Search

OBJECTIVES Standard treatment of children hospitalized for acute orbital cellulitis includes systemic antibiotics. Recent data from single-center studies suggest the addition of systemic corticosteroids may hasten clinical improvement and reduce hospital length of stay (LOS). We investigate the potential relationship between corticosteroid exposure and duration of hospitalization for pediatric orbital cellulitis. METHODS Using Pediatric Health Information System registry data from 51 children’s facilities, we performed a retrospective cohort study of children hospitalized for orbital cellulitis RESULTS Of the 5645 children included for study, 1347 (24%) were prescribed corticosteroids within 2 days of admission. Corticosteroid prescription was not associated with LOS in analyses adjusted for age; presence of meningitis, abscess, or vision issues; and operative episode and PICU admission within 2 days (eβ = 1.01, 95% confidence interval [CI]: 0.97–1.06). Corticosteroid exposure was associated with operative episodes after 2 days of hospitalization (odds ratio = 2.05, 95% CI: 1.29–3.27) and 30-day readmission (odds ratio = 2.40, 95% CI: 1.52–3.78) among patients with a primary diagnosis of orbital cellulitis. CONCLUSIONS In this database query, we were not able to detect a reduction in LOS associated with corticosteroid exposure during hospitalization for orbital cellulitis. Corticosteroid prescription was associated with PICU admission and operative episodes after 2 days of hospitalization. Before the adoption of routine corticosteroid use, prospective, randomized control trials are needed.

IgG4-related disease (IgG4-RD) is an inflammatory disorder characterized by tumor-like swelling in one or more organs, elevated serum IgG4 levels, and histological alterations with infiltration of IgG4-positive plasma cells. IgG4-RD is rare and likely underdiagnosed in children. We report a case of a 16-year-old girl with IgG4-positive colitis that developed weeks after IgG4-related ophthalmic disease and discuss diagnosis and treatment in the context of the literature available. Since the pathophysiology of IgG4-RD is unknown, treatment options are empiric and, for the most part, untargeted. Systemic corticosteroid treatment is the basis of anti-inflammatory treatment in IgG4-RD and induced early remission in our patient. During corticosteroid taper, the patient developed weight loss and intestinal inflammation. Histopathological assessment of the intestinal walls confirmed IgG4-positive colitis. Immune-modulating treatment with non-biologic (e.g., methotrexate (MTX) and mycophenolate mofetil) or biologic (rituximab) disease-modifying antirheumatic drugs has been reported in treatment refractory or corticosteroid-dependent patients. The patient responded to treatment with anti-inflammatory therapy with food rich in TGF-β2 (modulen) and MTX. This is one of the first pediatric patients reported with IgG4-related colitis extending the phenotype of pediatric IgG4-RD. International collaboration to prospectively document clinical presentation and treatment responses may help to further establish the phenotype and treatment options and to raise awareness for IgG4-RD.

Cel pracyCelem pracy była analiza ekspresji trzech genów związanych z regulacją osi podwzgórze-przysadka-nadnercza (PPN): GR, HSP90 i FKBP5 u pacjentów z rozpoznaniem depresji w przebiegu choroby afektywnej jednobiegunowej (CHAJ) przed rozpoczęciem leczenia oraz po 8 tygodniach farmakoterapii. Analizowano również stężenie izoform receptora glikokortykoidowego.MetodaBadano 30 pacjentek (18–60 lat) z depresją w przebiegu CHAJ rozpoznaną w oparciu o kwestionariusz SCID wg kryteriów DMS-IV. Do leczenia zastosowano jeden z dwóch leków: sertralinę lub wenlafaksynę.Nasilenie depresji oceniono na podstawie skali Hamiltona HDRS. Po 8 tygodniach leczenia wykonano te same badania kliniczne i molekularne. U wszystkich pacjentek wykonano test hamowania deksametazonem (DST). Z krwi obwodowej wyizolowano mRNA do oceny ekspresji genów metodą PCR w czasie rzeczywistym z użyciem sond typu TaqMan. Wykonano również oznaczenie stężenia izoform GR (α i β) w surowicy krwi metodą ELISA. Analizę statystyczną wykonano w programie Statistica v.12.0.WynikiNieprawidłowe stężenie kortyzolu zaobserwowano jedynie u 20% pacjentek. Zaburzone działanie osi PPN wykazano u 10% pacjentek. U wszystkich pacjentek zaobserwowano znaczącą poprawę kliniczną po 8 tygodniach farmakoterapii. Prawie wszystkie badane wykazały pełną remisję objawów po zastosowaniu farmakoterapii. Zaobserwowano istotną umiarkowaną korelację między stężeniem kortyzolu po DST przed rozpoczęciem terapii a stężeniem kortyzolu po 8 tygodniach terapii (r2=0,44). Wyniki nie wykazały istotnych różnic w ekspresji trzech badanych genów po 8 tygodniach terapii w porównaniu z ekspresją ocenianą przed rozpoczęciem terapii. Analiza ELISA wykazała, że stężenie izoformy α zmniejsza się po terapii farmakologicznej, niezależnie od stosowanego leku.WnioskiUzyskane wyniki nie wskazują na istotne zmiany ekspresji genów związanych z działaniem osi stresu w trakcie terapii przeciwdepresyjnej.

To investigate orbital biomechanical properties in patients with thyroid orbitopathy and in age- and gender-matched healthy subjects using the Corvis-ST (CST, Oculus Wetzlar, Germany).The CST allows a non-contact tonometry with an ultra-high-speed Scheimpflug device to record the deformation of the cornea during an air pulse. Biomechanical response parameters (intraocular pressure (IOP), whole eye movement length (WEMl) and time (WEMt), deflection amplitude 2 mm ratio max, deflection amplitude max, stiffness parameter, and biomechanically corrected IOP were measured in 39 patients with thyroid orbitopathy (= group I) and in 33 age- and gender-matched healthy subjects (= group II) using the CST.Mean age in group I was 54.3 ± 11.6 years and in group II 54.2 ± 12.3 years with no statistical significant difference between the groups (P = 0.98). The gender distribution between the groups was not statistically significantly different (P = 0.51). Mean central corneal thickness was 571 ± 30 µm in group I and 563 ± 36 µm in group II (P = 0.306). There were statistically significant differences (P 0.001) between groups I and II in mean IOP (19.3 ± 4.5 vs. 14.8 ± 2.3 mmHg, mean biomechanically corrected IOP (17.1 ± 3.4 vs. 13.4 ± 2.1 mmHg), mean WEMl (207 ± 57 vs. 322 ± 50 µm), mean WEMt (20.5 ± 1.0 vs. 21.9 ± 0.7 ms), mean IOP-adjusted WEMl (213 ± 56 vs. 314 ± 62 µm), and in mean stiffness parameter (132.5 ± 29.6 vs. 107.8 ± 23.3 mmHg/mm), respectively.Biomechanical parameters as measured by the CST were significantly reduced in patients with thyroid orbitopathy compared to age- and gender-matched healthy subjects, indicating a reduction in orbital compliance in thyroid orbitopathy. The parameters WEMl and WEMt might be a useful diagnostic tool to evaluate the condition of the eyeball within the orbit.

Non-infectious uveitis is associated with visual impairment and blindness. Non-biologic treatment for non-infectious uveitis is not based on strong evidence. A retrospective chart review was conducted to investigate treatment response to high-dose intravenous methylprednisolone (IVMP) in children with non-infectious uveitis. Fifty-six patients (93 eyes affected) were included. In 29% uveitis was associated with juvenile idiopathic arthritis. Uveitis predominately affected the anterior segment, was bilateral and recurrent. Complications were common and included visual loss, synechiae, cataract and/or retinal lesions. Patients received up to 5 IVMP at monthly intervals. Visual acuity improved at 3 and 6 months. Anterior chamber cells, synechiae, keratic precipitates, papillary and/or macular edema improved at 3 months. Children treated with ≥3 IVMP (vs 1 IVMP) experienced trends towards fewer relapses, fewer cataracts and less frequently required treatment with biologic agents. High-dose IVMP induce rapid improvement in children with non-infectious uveitis. Prospective randomized trials are required to confirm results.

Background Intraocular inflammation accounts for up to 10-15% of total blindness cases [1]. The incidence of uveitis in children ranges around 4.9/100.000, and a significant number of patients develop chronic courses and irreparable complications [2]. An impressive 74% of children with juvenile idiopathic arthritis (JIA)-associated uveitis are legally blind at diagnosis [3]. This underscores the importance of timely diagnosis and effective anti-inflammatory treatment. Objectives To evaluate the clinical response to high-dose intravenous methylprednisolone (IVMP) in children and adolescents with autoimmune uveitis. Methods A retrospective chart review was conducted in two tertiary referral centers in Germany (TU Dresden and University of Wurzburg) to investigate treatment responses to IVMP (10-30mg/kg/day on three successive days with a total of one to five IVMP at monthly intervals) in children and adolescents ( Results Fifty-six patients (93 affected eyes) with a median age of 7.4 (range: 2.5-16.7) years were included. In 29% of patients uveitis was associated with JIA. Uveitis was predominately located in the anterior segment (43%), bilateral (66%) and recurrent (43%). Complications occurred in 77% of patients and included visual loss, synechiae, cataract and/or retinal lesions. Patients with active uveitis received between 1 and 5 IVMP. Visual acuity improved significantly (0.52±0.33 to 0.69±0.30 at 3 months (p Conclusion High-dose IVMP induces rapid improvement in children with autoimmune uveitis. Data suggest improved outcomes in children treated with three or more courses of IVMP when compared to one course (without reaching statistical significance). Prospective randomized trials in larger cohorts are required to confirm results. References [1] Nussenblatt RB. The natural course of uveitis. Int Ophthalmol. 1990; 141:303–8. [2] [2] Paivonsalo-Hietanen T et al. Uveitis in children: population-based study in [3] Finland. Acta Ophthalmol Scand. 2000; 78(1):84-8. [4] [3] Woreta F at el. Risk factors for ocular complications and poor visual acuity at presentation among patients with uveitis associated with juvenile idiopathic arthritis (JIA). Am JOphthalmol 2007; 143:647–55. Disclosure of Interests Anja Schnabel: None declared, Elisabeth Unger: None declared, Normi Bruck: None declared, Annette Holl-Wieden: None declared, Henner Morbach: None declared, Reinhard Berner Grant/research support from: Local Principal Investigator in a Clinical Trial on Canakimumab for sJIA supported by Novartis (Trial Registration: NCT00886769, NCT00889863, NCT00426218 and NCT00891046) Local Principal Investigator in a Clinical Trial DAP-PEDOST-11-03 supported by Merck (Trial Registration EUDRACT 2013-000864-28), Anna Leszczynska: None declared, Christian Hedrich Grant/research support from: Novartis Pharmaceuticas for Research study on effector T cells in psoriasis, Speakers bureau: In 2016: Roche Pharmaceuticals, RheumatoLogisch, Dresden, Germany; Novartis, Advisory board > Travel costs.

To compare IL-6, sIL-6R, and IL-17 secretion in peripheral blood mononuclear cells (PBMCs) cultured with tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor), dexamethasone, and placebo, obtained from patients with thyroid eye disease (TED) and healthy controls. The study was a prospective proof of concept test. We cultured peripheral blood mononuclear cells from TED patients and healthy controls with tocilizumab, dexamethasone, and placebo. IL-6, sIL-6R, and IL-17 levels in supernatants obtained from PBMCs cultures were analyzed by ELISA. We included seventeen patients with thyroid eye disease (12 females and five males). The mean age was 49 years. Both dexamethasone and tocilizumab influenced IL-6 and IL-6Rs levels in patients’ group. Supernatants obtained from PBMCs treated with dexamethasone showed 77.2% and 82.8% lower IL-6 levels compared with those cultured with placebo and tocilizumab, respectively. Furthermore, overnight culture of PBMCs with dexamethasone showed significantly lower sIL-6R secretion compared with untreated (33.71%, p = 0.04) and tocilizumab treated (58.21%, p = 0.01) PBMCs. Neither dexamethasone nor tocilizumab affected IL-17 concentrations in PBMCs cultures. Both dexamethasone and tocilizumab affect the IL-6/sIL-6R system. Specifically, dexamethasone reduces and tocilizumab increases the levels of these cytokines in PBMCs cultures. These results strengthen the molecular rationale for interrogating the efficacy of tocilizumab in steroid-resistant TED, as IL-6 seems to be a common target for both anti-IL-6R antibody and steroids.

IntroductionThe influence of personality traits on suicidal behaviour risk has been well documented. Personality traits and suicidal behaviour are partially genetically determined and personality has been described as an endophenotype of suicidal behaviour. The aim of this study was to investigate a possible association between personality traits with suicidal behaviour and selected serotonergic gene polymorphisms.MethodsIn the study we included 156 patients meeting DSM-IV criteria for bipolar disorder (BP) and 93 healthy controls. The personality dimensions were assessed using the Temperament and Character Inventory (TCI). We genotyped two selected polymorphisms of the tryptophan hydroxylase 1 (TPH1) gene (rs1800532 218A>C and rs1799913 779A>C) and polymorphism in the promoter region of serotonin transporter gene (5-HTTLPR, rs25531) related to serotoninergic neurotransmission. Multiple poisson regression, logistic regression and Kruskal–Wallis tests were applied.ResultsWe found numerous differences between the BP patients and the control group in terms of their TCI dimensions/subdimensions. Significant differences were found between patients with, and without, suicidal attempts in fatigability and asthenia (Ha4), as well as in harm avoidance (Ha). We also found that the interactions between TCI subdimensions (the interaction of disordiness (Ns4) and spiritual acceptance (St3), disordiness (Ns4) and integrated conscience (C5), extravagance (Ns3) and resourcefulness (Sd3)) were significantly contributing for suicidal behaviour risk. We found association between all studied genetic polymorphisms and several TCI dimensions and subdimensions.ConclusionOur results confirm that personality traits are partially determined by genes. Both personality traits and the interactions between temperament and character traits, may be helpful in predicting suicidal behaviour.

Schizophrenia has been associated with a large range of autoimmune diseases, with a history of any autoimmune disease being associated with a 45% increase in risk for the illness. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission. In particular, increases or imbalance in cytokine before birth or during the early stages of life may affect neurodevelopment and produce vulnerability to the disease. A total of 27 polymorphisms of IL1N gene: rs1800587, rs17561; IL1B gene: rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627; IL1RN gene: rs419598, rs315952, rs9005, rs4251961; IL6 gene: rs1800795, rs1800797; IL6R gene: rs4537545, rs4845617, rs2228145, IL10 gene: rs1800896, rs1800871, rs1800872, rs1800890, rs6676671; IL10RA gene: rs2229113, rs3135932; TGF1B gene: rs1800469, rs1800470; each selected on the basis of molecular evidence for functionality, were investigated in this study. Analysis was performed on a group of 621 patients with diagnosis of schizophrenia and 531 healthy controls in Polish population. An association of rs4848306 in IL1B gene, rs4251961 in IL1RN gene, rs2228145 and rs4537545 in IL6R with schizophrenia have been observed. rs6676671 in IL10 was associated with early age of onset. Strong linkage disequilibrium was observed between analyzed polymorphisms in each gene, except of IL10RA. We observed that haplotypes composed of rs4537545 and rs2228145 in IL6R gene were associated with schizophrenia. Analyses with family history of schizophrenia, other psychiatric disorders and alcohol abuse/dependence did not show any positive findings. Further studies on larger groups along with correlation with circulating protein levels are needed.

Anna Leszczynska,* Lisa Ramm,* Eberhard Spoerl, Lutz E Pillunat, Naim Terai Department of Ophthalmology, University Hospital Dresden, Dresden, Germany *These authors contributed equally to this work Introduction: To investigate the effect of acupuncture on different ocular blood flow (OBF) parameters in patients with primary open-angle glaucoma (POAG). Patients and methods: In a prospective, randomized study, 56 POAG patients were randomly assigned either to an eye-specific acupuncture (group I, n=28) or to an eye-unspecific acupuncture treatment (group II, n=28). Blood flow parameters were measured before and 10 minutes after treatment. Parapapillary retinal blood flow was determined by the Heidelberg retina flowmeter. Retinal vessel diameters were measured by the dynamic vessel analyzer. Pulsatile ocular blood flow, ocular pulse amplitude, and IOP were investigated by the Langham OBF system. Systemic blood pressure was obtained additionally. Results: Pulsatile ocular blood flow increased significantly after the eye-specific acupuncture treatment from 5.6±4.3 to 6.7±4.9 µL/min (P=0.014). There was no significant change in parapapillary retinal blood flow, retinal vessel diameter, systemic blood pressure, or IOP after treatment in neither of the two groups. Conclusion: An eye-specific acupuncture treatment may affect OBF in POAG patients. Keywords: acupuncture, glaucoma, ocular blood flow, retinal vessel diameter, Heidelberg retina flowmeter, Langham ocular blood flow system, dynamic vessel analyzerA Letter to the Editor has been received and published for this article.

Genetic variations in clock-related genes were hypothesized to be involved to in the susceptibility of mood disorders MD (both unipolar (UPD) and bipolar (BPD) disorders). In our work we investigated role of gene variants form four core period proteins: CLOCK, ARNTL, TIM and PER3. The total sample comprised from 744 mood disorders inpatients (UPD = 229, BPD = 515) and 635 healthy voluntary controls. The 42 SNPs from four genes of interest were genotyped. We used single polymorphisms, haplotypes, SNPs interactions and prediction analysis using classical statistical and machine learning methods. We observed association between two polymorphisms of CLOCK (rs1801260 and rs11932595) with BPDII and two polymorphisms of TIM (rs2291739, rs11171856) with UPD. We also detected ARNTL haplotype variant (rs1160996C/rs11022779G/rs1122780T) to be associated with increased risk of MD, BPD (both types). We established significant epistatic interaction between PER3 (rs2172563) and ARNTL (rs4146388 and rs7107287) in case of BPD. Additionally relation between PER3 (rs2172563) and CLOCK (rs1268271 and rs3805148) appeared in case of UPD. Classification and Regression Trees (C and RT) showed significant predictive value for 10 polymorphisms in all analyzed genes. However we failed to obtain model with sufficient predictive power. During analyses of sleep disturbances sample, we found carriers of homozygote variants (ARNTL: rs11022778 TT, rs1562438 TT, rs1982350 AA and PER3: rs836755 CC) showing more frequent falling asleep difficulties when compare to other genotypes carriers. Our study suggested a putative role of the CLOCK, TIM, ARNTL and PER3 and polymorphisms in MD susceptibility. In our analyses we showed association of specific gene variants with particular types of MD. We also confirmed necessity of performing separate analyzes for BPD and UPD patients. Comprehensive statistical approach is required even with individual symptoms analyses.

Genes involved in the regulation of the hypothalamus-pituitary-adrenal axis are responsible for altered susceptibility to mood disorders. The aim of this study was to analyze the possible association of CRHR1 and AVPR1b gene variants with bipolar disorder and major depressive disorder (MDD).In the study, we included 486 patients with bipolar disorder and 215 patients with MDD. Consensus diagnosis was made according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria, using the Structured Clinical Interview for DSM Disorders. The control group consisted of 712 healthy participants. Genotyping of CRHR1 and AVPR1b polymorphisms was performed using TaqMan single nucleotide polymorphism genotyping assays. Linkage disequilibrium analysis was carried out on Haploview. Gene-gene interactions were analyzed using the multifactor dimensionality reduction method.By single marker analysis we have found an association of rs28536160 of AVPR1b and rs4076452 and rs16940655 of CRHR1 with mood disorders (P=0.036, 0.0013, and 0.003, respectively). We observed strong linkage disequilibrium between seven CRHR1 polymorphisms grouped in two haplotype blocks; however, none of them showed an association with MDD or bipolar disorder. Similarly, no association was found for three of four strongly linked AVPR1b polymorphisms. Gene-gene interaction analysis revealed a significant epistatic interaction between AVPR1b and CRHR1 genes in susceptibility to MDD (P=0.017).Polymorphisms of CRHR1 and AVPR1b may modify susceptibility to mood disorders.

The aim of the study was to investigate the possible association between polymorphisms of HPA axis genes-CRHR1 (corticotrophin-releasing hormone receptor), NR3C1 (glucocorticoid receptor) and AVPR1B (arginine vasopressin receptor) and dimensions of bipolar disorder assessed by OPCRIT. We examined 560 patients with diagnosis of bipolar disorder (n=457) and unipolar disorder (n=103). Diagnosis was established by SCID and OPCRIT. We found association between polymorphisms of AVPR1b gene and psychotic dimension and CRHR1 polymorphisms and excitement and psychotic dimension. Our results suggest possible involvement of the AVPR1b and CRHR1 genes in the ethiology of psychotic features in the course of affective disorders, and possible involvement of CRHR1 gene in the ethiology of bipolar disorder.

Introduction Studies have not given yet a clear answer what is the genetic background of suicidal predisposition. The associations between polymorphisms of the TPH1 and 5-HTTLPR genes and violent suicidal behavior was revealed with the least inconsistencies. Method We selected 10 “strong candidate genes” and 35 SNPs, SLC6A4 and ACP1 for replication study. We searched associations between precisely described suicidal phenotype in 825 affective patients and polymorphisms of selected neurobiological pathways genes as well as their interactions that constitute suicidal risk. Results The results confirm the role of TPH1, TPH2, 5HT2A, CRHR1 and ACP1 variants in the risk of suicidal behavior. Limitations In our study we analyzed limited number of candidate genes and only one of them is linked to lithium mechanism of action. We had no data on pharmacological treatment of investigated patients and its relation to the time of suicide attempt. Conclusion Our results indicate that polymorphisms of various signaling pathways are involved in the pathogenesis of suicidal behavior. Non-genetic factors are also involved in the risk of suicidal attempts.

A number of candidate genes for lithium prophylactic efficacy have been proposed, some of them being also associated with a predisposition to bipolar illness. The aim of the present study was to investigate a possible association between polymorphisms of 14 common genes with the quality of prophylactic lithium response in patients with bipolar mood disorder, in relation to the putative role of these genes in the pathogenesis of this disorder. Some association with lithium prophylactic efficacy was found for the polymorphisms of 5HTT, DRD1, COMT, BDNF and FYN genes, but not for 5HT2A, 5HT2C, DRD2, DRD3, DRD4, GSK-3, NTRK2, GRIN2B and MMP-9. Possible aspects of these genes with regard to the mechanism of lithium activity and pathogenesis of bipolar mood disorder are discussed.

The aim of this report is to present a case of a patient with bilateral lacrimal gland abscesses in the course of dacryoadenitis. A 45-year-old female patient with a long history of cocaine abuse presented with bilateral bacterial dacryoadenitis and upper lid inflammation with purulent discharge from a palpebral wound of the right upper lid. The diagnosis was confirmed with microbiology culture and an orbital CT scan, which revealed lacrimal gland abscesses. The patient admitted to vigorous eye scratching, which we believe was the mechanism responsible for the process. The infection resolved on targeted antibiotic therapy. This is the first reported case of bilateral infectious dacryoadenitis produced in a self-inflicted mechanism in a cocaine addict.

Several genes of the glutamatergic system have been implicated in both schizophrenia and bipolar disorder. The Src family tyrosine kinase FYN plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate. Although no association between FYN gene polymorphisms and schizophrenia has been demonstrated, in our previous paper we found an association between FYN polymorphisms and cognitive test performance in schizophrenic patients. The aim of this study was to find a possible association of three polymorphisms of the FYN gene with bipolar disorder. We analyzed 425 bipolar patients and 518 control subjects. Genotypes of three analyzed polymorphisms, i.e. rs706895 (–93A/G in the 5′-flanking region), rs6916861 (Ex12+894T/G in the 3′-UTR) and rs3730353 (IVS10+37T/C in intron 10) were established by PCR-RFLP. A significant association was found between rs6916861 T/G and rs3730353 T/C polymorphisms of the FYN gene and bipolar disorder. These results were also significant in the subgroups of bipolar I and early-onset (2 = 0.86, D′ = 0.93 with 95% CI = 0.9–0.97). The results suggest that the glutamatergic FYN gene may be associated with bipolar disorder, particularly with type I illness and early age of onset.

We investigated three polymorphisms in the NMDA receptor 2B subunit gene (GRIN2B), involved in glutamatergic neurotransmission, as a candidate gene for bipolar disorder. In the study we included 419 patients with bipolar disorder. Consensus diagnosis by at least two psychiatrists was made, according to DSM-IV criteria, using SCID. The control group consisted of 487 healthy subjects. Genotypes for − 200G/T, 366C/G and rs890G/T of GRIN2B polymorphisms were established by PCR-RFLP method. Linkage disequilibrium analysis was done with Haploview. Genotype distributions were in Hardy–Weinberg equilibrium for the three polymorphisms in the group of patients and control subjects. No association was found between the three polymorphisms and bipolar disorder. In linkage disequilibrium analysis we did not find linkage between the three polymorphisms of GRIN2B gene. The polymorphisms of GRIN2B gene analysed in this study are not likely to be associated with bipolar disorder.

The neuroplasticity hypothesis of bipolar disorder indicates that the BDNF/Trk signaling pathway is associated with the pathogenesis of this illness and treatment with mood stabilizers, such as lithium. This paper describes a relationship between response to lithium prophylaxis and polymorphisms of two functionally connected genes: BDNF and NTRK2, in bipolar illness. Analyses of four SNPs of the BDNF gene (rs2030324, rs988748, rs6265 [Val66Met]and rs2203877) and three of the NTRK2 gene (rs1187326, rs2289656, rs1187327) were performed in the 108 bipolar patients, classified as excellent responders (23%), partial responders (51%) and nonresponders (26%) to lithium. An association of C/G (rs988748) and G/A (rs6265) polymorphisms of the BDNF gene with a degree of prophylactic lithium response were found. No association with lithium response was revealed with the polymorphism of NTRK2 gene, neither with interaction of BDNF and NTRK2 genes.

Background/Aims: Schizophrenia (SCH) and bipolar affective disorder (BPAD) are complex disorders with significant participation of genetic risk factors. Several lines of evidence point to the role of shared neurobiological mechanisms and common genetic background in SCH and BPAD. Immune disturbances have been suggested as contributing factor in the pathogenesis of both SCH and BPAD. The gene coding cytokine tumor necrosis factor (TNF) has been the object of a number of association studies in SCH, with ambiguous results. Only 3 such studies were performed in BPAD. The aim of our study was to perform a case-control association analysis of the TNF –308G/A polymorphism in a Polish sample of patients with SCH, BPAD and healthy controls. Methods: We genotyped the TNF –308G/A polymorphism (rs1800629) by PCR-RFLP in 348 patients with SCH, 361 patients with BPAD and in 351 controls. Results: We observed an association of the –308G allele with both SCH (p = 0.008) and BPAD (p = 0.039), and also with a positive family history in patients with SCH (p = 0.048) and BPAD (p = 0.027). For TNF genotypes, the association was only seen in SCH (p = 0.018). Conclusions: Our results may point to an association of the TNF –308G allele and –308G/G genotype with both SCH and BPAD, and to a relationship of the –308G allele with the risk of SCH and BPAD in patients with a positive family history. TNF could be potentially a susceptibility gene, shared between SCH and BPAD. Complex TNF gene studies – based on multiple single-nucleotide polymorphisms and involving haplotype analysis – are necessary for the clarification of currently contradictory findings.

Both serotonin transporter and brain-derived neurotrophic factor (BDNF) genes have been previously implicated in the efficacy of lithium prophylaxis. The aim of the present study was to assess a possible interaction between serotonin transporter genotype (5HTTLPR) and BDNF Val66Met polymorphism, and the prophylactic response to lithium. The study was performed on 111 patients with bipolar mood disorders (43 male, 68 female), aged 30–77 (mean 54 years) who have been treated with lithium carbonate for at least 5 years (5–27 years, mean 15 years). In the group studied, 31 patients (28%) were classified as excellent responders (ER), 54 (49%) as partial responders (PR), and 26 (23%) as non-responders (NR) to lithium prophylaxis. Age at onset of the illness, duration of illness before treatment introduction and on lithium as well as number of affective episodes before lithium treatment did not differ between these three subgroups of patients. A significant interaction between BDNF and 5HTTLPR polymorphism and lithium response was found. S individuals (patients with s/s or s/l genotype) having Val/Val genotype were significantly more frequent in NR compared with ER or/and PR. Also, S individuals showed extreme differences in response to lithium prophylaxis depending on having either Val/Val or (Val/Met + Met/Met) genotypes of BDNF polymorphism: 9/48 (19%) of ER and 18/48 (37%) of NR in the first group, and 12/30 (40%) and 1/30 (3%) in the second group, respectively. The results obtained may show a significant epistatic interaction between 5-HTTLPR and BDNF polymorphism, and response to lithium prophylaxis. © 2007 Wiley-Liss, Inc.

The measures of prefrontal cognition have been used as endophenotype in molecular-genetic studies. Brain-derived neurotrophic factor (BDNF) has been implicated in cognitive functions and in the pathogenesis of major psychoses. This study investigates the relationship between Val66Met polymorphisms of the BDNF gene and prefrontal cognitive function in 129 patients with schizophrenia and 111 patients with bipolar mood disorder. Cognitive tests included the Wisconsin Card Sorting Test (WCST), with such domains as number of perseverative errors, non-perseverative errors, completed corrected categories, conceptual level responses, and set to the first category, and the N-back test, where mean reaction time and percent of correct reactions were measured. Genotyping for Val66Met BDNF polymorphism was done by polymerase chain reaction method. In schizophrenia, no relationship between Val66Met polymorphism of the BDNF gene and the results of the WCST was observed. Patients with Val/Val genotype had a higher percentage of correct reactions in the N-back test than those with the remaining genotypes. Bipolar patients with Val/Val genotype obtained significantly better results on three of five domains of the WCST. No relationship between BDNF polymorphism and the results of the N-back test was found in this group. A limitation to the results could be variable psychopathological state and medication during cognitive testing and lack of Hardy-Weinberg equilibrium in schizophrenia group. Val66Met polymorphism of the BDNF gene may be associated with cognitive performance on the WCST in bipolar mood disorder but not in schizophrenia. An association of this polymorphism with performance on the N-back test in schizophrenia and not in bipolar illness may suggest that in schizophrenia, the BDNF system may be connected with early phases of information processing.

Glycogen synthase kinase-3β (GSK-3β) has been implicated in the pathogenesis of major psychoses. In this paper, the T–50C polymorphism of the GSK-3β gene has been studied in patients with schizophrenia (n = 432), patients with bipolar disorder (n = 416) and in a healthy control group (n = 408). Consensus diagnosis by at least two psychiatrists was made for each patient, according to DSM-IV and ICD-10 criteria, using the Structured Clinical Interview for DSM-IV Axis I Disorders. Genotypes were established by the polymerase chain reaction-restriction fragment length polymorphism method. We have found a trend towards an association for the C allele in the whole group of schizophrenic patients (p = 0.088) and for the heterozygous T/C genotype of bipolar patients (0.095). Significant differences of genotype distribution and allele frequencies of the T–50C polymorphism were found in the female group of bipolar II patients (p = 0.015 for genotypes and p = 0.009 for alleles). In conclusion, this polymorphism may be associated with female gender in bipolar II disorder.

Dysregulation of dopaminergic neurotransmission has been implicated in the etiology of major psychoses. The dopamine D1 receptor (DRD1) plays a role in some brain functions and mechanisms of psychotropic drugs. Therefore, the DRD1 gene makes a good candidate gene for molecular genetic studies in schizophrenia and bipolar affective disorder. In the present study, the –48A/G polymorphism of the DRD1 gene was estimated in patients with schizophrenia (n = 407) or bipolar affective disorder (n = 380), and in healthy controls (n = 399). No association was found between the polymorphism studied and schizophrenia, either in the whole group of patients or in subgroups divided by gender, age at onset or predominance of positive or negative symptoms. A statistical trend was obtained for an association between this polymorphism and bipolar affective disorder (p = 0.059 for genotypes, p = 0.073 for alleles). The G/G genotype and G allele were significantly more frequent in patients with bipolar disorder, type II (p = 0.016 for genotypes, p = 0.008 for alleles), especially in the women subgroup (p = 0.054 for genotypes, p = 0.024 for alleles). An association between the G/G genotype and bipolar affective disorder with disease onset after 18 years of age was also found (p = 0.022). These data suggest that the –48A/G polymorphism of the DRD1 gene may be involved in the etiology of bipolar disorder in a Polish population.

Introduction: Brain-derived neurotrophic factor (BDNF) has been involved in the pathogenesis of bipolar mood disorder and in the mechanism of mood-normalizing action of lithium. The aim of this study was to find a possible association between lithium prophylactic effect in bipolar patients and two polymorphisms of BDNF gene. Methods: Eighty-eight patients (35 males, 53 females) with bipolar illness were studied. Duration of lithium prophylaxis ranged between 5-27 years (mean 15 years). Three categories of prophylactic lithium response were delineated: excellent responders (ER), partial responders (PR) and non-responders (NR). All patients were genotyped for two polymorphisms of BDNF gene: Val66Met and -270C/T. Results: The Val/Met genotype of Val66Met polymorphism occurred more frequently (p = 0.037) and there was a trend for a higher incidence of Met allele (p = 0.076), in ER than in NR. A trend for C/T genotype and T allele of -270C/T polymorphism was observed to occur more frequently in ER than in NR (p = 0.057 and p = 0.065, respectively). Conclusion: The data obtained suggest that polymorphism of BDNF gene may be connected with a quality of lithium prophylaxis.

The present study included 130 patients with melancholic depression in the course of bipolar disorder and 732 healthy controls. No association was found for alleles, genotypes, or haplotype analysis for NR3C1, AVPR1b, and CRHR1 genes and melancholic depression.

The serotonin neurotransmitter has been associated with the pathogenesis of mood disorders and schizophrenia. Serotonin receptors genes may therefore be candidate genes for the study of the genetics of these disorders. In this study, patients with schizophrenia (n=235) and controls (nn=344) were analysed to determine the correlation between the 5HT2A receptor gene T102C polymorphism and schizophrenia. No association was found between the studied polymorphism and schizophrenia (pn=0.854 for alleles and pn=0.945 for genotypes). Results were also not significant when analysed by gender (for male p-0.861—allele frequency and pn=0.467—genotype frequency, for female pn=0.857—allele frequency and pn=0.833—genotype frequency). Subgroups with regard to schizophrenia subtypes, age of onset and clinical course of schizophrenia were analysed with negative results.

Udgivelsesdato: 2009-Mar-6 BACKGROUND: Being overweight or obese may be associated with poor response to antidepressants. The present report explores the moderation of antidepressant response by body weight to establish the specificity to antidepressant mode of action, type of depressive symptoms and gender. METHODS: Height and weight were measured in 797 men and women with major depression treated with escitalopram or nortriptyline for twelve weeks as part of the Genome Based Therapeutic Drugs for Depression (GENDEP) project. Body mass index (BMI) and obesity (BMI>30) were tested as predictors of change in depressive symptoms using mixed linear models. RESULTS: Higher BMI and obesity predicted poor response to nortriptyline but did not significantly influence response to escitalopram. The moderation of response by body weight was due to differential improvement in neurovegetative symptoms, including sleep and appetite. The relationship between body weight and change in neurovegetative symptoms was moderated by gender with obese men responding less to nortriptyline and obese women having poorer response to both antidepressants. LIMITATIONS: As no placebo arm was included, the specificity of findings to antidepressants is relative. Lack of specific measures precluded accounting for differences in body fat distribution. CONCLUSIONS: Body weight should be considered in the assessment of depression as it may inform the selection of antidepressant treatment.

Juvenile systemic sclerosis (JSSc) is a rare but severe multi-system connective tissue disease of unknown etiology. It is one of the most difficult to treat rheumatic diseases in childhood and characterized by thickening and fibrosis of the skin and associated with fibrosis of internal organs. Eye involvement has rarely been reported. In a 7-year-old African girl, who presented with chorioretinitis and subsequently developed JSSc we discuss the possible association of chorioretinitis with JSSc and the putative implications of scleroderma vascular disease in the development of this complication and review the existing literature.

Suicidal behavior exhibits both circadian and annual rhythms. We were seeking an association between selected candidate clock genes and suicidal behavior in bipolar patients. The study included 441 bipolar patients and 422 controls and we genotyped 41 SNPs of the CLOCK , ARNTL , TIMELESS , PER3 genes. The main positive findings built up associations between selected polymorphisms and: –violent suicide attempts (CLOCK, TIMELESS); –multiple suicide attempts (TIMELESS); –a family history of suicide attempts (TIMELESS).

Anna Leszczyńska-Rodziewicz,1 Aleksandra Szczepankiewicz,2 Beata Narożna,2 Maria Skibińska,1 Joanna Pawlak,1 Monika Dmitrzak-Węglarz,1 Joanna Hauser11Psychiatric Genetics Unit, 2Laboratory of Molecular and Cell Biology, Department of Pulmonology, Pediatric Allergy and Clinical Immunology, Poznan University of Medical Sciences, Poznan, PolandAbstract: We aimed to analyzed the association between polymorphisms of the FKBP5 (FK506 binding protein 5) gene and subtypes of bipolar disorder. In the study, we included 195 bipolar disorder patients with psychotic features, 129 bipolar patients with melancholic depression, and 156 bipolar patients with a history of suicidal attempts. We found weak association between the haplotypes of the FKBP5 gene and bipolar patients with suicidal attempts. We did not find an association between polymorphisms of the FKBP5 gene and bipolar disorder with psychotic features, nor with bipolar disorder with melancholic depression. Limitations of our study are the absence of data about previous trauma exposure and the small sample size of patients, which of course can lead to false-positive results, so further validation and replication of the present findings are still needed.Keywords: FKBP5 gene, bipolar disorder, melancholic depression, psychotic features, suicide attempts

Background Altered activity of hypothalamus–pituitary–adrenal glands (HPA) axis in response to stress underlies the pathogenesis of mood disorders such as depression and bipolar disorder. Chaperone proteins regulate sensitivity of glucocorticoid receptor (GR) to steroids. We hypothesized that genetic variants within the FKBP5 – gene encoding co-chaperone protein essential in GR signaling – may influence the susceptibility to major depressive disorder and bipolar disorder. Methods In the study participated 528 bipolar patients, 218 patients with major depressive disorder and 742 subjects from control group. Genotypes for eight FKBP5 polymorphisms (rs1360780, rs755658, rs9470080, rs4713916, rs7748266, rs9296158, rs9394309, rs3800373) were established by TagMan SNP Genotyping Assays (Applied Biosystems). Linkage disequilibrium analysis for FKBP5 gene was done in Haploview. Gene–gene interactions between FKBP5 and NR3C1 polymorphisms (reported previously) were analyzed using the multidimensionality-reduction method (MDR). Results We have observed an association between five FKBP5 polymorphisms (rs1360780, rs9470080, rs4713916, rs9296158 and rs9394309) and major depressive disorder (p=0.011; p=0.007, p=0.038; p=0.030; p=0.018, respectively), but not bipolar disorder. In linkage disequilibrium analysis we found that seven FKBP5 polymorphisms build haplotype block (rs3800373, rs755658, rs9296158, rs7748266, rs1360780, rs9394309, rs9470080, respectively). We observed that two haplotype combinations (ACATTGT and CCACTAT) were significantly more frequent in the MDD patients than in controls (p=0.014 and p=0.043). We have not observed such an association for BD patients. We have found that interaction between rs9470080 of FKBP5 and rs6198 of NR3C1 influences MDD risk. Limitations The main limitations of this study include low power and limited sample size of MDD patients. Conclusions Single markers and haplotypes of FKBP5 gene and the interaction with glucocorticoid receptor gene (NR3C1) may influence MDD predisposition.

Family twin and adoption studies have noted the heritability of specific biological factors that influence suicidal behaviour. Exposure to stress is one of the factors that strongly contribute to suicide attempts. The biological response to stress involves the hypothalamic-pituitary-adrenal axis (HPA). Therefore, we found it interesting to study polymorphisms of genes involved in the HPA axis (CRHR1, NR3C1, and AVPBR1). The study was performed on 597 patients, 225 of whom had a history of suicide attempts. We did not observe any significant differences in the studied polymorphisms between the group of patients with a history of suicide attempts and the control subjects. Our haplotype analysis of the AVPR1b gene revealed an association between the GCA haplotype and suicide attempts; however, this association was not significant after correcting for multiple testing. We did not observe any other association in haplotype and MDR analysis. We report here a comprehensive analysis of the HPA axis genes and a lack of association for genetic variations regarding the risk of suicide attempts in affective disorder patients. Nonetheless, the inconsistencies with the previously published results indicate the importance of the further investigation of these polymorphisms with respect to the risk of suicide attempts.

Background An association between HPA — axis disturbances and susceptibility towards depression with psychotic features has been reported. NR3C1, CRHR1 and AVPR1b are the key components of this system. We investigated the possible involvement of the polymorphisms of those genes with the susceptibility to psychotic features in the course of BP I disorder. Methods The study was conducted on 194 patients with psychotic features in the course of BPI. Control group consisted of 732 healthy subjects. Genotyping for NR3C1, AVPR1b and CRHR1 polymorphisms was done with use of TagMan SNP Genotyping Assays. Results The association of polymorphisms rs28536160 genotype TT of the AVPR1b gene and polymorphisms rs1293651 of CRHR1 gene with psychotic features in the course of BPI. Limitations The main limitation of our study is the small sample size of the group of patients with psychotic features. Conclusions The results of our study suggest that the studied polymorphisms may increase susceptibility for obtaining psychotic features in the course of BP I.

Objective The main goal of our study was to examine factor structure of schizophrenia and bipolar affective disorder in the Wielkopolska population, using dimension reduction techniques. Methods Schizophrenia (n = 443) and bipolar affective disorder (n = 499) patients were assessed using Operational Criteria Checklist (OPCRIT). Principal component analysis and Maximum Likelihood Factor analysis were carried out to obtain factor structure with significance level for the factor loadings exceeding 0.4. Varimax and promax rotations were used to identify the meaningful factors. Results Rotated solution indicated multidimensional structure for depression and excitement as well as positive domains in the schizophrenia sample. Negative and disorganized dimensions existed as single factors, with item composition similar to that already described. Additionally, a new “social functioning” dimension was identified. In bipolar affective disorder sample, the interpretable dimensions included: depression, psychotic, atypical depression, negative, substance use, excitement and “social functioning”. Factor structure of the combined sample consisted of depression, excitement, disorganization, delusions, substance use, negative and social functioning factors. Conclusions Our results indicated multidimensional and hierarchical structures for some of the previously described dimensions. Additional use of items not exactly related to disease symptoms lead to discovery of “substance use” and “social functioning” dimensions.

Background A strong association has been found between dysregulation of hypothalamic–pituitary–adrenal (HPA) axis and depression and bipolar disorder. Glucocorticoid receptor is one of the involved receptors and its gene has been recognized as a candidate gene for major depressive disorder and bipolar disorder. Therefore, we investigated if polymorphism of the glucocorticoid receptor gene (NR3C1), involved in the regulation of HPA axis, may alter susceptibility as well as the course of major depressive disorder and bipolar disorder. Methods In the study we included 514 patients with bipolar disorder and 193 patients with major depressive disorder. Consensus diagnosis by at least two psychiatrists was made, according to DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria, using SCID (Structured Clinical Interview for DSM Disorders). Control group consisted of 732 healthy subjects. Genotyping for eight NR3C1 polymorphisms was done with use of TaqMan SNP (single nucleotide polymorphism) Genotyping Assays. Linkage disequilibrium analysis was done in Haploview. Results We have found three polymorphisms (rs6198, rs6191 and rs33388) to be associated with major depressive disorder (MDD) and the same polymorphisms were associated with the predominance of depressive symptoms in the course of bipolar disorder. In linkage disequilibrium analysis we observed two haplotype blocks, however, none of those shows involvement in susceptibility to MDD or bipolar disorder. Limitations The main limitation of this study is relatively small sample size of MDD patients group. Conclusions Polymorphisms of NR3C1 gene analyzed in this study may modify susceptibility to major depressive disorder and seem to influence the course of bipolar disorder.

Objective Matrix metalloproteinase 9 (MMP-9) has been implicated in a number of pathological conditions including cancer and heart diseases, and recently also in such neuropsychiatric disorders as schizophrenia and bipolar illness. Therefore, we investigated a possible association between functional polymorphisms of the MMP-9 gene and the response to lithium, the main mood-stabilizing drug in bipolar illness. Methods One hundred and nine bipolar patients treated with lithium for at least 5 years were analyzed. The lithium response was assessed as—excellent: no affective episodes during lithium treatment; partial: 50% or more reduction in the episode index; no response: less than 50% reduction, no change or worsening in the episode index. The -1562C/T MMP-9 gene polymorphism (rs3918242) was assessed by PCR-RFLP method. Results Genotype distributions were not in Hardy–Weinberg equilibrium. No association was found between polymorphism studied and the quality of response to prophylactic lithium administration. Conclusion The functional polymorphism of the MMP-9 gene, analyzed in this study, may not be associated with the treatment response to lithium in bipolar patients. Copyright © 2011 John Wiley & Sons, Ltd.

Matrix metalloproteinase-9 (MMP-9) plays a role in many pathological conditions (e.g., cancer and heart disease). Recently, MMP-9 has been implicated in various aspects of brain functions (e.g., neuroplasticity and epileptogenesis) and thus, we hypothesized that MMP-9 gene may be associated with bipolar mood disorder. The study was performed on 416 patients with bipolar mood disorder, including 75 patients with bipolar II type of the illness, and in 558 healthy control persons. A functional −1562C/T polymorphism of the MMP-9 gene was genotyped in all subjects. Patients with bipolar mood disorder had significant preponderance of T allele versus C allele of 1562C/T polymorphism of the MMP-9 gene, compared to healthy control subjects. The higher frequency of T allele compared to healthy subjects was especially evident in a subgroup of patients with bipolar disorder, type II. The results may provide the first evidence for an involvement of the MMP-9 gene in the pathogenesis of bipolar mood disorder. They may also contribute to explaining genetic connection between bipolar mood disorder and some somatic illnesses. In the light of our results obtained with this polymorphism in schizophrenia, we speculate that the MMP-9 gene may be a common susceptibility gene to major psychoses with different allelic variants occurring in bipolar illness and schizophrenia.