The gastrointestinal manifestations of telomere‐mediated disease

Defects in telomere maintenance genes cause pathological telomere shortening, and manifest in syndromes which have prominent phenotypes in tissues of high turnover: the skin and bone marrow. Because the gastrointestinal (GI) epithelium is highly proliferative, we sought to determine whether telomere syndromes cause GI disease, and to define its prevalence, spectrum, and natural history. We queried subjects in the Johns Hopkins Telomere Syndrome Registry for evidence of luminal GI disease. In sixteen percent of Registry subjects (6 of 38), there was a history of significant GI pathology, and 43 additional cases were identified in the literature. Esophageal stenosis, enteropathy, and enterocolitis were the recurrent findings. In the intestinal mucosa, there was striking villous atrophy, extensive apoptosis, and anaphase bridging pointing to regenerative defects in the epithelial compartment. GI disease was often the first and most severe manifestation of telomere disease in young children. These findings indicate that telomere dysfunction disrupts the epithelial integrity in the human GI tract manifesting in recognizable disease processes. A high index of suspicion should facilitate diagnosis and management.     

Assigning fossil specimens to a given recent classification when the distribution of character variation is not normal

To help assign fossil material to Recent taxa we present a methodology that offers systematic quantitative tools to explore several continuous characters. It also enables the quantitative determination of which characters amongst several alternatives give results more consistent with a given classification.

The Gini Mean Difference ('Gini') is the expected absolute difference between two randomly drawn observations. In a fossil assemblage comprising several taxa, the Gini of the overall assemblage may be decomposed into three components: the weighted sum of intra‐taxon Gini, the index of overlap, and the inter‐taxon Gini. The parameter that is additional to alternative methods is the overlap index, which serves as a quantitative measure for evaluating the quality of identification. The Gini is advantageous in that it does not require the assumption of a normal distribution in character variation.

The Gini methodology is described in both mathematical and non‐mathematical terms. We demonstrate it by application to a hypothetical gastropod genus consisting of five species, in which we show in orderly, quantitative terms that one character is better for identification of the various species than another character.     

The Influence of Adenosine Receptor Antagonists Ahinophylline (AMP) and Caffeine (CAF) on Seizure Protective Ability of Antiepileptic Drugs (AEDs) in Rats

Abstract

The acute effects of AMP and CAF on seizure protectivity of AEDs were examined against electro and chemo shock convulsions in rats. The results support the claim that adenosine receptors may be involved in action of some AEDs.     

Endoscopic Management of Genitourinary Foreign Bodies

Retrieval of foreign bodies from the genitourinary system, most commonly inserted for sexual satisfaction or as a result of a psychiatric illness, can pose a significant surgical challenge. Due to their breadth of size, shape, and location within the genitourinary system, endoscopic management can be difficult. Here, we review the management of four cases of foreign object insertion into the genitourinary system and their outcomes and management.Key words: Foreign body insertion, Sounding, Genitourinary foreign object, Endoscopic extractionForeign objects within the genitourinary tract present a challenging urologic finding due to the diversity and breadth of presentation. Although many objects are easily removed, more complex approaches may be required depending on the size, shape, and location of the object.^1,2 In this case series, we discuss the endoscopic management of four patients who presented with foreign bodies in the urethra. Two patients inserted beads into their genitourinary tract for the purpose of sexual stimulation and two patients had a history of psychiatric illness with multiple insertions of a diverse range of foreign objects. In all four cases, endoscopic management was successful in removing the objects, with no need for an open approach such as perineal urethrotomy or open cystostomy. In case 2, in which an open approach was attempted at an outside hospital, this open approach was associated with intraoperative complications.     

Synthesis of 3′-Thioribouridine, 3′-Thioribocytidine,and Their Phosphoramidites

Abstract

3′-Thio-3′-deoxyribonucleosides (U and C) have been synthesized via Vorbruggen-type glycosylation with 3-S-benzoyl-5-O-toluoyl-1,2-O-diacetylfuranose, which was obtained from 1,2-O-isopropylidene-5-O-toluoyl-3-O-trifluoromethanesulfonyl-α-D-xylofuranose. 3′-Thio-3′-deoxyuridine has been converted to its phosphoramidite.     

Solution NMR Conformational Analysis of the Potent Equilibrative Sensitive (ES) Nucleoside Transporter Inhibitor,S 6-(4-Nitrobenzyl)mercaptopurine Riboside (NBMPR)

Abstract

High resolution NMR analysis involving one-dimensional (1-D) ¹H and nuclear Overhauser (NOE) difference spectroscopy was applied to solutions of NBMPR in DMSO-d ₆. Coupling constants were obtained at different temperatures between 285 and 353 K, and used to analyze the rotamer preferences about the C-4′-C-5′ bond. The results revealed a rotamer distribution about the χ tortion angle that favors the high-anti range, a preponderance of the γ⁺ rotamer (at ～64 %) with respect to the γ torsion angle, and a higher population of the south (S) conformer, which was favored by as little as the 4 % to as much as 31 % over the north (N) conformer as calculated by the program PSEUROT 6.2. The high-anti glycosidic torsion orientation appears to be the major conformational difference between the solution structure of NBMPR determined in this study and the structure previously observed in the solid state.     

Metabolism of O6-Propyl and N6-Propyl-carbovir in CEM Cells

Abstract

The metabolism of O⁶-propyl-carbovir and N⁶-propyl-carbovir, two selective inhibitors of HIV replication, has been evaluated in CEM cells. Both compounds were phosphorylated in intact cells to carbovir-5′-triphosphate. The metabolism of these two agents was inhibited by deoxycoformycin and mycophenolic acid, but not erythro-9-(2-hydroxy-3-nonyl)adenine. No evidence of the 5′-triphosphate of either compound was detected in CEM cells.     

Synthesis of Cholesteryl Supports and Phosphoramidite for Automated DNA Synthesis of Triple-Helix Forming Oligonucleotides (Tfos)

Abstract

DMT-Cholesteryl succinylamino solid supports (CPG, loading: 33 μmole/gram and TentaGel loading: 152 μmole/gram) and DMT-cholesteryl phosphoramidite were prepared for use in automated DNA synthesis of cholesteryl modified TFOs in the synthesis scales from 0.2 to 300 μmole. The modified TFOs were found to have a 5 to 50 fold increase in their uptake properties.     

Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway

Prostate cancer (CaP) is the second leading malignancy in men. The role of epithelial cell adhesion molecule (EpCAM), also known as CD326, in CaP progression and therapeutic resistance is still uncertain. Here, we aimed to investigate the roles of EpCAM in CaP metastasis and chemo/radioresistance. Expression of EpCAM in CaP cell lines and human CaP tissues was assessed using immunofluorescence and immunohistochemistry, respectively. EpCAM was knocked down (KD) in PC-3, DU145 and LNCaP-C4-2B cells using small interfering RNA (siRNA), and KD results were confirmed by confocal microscope, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Cell growth was evaluated by proliferation and colony formation assays. The invasive potential was assessed using a matrigel chamber assay. Tumorigenesis potential was measured by a sphere formation assay. Chemo-/radiosensitivity were measured using a colony formation assay. Over-expression of EpCAM was found in primary CaP tissues and lymph node metastases including cancer cells and surrounding stromal cells. KD of EpCAM suppressed CaP proliferation and invasive ability, reduced sphere formation, enhanced chemo-/radiosensitivity, and down-regulated E-cadherin, p-Akt, p-mTOR, p-4EBP1 and p-S6K expression in CaP cells. Our findings suggest that EpCAM plays an important role in CaP proliferation, invasion, metastasis and chemo-/radioresistance associated with the activation of the PI3K/Akt/mTOR signaling pathway and is a novel therapeutic target to sensitize CaP cells to chemo-/radiotherapy.