Diagnostic accuracy of content-based dermatoscopic image retrieval with deep classification features.

BACKGROUND: Automated classification of medical images through neural networks can reach high accuracy rates but lacks interpretability. OBJECTIVES: To compare the diagnostic accuracy obtained by using content-based image retrieval (CBIR) to retrieve visually similar dermatoscopic images with corresponding disease labels against predictions made by a neural network. METHODS: A neural network was trained to predict disease classes on dermatoscopic images from three retrospectively collected image datasets containing 888, 2750 and 16 691 images, respectively. Diagnosis predictions were made based on the most commonly occurring diagnosis in visually similar images, or based on the top-1 class prediction of the softmax output from the network. Outcome measures were area under the receiver operating characteristic curve (AUC) for predicting a malignant lesion, multiclass-accuracy and mean average precision (mAP), measured on unseen test images of the corresponding dataset. RESULTS: In all three datasets the skin cancer predictions from CBIR (evaluating the 16 most similar images) showed AUC values similar to softmax predictions (0·842, 0·806 and 0·852 vs. 0·830, 0·810 and 0·847, respectively; P > 0·99 for all). Similarly, the multiclass-accuracy of CBIR was comparable with softmax predictions. Compared with softmax predictions, networks trained for detecting only three classes performed better on a dataset with eight classes when using CBIR (mAP 0·184 vs. 0·368 and 0·198 vs. 0·403, respectively). CONCLUSIONS: Presenting visually similar images based on features from a neural network shows comparable accuracy with the softmax probability-based diagnoses of convolutional neural networks. CBIR may be more helpful than a softmax classifier in improving diagnostic accuracy of clinicians in a routine clinical setting.

Hydrogeochemical investigations and groundwater quality assessment of Torbat-Zaveh plain, Khorasan Razavi, Iran.

Hydrogeochemical investigations of groundwater in Torbat-Zaveh plain have been carried out to assess the water quality for drinking and irrigation purposes. In this study, 190 groundwater samples were collected and analyzed for physicochemical parameters and major ion concentrations. The abundance of major cations and anions was in the following order: Na(+) > Mg(2+) > Ca(2+) > K(+), and Cl(-) > [Formula: see text] > [Formula: see text] > [Formula: see text]. As a result, alkaline element (Na(+)) exceeds alkaline earth elements (Mg(2+) and Ca(2+)), and strong acids (Cl(-) and [Formula: see text]) dominate weak acids ([Formula: see text] and [Formula: see text]) in majority of the groundwater samples. Statistical analyses including Spearman correlation coefficients and factor analysis display good correlation between physicochemical parameters (EC, TDS and TH) and Na(+), Mg(2+), Ca(2+), Cl(-) and [Formula: see text]. The results display that rock-weathering interactions and ion-exchange processes play important role in controlling groundwater chemistry. Saturation index values also indicate that water chemistry is significantly affected by carbonate minerals such as calcite, aragonite and dolomite. US Salinity Laboratory(USSL) and Wilcox diagrams together with permeability index values reveal that most of the groundwater samples are suitable for irrigation purpose. However, in some regions, the water samples do not indicate required irrigational quality.

Platelet hyperprocoagulant activity in Type 2 diabetes mellitus: attenuation by glycoprotein IIb/IIIa inhibition.

BACKGROUND: Platelets are hyperactive in Type 2 diabetes mellitus (T2DM), and antiplatelet treatment with glycoprotein (GP) IIb/IIIa inhibitors provides better thrombotic protection in DM than in non-diabetic subjects. OBJECTIVE: We hypothesized that diabetic platelets are hyperprocoagulant, and that this hyperactivity can be inhibited by GPIIb/IIIa blockade. METHODS: Patients with T2DM and gender/age/body mass index-matched non-diabetic controls were recruited (n = 12 for both) to study the effect of GPIIb/IIIa blockade on platelet procoagulant activity. Platelet phosphotidylserine (PS), factor (F) Va expression, and platelet-derived microparticle (PDMP) generation were measured by whole blood flow cytometry. Platelet-dependent thrombin generation and plasma clotting time were monitored in recalcified platelet-rich plasma. RESULTS: Compared to controls, basal platelet activation was similar, while thrombin receptor activating peptide stimulated activation was enhanced in patients with T2DM. Diabetic platelets also displayed more profound elevations of platelet PS exposure, FVa binding, and PDMP generation upon stimulation. These alterations resulted in a hyperprocoagulant state, as evidenced by a marked increase in the platelet procoagulant index, enhanced thrombin generation, and a shortened plasma clotting time. GPIIb/IIIa blockade by c7E3 or SR121566 decreased platelet PS exposure and FVa binding, and diminished platelet procoagulant activity in patients with T2DM. CONCLUSIONS: Platelets have increased procoagulant activity in patients with T2DM. The hyperprocoagulant activity is counteracted by GPIIb/IIIa blockade.

Glycoprotein IIb/IIIa blockade inhibits platelet aminophospholipid exposure by potentiating translocase and attenuating scramblase activity.

The present study investigated the mechanisms underlying the inhibition of platelet phosphatidylserine (PS) exposure by GPIIb/IIIa blockade. Platelet PS exposure induced by thrombin stimulation was cell-cell contact dependent. GPIIb/IIIa blockade by c7E3 or SR121566 inhibited thrombin-induced platelet PS exposure. Thrombin stimulation induced mild, while A23187 induced extensive platelet-derived microparticle (PDMP) generation. Thrombin-induced PDMP generation was not inhibited by GPIIb/IIIa blockade. Aminophospholipid translocase activity was reduced upon platelet activation by thrombin. The reduction of non-PS-exposing platelets was attenuated by GPIIb/IIIa blockade, while little translocase activity was seen in PS-exposing platelets. Thrombin increased scramblase activity slightly in non-PS-exposing platelets, which was inhibited by GPIIb/IIIa blockade, and markedly enhanced scramblase activity in PS-exposing platelets. Activation of platelet calpain and caspase-3 or cytosolic calcium mobilization were not altered by GPIIb/IIIa inhibition. Thus, GPIIb/IIIa blockade inhibits platelet PS exposure by enhancing translocase activity and attenuating scramblase activity, but does not inhibit PDMP generation.

Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins.

We report here the identification and functional characterization of two new human caspase recruitment domain (CARD) molecules, termed Pseudo-interleukin-1beta converting enzyme (ICE) and ICEBERG. Both proteins share a high degree of homology, reaching 92% and 53% identity, respectively, to the prodomain of caspase-1/ICE. Interestingly, both Pseudo-ICE and ICEBERG are mapped to chromosome 11q22 that bears caspases-1, -4- and -5 genes, all involved in cytokine production rather than in apoptosis. We demonstrate that Pseudo-ICE and ICEBERG interact physically with caspase-1 and block, in a monocytic cell line, the interferon-gamma and lipopolysaccharide-induced secretion of interleukin-1beta which is a well-known consequence of caspase-1 activation. Moreover, Pseudo-ICE, but not ICEBERG, interacts with the CARD-containing kinase RICK/RIP2/CARDIAK and activates NF-kappaB. Our data suggest that Pseudo-ICE and ICEBERG are intracellular regulators of caspase-1 activation and could play a role in the regulation of IL-1beta secretion and NF-kappaB activation during the pro-inflammatory cytokine response.

Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1.

Procaspase-9 contains an NH2-terminal caspase-associated recruitment domain (CARD), which is essential for direct association with Apaf-1 and activation. Procaspase-1 also contains an NH2-terminal CARD domain, suggesting that its mechanism of activation, like that of procaspase-9, involves association with an Apaf-1-related molecule. Here we describe the identification of a human Apaf-1-related protein, named Ipaf that contains an NH2-terminal CARD domain, a central nucleotide-binding domain, and a COOH-terminal regulatory leucine-rich repeat domain (LRR). Ipaf associates directly and specifically with the CARD domain of procaspase-1 through CARD-CARD interaction. A constitutively active Ipaf lacking its COOH-terminal LRR domain can induce autocatalytic processing and activation of procaspase-1 and caspase-1-dependent apoptosis in transfected cells. Our results suggest that Ipaf is a specific and direct activator of procaspase-1 and could be involved in activation of caspase-1 in response to pro-inflammatory and apoptotic stimuli.

Direct influence of the p53 tumor suppressor on mitochondrial biogenesis and function.

Mitochondrial localization of p53 has been observed in several cell systems, but an understanding of its organelle-based physiological activity remains incomplete. The purpose of the present study was to investigate the mitochondrial DNA genomic response to dominant-negative p53 mutant miniprotein (p53DD) fused to a mitochondrial import signal. Constructs were generated to express mitochondrial targeted enhanced green fluorescent protein (mEGFP) or dominant-negative mutant p53 miniprotein (m53DD) by in-frame fusion to the signal peptide sequence of murine Cox8l. Control cytosolic vectors (cEGFP, c53DD) had the signal sequence placed in antisense orientation. NIH 3T3 cells were transiently transfected with these vectors in various combinations. Mitochondrial 16S ribosomal RNA (16S rRNA) expression and fluorochrome staining with Mitotracker Red CMXRos (DeltaPsim) were decreased in cells expressing m53DD. Both alterations were specific for mitochondrial import competence (e.g., m53DD vs. c53DD) as well as the passenger protein (e.g., m53DD vs. mEGFP). The normal functional state of mitochondria was restored with PK11195, a specific ligand of the mitochondrial peripheral-type benzodiazepine receptor. Negative dominance of m53DD on 16S rRNA expression and CMXRos staining, and rescue of these parameters with PK11195, imply a direct positive effect of p53 on mitochondrial biogenesis and function.

Altered expression of mitochondrial 16S ribosomal RNA in p53-deficient mouse embryos revealed by differential display.

Inactivation of the tumor suppressor p53 is associated with neural tube defects and altered teratogenicity in early embryos. To gain insight into the function of p53 during early embryogenesis, RNA profiles of wild-type p53(+/+) and p53(-/-) null mutant mouse embryos were compared at the head-fold stage (day 8 post coitum) using HPLC-based mRNA differential display. The results of this screen revealed a deficiency of mitochondrial 16S ribosomal RNA in p53(-/-) embryos. RT-PCR showed abnormalities in 16S rRNA levels relative to some representative nuclear (COIV, beta-actin) and mitochondrial (COIII) transcripts in p53(-/-) embryos, and that 16S rRNA expression increased with development of p53(+/+) embryos during neurulation. Embryos that lack p53 also displayed weakened cytochrome c oxidase staining and reduced ATP content. During neurulation, the mouse embryo switches from an anaerobic (glycolytic) to an aerobic (oxidative) metabolism. The preliminary results of the present study suggest that p53 may be involved, directly or indirectly, in this transition.

Transcription of the JC virus archetype late genome: importance of the kappa B and the 23-base-pair motifs in late promoter activity in glial cells.

The transcription control region of the archetype strain of the human polyomavirus JC virus (JCV(Cy)), unlike its neurotropic counterpart (JCV(Mad-1)), contains only one copy of the 98-bp enhancer/promoter repeat with the 23-bp and the 66-bp insertion blocks. Early studies by us and others have indicated that the structural organization of JCV(Mad-1) is critical for glial cell-specific transcription of the viral genome. In addition, the kappa B regulatory motif found in the JCV(Mad-1) genome, which also exists in JCV(Cy), confers inducibility to the JCV(Mad-1) early and late promoters in response to extracellular stimuli. In this study, we have investigated the regulatory role of the 23- and the 66-bp blocks and their functional relationship to the kappa B motif in stimulating transcription of the Cy early and late promoters in glial cells. We demonstrate that mutations in the kappa B motif reduce the basal activity of the Cy early promoter and decrease the levels of its induction by phorbol myristate acetate or factors derived from activated T cells. Under similar circumstances, mutation in the kappa B motif completely abrogated the basal and the induced levels of transcription of the viral late promoter. Using deletion and hybrid promoter constructs, we have demonstrated that the 23-bp block of the Cy promoter plays a critical role in the observed inactivation of Cy late promoter transcription in glial cells. Results from DNA binding studies have indicated the formation of a common nucleoprotein complex with the 23-bp sequence, mutant kappa B (kappa B(mut)), and wild-type kappa B (kappa B(wt)). Analysis of this complex by UV cross-linking has identified a 40-kDa protein which binds to the 23-bp sequence and the kappa B motif. The importance of these findings for the activation of JCV(Cy) under various physiological conditions is discussed.

Calcified right ventricular fibroma causing outflow obstruction. Report of a case with successful excision.

A 5-year-old boy with clinical findings of pulmonic stenosis was found to have a large calcified mass in the right ventricular outflow region and a gradient of 120 mm Hg between the right ventricle and the pulmonary artery. At surgery, an ovalshaped tumor attached to the interventricular septum and obstructing the right ventricular outflow tract was removed. The child survived and is doing well. Histologically, the tumor had the characteristics of fibroma. A hemodynamic study three months after surgery showed almost complete abolishment of the gradient. To our knowledge this is the fifth reported case of calcified right ventricular fibroma with successful operation. In childhood intracardiac calcifications, together with obstruction, are highly suggestive of this lesion.