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BACKGROUND: Chronic tic disorders are neurodevelopmental disorders that can be treated with Habit Reversal Training (HRT) and Exposure Response Prevention (ERP). Intermediate and long-term effects have been examined after individual treatment with HRT, whereas evaluation of long-term outcome after an initial treatment with ERP, or a combination of HRT and ERP is lacking. The present study examines the long-term effect after a combined treatment with HRT and ERP delivered in an individual or a group setting METHODS: Fifty-nine children and adolescents diagnosed with a chronic tic disorder were randomised to manualised treatment combining HRT and ERP as individual or group training. Forty-seven were re-examined 1 year after acute outcome. Outcome measures included Total Tic Severity score (TTS) measured by the Yale Global Tic Severity Scale (YGTSS) and Beliefs About Tics Scale (BATS) RESULTS: In a mixed model, it was shown that the initial improvement with both individual and group treatment was maintained throughout the follow-up period. There were no significant differences between the two methods of treatment delivery. Of all participants completing the 12 months evaluation, 74.4% were considered responders. There was a significant positive association between the reduction of TTS and the reduction in BATS. In a latent class post-treatment trajectory analysis, two classes were identified, where high baseline severity increased the likelihood of being in the lesser responder class. Similar, but only as a trend, having ADHD, planning difficulties or hypersensitivity increased the risk of a lesser response. CONCLUSIONS: The present study compares the efficacy in individualised and group treatment of providing manualised therapy for child and adolescent tic disorders using two behavioural methods (combined HRT and ERP) both of which have been shown to have acute benefits but only one of which has been validated for longer term effectiveness. In the present study, both individualised and group treatments showed benefit throughout a 1-year follow-up period with several potential confounds affecting outcomes, while the relative benefits of either HRT and ERP were not addressed. Trial registration NCT04594044, 1-10-72-216-15, registered 19th October 2020, retrospectively registered, https://register.clinicaltrials.gov/prs/app/template/Home.vm?uid=U0005BW2&ts=9&sid=S000ABEY&cx=-wlx7vb The study is approved by the National Ethical Committee (1-10-72-216-15) and the Danish Data Protection Agency (1-16-02-490-15), registered 12 October 2015.

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BACKGROUND: Obsessive compulsive disorder (OCD) is a distressing psychiatric disorder. Traumas may trigger or aggravate OCD symptoms. COVID-19 pandemic has coursed a global crisis and has been associated with onset of psychiatric disorders in adults. Little is known about children/adolescents with OCD. The present study aimed to examine how children/adolescents with OCD react towards COVID-19 crisis. METHODS: A questionnaire was distributed to two separate groups of children/adolescents. One group was a clinical group newly diagnosed at a specialized OCD clinic. All the children/adolescents had a current close contact to a therapist or doctor. The other group was a survey group identified through the Danish OCD Association. Most of these children/adolescents were diagnosed years ago, and their primary treatment was completed. For the clinical group, data from patient files was available. RESULTS: In both groups, but most pronounced in the survey group, participants experienced a worsening of their OCD, anxiety, and depressive symptoms. The aggravation of OCD correlated with the worsening of anxiety, depressive symptoms, and the extent of avoidance behavior. For both groups, OCD aggressive symptoms predicted a significant worsening. Poor baseline insight showed a trend to predict a symptom worsening. The worsening was most pronounced in children with early age of onset and a family history of attention deficit hyperactivity disorder. CONCLUSIONS: To our knowledge, this is one of the first studies examining the effect of COVID-19 in children/adolescents with OCD. The effect was examined in two separate populations strengthening the findings. The study points towards an influence of the OCD phenotype, baseline insight suggesting a continued vulnerability, and a family history of psychiatric disorders. TRIAL REGISTRATION: The study is approved by the Danish Data Protection Agency (1-16-02-147-20) registered 1st of April 2020. Oral and written information was given to parents and patients and written consent from patients over 15 years and parents were received.

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BACKGROUND: Chronic tic disorders may have a major impact on a child's function. A significant effect has been shown for combined habit reversal training (HRT) and exposure response prevention (ERP) treatment delivered in an individual and group setting. AIMS: The present study examines predictors and moderators of treatment outcome after an acute therapeutic intervention. METHOD: Fifty-nine children and adolescents were randomised to manualised treatment combining HRT and ERP as individual or group training. Age, gender, baseline tic severity, Premonitory Urge for Tics Scale (PUTS) scores, Beliefs about Tic Scale (BATS) scores, hypersensitivity and comorbid psychiatric symptoms were analysed as predictors of outcome. The same characteristics were examined as moderators for individual versus group treatment. Outcome measures included the change in total tic severity (TTS) score and functional impairment score (as measured by the Yale Global Tic Severity Scale (YGTSS)). RESULTS: Internalising symptoms predicted a lesser decrease in functional impairment. The occurrence of obsessive-compulsive symptoms predicted a larger decrease in TTS. Baseline hypersensitivity and high scores on depressive symptoms favoured individual treatment. High baseline PUTS scores favoured group therapy. CONCLUSIONS: This is the first study examining factors predicting and moderating perceived functional impairment following a therapeutic intervention. The study adds to the knowledge on predictors and moderators of TTS. Furthermore, this is the first study examining the effect of the BATS score. The study points towards factors that may influence treatment outcome and that require consideration when choosing supplemental treatment. This applies to comorbid anxiety and depressive symptoms, and to the child's belief about their tics and premonitory urge. DECLARATION OF INTEREST: None.

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The underlying structure of obsessive-compulsive disorder (OCD) remains to be confirmed in child and adolescent populations. In this paper we report the first factor analytic study of individual OCD items from Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). OCD symptoms were assessed using the CY-BOCS symptom checklist in a sample of 854 patients with OCD (7-18 years of age) recruited from clinics in five countries. Pooled data were subjected to exploratory and confirmatory factor analysis (CFA) to identify the optimal factor structure. Various models were tested for age and gender subgroups. Also, the invariance of the solution across age and gender was tested and associations with demographic and clinical factors were explored. A three-factor model provided the best-fit solution. It consisted of the following factors: (1) harm/sexual, (2) symmetry/hoarding, (3) contamination/cleaning. The factor structure was invariant for age and gender across subgroups. Factor one was significantly correlated with anxiety, and factor two with depression and anxiety. Factor three was negatively correlated with tic disorder and attention-deficit/hyperactivity disorder (ADHD). Females had higher scores on factor two than males. The OCD symptom structure in children and adolescents is consistent across age and gender and similar to results from recent child and adolescents although hoarding may not be a separate factor. Our three-factor structure is almost identical to that seen in early studies on adults. Common mental disorders had specific patterns of associations with the different factors.

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Methionine-enkephalin (met-enk) detected in monocytes in psoriatic skin can modulate inflammatory processes and keratinocyte differentiation/proliferation in vitro. The purpose of the present study was to determine the effect of intradermal injection of met-enk on normal human skin and on the development of a delayed type skin hypersensitivity reaction. In 6 healthy volunteers, 50 microl of met-enk (16, 30, and 45 nmol) was injected once in the forearm and the reaction was evaluated clinically and by video-optical recording for 120 min. Compared to vehicle (0.9% saline), met-enk induced a time- and dose-dependent flare reaction, but no significant stimulation of a weal reaction. The flare reaction was maximal after 1 min and disappeared within 45 min. Pre-treatment with the antihistamine cetirizine reduced the flare reaction. Furthermore, the effect of met-enk on lymphocyte/monocyte infiltration and epidermal proliferation in normal skin and on a delayed type skin hypersensitivity reaction was assessed. Met-enk (45 nmol/ 50 microl) was injected at 0, 24 and 48 h. In normal skin, met-enk increased the number of dermal lymphocytes/monocytes (CD3/CD68 positive cells) and the degree of epidermal proliferation (MIBI-Ki67). In a delayed type hypersensitivity reaction induced by tuberculin (PPD), the degree of epidermal proliferation and the number of infiltrating lymphocytes/monocytes were reduced compared to PPD alone. Our study suggests that intradermal injection of met-enk in normal human skin induces an inflammatory reaction that may involve the release of histamine. In contrast, met-enk seems to down-regulate the development of a delayed type skin hypersensitivity reaction. These results may indicate that the direction of the effect of the opioid peptide met-enk on human skin depends on the rate of epidermal proliferation and the activity of immunocompetent cells.

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BACKGROUND: Enkephalins are opioid peptides that can modulate immune responses and inflammatory processes. Furthermore, they inhibit keratinocyte proliferation/differentiation in vitro. Previously, we have shown that enkephalins are present in increased amounts in lesional psoriasis. OBJECTIVE: To determine the effect of topical treatment with the vitamin D analogue calcipotriol and the corticosteroid mometasone furoate on the level of methionine-enkephalin (enk) in psoriatic lesions. METHODS: Twelve psoriatic patients were treated with calcipotriol and mometasone furoate for 14 days without or with hydrocolloid occlusion. Keratome biopsies were obtained from treated and untreated skin, and the extracted enk was quantified by radioimmunoassay. Furthermore, punch biopsies were obtained for immunohistochemical analysis. RESULTS: Clinically, both calcipotriol and mometasone furoate improved psoriasis to the same degree, the effects being more pronounced after occlusion. Histologically, treatment with mometasone furoate without occlusion decreased both the epidermal thickness/parakeratosis and the number of dermal immunocompetent cells (CD3- and CD68-positive cells). In contrast, treatment with calcipotriol without occlusion reduced the epidermal thickness and the degree of parakeratosis but decreased the number of CD3- and CD68-positive cells only slightly. The mean enk level was decreased by 26 and 86% by calcipotriol without and with occlusion and by 16 and 63% by mometasone furoate without and with occlusion, respectively. The decreases in the enk levels corresponded to the degree of clinical improvement but not to the histological changes. CONCLUSION: The increased levels of enk in psoriatic lesions are reduced in parallel with the clinical improvement induced by a topical vitamin D analogue and a corticosteroid. Because enkephalins can modulate epidermal differentiation and inflammatory processes, the findings indicate that enkephalins may play a role in the pathogenesis of psoriasis.

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The opioid peptides enkephalins have been shown to modulate inflammatory responses and keratinocyte proliferation and differentiation. Furthermore, increased levels of enkephalin are present in psoriatic lesions. The purpose of the present study was to determine the effect of natural sunlight combined with salt water bathing in the Dead Sea on the methionine-enkephalin (e.n.k.) level in psoriatic skin. Ten patients were treated at the Dead Sea for 4 weeks, and keratotome biopsies were obtained before and after treatment. The amount of enkephalin extracted from the biopsies was measured by radioimmunoassay. Treatment at the Dead Sea resulted in a complete clinical clearance of psoriasis, and immunohistochemical stainings of lesional skin showed that the treatment decreased both epidermal thickness/parakeratosis and the dermal infiltration of CD3- and CD68-positive cells, although the number of CD3- and CD68-positive cells became normal in only two of the 10 cases. However, there was only a slight decrease in the mean enk levels (21%). Furthermore, the level of enk was high in non-lesional psoriatic skin after treatment at the Dead Sea, and immunostaining showed that, in some patients, the treatment induced a mild epidermal hyperplasia and a dermal infiltration of CD3- and CD68-positive cells. Enkephalin-like immunoreactivity was detected in the cytoplasm of both epidermal keratinocytes and dermal infiltrating cells. To determine whether the relatively high skin enk levels after treatment at the Dead Sea was caused by ultraviolet (UV) radiation, normal volunteers were exposed to a single dose of UVA and UVB (2 minimal erythema doses). UVA, but not UVB, irradiation stimulated the mean enk level in the irradiated skin by about sixfold. Furthermore, multiple whole-body UVA irradiations not only resulted in increased skin levels of enk, but also in increased plasma levels. In conclusion, natural sunlight combined with salt water bathing cleared psoriasis without causing a significant decrease in lesional enk levels. Furthermore, non-lesional enk levels were increased. These findings may be the result of a direct stimulatory effect of UVA irradiation on enk formation in the skin. It is possible that the increased circulating levels of enk after UV exposure may contribute to the beneficial effects of UVA irradiation.

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Opioid peptides are synthesized in neurons, endocrine cells, monocytes/macrophages and B and T lymphocytes. They interact with opioid receptors located on immune cells and nociceptive nerve terminals. Because opioid peptides might be of importance in inflammatory skin diseases, for example psoriasis, sections of skin from psoriatic patients were immunohistochemically stained with antisera against methionine and leucine enkephalin, CD68 (KP1, PG-M1), calprotectin (M747), M130 (Ber-MAC3), CD1a and CD3. Enkephalin-like activity was detected selectively in dermal CD68-positive macrophages/monocytes. The activity showed no association with the activation markers M747 and Ber-MAC3. There was a statistically significant increase in enkephalin-positive cells in involved psoriatic skin compared with uninvolved and normal skin. These results were confirmed by radioimmunoassay which showed elevated levels in extracts from involved psoriatic skin compared with uninvolved skin (81%) and normal skin (204%). Furthermore, preproenkephalin mRNA of an expected size was detected in involved psoriatic skin. If the increased levels of enkephalins present in monocytes/macrophages in psoriatic skin lesions reach the threshold for biological activity, they may play a role in the regulation of the inflammatory processes seen in this skin disease.

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Opioid peptides are a group of neuropeptides which include enkephalins, endorphins and dynorphins. In addition to their central and peripheral antinociceptive function, opioids can modulate immune activity and cell proliferation. Previously, we have shown that enkephalins are present in macrophages infiltrating the dermal papillae in involved psoriatic skin and that the amount of enkephalin is significantly increased in involved psoriatic skin. Because enkephalins were detected close to the epidermis, we examined the effects of opioid peptides on the differentiation (transglutaminase type 1 activity and cytokeratin 10 expression) and proliferation (MTT assay) of cultured human keratinocytes. Enkephalins (methionine-enkephalin, leucine-enkephalin and the synthetic DADL) inhibited cell differentiation dose-dependently, while beta-endorphin had no effect. The opioid receptor antagonist naltrexone completely antagonized the inhibitory effect of methionine-enkephalin and leucine-enkephalin, but not that of DADL. Furthermore, methionine-enkephalin had a slight inhibitory effect on the proliferation of keratinocytes. Enkephalin was detected in unstimulated keratinocyte cultures, and naltrexone alone stimulated keratinocyte differentiation. These results indicate that enkephalins may play a role in the differentiation of epidermal keratinocytes. It remains to be determined whether the enkephalin detected in psoriatic skin are sufficient to affect epidermal differentiation in vivo.

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Leukotriene A4 hydrolase is a bifunctional cytosolic enzyme, which both hydrolyses leukotriene A4 (LTA4) into leukotriene B4 (LTB4) and exerts aminopeptidase activity against opioid peptides. In the present study we have investigated whether the peptides angiotensin I and II, bradykinin, kallidine, histamine, dynorphin fragment 1-7 and substance P can act as substrates for epidermal and neutrophil LTA4 hydrolase. Among the tested substrates, dynorphin fragment 1-7 was found to be the best substrate for the enzyme. The aminopeptidase activity of epidermal and neutrophil LTA4 hydrolase against dynorphin fragment 1-7 was further characterized. The enzyme was purified from human epidermis and human neutrophils by anion exchange chromatography (Q-Sepharose) and affinity chromatography on a column with the LTA4 hydrolase inhibitor bestatin coupled to AH-Sepharose. The incubation of the dynorphin fragment 1-7 with LTA4 hydrolase resulted in the formation of tyrosine. The presence of the N-terminal amino acid tyrosine is essential for the interaction of opioids with their receptors, and this finding indicates that the LTA4 hydrolase can inactivate dynorphin fragment 1-7. After the two purification steps no other aminopeptidases acting at the N-terminal tyrosine of dynorphin fragment 1-7 was present in the preparation. This was demonstrated by the abolishment of the degradation at the N-terminal end of dynorphin fragment 1-7 when preincubating the enzyme preparation with LTA4 before the incubation with the dynorphin fragment 1-7. The abolishment of the aminopeptidase activity shows that activation of the hydrolase part of the enzyme, with conversion of LTA4 into the potent proinflammatory compound LTB4, results in an inhibition of the aminopeptidase activity of the enzyme. As a result, the catabolism of dynorphin fragment 1-7 and probably of other opioid peptides is inhibited, resulting in sustained biological effects of these opioids. This phenomenon may be important for the maintenance of inflammation in skin conditions, such as psoriasis and atopic dermatitis, in which LTB4 is formed.

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The leukotriene A4 hydrolase is a central enzyme in leukotriene B4 formation. Unlike 5-lipoxygenase, leukotriene A4 hydrolase activity is present in normal human epidermis, where it is likely to be involved in transcellular leukotriene formation. In this study the leukotriene A4 hydrolase was purified from human epidermis and human cultured keratinocytes and compared with leukotriene A4 hydrolase from human neutrophils. To purify leukotriene A4 hydrolase from human epidermis a new non-specific affinity chromatography column, with the leukotriene A4 hydrolase inhibitor bestatin coupled to AH-Sepharose, was introduced. The epidermal leukotriene A4 hydrolase was purified to apparent homogeneity and the molecular weight was determined to be approximately 70,000 Da by SDS-PAGE. The pI was 5.1-5.4 for the epidermal as well as the keratinocyte and neutrophil leukotriene A4 hydrolase, as determined by chromatofocusing. Only minor differences in the amino acid composition were seen between the three enzyme sources. The optimal pH for the hydrolase activity was 7.5-8.5 for the epidermal and neutrophil leukotriene A4 hydrolases. Finally, it was also shown that the epidermal leukotriene A4 hydrolase undergoes suicide inactivation when transforming leukotriene A4 into leukotriene B4. It was concluded that there is a close resemblance between the epidermal leukotriene A4 hydrolase and the hydrolase found in other cell types. Therefore, the human epidermis may be a good model for the in vivo study of transcellular leukotriene formation.

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