Denosumab is not associated with risk of malignancy: systematic review and meta-analysis of randomized controlled trials.

The immunomodulatory effects of denosumab have raised concerns for risk of malignancy. This meta-analysis of 25 randomized controlled trials (21,523 patients) shows similar risk of malignancy between denosumab (60 mg every 6 months, up to 48 months) and any comparator. Post-marketing surveillance may detect rare or late-occurring drug effects. Possible increased risk of malignancy in patients treated with denosumab has been concerned due to inhibition of the immune modulator receptor activator of nuclear factor κ-Β ligand (RANKL). We aimed to assess the risk of malignancy associated with denosumab treatment. PubMed and Cochrane Central Register of Controlled Trials were searched up to May 27, 2019 to include all randomized controlled trials of denosumab (60 mg every 6 months) versus any comparator. Trials using higher drug doses for prevention of skeletal-related events were excluded. Data were independently extracted by two reviewers and analyzed using a fixed-effect model to pool risk ratios (RRs) with 95% confidence intervals (CI). Twenty-five trials (21,523 patients) were included. The risk of malignancy was similar between denosumab and other comparators (absolute risk difference 0%, RR 1.08 [95% CI, 0.93-1.24], I2 = 0%). Sensitivity analysis based on adequate allocation concealment showed similar results. The risk of malignancy did not differ between groups in any of the subgroup analyses, including stratification by race, individual comparators, indications for treatment, and longer drug exposure (≥ 24 months, 9 studies). The risk ratio of malignancy-related death was similar between groups. Early concerns about a potential increased risk of malignancy resulting from an immunomodulatory effect of denosumab are not supported by evidence from this meta-analysis of 25 RCTs with drug exposure of up to 48 months. Since RCTs with longer observation for safety outcomes are not expected, post-marketing surveillance will be the main means for detection of rare or late-occurring events.

Filaroidosis Infection in an Immunocompetent Adult Dog from France.

A dog from Paris (France) was referred with a 2-week history of dry cough, intermittent acute onset of dyspnoea, and acute abdominal pain. A generalised bronchoalveolar infiltrate with a patchy distribution was observed at chest x-rays and computed tomography (CT) scans. Negative results were obtained through several faecal examinations for cardiorespiratory nematodes by using the Baermann technique and at two blood analysis with a commercially available test for the detection of A. vasorum antigen (the first one at the first visit and second one at the control visit, one month later). PCR methods for the identification of A. vasorum and C. vulpis were also accomplished. At the control visit, nematode L1s were found during direct microscopic examination of bronchoalveolar lavage fluid (BALF). Thus, a different antigen-based assay for the detection of A. vasorum was performed with a positive result. Moreover, based on morphology, isolated larvae were identified as Filaroides hirthi. The dog was treated with fenbendazole (50 mg/kg per os once daily) for two consecutive weeks. After five months, the dog was referred again for the intermittent acute onset of dyspnoea and was found to be still positive for F. hirthi larvae at BALF examination. A 15-day treatment regimen with fenbendazole in combination with three subcutaneous injections of ivermectin (0.4 mg/kg, once every two weeks), was then performed. No larvae were detected at two BALF microscopical examinations performed one month apart. Results from this case report underline the importance of including F. hirthi infections in the differential diagnosis of dog bronchopneumonia.

Correction to: Variations of characteristic time scales in rotating stratified turbulence using a large parametric numerical study.

After publication of the paper, an error in computing the ratio γ of kinetic to potential energy transfer times has been detected, which has led the authors to amend two figures, as explained in the main text.

A setup for synchrotron-radiation-induced total reflection X-ray fluorescence and X-ray absorption near-edge structure recently commissioned at BESSY II BAMline.

An automatic sample changer chamber for total reflection X-ray fluorescence (TXRF) and X-ray absorption near-edge structure (XANES) analysis in TXRF geometry was successfully set up at the BAMline at BESSY II. TXRF and TXRF-XANES are valuable tools for elemental determination and speciation, especially where sample amounts are limited (<1 mg) and concentrations are low (ng ml(-1) to µg ml(-1)). TXRF requires a well defined geometry regarding the reflecting surface of a sample carrier and the synchrotron beam. The newly installed chamber allows for reliable sample positioning, remote sample changing and evacuation of the fluorescence beam path. The chamber was successfully used showing accurate determination of elemental amounts in the certified reference material NIST water 1640. Low limits of detection of less than 100 fg absolute (10 pg ml(-1)) for Ni were found. TXRF-XANES on different Re species was applied. An unknown species of Re was found to be Re in the +7 oxidation state.

Variations of characteristic time scales in rotating stratified turbulence using a large parametric numerical study.

We study rotating stratified turbulence (RST) making use of numerical data stemming from a large parametric study varying the Reynolds, Froude and Rossby numbers, Re, Fr and Ro in a broad range of values. The computations are performed using periodic boundary conditions on grids of 1024(3) points, with no modeling of the small scales, no forcing and with large-scale random initial conditions for the velocity field only, and there are altogether 65 runs analyzed in this paper. The buoyancy Reynolds number defined as R(B) = ReFr2 varies from negligible values to ≈ 10(5), approaching atmospheric or oceanic regimes. This preliminary analysis deals with the variation of characteristic time scales of RST with dimensionless parameters, focusing on the role played by the partition of energy between the kinetic and potential modes, as a key ingredient for modeling the dynamics of such flows. We find that neither rotation nor the ratio of the Brunt-Väisälä frequency to the inertial frequency seem to play a major role in the absence of forcing in the global dynamics of the small-scale kinetic and potential modes. Specifically, in these computations, mostly in regimes of wave turbulence, characteristic times based on the ratio of energy to dissipation of the velocity and temperature fluctuations, T(V) and T(P), vary substantially with parameters. Their ratio γ=T(V)/T(P) follows roughly a bell-shaped curve in terms of Richardson number Ri. It reaches a plateau - on which time scales become comparable, γ≈0.6 - when the turbulence has significantly strengthened, leading to numerous destabilization events together with a tendency towards an isotropization of the flow.

Resolving the paradox of oceanic large-scale balance and small-scale mixing.

A puzzle of oceanic dynamics is the contrast between the observed geostrophic balance, involving gravity, pressure gradient, and Coriolis forces, and the necessary turbulent transport: in the former case, energy flows to large scales, leading to spectral condensation, whereas in the latter, it is transferred to small scales, where dissipation prevails. The known bidirectional constant-flux energy cascade maintaining both geostrophic balance and mixing tends towards flux equilibration as turbulence strengthens, contradicting models and recent observations which find a dominant large-scale flux. Analyzing a large ensemble of high-resolution direct numerical simulations of the Boussinesq equations in the presence of rotation and no salinity, we show that the ratio of the dual energy flux to large and to small scales agrees with observations, and we predict that it scales with the inverse of the Froude and Rossby numbers when stratification is (realistically) stronger than rotation. Furthermore, we show that the kinetic and potential energies separately undergo a bidirectional transfer to larger and smaller scales. Altogether, this allows for small-scale mixing which drives the global oceanic circulation and will thus potentially lead to more accurate modeling of climate dynamics.

Neural dysfunction in ADHD with Reading Disability during a word rhyming Continuous Performance Task.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous, neurodevelopmental disorder which co-occurs often with Reading Disability (RD). ADHD with and without RD consistently have higher inattentive ratings compared with typically developing controls, with co-occurring ADHD and RD also demonstrating impaired phonological processing. Accordingly, inattention has been associated with greater phonological impairment, though the neural correlates of the association are poorly understood from a functional neuroimaging perspective. It was postulated that only the co-occurring subgroup would demonstrate hypoactivation of posterior, left hemispheric, reading-related areas and, to a lesser extent, alterations in right hemispheric, attention areas compared with controls. METHODS: A novel word rhyming Continuous Performance Task assesses functional activation differences in phonology- and attention-related areas between three groups: ten boys with ADHD and RD, fourteen boys with ADHD without RD, and fourteen typically developing controls. Subjects respond to words that rhyme with a target word as mono- and disyllabic, English words are visually presented over 90s blocks. RESULTS: Behavioral performance was not different between groups. Some hypoactivation of left hemispheric, reading-related areas was apparent in ADHD and RD, but not ADHD without RD, compared with controls. Right hemispheric, attention areas showed alterations in both ADHD subgroups relative to controls; however, the differences for each subgroup were dissimilar. CONCLUSIONS: The dorsal decoding subnetwork may not be grossly compromised in ADHD with Reading Disability. The role of cognitive impairments, including the level of inattention, on phonology requires clarification from a neuroimaging perspective.

Genome-wide association study of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Description of serum symmetric dimethylarginine concentration and of urinary SDS-AGE pattern in dogs with ACTH dependent hyperadrenocorticism.

Serum symmetric dimethylarginine (SDMA) and patterns of urinary protein separated by sodium dodecyl sulfate agarose gel electrophoresis (SDS-AGE) have not been investigated as biomarkers in dogs with ACTH-dependent hyperadrenocorticism (ADHAC). This exploratory prospective study aimed to evaluate SDMA, serum creatinine (sCR), and SDS-AGE in dogs with ADHAC with and without proteinuria (ADHAC-P and ADHAC-nP, respectively). Thirty-five pet dogs classified as ADHAC-P (n=16), ADHAC-nP (n=6) and healthy (n=13) were included. Renal biomarkers were evaluated in all dogs at diagnosis. Baseline concentration of SDMA was not significantly different between the three groups (P = 0.15) whereas sCr was significantly lower in dogs in ADHAC dogs compared to healthy dogs (88.0 µmol/L [70.4-132.6; 79.2-114.4]) whether they had proteinuria or not (P = 0.014 and 0.002, respectively). However, baseline concentrations of sCr and SDMA were not significantly different between dogs with ADHAC-P dogs (SDMA, 8 µg/dL [5-12; 7-9]; sCr, 57.2 µmol/L [35.2-212.2; 52.8-92.4]) and ADHAC-nP dogs (SDMA, 8.5 µg/dL [7-13; 8-10]; sCr, 70.4 µmol/L [61.6-79.2; 61.6-70.4]) (P = 0.35 and P = 0.41, respectively). Proteinuria in dogs with ADHAC-P was mainly of glomerular origin (SDS-AGE pattern: glomerular in 10/16 dogs; mixed glomerular/tubular in four dogs). In our study, SDMA was neither significantly different in dogs with ADHAC whether they were proteinuric or not, nor between ADHAC and healthy dogs. Urinary electrophoresis provides additional information to the UPC and further investigations are needed to determine whether it may help identify dogs with ADHAC-P requiring specific antiproteinuric treatment.

High-speed and high-efficiency superconducting nanowire single photon detector array.

Superconducting nanowire single photon detectors (SNSPDs) have separately demonstrated high efficiency, low noise, and extremely high speed when detecting single photons. However, achieving all of these simultaneously has been limited by detector subtleties and tradeoffs. Here, we report an SNSPD system with <80 ps timing resolution, kHz noise count rates, and 76% fiber-coupled system detection efficiency in the low-flux limit at 1550 nm. We present a model for determining the detection efficiency penalty due to the detection recovery time, and we validate our method using experimental data obtained at high count rates. We demonstrate improved performance tradeoffs, such as 68% system detection efficiency, including losses due to detector recovery time, when coupled to a Poisson source emitting 100 million photons per second. Our system can provide limited photon number resolution, continuous cryogen-free operation, and scalability to future imaging and GHz-count-rate applications.

Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of death in the United States. Increased level of interleukin-8 (IL-8) and CXCR2 on tumours and in the tumour microenvironment has been associated with CRC growth, progression and recurrence in patients. Here, we aimed to evaluate the effects of tissue microenvironment-encoded IL-8 and CXCR2 on colon cancer progression and metastasis. METHODS: A novel immunodeficient, skin-specific IL-8-expressing transgenic model was generated to evaluate colon cancer growth and metastasis. Syngeneic mouse colon cancer cells were grafted in CXCR2 knockout (KO) mice to study the contribution of CXCR2 in the microenvironment to cancer growth. RESULTS: Elevated levels of IL-8 in the serum and tumour microenvironment profoundly enhanced the growth of human and mouse colon cancer cells with increased peri-tumoural angiogenesis, and also promoted the extravasation of the cancer cells into the lung and liver. The tumour growth was inhibited in CXCR2 KO mice with significantly reduced tumour angiogenesis and increased tumour necrosis. CONCLUSION: Increased expression of IL-8 in the tumour microenvironment enhanced colon cancer growth and metastasis. Moreover, the absence of its receptor CXCR2 in the tumour microenvironment prevented colon cancer cell growth. Together, our study demonstrates the critical roles of the tumour microenvironment-encoded IL-8/CXCR2 in colon cancer pathogenesis, validating the pathway as an important therapeutic target.

Conformal invariance in three-dimensional rotating turbulence.

We examine turbulent flows in the presence of solid-body rotation and helical forcing in the framework of stochastic Schramm-Löwner evolution (SLE) curves. The data stem from a run with 1536³ grid points, with Reynolds and Rossby numbers of, respectively, 5100 and 0.06. We average the parallel component of the vorticity in the direction parallel to that of rotation and examine the resulting <ω(z)>(z) field for scaling properties of its zero-value contours. We find for the first time for three-dimensional fluid turbulence evidence of nodal curves being conformal invariant, belonging to a SLE class with associated Brownian diffusivity κ = 3.6 ± 0.1. SLE behavior is related to the self-similarity of the direct cascade of energy to small scales and to the partial bidimensionalization of the flow because of rotation. We recover the value of κ with a heuristic argument and show that this is consistent with several nontrivial SLE predictions.

Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system.

Multiple sclerosis is a demyelinating disorder of the central nervous system (CNS), in which an immune attack directed against myelin constituents causes myelin destruction and death of oligodendrocytes, the myelin-producing cells. Here, the efficacy of nerve growth factor (NGF), a growth factor for neurons and oligodendrocytes, in promoting myelin repair was evaluated using the demyelinating model of experimental allergic encephalomyelitis (EAE) in the common marmoset. Surprisingly, we found that NGF delayed the onset of clinical EAE and, pathologically, prevented the full development of EAE lesions. We demonstrate by immunocytochemistry that NGF exerts its antiinflammatory effect by downregulating the production of interferon gamma by T cells infiltrating the CNS, and upregulating the production of interleukin 10 by glial cells in both inflammatory lesions of EAE and normal-appearing CNS white matter. Thus, NGF, currently under investigation in human clinical trials as a neuronal trophic factor, may be an attractive candidate for therapy of autoimmune demyelinating disorders.

Reciprocal thalamocortical connectivity of the medial pulvinar: a depth stimulation and evoked potential study in human brain.

The thalamic medial pulvinar nucleus (PuM) is fully developed only in primates and reaches its greatest extent in humans. To assess the reciprocal functional connectivity between PuM and cortex, we studied intracerebral-evoked responses obtained after PuM and cortical electrical stimulation in 7 epileptic patients undergoing depth electroencephalographic recordings. Cortical-evoked potentials (CEPs) to PuM stimulation were recorded from all explored cortical regions, except striate cortex, anterior cingulated, and postcentral gyrus. Percentages of cortical contacts pairs responding to PuM stimulation (CEPs response rate) ranged from 80% in temporal neocortex, temporoparietal (TP) junction, insula, and frontoparietal opercular cortex to 34% in mesial temporal regions. Reciprocally, PuM-evoked potentials (PEPs) response rates were 14% after cortical stimulation in insula and frontoparietal opercular cortex, 67% in the TP junction, 76% in temporal neocortex, and 80% in mesial temporal regions. Overall, our study of functional PuM connectivity in the human brain converges with most of the data from anatomical studies in monkeys, except for a strong amygdalohippocampal functional projection to PuM and an unexpected imbalance between some of the reciprocal pathways explored. This functional quantitative approach helps to clarify the functional role of PuM as well as its implication in temporal lobe epileptic seizures.

Ultrasonography criteria for differentiating ACTH dependency from ACTH independency in 47 dogs with hyperadrenocorticism and equivocal adrenal asymmetry.

BACKGROUND: Adrenal ultrasonography (US) in dogs with hyperadrenocorticism (HAC) is commonly used to distinguish adrenocorticotropic hormone (ACTH)-independent (AIHAC) and ACTH-dependent hyperadrenocorticism (ADHAC). To date, no cut-off values for defining adrenal atrophy in cases of adrenal asymmetry have been determined. Given that asymmetrical hyperplasia is sometimes observed in ADHAC, adrenal asymmetry without ultrasonographic proof of adrenocortical tumor such as vascular invasion or metastasis can be equivocal. OBJECTIVE: The purpose of this study was to compare adrenal US findings between cases of ADHAC and AIHAC in dogs with equivocal adrenal asymmetry (EAA), and to identify useful criteria for their distinction. ANIMALS: Forty dogs with EAA were included. METHODS: Ultrasound reports of HAC dogs with adrenal asymmetry without obvious vascular invasion or metastases were reviewed. Dogs were classified as cases of ADHAC (n = 28) or AIHAC (n = 19), determined by plasma ACTH concentration. The thickness, shape, and echogenicity of both adrenal glands and presence of adjacent vascular compression were compared between AIHAC and ADHAC groups. RESULTS: The maximal dorsoventral thickness of the smaller gland (SDV) ranged from 2.0 to 5.0 mm in AIHAC and from 5.0 to 15.0 mm in ADHAC. The 95% confidence intervals for estimated sensitivity and specificity of a SDV cut-off set at 5.0 mm in the diagnosis of AIHAC were 82-100 and 82-99%, respectively. Other tested US criteria were found to overlap extensively between the 2 groups, precluding their usefulness for distinction. CONCLUSION AND CLINICAL IMPORTANCE: In EAA cases, an SDV ≤5.0 mm is an appropriate cut-off for AIHAC ultrasonographic diagnosis.

Cynomolgus monkeys.

In the report "Tick anticoagulant peptide (TAP) is a novel inhibitor of blood coagulation factor Xa" by L. Waxman et al. (4 May, p. 593), the second sentence of the caption of figure 2 was printed incorrectly. It should have read, "Determination of the Intrinsic K(i) was done by fitting the observed data (*) with nonlinear regression analysis to the ratio of inhibited velocity (v(i)) to uninhibited velocity (V(o)) described by the equation V(i)/V(o) = [E(t) - I(t) K(*)(i)] + [(I(t) + K(*)(i) - E(t))(2) + 4K(i)E(t)](1/2)/2E(t) derived by Morrison for tight-binding inhibition (7) (solid line), where E(t) and I(t) are the total amount of enzyme and inhibitor, respectively, included in the assay."

Late complications of immune deviation therapy in a nonhuman primate.

The administration of antigens in soluble form can induce antigen-specific immune tolerance and suppress experimental autoimmune diseases. In a marmoset model of multiple sclerosis induced by myelin oligodendrocyte glycoprotein (MOG), marmosets tolerized to MOG were protected against acute disease, but after tolerization treatment a lethal demyelinating disorder emerged. In these animals, MOG-specific T cell proliferative responses were transiently suppressed, cytokine production was shifted from a T helper type 1 (TH1) to a TH2 pattern, and titers of autoantibodies to MOG were enhanced. Thus, immune deviation can increase concentrations of pathogenic autoantibodies and in some circumstances exacerbate autoimmune disease.

Thyroid function and infertility in the dog: a survey in five breeds.

In our study, a clinical and reproductive examination was undertaken in 204 dogs of five different breeds. Thyroxine and thyroid-stimulating hormone plasma concentrations were assayed in order to assess the real incidence of hypothyroidism associated with reproductive disease. Among these animals, only two breeds were affected by hypothyroidism (4.5% of the Dogue de Bordeaux and 2.4% of the Leonbergers). Moreover, these animals did not suffer from any reproductive disease. Our study showed also that 70% of the male Dogue de Bordeaux were hypothyroxinemic compared with Great Danes, English Mastiff and Leonbergers whose male population was 100% normothyroidic. We found the same tendency in bitches. In our data, there was no difference in thyroxin plasma concentrations between normo- and hypofertile dogs, but our results were not statistically significant.

Accuracy of an adrenocorticotropic hormone (ACTH) immunoluminometric assay for differentiating ACTH-dependent from ACTH-independent hyperadrenocorticism in dogs.

BACKGROUND: Adrenocorticotropic hormone (ACTH) determination has been used for 30 years to distinguish ACTH-dependent hyperadrenocorticism (ADHAC) from ACTH-independent hyperadrenocorticism (AIHAC) in dogs. However, the few studies that have evaluated its diagnostic accuracy, based in the majority of cases on older assays, have been associated with systematic, but highly variable proportions of misclassified or unclassified cases. OBJECTIVE: The purpose of the present study is to evaluate the accuracy of a validated ACTH immunoluminometric assay (ILMA) for differentiating between ADHAC and AIHAC. ANIMALS: One hundred and nine dogs with hyperadrenocorticism were included: 91 with ADHAC and 18 with AIHAC. METHODS: Retrospective study. Dogs displaying feedback inhibition after the dexamethasone suppression test, adrenal symmetry, or both were considered to have ADHAC. AIHAC was demonstrated by adrenal tumor histology. For each group, ACTH determination by ILMA was reviewed. RESULTS: In the ADHAC group, plasma ACTH measurements ranged between 6 and 1250 pg/mL (median, 30 pg/mL). In the AIHAC group, all ACTH concentrations were below the lower quantification limit of the assay (<5 pg/mL). The 95% confidence interval was 85-100% for sensitivity and 97-100% for specificity in AIHAC diagnosis. CONCLUSION AND CLINICAL IMPORTANCE: No overlap in ACTH concentrations was observed between dogs with ADHAC and dogs with AIHAC. The use of a new technique with high analytical sensitivity made it possible to use a low threshold (5 pg/mL), avoiding the misclassification of some ADHAC cases with low, but quantifiable concentrations of ACTH. The assessment of ACTH concentrations by ILMA is an accurate tool for differentiating between ADHAC and AIHAC.