Fronto-parietal alpha ERD and visuo-spatial attention in pregnant women.

Many pregnant women report impairments in their attentional capacities. However, comparative studies between pregnant and non-pregnant women using standardised attention paradigms are rare and inconsistent. During attention tasks alpha activity is known to suppress irrelevant sensory inputs and previous studies show that a large event-related desynchronisation (ERD) in the alpha range prior to target-onset predicts enhanced attentional processing. We quantified the relationship between performance (accuracy, response time) in a standardised visuo-spatial attention task and alpha ERD (∼6-12 Hz) as well as saliva estradiol level in fifteen pregnant women (M = 26.6, SD = 3.0 years) compared to fifteen non-pregnant, naturally cycling women (M = 23.1, SD = 4.3 years). Compared to non-pregnant women, alpha frequency was increased in pregnant women. Furthermore, pregnant women showed a greater magnitude of the alpha ERD prior to target-onset and a moderate increase in accuracy compared to non-pregnant women. In addition, accuracy correlated negatively with estradiol in pregnant women as well as with frontal alpha ERD in all women. These correlational findings indicate that pregnancy-related enhancement in alpha desynchronisation in a fronto-parietal network might modulate accuracy during a visuo-spatial attention task.

High-dimensional profiling reveals Tc17 cell enrichment in active Crohn's disease and identifies a potentially targetable signature.

The immune-pathology in Crohn's disease is linked to dysregulated CD4+ T cell responses biased towards pathogenic TH17 cells. However, the role of CD8+ T cells able to produce IL-17 (Tc17 cells) remains unclear. Here we characterize the peripheral blood and intestinal tissue of Crohn's disease patients (n = 61) with flow and mass cytometry and reveal a strong increase of Tc17 cells in active disease, mainly due to induction of conventional T cells. Mass cytometry shows that Tc17 cells express a distinct immune signature (CD6high, CD39, CD69, PD-1, CD27low) which was validated in an independent patient cohort. This signature stratifies patients into groups with distinct flare-free survival associated with differential CD6 expression. Targeting of CD6 in vitro reduces IL-17, IFN-γ and TNF production. These results identify a distinct Tc17 cell population in Crohn's disease with proinflammatory features linked to disease activity. The Tc17 signature informs clinical outcomes and may guide personalized treatment decisions.

Composição química e cinética de degradação ruminal in vitro de aveia branca cv. URS guapa sob diferentes níveis de adubação nitrogenada / Chemical compounds and kinects of in vitro ruminal degradation of white oats URS Guapa under distinct levels of nitrogen fertilization

Avaliaram-se as doses de nitrogênio 0, 60, 120 e 240kg ha-1 sobre a composição bromatológica e os parâmetros da cinética de degradação ruminal da aveia branca obtida de dois anos de cultivo (2013-2014). Foram realizadas as análises de matéria seca, matéria mineral (MM), proteína bruta (PB), extrato etéreo, fibra em detergente neutro (aFDNmo), lignina, carboidratos solúveis (CHOs) e proteína insolúvel em detergente ácido (PIDA). Não foi observado efeito da adubação nitrogenada sobre as variáveis em nenhum dos anos de cultivo. As variáveis bromatológicas foram influenciadas pelos fatores ambientais. A cinética de degradação ruminal foi correspondente à composição bromatológica. No ano de 2013, foram observados valores superiores para as variáveis PB, MM, PIDA, CHOs e carboidratos não fibrosos, o que influenciou positivamente nos parâmetros da cinética de produção de gás in vitro, Vf 1 e k 2. A composição da cultivar em 2014 tendeu a maiores teores de aFDNmo, lignina e carboidratos totais e a valores superiores para os parâmetros Vf 2 e L. O parâmetro k 1 não foi significativo nos períodos avaliados. Em 2014 o valor nutritivo foi negativamente influenciado pelo atraso na semeadura e pela soma de períodos de restrição hídrica combinados com a elevação da temperatura.(AU)

Doses of Nitrogen were evaluated: 0, 60, 120 and 240kg ha-1 on the chemical composition and rumen degradation kinetics of white oats obtained from two consecutive years (2013-2014). For nutritional characterization the following parameters were analyzed: dry matter; ash, crude protein, ethereal extract, neutral detergent fiber, lignin, soluble carbohydrates and insoluble acid detergent protein. No effect of nitrogen fertilization was observed on the variables analyzed in any of the growing years. The nutritional variables were influenced by environmental factors that occurred in the respective experimental periods and the parameters of ruminal degradation kinetics corresponded to the effects in these compounds. In year 2013, higher values were observed for the variables crude protein, ash, insoluble acid detergent protein, soluble CHO and no fibrous carbohydrates, resulting in higher values also for the in vitro gas production kinetics, Vf1 and k2. Nutritional contents in 2014 tended to higher levels of NDF, lignin and total carbohydrates, and higher values for the parameters Vf2 and L. The parameter k1 was not significant in any of the experimental periods evaluated. In 2014 the forage has its nutritive value negatively influenced by the delay in sowing and the periods of water restriction combined with higher temperatures.(AU)

Familial hypercholesterolaemia in patients with ischaemic stroke or transient ischaemic attack.

BACKGROUND AND PURPOSE: Identification of patients with familial hypercholesterolaemia (FH) is a prerequisite for the appropriate management of their excess cardiovascular risk. It is currently unknown how many patients with acute ischaemic stroke or transient ischaemic attack (TIA) are affected by FH and whether systematic screening for FH is warranted in these patients. METHODS: The prevalence of a clinical diagnosis of FH was estimated in a large representative series of patients with acute ischaemic stroke or TIA (ABCD2 score ≥ 3) using the Dutch Lipid Clinic Network Algorithm (DLCNA; possible FH ≥3, probable/definite FH ≥6). RESULTS: Out of 1054 patients included in the present analysis, 14 had probable/definite FH (1.3%; 95% confidence interval 0.6-2.0) and 107 possible FH (10.2%; 8.4-12.0) corresponding to an overall prevalence of potential FH of 11.5%. Prevalences were even higher in patients with stroke/TIA manifestation before age 55 in men or 60 in women (3.1%, 0.6-5.6; and 13.1%, 8.3-17.9) and those with a prior history of cardiovascular disease (2.6%, 0.9-4.3; and 15.1%, 11.3-18.9). Of note, in two-thirds of our patients with probable/definite and possible FH, stroke or TIA was the initial clinical disease manifestation. CONCLUSIONS: The frequency of potential FH, based on clinical criteria, in patients with acute ischaemic stroke or TIA was 11.5% and that of probable/definite FH (1.3%) was similar to recently reported counts for patients with acute coronary syndrome (1.6%). FH screening using the DLCNA is feasible in clinical routine and should be considered as part of the usual diagnostic work-up.

GC/MS analysis and potential cytotoxic activity of Calyptranthes grandifolia (O. Berg), Calyptranthes tricona (D. Legrand) and Myrciaria plinioides (D. Legrand) essential oil in RAW264.7 and CHO-K1 cells.

The search for new bioactive substances derived from natural products is daily growing. Among biologically active products used in therapeutic approaches, essential oils are described with wide range of therapeutic and pharmacological potential. Plants from Myrtaceae family have the presence of essential oils in its composition. Calyptranthes grandifolia, Calyptranthes tricona and Myrciaria plinioides species belong to this family and are used by the local population. However, there are no reports in the literature describing relevant characteristics about the potential and possible activities of these species. The aim of this study was to identify the main compounds, evaluate the antioxidant potential and investigate, in RAW264.7 and CHO-K1 cells, the cytotoxic activity of the essential oils from the leaves of C. grandifolia, C. tricona and M. plinioides plants, in order to ensure their use. The compounds were identified by GC-MS, antioxidant activity was determined by DPPH method and cytotoxicity was assessed by the Alamar Blue method, at 48 and 72h. The main compounds found in the essential oils were sesquiterpenes. None of the essential oils have antioxidant potential. In cytotoxicity assays, the essential oils from the plants in analysis showed moderate activity in the proposed conditions. The alterations observed between the data provided by the essential oils in question, between different cell lines, may be associated with their composition, suggesting action of minor compounds. These results may suggest that the essential oils from C. grandifolia, C. tricona and M. plinioides have considerable potential to be explored. Future studies will be conducted to obtain more information about the action pathway and potential of the identified compounds.

Combined cell index in assessing blood donor iron stores.

OBJECTIVES: The aim of this study was to assess the appropriateness of using combined cell index (CCI) in the assessment of iron stores in blood donors. This index is calculated by the formula: red blood cell distribution width (RDW) × 104 × mean corpuscular volume (MCV)-1 × mean corpuscular haemoglobin (MCH)-1 . BACKGROUND: Ferritin measurement is a reliable method for estimating iron stores in blood donors. The sensitivity of red blood cell (RBC) parameters of complete blood count in detecting non-anaemic iron deficiency is significantly lower. Consequently, there were several attempts to increase the detection sensitivity by combining these parameters in different indices. METHODS: This study included 1084 male and 792 female whole blood donors accepted for blood donation. For six RBC parameters with the highest level of correlation relative to ferritin [Hgb, MCV, MCH, mean corpuscular haemoglobin concentration (MCHC), RDW and CCI], diagnostic efficacy in the detection of iron depletion (ferritin <12 µg L-1 ) was assessed using receiver operating characteristic (ROC) analysis. RESULTS: CCI showed the highest degree of correlation with ferritin (r = -0·373 for men and r = -0·590 for women) and the highest area under the curve (0·961 for men and 0·864 for women). Using the cut-off value of 52·6 for men and 50·6 for women, the corresponding Youden index was the highest for CCI in both genders (0·851 for men and 0·612 for women). The sensitivity and specificity of CCI in the population of male donors were higher in comparison to female donors (0·941 and 0·910 vs 0·851 and 0·761, respectively). CONCLUSIONS: Study results confirmed the satisfactory diagnostic value of CCI in detecting depleted iron stores in blood donors.

Low-level laser therapy improves peri-implant bone formation: resonance frequency, electron microscopy, and stereology findings in a rabbit model.

Previous studies have reported positive effects of low-level laser therapy (LLLT) on bone healing. This study evaluated the effects of LLLT on peri-implant healing in vivo. Thirty-two rabbits had their mandibular left incisors removed, followed by immediate insertion of a dental implant into the fresh socket. Animals were assigned randomly to four groups: control (non-irradiated) or LLLT at three different doses per session: 5J/cm(2), 10J/cm(2), and 20J/cm(2). A GaAlAs laser (830nm, 50mW) was applied every 48h for 13 days, starting immediately after surgery. The implant stability quotient (ISQ) was measured using resonance frequency analysis upon implant insertion and immediately after death, 30 days after the last application. Tissues were prepared for scanning electron microscopy (SEM) and stereology. Variables measured were bone-implant contact (BIC) and bone neoformation within implant threads at three different sites. The results showed better ISQ for the 20J/cm(2) group (P=0.003). BIC values were significantly higher (P<0.05) in the 20J/cm(2) group, on both SEM and stereology. Bone area values were better in the 10J/cm(2) (P=0.036) and 20J/cm(2) (P=0.016) groups compared to the control group. Under these conditions, LLLT enhanced peri-implant bone repair, improving stability, BIC, and bone neoformation. The findings support and suggest parameters for the design of clinical trials using LLLT after implant placement.

Gene expression changes in cancellous bone of type 2 diabetics: a biomolecular basis for diabetic bone disease.

PURPOSE: Diabetes mellitus type 2 (2DM) is associated with altered bone quality. In order to analyze associated changes on a molecular level, we investigated the gene expression of key factors of osteoblast metabolism in type 2 diabetics. METHODS: Total mRNA and protein of bone samples from 2DM patients and non-diabetic patients were isolated, and subsequently, reverse transcription polymerase chain reaction (RT-PCR) or Western blot was performed. Furthermore, pro- and anti-inflammatory serum cytokine levels were determined using a cytokine array. RESULTS: Expression of runt-related transcription factor 2 (RUNX2) was increased by 53 %. Expression of the bone sialoproteins, secreted phosphoprotein 1 (SPP1; osteopontin), and integrin-binding sialoprotein (IBSP), was elevated by more than 50 %, and activating transcription factor 4 (ATF4) expression was 13 % lower in the investigated diabetes group compared to the control group. Similarly, the expression of versican (VCAN) and decorin (DCN) was upregulated twofold in the diabetic group. At the same time, 2DM patients and controls show alterations in pro- and anti-inflammatory cytokine levels in the serum. CONCLUSIONS: This study identifies considerable changes in the expression of transcription factors and extracellular matrix (ECM) components of bone in 2DM patients. Furthermore, the analysis of key differentiation factors of osteoblasts revealed significant alterations in gene expression of these factors, which may contribute to the dysregulation of energy metabolism in 2DM.

Characterizing CEACAM5 interaction with CD8α and CD1d in intestinal homeostasis.

Normal intestinal epithelial cells (IECs) could act as non-professional antigen-presenting cells, selectively activating CD8(+)-suppressor T cells. An epithelial cell surface glycoprotein, gp180, recognized by monoclonal antibodies B9 and L12 was determined to be critical in this process. Purification and sequence analysis of mAb B9 reactive material revealed amino-acid sequence homology with CEACAM5. We demonstrate that CEACAM5 has properties attributed to gp180, such as CD8α binding and activation of CD8-associated Lck. CEACAM5 is the only CEACAM member interacting with CD1d through the B3 domain. Its N domain (recognized by B9) is required for CD8α binding. Removal of the N-domain glycosylated residues reduces B9 recognition, CD8α binding affinity, and activation of LcK. Therefore, conformational changes in CEACAM5 glycosylation site are critical for its interaction with CD8α. CEACAM5-activated CD8(+) T cells acquire the ability to suppress the proliferation of CD4(+) T cells in vitro in the presence of interleukin (IL)-15 or IL-7. We provide new insights into the role of CEACAM5 and define its specific immunoregulatory properties among the CEACAMs expressed on IECs. We suggest that unique set of interactions between CEACAM5, CD1d, and CD8 render CD1d more class I-like molecule, facilitating antigen presentation and activation of CD8(+)-suppressor regulatory T cells.

Oligoclonal expansions of mucosal T cells in Crohn's disease predominate in NKG2D-expressing CD4 T cells.

Crohn's disease (CD) is an inflammatory pathology of the mucosal intestine that results from uncontrolled immune response towards commensal microbes. Clonal expansions of T cells have been found in patients with CD suggesting an antigen-specific stimulation of pathogenic T cells. Here we show, using T-cell receptor repertoire analysis by real-time PCR, that oligoclonal expansions are found in both CD8+ and CD4+ T cells in the blood and intestinal mucosa of CD patients. The majority of CD4+ T-cell-expanded clones are CD4+NKG2D+ T cells. These clonal expansions were found in both inflamed and neighboring healthy tissue and were persisting during the course of the disease. The presence of these CD4+NKG2D+ T-cell clones at the macroscopically normal edge of the surgical resection might be predictive of inflammation relapse post surgery.

Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3.

The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn's disease (CD) compared with non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to CD etiology in this population, most notably at NOD2, in which three causal, uncommon and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes that showed significantly greater association to CD in the Ashkenazi Jewish population compared with a non-Jewish population (145 haplotypes and no haplotypes with P-value <10(-3), respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established CD loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare CD-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.

Assessment of the systemic effects of low-level laser therapy (LLLT) on thyroid hormone function in a rabbit model.

The aim of this study was to assess the effects of low-level laser therapy (LLLT) applied to a dental extraction socket on thyroid gland function in a rabbit model, based on serum triiodothyronine and thyroxine levels. Sixteen male New Zealand rabbits were randomly distributed into two groups: a control group (non-irradiated animals) and an experimental group (irradiated animals: one irradiation point in the extraction socket of the lower incisor). Animals in the experimental group were irradiated with an aluminium gallium arsenide diode laser (AlGaAs; wavelength 830 nm, 40 mW, CW laser), for 13 days, every 48 h, at a dose of 6 J/cm(2) per session, resulting in a total dose of 42 J/cm(2). Serum triiodothyronine and thyroxine levels were measured in both groups before extraction and on the last day of observation (day 15). There were no statistically significant differences between the groups in pre- and post-irradiation triiodothyronine and thyroxine values. With the irradiation protocol used in this study, LLLT did not affect thyroid function in rabbits as assessed by circulating serum triiodothyronine and thyroxine levels.

Lidocaine/tetracaine patch (Rapydan) for topical anaesthesia before arterial access: a double-blind, randomized trial.

BACKGROUND: Arterial catheterization is painful and is associated with patient stress and anxiety. Analgesia is usually provided by subcutaneous injection of local anaesthetic. An alternative is topical anaesthesia, such as Rapydan which is a novel topical anaesthetic patch containing 70 mg each of lidocaine and tetracaine. We therefore tested the hypothesis that Rapydan patch analgesia is non-inferior to subcutaneous local anaesthetic. METHODS: Ninety patients undergoing elective major cardiac surgery were included in this prospective, double-blind clinical trial. Patients were randomly assigned to receive either a lidocaine/tetracaine patch, followed by subcutaneous injection 0.5 ml of normal saline solution, or placebo patch with subsequent subcutaneous injection of 0.5 ml of lidocaine 1%. Pain during arterial catheterization using 100-mm-long visual analogue scale (VAS) was the primary outcome. Other outcomes were pain during anaesthetic/saline injection and plasma tetracaine concentrations. RESULTS: VAS pain scores during arterial puncture were comparable in both groups and Rapydan was non-inferior to subcutaneous lidocaine. Pain scores at the time of subcutaneous injection were significantly lower (better) in patients assigned to the lidocaine/tetracaine patch than to lidocaine (P=0.001). Plasma tetracaine concentrations never exceeded the detection limit of 25 ng ml(-1) at any time in any patient. CONCLUSIONS: Both the lidocaine/tetracaine patch and subcutaneous injection of lidocaine provided comparable pain control during arterial catheter insertion. Subcutaneous lidocaine caused discomfort during injection, whereas the lidocaine/tetracaine patch required placement 20 min before the procedure. Given adequate time, the patch provided better overall analgesia by obviating the need for subcutaneous infiltration.

Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine:daunorubicin, in patients with advanced leukemia.

Forty-eight patients received CPX-351 (liposome-encapsulated cytarabine:daunorubicin at a 5:1 molar ratio) every other day for 3 doses at 10 dose levels. Pharmacokinetic parameters were dose-independent and exhibited low inter-patient variability. CPX-351 showed a negligible distribution phase and prolonged mono-exponential first-order plasma elimination (t(1/2)∼24 h). The plasma ratio of 5:1 was maintained at all dose levels. Nearly all of the detectable cytarabine and daunorubicin in circulation following CPX-351 administration was in the form of liposome encapsulated drug. Dose-dependent hematopoietic effects had early onset with cytopenias at 12 units/m(2), and a gradual increase in frequency and severity, until single induction complete response was achieved at 43 units/m(2). Non-hematologic effects had onset by 24 units/m(2) with shallow dose-response until maximum frequency and severity were observed at the 101-134 units/m(2) dose levels. Single induction response occurred over a 2.3-fold range of doses indicating that CPX-351 may be useful at high doses for patients suitable for intensive chemotherapy and at reduced doses for patients at increased risk of treatment-related mortality. The unique pharmacologic features of CPX-351 contribute to its promising antileukemic efficacy.

Direct formation of supermassive black holes via multi-scale gas inflows in galaxy mergers.

Observations of distant quasars indicate that supermassive black holes of billions of solar masses already existed less than a billion years after the Big Bang. Models in which the 'seeds' of such black holes form by the collapse of primordial metal-free stars cannot explain the rapid appearance of these supermassive black holes because gas accretion is not sufficiently efficient. Alternatively, these black holes may form by direct collapse of gas within isolated protogalaxies, but current models require idealized conditions, such as metal-free gas, to prevent cooling and star formation from consuming the gas reservoir. Here we report simulations showing that mergers between massive protogalaxies naturally produce the conditions for direct collapse into a supermassive black hole with no need to suppress cooling and star formation. Merger-driven gas inflows give rise to an unstable, massive nuclear gas disk of a few billion solar masses, which funnels more than 10(8) solar masses of gas to a sub-parsec-scale gas cloud in only 100,000 years. The cloud undergoes gravitational collapse, which eventually leads to the formation of a massive black hole. The black hole can subsequently grow to a billion solar masses on timescales of about 10(8) years by accreting gas from the surrounding disk.

Attenuation of TNF-driven murine ileitis by intestinal expression of the viral immunomodulator CrmD.

Tumor necrosis factor α (TNFα) is a key pathogenic factor in Crohn's disease and rheumatoid arthritis. TNF(ΔARE) mice express high levels of TNFα and present Crohn's-like ileitis and arthritis. Alterations in the chemokine network could underline the TNF-driven ileitis. The aim of this study was to evaluate the role of TNF and chemokines in ileitis using ectromelia virus cytokine response modifier D (CrmD), a protein that binds TNFα and a limited number of chemokines. We generated transgenic mice expressing CrmD in intestinal epithelial cells (vCrmD mice) and crossed them with the TNF(ΔARE) mice to test whether CrmD could affect TNF-driven inflammatory processes. During homeostasis, only the number of B cells in the lamina propria was reduced by CrmD expression. Interestingly, CrmD expression in the intestine markedly attenuated the inflammatory infiltrates in the ileum of TNF(ΔARE) mice, but did not affect development of arthritis. Our results suggest that CrmD affects development of ileitis by locally affecting both TNF and chemokine function in the ileum.

Suppression of Th1 and Th17, but not Th2, responses in a CD8(+) T cell-mediated model of oral tolerance.

The role of CD8(+) T cells in oral tolerance remains unclear. To address this, we developed a model to induce CD8(+) Tregs by feeding the major histocompatibility complex class I immunodominant epitope of OVA, OVA((257-264)). OVA((257-264)) feeding induced tolerance similar to that observed in OVA protein-fed mice, capable of suppressing the production of Th1 and Th17 cytokines and inhibiting a Th1-driven delayed-type hypersensitivity response following immunization with whole OVA (wOVA) protein. OVA((257-264)) peptide-induced suppression could be transferred to naive mice with CD8(+) cells, but not CD8-depleted cells, isolated from mesenteric lymph nodes of peptide-fed mice. Interestingly, while capable of inhibiting Th1 and Th17 responses, OVA((257-264)) feeding could not suppress any feature of a Th2 inflammatory response, though OVA protein feeding could, suggesting that these cells function through a different mechanism than their CD4(+) counterparts generated in response to feeding with wOVA. Thus, CD8(+) T cells are functionally capable of mediating tolerance to Th1 and Th17 responses.

Early clinical experience with adalimumab in treatment of inflammatory bowel disease with infliximab-treated and naïve patients.

BACKGROUND: Adalimumab, at an induction dose of 160/80 mg followed by 40 mg every other week is approved for treatment of refractory Crohn's disease (CD) and for patients with loss of response to infliximab. AIM: To evaluate the indications for adalimumab, the proportion of inflammatory bowel disease patients who require dose escalation and to identify whether this strategy is effective in inducing or maintaining remission. METHODS: Patients prescribed adalimumab for CD were identified and included for analysis, if they had follow-up of at least 6 weeks. Adalimumab dose was escalated if patients had return of symptoms prior to next dose. Clinical judgment was used to determine severity of disease. A second GI physician confirmed disease severity as determined by the first physician. RESULTS: A total of 48 out of 60 patients met inclusion criteria. Adalimumab was used to treat CD in 47/48 (98%) and ulcerative colitis in one (2%). Most patients had moderate 30/48 (63%) or severe 17/48 (35%) disease. Prior infliximab exposure was present in 42/48 (88%). Adalimumab dose escalation occurred in 14/48 (29%) within an average time of 2.2 months (s.d. 1.5 months). A majority of patients who required dose escalation, nine of 14 (64%) did not improve clinically. Steroids could be discontinued in three of 16 (18.8%). Clinical improvement was noted in 21/48 (43.8%) and one of 48 (2%) patients achieved clinical remission. Adverse drug reactions necessitated drug discontinuation in four of 48 (8%) of patients. CONCLUSIONS: This retrospective review from a single academic medical centre suggests that a minority of patients, who cannot be maintained on 40 mg every other week, of adalimumab benefit from an increased dose. This suggests the need for a treatment with an alternative mode of action in anti-TNF failures.

Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and childhood-onset mood disorders.

BACKGROUND/AIMS: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. METHODS: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. RESULTS: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. CONCLUSION: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.

Rapid formation of supermassive black hole binaries in galaxy mergers with gas.

Supermassive black holes (SMBHs) are a ubiquitous component of the nuclei of galaxies. It is normally assumed that after the merger of two massive galaxies, a SMBH binary will form, shrink because of stellar or gas dynamical processes, and ultimately coalesce by emitting a burst of gravitational waves. However, so far it has not been possible to show how two SMBHs bind during a galaxy merger with gas because of the difficulty of modeling a wide range of spatial scales. Here we report hydrodynamical simulations that track the formation of a SMBH binary down to scales of a few light years after the collision between two spiral galaxies. A massive, turbulent, nuclear gaseous disk arises as a result of the galaxy merger. The black holes form an eccentric binary in the disk in less than 1 million years as a result of the gravitational drag from the gas rather than from the stars.