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A convergent synthesis of the tricyclic architecture of the guanacastepenes featuring a selective ring fragmentation.

[reaction: see text] This Letter describes a concise, diastereoselective synthesis of the tricyclic carbon framework of the guanacastepene family of natural products. An intermolecular Diels-Alder reaction established a remote stereochemical relationship and facilitated a synthesis of allylic acetate 3, which was subsequently joined with vinylstananne 9 via a Stille coupling. An intramolecular [2 + 2] photocycloaddition then afforded complex cyclobutyl ketone 19, which underwent a stereoelectronically controlled fragmentation to the guanacastepene architecture on treatment with samarium diiodide.

Diterpenes↗

Hepatosplenic cat-scratch disease in children: selected clinical features and treatment.

We reviewed 19 cases of hepatosplenic cat-scratch disease at Texas Children's Hospital (Houston). The range of the patients' ages was 2 years 4 months to 11 years 8 months. The chief complaint was fever for all patients. The duration of fever before diagnosis was 7 to 56 days (mean, 22 days). Abdominal pain was present in 13 patients (68%). Thirteen children were treated with rifampin alone, and three received rifampin therapy plus gentamicin or trimethoprim-sulfamethoxazole. Once rifampin therapy was initiated alone or in combination, improvement was noted within 1 to 5 days (mean, 2.6 days) for patients who had had prolonged fever the duration of which before rifampin therapy averaged 3 weeks. The most common dosage and duration for our patients were 20 mg/[kg x d] every 12 hours and 14 days, respectively. Rifampin should be considered in the initial antimicrobial treatment of hepatosplenic cat-scratch disease.

Animals↗

Bayesian class discovery in microarray datasets.

A novel approach to class discovery in gene expression datasets is presented. In the context of clinical diagnosis, the central goal of class discovery algorithms is to simultaneously find putative (sub-)types of diseases and to identify informative subsets of genes with disease-type specific expression profile. Contrary to many other approaches in the literature, the method presented implements a wrapper strategy for feature selection, in the sense that the features are directly selected by optimizing the discriminative power of the used partitioning algorithm. The usual combinatorial problems associated with wrapper approaches are overcome by a Bayesian inference mechanism. On the technical side, we present an efficient optimization algorithm with guaranteed local convergence property. The only free parameter of the optimization method is selected by a resampling-based stability analysis. Experiments with Leukemia and Lymphoma datasets demonstrate that our method is able to correctly infer partitions and corresponding subsets of genes which both are relevant in a biological sense. Moreover, the frequently observed problem of ambiguities caused by different but equally high-scoring partitions is successfully overcome by the model selection method proposed.

Algorithms↗

Structural features underlying selective inhibition of protein kinase CK2 by ATP site-directed tetrabromo-2-benzotriazole.

Two novel crystal structures of Zea mays protein kinase CK2alpha catalytic subunit, one in complex with the specific inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) and another in the apo-form, were solved at 2.2 A resolution. These structures were compared with those of the enzyme in presence of ATP and GTP (the natural cosubstrates) and the inhibitor emodin. Interaction of TBB with the active site of CK2alpha is mainly due to van der Waals contacts, with the ligand fitting almost perfectly the cavity. One nitrogen of the five-membered ring interacts with two charged residues, Glu 81 and Lys 68, in the depth of the cavity, through two water molecules. These are buried in the active site and are also generally found in the structures of CK2alpha enzyme analyzed so far, with the exception of the complex with emodin. In the N-terminal lobe, the position of helix alphaC is particularly well preserved in all the structures examined; the Gly-rich loop is displaced from the intermediate position it has in the apo-form and in the presence of the natural cosubstrates (ATP/GTP) to either an upper (with TBB) or a lower position (with emodin). The selectivity of TBB for CK2 appears to be mainly dictated by the reduced size of the active site which in most other protein kinases is too large for making stable interactions with this inhibitor.

Adenosine Triphosphate↗

Computer-aided diagnosis of pulmonary nodules on CT scans: segmentation and classification using 3D active contours.

We are developing a computer-aided diagnosis (CAD) system to classify malignant and benign lung nodules found on CT scans. A fully automated system was designed to segment the nodule from its surrounding structured background in a local volume of interest (VOI) and to extract image features for classification. Image segmentation was performed with a three-dimensional (3D) active contour (AC) method. A data set of 96 lung nodules (44 malignant, 52 benign) from 58 patients was used in this study. The 3D AC model is based on two-dimensional AC with the addition of three new energy components to take advantage of 3D information: (1) 3D gradient, which guides the active contour to seek the object surface, (2) 3D curvature, which imposes a smoothness constraint in the z direction, and (3) mask energy, which penalizes contours that grow beyond the pleura or thoracic wall. The search for the best energy weights in the 3D AC model was guided by a simplex optimization method. Morphological and gray-level features were extracted from the segmented nodule. The rubber band straightening transform (RBST) was applied to the shell of voxels surrounding the nodule. Texture features based on run-length statistics were extracted from the RBST image. A linear discriminant analysis classifier with stepwise feature selection was designed using a second simplex optimization to select the most effective features. Leave-one-case-out resampling was used to train and test the CAD system. The system achieved a test area under the receiver operating characteristic curve (A(z)) of 0.83 +/- 0.04. Our preliminary results indicate that use of the 3D AC model and the 3D texture features surrounding the nodule is a promising approach to the segmentation and classification of lung nodules with CAD. The segmentation performance of the 3D AC model trained with our data set was evaluated with 23 nodules available in the Lung Image Database Consortium (LIDC). The lung nodule volumes segmented by the 3D AC model for best classification were generally larger than those outlined by the LIDC radiologists using visual judgment of nodule boundaries.

Biopsy↗

Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study. Italian Society of Paediatric Gastroenterology and Hepatology (SIGEP) and "Club del Tenue" Working Groups on Coeliac Disease.

BACKGROUND: Selective immunoglobulin A (IgA) deficiency (SIgAD) is associated with coeliac disease (CD). AIM: To make a retrospective study of the association of SIgAD with CD in Italy. METHODS: Hospital medical records of 2098 patients consecutively diagnosed as having CD were reviewed. RESULTS: Of 2098 patients with CD, 54 (2.6%) had SIgAD, representing a 10-16-fold increase over that in the population in general. This increase was not influenced by age or geographical factors. Patients with SIgAD had a higher incidence of silent forms (7/54, 13%), recurrent infections (16/54, 29.6%), and atopic diseases (7/54, 13%) than those without. The association with autoimmune and malignant diseases and the outcome after eating a gluten free diet were similar in patients with or without SIgAD. In all patients with SIgAD, antibodies for IgA gliadin and endomysium were absent, but serum levels of IgG anti-gliadin antibodies were high in almost all of them (51/54). CONCLUSIONS: Serum IgA should be measured in order to be able to interpret negative results for IgA anti-gliadin antibodies and anti-endomysial antibodies in patients being screened for CD. Since some patients with CD and SIgAD may be negative for IgG anti-gliadin antibodies, an intestinal biopsy should be performed in all suspected cases.

Adolescent↗

New feature subset selection procedures for classification of expression profiles.

BACKGROUND: Methods for extracting useful information from the datasets produced by microarray experiments are at present of much interest. Here we present new methods for finding gene sets that are well suited for distinguishing experiment classes, such as healthy versus diseased tissues. Our methods are based on evaluating genes in pairs and evaluating how well a pair in combination distinguishes two experiment classes. We tested the ability of our pair-based methods to select gene sets that generalize the differences between experiment classes and compared the performance relative to two standard methods. To assess the ability to generalize class differences, we studied how well the gene sets we select are suited for learning a classifier. RESULTS: We show that the gene sets selected by our methods outperform the standard methods, in some cases by a large margin, in terms of cross-validation prediction accuracy of the learned classifier. We show that on two public datasets, accurate diagnoses can be made using only 15-30 genes. Our results have implications for how to select marker genes and how many gene measurements are needed for diagnostic purposes. CONCLUSION: When looking for differential expression between experiment classes, it may not be sufficient to look at each gene in a separate universe. Evaluating combinations of genes reveals interesting information that will not be discovered otherwise. Our results show that class prediction can be improved by taking advantage of this extra information.

Colon↗

Canine motor neuron disease: clinicopathologic features and selected indicators of oxidative stress.

Hereditary canine spinal muscular atrophy (HCSMA) is an inherited motor neuron disease affecting a kindred of Brittanies. We have examined the clinicopathologic abnormalities in 57 animals with HCSMA, including 43 affected adult dogs and 14 homozygote pups. We also measured selected biochemical indices of oxidative stress: serum vitamin E (alpha-tocopherol) and Se concentrations; serum concentrations of Cu, Zn, Mg, and Fe; and total superoxide dismutase and glutathione peroxidase activities in red blood cells. Dogs with HCSMA had the following abnormalities: regenerative anemia, hypoglobulinemia, hypochloremia, and abnormally high creatine kinase and liver alkaline phosphatase activities. Serum Cu concentration was significantly (P = .01) increased in adult dogs with HCSMA compared to control dogs. Serum vitamin E concentrations tended to be lower in adult dogs with HCSMA compared to controls, and were significantly (P = .01) lower in homozygote pups compared to control pups.

Animals↗

[Selected anatomical features of the foot with hallux valgus].

Hallux valgus is still an open problem consists of many unexplained questions related to, not only its etiopathogenesis and biomechanics but also to treatment of this deformity. The purpose of investigation: 1) To find out hallux valgus predisposing factors; 2) To recognise anatomic features of the foot in hallux valgus patients, basing on orthopaedic physical examination as well as to find out the frequency of the occurrence of foot skeleton disorders in rentgenometric and plantoconturographic (foot prints) measurements. 335 feet in 173 patients (females) treated operatively due to hallux valgus in Orthopaedic Department of Wrocław Medical Academy in years 1980-1994 were examined. Those patients were operated on according to Keller, Dega and McBride method. All the patients underwent preoperative orthopaedic physical examination as well as rentgenographic and plantoconturographic one. Such factors as heredity and Egyptian shape of the foot as well as metatarsal index "plus" were recognised as hallux valgus predisposing factors. Most of the parameters evaluated in orthopaedic, rentgenographic and plantocontourographic examination presented pathologic values that indicated pathology within foot in hallux valgus patients.

Adolescent↗