Comparing two artificial intelligence software packages for normative brain volumetry in memory clinic imaging.

PURPOSE: To compare two artificial intelligence software packages performing normative brain volumetry and explore whether they could differently impact dementia diagnostics in a clinical context. METHODS: Sixty patients (20 Alzheimer's disease, 20 frontotemporal dementia, 20 mild cognitive impairment) and 20 controls were included retrospectively. One MRI per subject was processed by software packages from two proprietary manufacturers, producing two quantitative reports per subject. Two neuroradiologists assigned forced-choice diagnoses using only the normative volumetry data in these reports. They classified the volumetric profile as "normal," or "abnormal", and if "abnormal," they specified the most likely dementia subtype. Differences between the packages' clinical impact were assessed by comparing (1) agreement between diagnoses based on software output; (2) diagnostic accuracy, sensitivity, and specificity; and (3) diagnostic confidence. Quantitative outputs were also compared to provide context to any diagnostic differences. RESULTS: Diagnostic agreement between packages was moderate, for distinguishing normal and abnormal volumetry (K = .41-.43) and for specific diagnoses (K = .36-.38). However, each package yielded high inter-observer agreement when distinguishing normal and abnormal profiles (K = .73-.82). Accuracy, sensitivity, and specificity were not different between packages. Diagnostic confidence was different between packages for one rater. Whole brain intracranial volume output differed between software packages (10.73%, p < .001), and normative regional data interpreted for diagnosis correlated weakly to moderately (rs = .12-.80). CONCLUSION: Different artificial intelligence software packages for quantitative normative assessment of brain MRI can produce distinct effects at the level of clinical interpretation. Clinics should not assume that different packages are interchangeable, thus recommending internal evaluation of packages before adoption.

Technical and clinical validation of commercial automated volumetric MRI tools for dementia diagnosis-a systematic review.

Developments in neuroradiological MRI analysis offer promise in enhancing objectivity and consistency in dementia diagnosis through the use of quantitative volumetric reporting tools (QReports). Translation into clinical settings should follow a structured framework of development, including technical and clinical validation steps. However, published technical and clinical validation of the available commercial/proprietary tools is not always easy to find and pathways for successful integration into the clinical workflow are varied. The quantitative neuroradiology initiative (QNI) framework highlights six necessary steps for the development, validation and integration of quantitative tools in the clinic. In this paper, we reviewed the published evidence regarding regulatory-approved QReports for use in the memory clinic and to what extent this evidence fulfils the steps of the QNI framework. We summarize unbiased technical details of available products in order to increase the transparency of evidence and present the range of reporting tools on the market. Our intention is to assist neuroradiologists in making informed decisions regarding the adoption of these methods in the clinic. For the 17 products identified, 11 companies have published some form of technical validation on their methods, but only 4 have published clinical validation of their QReports in a dementia population. Upon systematically reviewing the published evidence for regulatory-approved QReports in dementia, we concluded that there is a significant evidence gap in the literature regarding clinical validation, workflow integration and in-use evaluation of these tools in dementia MRI diagnosis.

Synergy between RA and TLR3 promotes type I IFN-dependent apoptosis through upregulation of TRAIL pathway in breast cancer cells.

Due to its ability to regulate the growth, differentiation and apoptosis of cancer cells, retinoic acid (RA) is considered a signaling molecule with promising therapeutic potential in oncology. In this study, we show that RA is able to induce the intrinsic ability of breast cancer cells to recognize double-stranded RNA (dsRNA) through the upregulation of Toll-like receptor 3 (TLR3) expression. RA, co-administered with the dsRNA mimicker polyinosinic-polycytidylic acid (poly(I:C)), synergizes to mount a specific response program able to sense dsRNA through the concurrent upregulation of TLR3, the dsRNA helicases melanoma differentiation-associated antigen-5 (MDA-5) and RA-inducible gene-1 (RIG-1), and the dsRNA-activated protein kinase (PKR) expression, leading breast cancer cells to specifically express downstream transcriptional targets of dsRNA sensors, such as interferon-ß (IFNß), interleukin-8 (IL-8), chemokine (C-C motif) ligand 5 (CCL5), and C-X-C motif Chemokine 10 (CXCL10). A TLR3-dependent apoptotic program is also induced by RA and poly(I:C) co-treatment that correlates with the induction of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and contributes to block breast cancer cell proliferation. The mechanisms of apoptosis induced by RA/poly(I:C) in breast cancer cells involve type I IFN autocrine signaling, caspase-8 and caspase-3 activation, as well as TRAIL signaling. Our results reveal important links among RA, TLR3 and TRAIL and highlight the combined use of RA and poly(I:C) as a potential effective tumor therapy by improving the apoptotic response of cancer cells with low sensitivity to the action of synthetic dsRNA.

High performance liquid chromatography, thin layer chromatography and spectrophotometric studies on the removal of biogenic amines from some Egyptian foods using organic, inorganic and natural compounds.

This work has been carried out to investigate the conditions which lead to removal of the biogenic amines through the model system. Also, the main goal of this research work is trying to remove biogenic amines; histamine and tyramine, from some Egyptian foods such as tomato, strawberry, banana and mango to prevent their allergy effect. Histamine and tyramine have been affected by pyrogallol, catechol, starch, ascorbic and chlorogenic acids at different levels with different conditions. Some natural additives like glucose, spices, milk, vanillin, starch, orange juice, ascorbic and citric acids, showed an effective effect on disappearance of histamine and tyramine. By studying the effect of some additives on biogenic amines, it was found that tomato showed a decrease in histamine and tyramine concentrations by adding spices. Strawberry and banana showed a clear decrease in histamine and tyramine concentrations by treating them with ascorbic acid. Treating mango by milk led to increase of histamine level while milk with chocolate increases both histamine and tyramine concentrations.

Persistent trigeminal artery: angio-tomography and angio-magnetic resonance finding.

The trigeminal artery (TA) is the most common embryonic carotid-vertebrobasilar anastomosis to persist into adulthood. It typically extends from the internal carotid artery to the basilar artery. Persistent primitive arteries are usually found incidentally, but are often associated with vascular malformation, cerebral aneurysm and, in case of TA, with trigeminal neuralgia. We present one patient with TA as a cause of trigeminal neuralgia and in other three as an incidental finding, on TC and MR angiograms.

An empirical model for treatment of arsenic contaminated underground water by electrocoagulation process employing a bipolar cell configuration with continuous flow.

Arsenic (As) was removed electrochemically from underground water (GW) by electrocoagulation (EC) process employing a bipolar cell configuration with continuous flow using iron electrodes. A kinetic model derived from the Lagergren equation was applied to specify the kinetics of the arsenic removal reaction. Elucidation of the effect of the liquid flow rate on the treatment time and on the simulation results of the model was achieved. The results showed that treatment times decreased from 10.50 min to 0.75 min as the flow rate decreased from 3.500 to 0.875 L min(-1) and the current density varied from 15 to 45 A m(-2) respectively. The used sorption kinetic model successfully describes the arsenic removal by this process. The coefficients of determination were found to be very high in all cases (R(2)>0.99) indicating a good fit of the experimental data to Lagergren model.

Energy and electrode consumption analysis of electrocoagulation for the removal of arsenic from underground water.

A systematic study of the effect of design and operation conditions of an electrochemical reactor on the treatment time for arsenic (As) electro-removal from underground water (GW) was carried out to analyse the energy and electrode consumption. The effects of four factors--current density, interelectrode distance, electrode area-volume ratio, and liquid motion driving mode--were evaluated. The response variables were the energy and the electrode consumption and the treatment time to reduce the GW residual As concentration to 10 microg L(-1), which is the maximum contaminant level (MCL) established by the World Health Organization (WHO) in drinking water. The results obtained in this study showed that the factor that had the greatest effect on most of the response variables was the liquid motion driving mode. The best residence time was 20s, which favoured low energy consumption (58.78 Wh m(-3)) and low electrode material loss (9.59 g m(-3)).

Persistent trigeminal artery: angio-tomography and angio-magnetic resonance finding / Artéria trigeminal persistente: achado na angio-tomografia e angio-ressonância magnética

The trigeminal artery (TA) is the most common embryonic carotid-vertebrobasilar anastomosis to persist into adulthood. It typically extends from the internal carotid artery to the basilar artery. Persistent primitive arteries are usually found incidentally, but are often associated with vascular malformation, cerebral aneurysm and, in case of TA, with trigeminal neuralgia. We present one patient with TA as a cause of trigeminal neuralgia and in other three as an incidental finding, on TC and MR angiograms.

Artéria trigeminal (AT) é a anastomose carótido-vertebrobasilar mais comum a persistir na vida adulta. Tipicamente estende-se da artéria carótida interna até a artéria basilar. Artérias primitivas persistentes são usualmente um achado incidental, mas freqüentemente estão associadas a malformações vasculares, aneurismas e, no caso da AT, a neuralgia do trigêmio. Apresentamos um paciente com AT como causa de neuralgia do trigêmio e em outros três como um achado incidental, em angiogramas por tomomografia computadorizada e ressonância magnética.

Retinoic-acid-induced apoptosis in leukemia cells.

Retinoic acid (RA) cures more than 75% of patients with acute promyelocytic leukemia (APL). Here, we review the various anti-cancer activities of retinoids and rexinoids, alone and in combination with other drugs, with emphasis on the RA-dependent induction of a cancer-cell-selective apoptosis signaling pathway to which multiple anti-cancer signals converge. These findings identify the TRAIL (tumor-necrosis-factor-related apoptosis-inducing ligand) pathway as a central cell-autonomous anti-cancer weapon that can act independently of the immune system.

Colonic carcinogenesis in vagotomyzed rats.

INTRODUCTION: An increased incidence of colorectal cancer (CRC) has been reported in patients with peptic ulcer disease treated with truncal vagotomy. Inhibition of gastric acid output and its hormonal consequence, hypergastrinemia, have been considered risk factors for the development of CRC. The aim of the present study was to determine whether truncal vagotomy increases, in the short (7 days) and long term (120 days), the incidence of CRC in a model of carcinogenesis. MATERIAL AND METHOD: We used 86 Wistar rats distributed in 7 groups to which DMH (1,2-dimethylhydrazine dihydrochloride) was administered for the induction of colon tumors, at doses of 5 and 20 mg/kg of weight. The first three groups were used as control groups; the rats of the four other groups underwent a truncal vagotomy with pyloroplasty and Heller myotomy prior to the administration of DMH. Finally, we compared the incidence of colonic tumors in vagotomized vs non-vagotomized groups receiving the same dose of DMH. RESULTS: In the non-vagotomized rats that received low doses of DMH (5 mg/kg of weight), mortality was 0% and 0% developed cancer as compared to 40% and 0%, respectively, of rats vagotomized 7 days before the administration of DMH and 20% and 0%, respectively, of rats vagotomized 120 days before the administration of DMH. After the administration of high doses of DMH, mortality was 50% and 80% developed cancer as compared to 100% and 0%, respectively, of rats vagotomized 7 days before the administration of DMH and 61.11% and 42.8%, respectively, of rats vagotomized 120 days before the administration of DMH. CONCLUSION: Truncal vagotomy does not increase the incidence of CRC induced by DMH in the rat.

Association with Ets-1 causes ligand- and AF2-independent activation of nuclear receptors.

The vitamin D receptor (VDR) normally functions as a ligand-dependent transcriptional activator. Here we show that, in the presence of Ets-1, VDR stimulates the prolactin promoter in a ligand-independent manner, behaving as a constitutive activator. Mutations in the AF2 domain abolish vitamin D-dependent transactivation but do not affect constitutive activation by Ets-1. Therefore, in contrast with the actions of vitamin D, activation by Ets-1 is independent of the AF2 domain. Ets-1 also conferred a ligand-independent activation to the estrogen receptor and to peroxisome proliferator-activated receptor alpha. In addition, Ets-1 cooperated with the unliganded receptors to stimulate the activity of reporter constructs containing consensus response elements fused to the thymidine kinase promoter. There is a direct interaction of the receptors with Ets-1 which requires the DNA binding domains of both proteins. Interaction with Ets-1 induces a conformational change in VDR which can be detected by an increased resistance to proteolytic digestion. Furthermore, a retinoid X receptor-VDR heterodimer in which both receptors lack the core C-terminal AF2 domain can recruit coactivators in the presence, but not in the absence, of Ets-1. This suggests that Ets-1 induces a conformational change in the receptor which creates an active interaction surface with coactivators even in the AF2-defective mutants. These results demonstrate the existence of a novel mechanism, alternative to ligand binding, which can convert an unliganded receptor from an inactive state into a competent transcriptional activator.

The occurrence of two opecoeliid digeneans in Mullus barbatus and M. surmuletus from the Spanish south-eastern Mediterranean.

The infection by Opecoeloides furcatus and Poracanthium furcatum (Opecoeliidae) was studied in 121 Mullus barbatus and 113 M. surmuletus collected from the Spanish south-eastern Mediterranean. The prevalence of infection was most frequent in M. surmuletus with values of 81.42% for O. furcatus and 38.05% for P. furcatum. In M. barbatus the prevalences of O. furcatus and P. furcatum were 54.54% and 14.88% respectively. Statistically significant differences were found between the infection of the two hosts with P. furcatum. No significant differences in worm burdens could be attributable to host size or to seasonal changes, although a lower infection of M. barbatus by O. furcatus occurred in the autumn. Furthermore, the electrophoretic mobility of the enzyme malic dehydrogenase (MDH) was also studied and both digeneans presented different patterns, corresponding in both cases to homozygotic genotypes.

Cloning of a mouse glucocorticoid modulatory element binding protein, a new member of the KDWK family.

A mouse cDNA that encodes a nuclear DNA binding protein was identified by yeast two-hybrid screening using the activation domain 2 of the nuclear receptor coactivator TIF2 as a bait. BLAST analysis revealed that the identified cDNA encodes a KDWK domain and contains sequences almost identical to three tryptic peptides of rat GMEB-1 which together with the GMEB-2 heterodimeric partner binds to the GME/CRE sequence (glucocorticoid modulatory element) of the tyrosine aminotransferase (TAT) promoter. Mouse GMEB-1 is ubiquitously expressed in all the tissues examined. In vitro translated mGMEB-1 bound specifically to GME oligonucleotides, either alone or as a heterodimer with rGMEB-2. Transient transfection experiments with TAT promoter reporter genes suggest a potential role for mGMEB-1 as a transcriptional regulator of the TAT promoter.

Interaction of vitamin D and retinoid receptors on regulation of gene expression.

Vitamin D and retinoic acid (RA) receptors (VDRs and RARs, respectively), bind as heterodimers with the retinoid X receptor (RXR) to hormone response elements (HREs) in target genes. In some cases RA and vitamin D can cooperate to stimulate transcription through the same HRE. However, VDR/RXR heterodimers bind in a transcriptionally unproductive manner and without a defined polarity on certain RA response elements, and under these circumstances vitamin D inhibits the response to RA. Although competition for binding to DNA may contribute to this inhibitory response, titration of common coactivators by VDR also appears to be involved in transrepression. Therefore, the transcriptional response to RA and vitamin D depends on a complex combinatory pattern of interaction among different receptors wih DNA and coactivators.

Synergistic activation of the prolactin promoter by vitamin D receptor and GHF-1: role of the coactivators, CREB-binding protein and steroid hormone receptor coactivator-1 (SRC-1).

PRL gene expression is dependent on the presence of the pituitary-specific transcription factor GHF-1/Pit-1, which is transcribed in a highly restricted manner in cells of the anterior pituitary. In pituitary GH3 cells, vitamin D increases the levels of PRL transcripts and stimulates the PRL promoter. We have analyzed the role of GHF-1 and of the vitamin D receptor (VDR) to confer vitamin D responsiveness to the PRL promoter. For this purpose we have used nonpituitary HeLa cells, which do not express GHF-1. We found that VDR activates the PRL promoter both in a ligand-dependent and -independent manner through a sequence located between positions -45/-27 in the proximal 5'-flanking region. This sequence also confers VDR and vitamin D responsiveness to a heterologous promoter. In the context of the PRL gene, VDR requires the presence of GHF-1 to activate the promoter. Truncation of the last 12 C-terminal amino acids of VDR, which contain the ligand-dependent activation function (AF2), abolishes regulation by vitamin D, suggesting that binding of coactivators to this region mediates ligand-dependent stimulation of the PRL promoter by the receptor. Indeed, expression of the coactivators, steroid hormone receptor coactivator-1 (SRC-1) and CREB-binding protein (CBP), significantly enhances the stimulatory effect of vitamin D mediated by the wild-type VDR but not by the AF2 mutant receptor. Furthermore, CBP also increases the activation of the PRL promoter by GHF-1 and the ligand-independent activation by both wild-type and mutant VDR.

Vitamin D represses retinoic acid-dependent transactivation of the retinoic acid receptor-beta2 promoter: the AF-2 domain of the vitamin D receptor is required for transrepression.

Retinoic acid (RA)-dependent activation of the RA receptor beta2 (RARbeta2) gene in embryonal carcinoma cells is mediated by binding of retinoid receptor heterodimers (RAR/RXR) to a RA response element (RARE) located closely to the TATA box. We have analyzed the effect of vitamin D on the response of the RARbeta2 promoter to RA in pituitary GH4C1 cells that coexpress receptors for retinoids and vitamin D. Incubation with vitamin D markedly reduced the response to RA caused by transcriptional interference of the vitamin D receptor (VDR) on the RARE. This DNA element binds VDR/RXR heterodimers with high affinity, and these inactive heterodimers can displace active RAR/RXR from the RARE. Overexpression of RXR in GH4C1 cells, as well as incubation with BMS649 (a RXR-specific ligand), increased the inhibitory effect of vitamin D, suggesting that the VDR/RXR heterodimer is the repressive species and that titration of RXR is not responsible for this inhibition. Although DNA binding could be required for full potency of the inhibitory activity of VDR, it is not absolutely required because a truncated receptor (VDR delta1-111), lacking the DNA binding domain, also displays repressor activity. Furthermore, the ability to mediate transrepression by vitamin D was strongly decreased when a mutant VDR in which the last 12 C-terminal aminoacids have been deleted (VDR deltaAF-2) was used. Because this region contains the domain responsible for ligand-dependent recruitment of coactivators, titration of common coactivators for VDR and RAR could be involved in the inhibitory effect of vitamin D. In agreement with this hypothesis, overexpression of E1A, which can act as a RARbeta2 promoter-specific coactivator, significantly reversed repression by vitamin D.

Lysine 246 of the vitamin D receptor is crucial for ligand-dependent interaction with coactivators and transcriptional activity.

Mutant K246A in the predicted helix 3 of the ligand-binding domain, as well as mutants L417S and E420Q in helix 12, which contains the core ligand-dependent transcriptional activation domain (AF-2), were generated to examine AF-2 activity of the vitamin D receptor (VDR). These mutations abolished vitamin D-dependent transactivation. In addition, VDR mediates a ligand-dependent repression of the response of the retinoic acid receptor beta2 promoter to retinoic acid, and the helix 3 and helix 12 mutants were unable to mediate transrepression. Furthermore, the VDR mutants, but not the native receptor, enhanced phorbol ester induction of the activator protein-1-containing collagenase promoter. The helix 3 and helix 12 mutations strikingly reduced the ability of VDR to interact with the coactivators steroid receptor coactivator-1, ACTR, and the CREB-binding protein. As a consequence, overexpression of steroid receptor coactivator-1 increased vitamin D-dependent transactivation by VDR but not by the K246A mutant. These results indicate that the lysine 246 participates, together with residues in helix 12, in the recruitment of coactivators and that AF-2 activity is involved both in ligand-dependent transactivation and in transrepression by VDR.

The vitamin D receptor binds in a transcriptionally inactive form and without a defined polarity on a retinoic acid response element.

Heterodimers of the vitamin D receptor (VDR) with the retinoid X receptor (RXR) bind in a transcriptionally unproductive manner to the retinoic acid response element present in the retinoic acid receptor-beta2 promoter. This element is composed of a direct repeat (DR) of the sequence PuGTTCA spaced by five nucleotides. However, the same sequence separated by three nucleotides (DR3) acts as a strong vitamin D response element. Here we show that the polarity of binding of the heterodimers to the DR3 was 5'-RXR-VDR-3', whereas on the DR5, both heterodimeric partners bind indistinctly to the 5' or 3' hemi-sites. These results suggest that the response elements can allosterically regulate the conformation of the receptors to determine positive or negative regulation of gene expression. Despite the altered polarity, the DR5-bound heterodimer was able to recruit the nuclear receptor coactivator ACTR in a vitamin D-dependent fashion. Furthermore, binding of the corepressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) to the RXR/VDR heterodimer on a DR5 was not observed. Binding of RXR/VDR heterodimers to DRs with different transcriptional outcomes may generate selectivity and provide a greater complexity and flexibility to the vitamin D responses.