A and STRA6, as well as at-RA/retinol ratio, were significantly reduced. In contrast, clozapine-treated patients did not differ from healthy controls in this regard. Our findings provide the first evidence for altered peripheral retinoid homeostasis in schizophrenia and suggest modulation of RA catabolism as a novel mechanism of action of clozapine, which may be useful in future antipsychotic drug development

Odor identification performance in children aged 3–6 years

Background!#!While valid and reliable olfactory tests have been developed for children aged >5 years, olfactory testing has not systematically been evaluated in younger children. The aim of this study was to evaluate the reliability and validity of the 'U-Sniff' odor identification test in children aged 3-6 years.!##!Methods!#!We included 160 healthy children (age range 3-6 years) and 14 congenitally anosmic children. Participants were investigated in two identical sessions. The 'U-Sniff' test was used to evaluate olfactory function. A picture identification test (PIT) and the Kasel-Concentration-Task (KKA) were administered to identify factors influencing odor identification performance.!##!Results!#!Age significantly influenced odor identification performance, with older children achieving higher scores. PIT and KKA scores correlated positively with odor identification scores. The 'U-Sniff' test demonstrated a high test-retest reliability (r!##!Conclusions!#!The 'U-Sniff' test is feasible for children starting at age 3 years. In children aged ≥4 years, it is a reliable and valid method to distinguish between normal olfactory function and anosmia.!##!Impact!#!Olfactory testing is reliable and valid starting at an age of 4 years. The study adds a systematic evaluation of olfactory testing in young children. Results of this study are especially interesting for clinicians in the diagnosis of olfactory dysfunction

Olfactory threshold and odor discrimination ability in children – evaluation of a modified “Sniffin’ Sticks” test

The clinical diagnostics of olfactory dysfunction in children turns out to be challenging due to low attention span, insufficient linguistic development and lack of odor experiences. Several smell tests have been developed for adults. Most of these examinations take a relatively long time and require a high level of concentration. Therefore, the aim of the current study was to evaluate an odor discrimination and olfactory threshold test using the frequently used “Sniffin’ Sticks” in children and adolescents in a simplified two-alternative-forced-choice version (2AFC) and compare it to the original three-alternative-forced-choice test (3AFC). One-hundred-twenty-one healthy participants aged between 5 and 17 years took part in this study. Within each of the two sessions participants underwent olfactory testing using the modified 2AFC as well as the standard 3AFC method. A better test-retest reliability was achieved using the original 3AFC method compared to the modified 2AFC. This was true for the odor discrimination as well as the olfactory threshold. Age had a significant influence on both tests, which should be considered when testing young children. We discuss these findings with relation to the existing norms and recommend using the 3AFC version due to a better test-retest reliability to measure olfactory function in children

Central Nervous System Processing of Floral Odor and Mother's Milk Odor in Infants

Newborns have a functioning sense of smell at birth, which appears to be highly significant for feeding and bonding. Still, little is known about the cerebral odor processing in this age group. Studies of olfactory function relied mostly on behavioral, autonomic, and facial responses of infants.The aim of the present study was to investigate central odor processing in infants focusing on electroencephalography (EEG)-derived responses to biologically significant odors, namely a food and a non-food odor. A total of 21 term-born, healthy infants participated (11 boys and 10 girls; age range 2-9 months, mean 5.3 +/- 2.2 months). Odor stimuli were presented using a computer-controlled olfactometer. Breast milk was used as food odor. Farnesol was presented as a non-food odor. In addition, odorless air was used as a control stimulus. Each stimulus was presented 30 times for 1 s with an interstimulus interval of 20 s. EEG was recorded from 9 electrodes and analyzed in the frequency domain. EEG amplitudes in the delta frequency band differed significantly after presentation of food (breast milk) odor in comparison to the control condition and the non-food odor (farnesol).These changes were observed at the frontal recording positions. The present study indicates that central odor processing differs between a food and a non-food odor in infants. Results are interpreted in terms of focused attention towards a physiologically relevant odor (breast milk), suggesting that olfactory stimuli are of specific significance in this age group

Children’s Personal Significance of Olfaction — the ChiPSO Questionnaire

Introduction The human sense of smell has different functions which can be categorized as “food,” “social,” and “environment.” Different questionnaires about the importance of olfaction in adults are available, but little attention has been paid to children and adolescents. Therefore, we aimed to develop a questionnaire about children’s personal significance of olfaction (ChiPSO). Methods The questionnaire was developed in two steps. The first questionnaire included 33 statements about the importance of olfactory information in daily life — covering three subscales “food,” “environment,” and “social” administered to 191 participants (mean age: 14.4 ± 1.7 years). The five best fitting items of each subscale were chosen for the final 15-item questionnaire. In the second part, we administered the developed questionnaire to 208 children and adolescents (mean age: 11.5 ± 3.5 years) who additionally underwent olfactory testing to investigate the association between olfactory function and questionnaire results. Participants were separated in two age groups: (i) 6–11 years (children), (ii) 12–17 years (adolescents). Results A significant influence of age on the total ChiPSO score and all three subscales with adolescents scoring higher than children was found. Additionally, there was a significant influence of sex in adolescents on total ChiPSO score and subscales “social” and “food” with girls scoring higher than boys. Conclusion We report an association between questionnaires results and olfactory performance. Additionally, olfactory information seems to be more important to adolescents compared to children and girls compared to boys. Implications The ChiPSO questionnaire is a practical tool to evaluate the importance of olfactory information in children and adolescents aged 6–17 years

CD56‐positive haematological neoplasms of the skin: a multicentre study of the Cutaneous Lymphoma Project Group of the European Organisation for Research and Treatment of Cancer

Cutaneous lymphomas expressing CD56, a neural cell adhesion molecule, are characterised in most cases by a highly aggressive clinical course and a poor prognosis. However, prognostic subsets within the CD56+ group have been difficult to identify due to the lack of uniform clinicopathological and immunophenotypical criteria. A multicentre study was conducted by the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer to define prognostic parameters and establish diagnostic and therapeutic guidelines for CD56+ haematological neoplasms presenting primarily in the skin. Four different subtypes of lymphoproliferations with CD56 expression were identified: (1) haematodermic neoplasm; (2) skin infiltration as the first manifestation of CD56+ acute myeloid leukaemia; (3) nasal-type extranodal natural killer/T-cell lymphoma; and (4) "classical" cases of cutaneous T-cell lymphoma (CTCL) with co-expression of the CD56 molecule. Patients in the first three groups had a poor outcome (93% died) with a median survival rate of 11 months (95% CI 2-72 months), whereas all patients with CD56+ CTCL were alive at the last follow-up. Results show that CD56+ cutaneous lymphoproliferative disorders, with the exception of CD56+ CTCL have a very poor prognosis. It is therefore clinically important to separate CD56+ CTCL from the remaining CD56+ haematological disorder