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Introduction: The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet. Objectives: We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression. Methods: Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal. Results: High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75–225 mg/day). The population-based concentration ranges (25–75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225–450 ng/ml for the AM and (ii) 144–302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140–600 ng/ml. Conclusion: VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN's dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations. [ABSTRACT FROM AUTHOR]

All patients continued to use TCS, one patient received concomitant acitretin, which had been initiated approximately 5 years before the anti-IL-23 treatment, and one patient received concomitant methotrexate, which was initiated 16 weeks after the beginning of the biological therapy. 56.3% (9/16) and 25.0% (4/16) of the patients reached PPPASI-50 and PPPASI-75 improvement at week 12, respectively, and at 12 months of treatment PPPASI-50 and PPPASI-75 response was observed in 62.5% (10/16) and 43.8% (7/16) of patients, respectively (Figure 1a-c). The patients in this manuscript have given written informed consent to the publication of their case details (photographs). [Extracted from the article]

Biologic switching is common in psoriasis patients with non-response to or adverse events under therapy with a biologic. However, evidence on efficacy of switching between newly approved biologics of similar mode of action is scarce. The objective was to assess the efficacy of treating psoriasis patients with an IL-17-receptor A antagonist after failure of any IL-17A antagonist and to identify predictors of treatment response. A retrospective multicenter chart review on psoriasis patients who received brodalumab after failure of ixekizumab or secukinumab therapy was conducted in five German University Medical centers. Overall, 23 patients were identified. PASI75 response to brodalumab was reached by 47.8% (11/23) of all patients at week 12 and at week 24. 3 patients experienced mild adverse events which did not lead to drug discontinuation. Brodalumab appears to be an efficacious and safe treatment option in psoriasis patients with prior exposure to IL-17A antagonists. [ABSTRACT FROM AUTHOR]

Background: Palmoplantar pustulosis (PPP) is a chronic skin disease with painful erythematous scaly or crusty lesions and pustules on the palms and soles. Apremilast is a phosphodiesterase 4 inhibitor that has proven effective in the therapy of psoriasis, psoriatic arthritis and in oral ulcers associated with Behcet's disease. Objective: To explore the efficacy of apremilast in PPP. Methods: APLANTUS was a phase 2 single‐arm multicentre study of apremilast in 21 subjects with moderate‐to‐severe PPP. Primary endpoint was the per cent change of the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at week 20 compared to baseline. Results: 20 weeks of oral treatment with apremilast in patients with moderate‐to‐severe PPP resulted in a significant decrease of the PPPASI with a median reduction of 57.1% (p < 0.001), and 61.9% of patients achieved at least a 50% improvement of the PPPASI relative to baseline. The total number of pustules per patient decreased significantly relative to baseline with 76.2% of patients achieving at least a 50% reduction in total pustules count at week 20. Improvement of PPP was also apparent in a significant decrease of the dermatologic life quality index (DLQI). The median DLQI score dropped from 8.5 at baseline to 2.0 at week 20 (p = 0.030). Apremilast was generally well tolerated, and no serious adverse events occurred. Conclusions: Patients with PPP treated with apremilast showed benefit both in objective and subjective disease parameters. Apremilast should be investigated further in this difficult‐to‐treat skin condition. EudraCT number: 2016‐005122‐11. [ABSTRACT FROM AUTHOR]

Switching of biologic agents in treatment of plaque psoriasis is a common strategy. Only a few studies are available on switching between IL17Ablockers. In a retrospective study, we identified 22 psoriasis patients who, after failing secukinumab as a first IL17A-blocker received ixekizumab with an observation period of at least 24 weeks. At last observation 10/22 patients had a good response (PASI75 or PASI<3) using ixekizumab therapy. None of five patients with primary non-response to secukinumab reached a good, durable response to ixekizumab. In conclusion, ixekizumab appears to be a therapeutic option as a second IL17A-blocker in psoriasis patients who did not show a primary non-response to secukinumab. [ABSTRACT FROM AUTHOR]

Summary: Background: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). Objectives: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. Methods: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients – 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy‐number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype–phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. Results: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype–phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. Conclusions: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease‐causing genetic factors outside IL36RN. [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs. [ABSTRACT FROM AUTHOR]

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Importance BRAF inhibitors have been licensed for the therapy of BRAF-mutated melanoma. Recently, inflammatory skin lesions clinically resembling erythema nodosum have been reported as therapy side-effects that may lead to treatment discontinuation. Objective To identify and characterize cases with BRAF inhibitor-associated erythema nodosum-like inflammatory skin lesions and development of an algorithm for their management. Design and Setting Retrospective chart review of melanoma patients treated with BRAF inhibitors in 14 departments of Dermatology in Germany and Austria and PubMed search for cases in the literature. Results Sixteen patients were identified who developed erythema nodosum-like lesions under BRAF inhibitor therapy; 14 had received vemurafenib and two dabrafenib plus trametinib. The most frequently involved body sites were the legs. Histopathology was performed in five cases and revealed panniculitis in three and vasculitis in two patients respectively. Arthralgia and fever were associated symptoms in 44% and 31% of patients respectively. Inflammatory symptoms led to discontinuation of treatment in three patients, while in the majority of cases symptomatic management was sufficient. Skin lesions finally resolved despite continued BRAF inhibitor therapy in seven patients. In the literature, 19 additional patients with similar cutaneous appearance under BRAF inhibitors could be identified. An algorithm for the management of such lesions is proposed. Conclusion Erythema nodosum-like skin lesions histologically correspond to panniculitis and/or vasculitis. Symptomatic treatment may be sufficient. However, additional work-up and interruption of BRAF inhibitor therapy may be necessary in severe cases which are commonly associated with systemic symptoms. [ABSTRACT FROM AUTHOR]

The article presents details regarding the chronic recurrent inflammatory skin disease known as hidradenitis suppurativa and outlines the effects of the lipocalin-2 protein on the disease. It references the article by author Kerstin Wolk and colleagues in the issue. It describes the effect of the protein which creates a self-amplifying loop in the disease.

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Objective:Mice deficient of the serotonin transporter (5-HTT ko) mice have a reduced brain serotonin content and develop late-onset obesity. To elucidate the pathophysiology of this obesity, we analyzed the expression of the interrelated weight-regulatory molecules: brain-derived neurotrophic factor (BDNF) and leptin receptor (LR) in brain areas associated with nutrition and activity.Research Design and Methods:We investigated feeding behavior, physical activity and metabolic parameters of 5-HTT ko and wild-type mice and measured the expression of BDNF and LR in brain areas associated with nutrition and activity using quantitative real-time PCR. The influence of age, gender and fasting was analyzed.Results:Male 5-HTT ko mice developed obesity without hyperphagia from the age of 5 months. Physical activity was reduced in old male, but not old female, 5-HTT ko mice. The BDNF gene expression in frontal cortex was elevated in young, but reduced in old 5-HTT ko mice. Fasting failed to increase the BDNF gene expression in frontal cortex of young 5 HTT ko mice and in the hypothalamus in old 5-HTT ko mice. The fasting-induced hypothalamic increase of LR was absent in both young and old 5-HTT ko mice.Conclusions:We propose that low brain serotonin level due to the 5-HTT ko genotype leads to reduced physical activity and low BDNF, which together with the lack of fasting-induced hypothalamic BDNF and LR production results in late-onset obesity. Although lack of the 5-HTT is a genetic vulnerability factor for obesity, female gender is protective. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a genetically complex, chronic inflammatory skin disease. The authors have previously identified a susceptibility locus on chromosome 19p13 (PSORS6). Methods and results: In a follow-up linkage disequilibrium (LD) study in an independent family based cohort, the authors found evidence for association to a newly discovered microsatellite at this locus (D19SPS21, p<5.3 x 10-5). An LD based association scan in 300 trios revealed association to several single, single nucleotide polymorphisms (SNPs) in one LD block. When the authors stratified this cohort for carrying the PSORS1 risk allele at the HLA-C locus, evidence for association became much stronger at single SNP and haplotype levels (p values between 1.0 x 10-4 and 8.0 x 10-4). In a replication study of 1114 patients and 937 control individuals, evidence for association was also observed after stratification to the PSORS1 risk allele. In both study groups, logistic regression showed evidence for interaction between the risk alleles at PSORS1 and PSORS6. Best p values for rs12459358 in both study groups remained significant after correction for multiple testing. The associated LD block did not comprise any known genes. Interestingly, an adjacent gene, MUC16, coding for a large glycosylated protein expressed in epithelia and of unknown function, could be shown to be also expressed in tissues relevant for pathogenesis of psoriasis such as skin and thymus. Immunohistochemical analyses of skin revealed focal staining for MUC16 in suprabasal epidermal cells. Further functional studies are required to clarify its potential role in psoriasis and identify the causal variant(s) at this locus. [ABSTRACT FROM AUTHOR]

Inherited promoter polymorphisms of the interleukin (IL)-10 gene resulting in altered IL-10 production may contribute to a genetic susceptibility for melanoma. We investigated the role of a haplotype from distal as well as proximal polymorphic sites [−7400InDel, −6752AT (rs6676671), −3538AT (rs1800890), −1087AG (rs1800896), −597AC (rs1800872)] of the IL-10 5′-flanking region in a hospital-based case–control study of 165 Caucasian patients with cutaneous melanoma from Germany in comparison with 162 healthy cancer-free Caucasian control participants from the same area matched by age. Using multivariate analysis for the number of nevi and skin type, the IL-10 ‘higher producing’ haplotype ITAGC was found to be significantly associated with a reduced risk of developing melanoma (adjusted P=0.02). Although our findings need to be confirmed by independent and larger multicenter studies, we have described for the first time the association of distal gene variants of the IL-10 gene as an independent risk factor for melanoma. [ABSTRACT FROM AUTHOR]

Background Because psoriatic arthritis (PsA) usually develops years after the first manifestation of skin symptoms, in many cases the initial diagnosis of PsA depends on the dermatologist. Objectives To investigate the prevalence and clinical pattern of PsA in a daily practice population of patients with psoriasis. Methods Patients were enrolled in an observational prospective cross-sectional cohort study at 48 community and academic centres. Demographic and medical parameters were recorded, including severity of skin symptoms (Psoriasis Area and Severity Index, PASI), previous and current treatments, concomitant diseases, and the impact of psoriasis on productivity and health-related quality of life (Dermatology Life Quality Index, DLQI). Patients with joint symptoms were referred to a rheumatologist for diagnosis and to record the activity and pattern of arthritis. Results Among 1511 patients 20·6% had PsA; in 85% of the cases PsA was newly diagnosed. Of these patients more than 95% had active arthritis and 53·0% had five or more joints affected. Polyarthritis (58·7%) was the most common manifestation pattern, followed by oligoarthritis (31·6%) and arthritis mutilans (4·9%). Distal interphalangeal involvement was present in 41·0% and dactylitis in 23·7% of the patients. Compared with patients without arthritis, patients with PsA had more severe skin symptoms (mean PASI 14·3 vs. 11·5), a lower quality of life (mean DLQI 11·6 vs. 7·7) and greater impairment of productivity parameters. Conclusions The findings are consistent with a high prevalence of undiagnosed cases of active PsA among patients with psoriasis seen by dermatologists. As many of these patients also have significant skin symptoms, treatment strategies are required that are equally effective in the control of skin and joint symptoms of psoriasis. [ABSTRACT FROM AUTHOR]

The interleukin-20-receptor I complex (IL-20-RI) is composed of two chains, IL20RA and IL20RB. Its ligands are the three members of the IL19 subfamily of cytokines, IL-19, IL-20 and IL-24. These cytokines are important in the manifestation of psoriatic lesions and, recently, an association of polymorphisms of IL20 with psoriasis has been described. In the present study we tested the hypotheses that genetic variations of the IL-20-RI influence susceptibility to psoriasis and investigated single nucleotide polymorphisms (SNPs) in the IL20RA and IL20RB genes in psoriasis patients (n=254) and healthy controls (n=224). We found no association of any of the investigated SNPs with the disease. Analysis of pairwise linkage disequilibrium (LD) across studied markers revealed a strong level of LD between SNPs within the IL20RA gene and SNPs within the IL20RB gene, and, for both genes six common haplotypes were identified with an estimated frequency 1%. Haplotype analyses suggested that the IL20RA haplotype CCG (rs1184860, rs1167846, rs1167849) is significantly associated with psoriasis (OR 3.14, 95% CI 1.61–6.14), whereas the TTG haplotype had a protective effect (OR 0.20, 95% CI 0.07–0.55). The risk haplotype defining SNPs 1167846 and 1184860 were found to modify paired box 5 and homeobox A9 sites, respectively, two transcription factors related to the differentiation of immune cells. Further studies are needed to confirm the genetic association and to investigate the functional relevance of IL20RA haplotypes in psoriasis.Genes and Immunity (2008) 9, 445–451; doi:10.1038/gene.2008.36; published online 15 May 2008 [ABSTRACT FROM AUTHOR]

Migraine is regarded as a polygenic disease and serotonergic pathways appear to play a major role in its pathogenesis. In the present study, the role of the 5-HT1A and 5-HT1B receptors in migraine was evaluated. The human 5-HT1A receptor gene transcription is modulated by a functional C-1019G promoter polymorphism. The 5-HT1B receptor is the main effector of vasoconstriction in meningeal and cerebral arteries and its functional G861C promoter polymorphism was investigated. We report a positive association of the GG genotype of the 5-HT1A promoter polymorphism with avoidance of physical activity during a migraine attack in comparison to the CC genotype ( p = 0.008). Moreover, a positive association of the CC genotype of the G861C polymorphism of the 5-HT1B receptor with the reported intensity of the headache attack on the visual analogue scale was observed (CC 8.3 ± 1.5 vs. GG 6.9 ± 1.8; p < 0.05). An association of either polymorphism with migraine with or without aura could not be found. For the first time, our results indicate a role of allelic variation of the 5-HT1A receptor in motion related discomfort in migraineurs and a role of the 5-HT1B receptor polymorphism in headache intensity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor gene TNF at positions -238 and -308 have been associated with psoriasis vulgaris and psoriatic arthritis (PsA). The strong linkage disequilibrium (LD) at chromosome region 6p21, a region known to harbor risk factors for psoriasis susceptibility (PSORS1) other than just SNPs of the TNF gene, renders the interpretation of these findings difficult. The aim of this study was to analyze several SNPs of the TNF gene and its neighboring LTA gene for independent and dependent carriage of the PSORS1 risk allele. METHODS: SNPs in the promoter of the TNF (-238G/A, -308G/A, -857C/T, and -1031T/C), LTA (+252A/G), TNLFRSF1A (+36A/G), and TNLFRSF1B (+676T/G) genes were genotyped in 375 psoriasis patients, 375 PsA patients, and 376 controls. The Trp- Trp-Cys-Cys haplotype of the CCHCR1 gene (CCHCR1*WWCC) was used as an estimate of the risk allele PSORS1. RESULTS: Whereas we were able to confirm the previously described strong association of allele TNF*-238A with psoriasis, our study revealed that this association was completely dependent on carriage of the PSORS1 risk allele. For PsA, but not psoriasis vulgaris without joint involvement, a strong association with the allele TNF*-857T (odds ratio 1.956 [95% confidence interval 1.334-2.881]; corrected P = 0.0025) was also detected in patients negative for the PSORS1 risk allele. CONCLUSION: Our results indicate that there are genetic differences between psoriasis vulgaris patients with and without joint manifestations. While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect LD with PSORS1, TNF*-857T may represent a risk factor for PsA that is independent of the PSORS1 allele. [ABSTRACT FROM AUTHOR]

Background Interleukin (IL) 19, IL-20 and IL-24 belong to the IL-10 cytokine family and have been identified to play a role in the regulation of epidermal functions and in inflammation. The genes encoding IL-19, IL-20 and IL-24 are located within a gene cluster on chromosome 1q31–32 and carry frequent genetic variations. Objectives This study investigated whether variations in the IL19, IL20 and IL24 genes that have previously been associated with plaque-type psoriasis may also play a role in palmoplantar pustulosis (PPP). Patients Fifteen polymorphisms were analysed in 43 patients with PPP and in 149 healthy control subjects. Results The rare allele of IL20 1380 A→G (rs2981573) was less frequent in patients with PPP compared with healthy controls (OR 1·95, 95% CI 1·00–3·79). Haplotype analyses of IL19 and IL20 suggested an increased risk for PPP associated with IL20 haplotype GAA (OR 2·39, 95% CI 1·17–4·86) and a reduced risk for PPP associated both with IL19 haplotype GATGATA (OR 0·41, 95% CI 0·16–1·05) and IL20 haplotype GGG (OR 0·48, 95% CI 0·23–0·98). Extended haplotype analysis revealed an association of IL19/ IL20 haplotype GACACCGGAA with a higher risk for PPP (OR 2·31, 95% CI 1·05–5·10) and of IL20/IL24 haplotype CAAAC with a reduced risk for PPP (OR 0·12, 95% CI 0·02–0·82). Conclusions This exploratory study supports the hypothesis that variations of genes of the IL-19 subfamily of cytokines influence susceptibility to PPP. However, due to the limited size of the study samples, this current concept should be considered as preliminary and the results need to be confirmed in future independent studies. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine, 5-HT) is one of the most extensively studied neurotransmitters of the central nervous system. It also has been identified in constituents of the immune system. Therefore serotonin has been suggested to serve as a mediator of bidirectional interactions between the nervous system and the immune system. We investigated this interaction in experimental autoimmune encephalomyelitis (EAE), a well-defined animal model of autoimmune disease of the central nervous system (CNS) mimicking features of the human disease multiple sclerosis. EAE was induced by immunization with the autoantigens myelin basic protein (MBP) or the immunodominant peptide of myelin oligodendrocyte glycoprotein (MOG) spanning amino acids 35–55 (MOGp 35–55). We studied EAE in knockout (KO) mice lacking the 5-HT transporter (5-HTT) on a C57.BL/6 background, in comparison with wild-type C57.BL/6 animals. After immunization with MOGp 35–55, or with rat MBP, the disease courses of the 5-HTT knockout mice were attenuated as compared to wildtype control mice. This difference was more pronounced in female animals. To dissect potential immune mechanisms underlying this phenomenon, histological studies of the CNS and cytokine measurements in mononuclear cells from the spleens of 5-HTT KO mice and wild-type controls were performed. We found a reduction of the inflammatory infiltrate in the CNS and of the neuroantigen-specific production of IFN-γ in splenocytes, again accompanied by a gender difference. These findings suggest a potential role of extracellular 5-HT homeostasis in the fine-tuning of neuroantigen-specific immune responses. [ABSTRACT FROM AUTHOR]

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Dermatomyositis/polymyositis (DM/PM) and Lambert-Eaton myasthenic syndrome (LEMS) are two autoimmune disorders that have very rarely been reported to occur together in the same patient. We report on two patients with DM who were later diagnosed with concomitant LEMS, and point out diagnostic challenges in identifying LEMS in patients with DM/PM. As specific treatment for LEMS is available, it is important to identify those DM/PM patients who suffer from concomitant LEMS. [ABSTRACT FROM AUTHOR]

Mössner R, Beckmann I, Hallermann C, Neumann C, Reich K. Granulocyte colony-stimulating-factor-induced psoriasiform dermatitis resembles psoriasis with regard to abnormal cytokine expression and epidermal activation. Psoriasis is a chronic inflammatory skin disorder characterized by accumulation of Th1-type T cells and neutrophils, regenerative keratinocyte proliferation and differentiation, and enhanced epidermal production of antimicrobial peptides. The underlying cause is unknown, but there are some similarities with the immunologic defense program against bacteria. Development of psoriasiform skin lesions has been reported after administration of granulocyte colony-stimulating factor (G-CSF), a cytokine induced in monocytes by bacterial antigens. To further investigate the relation between this type of cytokine-induced dermatitis and psoriasis, we analyzed the cutaneous cytokine profile [tumor necrosis factor-α (TNF-α), interferon-γ, transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), IL-12p35 and p40, and IL-8] and expression of markers of epidermal activation [Ki-67, cytokeratin-16, major histocompatibility complex (MHC) class II, intercellular adhesion molecule-1 (ICAM-1)] in a patient who developed G-CSF-induced psoriasiform dermatitis by using quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistology. The histologic picture resembled psoriasis with regard to epidermal hyperparakeratosis and the accumulation of lymphocytes in the upper corium. CD8+ T cells were found to infiltrate the epidermis which was associated with an aberrant expression of Ki-67, cytokeratin-16, MHC class II, and ICAM-1 on adjacent keratinocytes. As compared to normal skin ( n = 7), there was an increased expression of TNF-α, IL-12p40, and IL-8, a decreased expression of TGF-β1, and a lack of IL-10, similar to the findings in active psoriasis ( n = 8). Therefore, G-CSF may cause a lymphocytic dermatitis that, similar to psoriasis, is characterized by a pro-inflammatory Th1-type cytokine milieu and an epidermal phenotype indicative of aberrant maturation and acquisition of non-professional immune functions. [ABSTRACT FROM AUTHOR]

Summary. Migraine affects about 15% of the adult population. Serotonergic and dopaminergic systems are believed to be involved in its pathophysiology. One of the key enzymes in the degradation of serotonin and to a lesser extent of dopamine is monoamine oxidase A (MAO-A). In this study we investigated a functionally relevant gene-linked polymorphic repetitive sequence (LPR) located approximately 1.2 kb upstream of the ATG codon in the MAO-A-promotor gene. 119 patients with migraine and 229 controls were tested. The allelic distribution of the controls and the migraine patients did not show significant differences with respect to the low- and high-activity alleles. Moreover, effectiveness of the potent serotonergic antimigraine agents, triptans, which are metabolized by MAO-A, was clinically not affected by the MAO-A-LPR in our patients. These findings thus indicate that there is no association between the functional MAO-A-LPR and susceptibility to migraine. [ABSTRACT FROM AUTHOR]

Summary. Mice deficient in the serotonin transporter (5HTT) display highly elevated extracellular 5HT levels. 5HT exerts ist effects via at least fourteen different cloned 5HT receptors located pre- and postsynaptically. In contrast to the other 5HT receptors, the 5HT3 receptor is a ionotropic receptor with ligand-gated cation channel function. Since G-protein-coupled 5HT receptors show extensive adaptive changes in 5HTT-deficient mice, we investigated whether 5HT3 receptors are also altered in these mice. Using quantitative autoradiography, we found that 5HT3 receptors are upregulated in frontal cortex (+46%), parietal cortex (+42%), and in stratum oriens of the CA3 region of the hippocampus (+18%) of 5HTT knockout mice. Changes in 5HT3 receptor mRNA expression, as determined by quantitative in situ hybridisation, were less pronounced. The adaptive changes of 5HT3 receptor expression constitute a part of the complex regulatory pattern of 5HT receptors in 5HTT knockout mice. [ABSTRACT FROM AUTHOR]

Summary. The 5-HT1A receptor plays a critical role in the pathophysiology of anxiety and depression as well as in the mode of action of anxiolytic and antidepressant drugs. Human 5-HT1A gene transcription is modulated by a common C-1016G single nucleotide polymorphism (SNP) in its upstream regulatory region. In the present study, we evaluated the role of the HTR1A-1019 polymorphism in the modulation of individual differences in personality traits by an association study of a sample of healthy volunteers. Personality traits were assessed with two different methods, NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant effect of the HTR1A-1019 polymorphism on NEO Neuroticism with carriers of the G allele showing higher scores than individuals homozygous for the C variant. The effect was primarily due to associations with the Neuroticism facets Anxiety and Depression. Carriers of the G allele also exhibited higher TPQ Harm Avoidance scores. Our findings indicate a role of allelic variation in 5-HT1A receptor expression in the development and modulation of anxiety- and depression-related personality traits. [ABSTRACT FROM AUTHOR]

Abstract Mood, emotion and cognition are modulated by serotonergic neurotransmission, while the physiological function of serotonergic synapses depends on serotonin reuptake, which is mediated by the serotonin transporter (5-HTT). Allelic variation of 5-HTT expression in humans is caused by a functional gene-promoter polymorphism with two predominant variant alleles, which are associated with variations in anxiety measures as previously reported. Here we report that administration of dexamethasone, a potent glucocorticosteroid hormone, results in an increase in 5-HTT expression in immortalized human B-lymphoblastoid cells, which express the human 5-HTT. Functional reporter gene assays as well as 5-HT uptake and inhibitor binding measures revealed a genotype-dependent dose–response to glucocorticosteroid administration, which was antagonized by RU 38486, a non-specific glucocorticosteroid hormone antagonist. The allele-specific differences after administration of dexamethasone depended on the repetitive GC-rich sequence located approximately 1.4 kb upstream of the 5-HTT gene transcription site because of absence of a significant steroid effect after transfecting a deletional mutant reporter gene construct, which lacks this repetitive promoter sequence. Our findings may contribute to explain the vulnerability to stress-related disorders in susceptible individuals, in whom further clinical studies should follow up on these in vitro findings. [ABSTRACT FROM AUTHOR]

Summary. The human MLC1 (WKL1, KIAA0027) gene encodes a putative transmembrane protein expressed exclusively in brain. Recessive mutations within this gene cause megalencephalic leukoencephalopathy with subcortical cysts (MLC, MIM 604004, 605908). Furthermore, a missense mutation in this gene is suggestively linked with hereditary catatonic schizophrenia in a large pedigree. The murine gene Mlc1 is composed of 12 exons spanning ∼20 kb, and all exon-intron boundaries conform to the GT/AG consensus. The single copy transcript after splicing is ∼2.8 kb in length, it contains 496 bp of 5′ untranslated region (5′-UTR) and 1143 bp of 3′-UTR, and encodes a protein of 382 amino acids. Potential binding sites for transcription factors including CCAAT-boxes are present in the 5′-flanking region. Fluorescent in situ hybridization localizes the gene to mouse chromosome 15E-F, a region syntenic to human chromosome 22q13. The characterization of the genomic structure of the murine gene will facilitate studies of gene function and physiological properties of the encoded protein in transgenic mouse models. [ABSTRACT FROM AUTHOR]

Summary. Two polymorphic dinucleotide repeats separated by a short spacer are localized in the promoter region of the serotonin receptor 2C gene (HTR2C). One of the repeats was found to be evolutionary conserved between humans and rhesus monkeys. Although promoter-associated microsatellites have previously been shown to regulate expression of different genes, we did not find any significant influence of distinct HTR2C promoter microsatellite alleles on transcriptional efficiency as measured by luciferase activity and receptor availiability as assayed by [3H]-mesulergine binding. Furthermore, no association of specific alleles with bipolar disorder was found. These results indicate that the HTR2C promoter polymorphism does not contribute significantly to the etiopathogenesis of bipolar disorder in females. [ABSTRACT FROM AUTHOR]

Summary. Clinical neuroscience enters a new era in understanding the pathophysiology of depressive illness and the mode of action of antidepressant therapy. While elucidation of factors that lead to depression is still in its infancy, biochemical malfunctions appear to have well defined morphological correlations, especially in the hippocampus. Hippocampus is one of the main sites in the brain habouring neural stem cells. Cytokines and neurotrophic factors like brain-derived neurotrophic factor (BDNF) play a pivotal role in neural plasticity and potentially influence growth and migration of these progenitors. Not surprisingly, antidepressant drugs interfering with neurotransmitters such as serotonin (5-HT) influence neurotrophins like BDNF, since 5-HT homeostasis is essential for brain development, neurogenesis, and neuroplasticity as well as complex behavior. In this review, the new area of neural stem cell research and the avenues of ongoing and future research sustaining the development of novel treatments for depression will be explored. [ABSTRACT FROM AUTHOR]

Summary. The serotonin transporter (5HTT) is the molecule responsible for the high-affinity reuptake of 5HT from the synaptic cleft. Mice lacking the 5HTT exhibit highly elevated extracellular concentrations of 5HT. We assessed whether the glutathione detoxification system is altered in 5HTT-deficient mice. While levels of reduced and oxidized glutathione were unchanged, glutathione metabolising enzymes showed a differential pattern of modulation. Glutathione peroxidase was reduced in frontal cortex, brainstem, and cerebellum of 5HTT-deficient mice, though not to a statistically significant extent, while a putative isoform of the detoxifying enzyme glutathione-S-transferase pi was decreased in a number of brain regions, especially in brainstem. At the level of the DNA, we found an increase of oxidative DNA adducts in the hippocampus of 5HTT-deficient mice. Given the importance of the hippocampus in learning and memory, this may be the most important neurochemical consequence of the absence of the 5HTT. [ABSTRACT FROM AUTHOR]

Schizophrenia is a common and etiologically heterogeneous disorder. Although inheritance of schizophrenic syndromes is complex with genetic and environmental factors contributing to the clinical phenotype, periodic catatonia, a familial subtype of catatonic schizophrenia, appears to be transmitted in an autosomai dominant manner. We report here that a Leu309Met mutation in WKL1, a positional candidate gene on chromosome 22q13.33 encoding a putative non-selective cation channel expressed exclusively in brain, co-segregates with periodic catatonia in an extended pedigree. Structural analyses revealed that this missense mutation results in conformational changes of the mutant protein. Our results not only underscore the importance of genetic mechanisms in the etiology of schizophrenic syndromes, but also provide a better understanding of the pathogenesis and incapacitating course of catatonic schizophrenia and related disorders. [ABSTRACT FROM AUTHOR]

Pheochromocytomas are a feature of the von Hippel–Lindau disease spectrum, a multisystem disorder of autosomal dominant inheritance. Pheochromocytomas are, however, observed during life with a lower frequency than other features of this disease, such as retinal angiomas, haemangioblastomas of the CNS, and renal carcinomas. We present the highly unusual case of a patient who required an emergency operation for an intradural extramedullary thoracic tumour which was clinically suggestive initially of neurinoma. We present evidence from NMR, histological and isotope scan investigations of this being a pheochromocytoma metastasis and of an additional right-sided paraganglioma at the same height. A detailed history revealed that this patient had suffered from four other pheochromocytomas and two other paragangliomas, in addition to retinal angiomatosis of von Hippel–Lindau disease. This case is extraordinary due to (i) the unusual site of the metastasis, (ii) the neurological requirement for an emergency operation of pheochromocytoma, (iii) metastasis of pheochromocytoma in von Hippel–Lindau disease (only eight previous cases), and (iv) the number of recurrent pheochromocytomas. It clearly demonstrates the necessity for frequent and life-long follow-up in von Hippel–Lindau disease. [ABSTRACT FROM AUTHOR]

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Transcriptional activity of the human serotonin transporter gene ( 5HTT) is modulated by complex interaction of multiple genomic and cellular factors. Variability of a polymorphic repetitive element (5HTTLPR) is associated with anxiety, depression, and aggression-related traits and may influence the risk to develop affective spectrum disorders. 5HTTLPR variants display a unique DNA secondary structure that has the potential to regulate the transcriptional activity of the associated 5HTT promoter. The structure of the 5HTTLPR is also likely to precipitate a 381-bp somatic deletion in the 5HTT's promoter region [del(17)(q11.2)] that is observed in 20–60% of genomic DNA isolated from mononuclear blood cells and postmortem brain. The localization of the deletion breakpoints adjacent to identical putative signal sequences (CAGCC) suggests a V(D)J recombinase-like rearrangement event. In comparison with healthy controls, del(17)(q11.2)/wildtype sequence ratios showed a decrease of the deleted variant in recurrent unipolar depression. Our results also suggest that mosaicism of del(17)(q11.2) is likely to be regulated by tissue-specific as well as 5HTTLPR-dependent mechanisms. The findings confirm that the pericentric region of human chromosome 17 is highly unstable and furnishs additional evidence for intricate complexity of 5HTT regulation under physiological condition and in disease. [ABSTRACT FROM AUTHOR]

A possible dysregulation of dopaminergic neurotransmission has been implicated in the aetiology of schizophrenic psychoses, in particular of paranoid-hallucinatory states, and of the manic episodes of bipolar affective disorder. In the present study we analysed allelic and genotypic variations of a recently described functional deletion/insertion variant (−141C Ins/Del) in the 59 flanking region of the human dopamine D2 receptor gene. We investigated a total of 620 unrelated individuals, comprising 260 schizophrenic patients, 70 patients with bipolar affective disorder, and 290 population controls. Analysis of the −141C Ins/Del variant revealed that the schizophrenic, bipolar affective and control groups did not differ significantly regarding genotype frequencies and allele frequencies. No evidence of an allelic association with either a family history of schizophrenic psychosis or a diagnosis of schizophrenia of the paranoid type (according to ICD 10) was found. Our findings indicate that the −141C Del variant in the 5′ flanking region of the human dopamine D2 receptor gene is unlikely to play a substantial role in genetic predisposition to major psychiatric disorders in Caucasians. [ABSTRACT FROM AUTHOR]

By conferring allele-specific transcriptional activity on the 5-HT transporter gene promoter in humans, the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) influences a constellation of personality traits related to anxiety and increases the risk for neurodevelopmental, neurodegenerative, and psychiatric disorders. Here we have analyzed the presence and variability of the 5-HTTLPR in several species of primates including humans, and other mammals. PCR, Southern blot, and sequence analyses of the 5-HT transporter gene's 5′-flanking region in different mammalian species confirmed the presence of the 5-HTTLPR in platyrrhini and catarrhini (hominoids, cercopithecoids) but not in prosimian primates and other mammals. Since the 5-HTTLPR is unique to humans and simian primates, a progenitor 5-HTTLPR sequence may have been introduced into the genome some 40 Mio. years ago. In humans the majority of alleles are composed of either 14 or 16 repeat elements, while alleles with 18 or 20 repeat elements are rare. In contrast, great apes including orang-utan, gorilla, and chimpanzee display a high prevalence of alleles with 18 and 20 repeat elements. In hominoids all alleles originate from variation at a single locus (polymorphic locus 1). In the 5-HTTLPR of rhesus monkeys (rh5-HTTLPR) we found an alternative locus for length variation (polymorphic locus 2) generated by a 21 bp insertion/deletion event. The existence of a distinct biallelic variation of the 5-HTTLPR in rhesus monkeys but similar allele and genotype frequencies in this species and humans supports the notion that there may be a relationship between functional 5-HT transporter expression, anxiety-related traits, and the complexity of socialization in human and nonhuman primate populations. [ABSTRACT FROM AUTHOR]

Mood, emotion, and cognition are modulated by the serotonergic midbrain raphe system, which seems to be involved in the pathogenesis of psychiatric disorders like those of the affective spectrum. Since a dysregulation of serotonin transporter expression might be important in the course of those disorders, we isolated and cloned the 5′-regulatory region of the serotonin transporter gene, which is inducible by cAMP-and PKC-dependend signal transduction pathways. Systematic screening for length variations and functional promoter analyses revealed a genetic polymorphism with allelic variation in transcriptional activity and protein expression. This 5-HTT gene polymorphism comprises a tandemly repeated sequence in the 5′-regulatory promoter region of the serotonin transporter gene. Recent population association studies demonstrated the 5-HTT gene promoter polymorphism accounting for 4–5% of population variation of anxiety-related behavioral traits. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 47-year-old woman tiwht a history of plaque-type psoriasis and generalized pustular psoriasis (GPP) carrying IL36RN mutations who was treated with anakinra successfully.

A letter to the editor about the genetic variation role of tryptophan hydroxylase 2 in the pathogenesis of Tourette syndrome is presented.

Idiopathic Parkinson's disease (PD) is a common neurodegenerative disorder with prominent motor symptoms. However, depression is common in PD, affecting about 40% of PD patients. Since there is extensive evidence of degeneration of serotonin (5HT) neurons and loss of the 5HT transporter (5HTT) in PD, we assessed whether a functional polymorphism in the promoter of the 5HTT gene (5HTT gene-linked polymorphic region, 5HTTLPR), which determines high or Iow 5HT uptake, is associated with depressive symptomatology in PD patients. We found that patients with the short allele of the 5HTTLPR had significantly higher scores on the Hamilton Depression Scale. A functional promoter polymorphism of the monoamine oxidase A (MAOA) gene showed no association. Thus, the 5HTTLPR but not the MAOA gene promoter-associated polymorphism may be a risk factor for depression in PD patients, while neither polymorphism increases the risk for development of Parkinson's disease itself. [ABSTRACT FROM AUTHOR]

Background: Both psoriasis (Ps) and psoriasis arthritis (PsA) have been associated with increased cardiovascular risk. Also, both are characterized by increased neovascularization. Endothelial progenitor cells (EPCs) have been implicated in promoting vascular repair in ischemic diseases. The aim of the study was to correlate the EPC system with CV risk factors and with parameters of vascular stiffness in Ps and PsA. Methods: Twenty-six healthy subjects, 30 patients with Ps, and 31 patients PsA were included in the study. eEPC regeneration was evaluated by a colony-forming assay, circulating eEPCs were measured by cytometric analysis. For vascular analysis, all subjects underwent quantification of pulse wave velocity (PWV) and augmentation index (AIX). Results: Patients were categorized upon the duration of disease, severity of skin involvement (PASI-Ps), individual pain as reflected by the VAS (PsA), CRP values, and history of treatment with one or more biologicals. Regarding the eEPC system, no significant differences were observed between the respective categories. Correlation analyses between parameters of vascular stiffness (PWV and AIX) and patterns of colony formation/circulating eEPCs did not show any correlation at all. Conclusion: Parameters of vascular stiffness are not significantly deteriorated in Ps/PsA. Thus, pulse wave analysis may not be suitable for CVR assessment in certain autoimmune-mediated diseases. Regenerative activity of the eEPC system/circulating eEPC numbers are not altered in Ps/PsA. One may conclude that malfunctions of the eEPC are not substantially involved in perpetuating the micro-/macrovascular alterations in Ps/PsA. [ABSTRACT FROM AUTHOR]