miRNA-27a-3p and miRNA-222-3p as Novel Modulators of Phosphodiesterase 3a (PDE3A) in Cerebral Microvascular Endothelial Cells.

Endothelial dysfunction is a key element in cerebral small vessel disease (CSVD), which may cause stroke and cognitive decline. Cyclic nucleotide signaling modulates endothelial function. The cyclic adenosine monophosphate-degrading enzyme phosphodiesterase 3 (PDE3) is an important treatment target which may be modulated by microRNAs (miRNAs) important for regulating gene expression. We aimed to identify PDE3-targeting miRNAs to highlight potential therapeutic targets for endothelial dysfunction and CSVD. PDE3-targeting miRNAs were identified by in silico analysis (TargetScan, miRWalk, miRanda, and RNA22). The identified miRNAs were ranked on the basis of TargetScan context scores and their expression (log2 read counts) in a human brain endothelial cell line (hCMEC/D3) described recently. miRNAs were subjected to co-expression meta-analysis (CoMeTa) to create miRNA clusters. The pathways targeted by the miRNAs were assigned functional annotations via the KEGG pathway and COOL. hCMEC/D3 cells were transfected with miRNA mimics miR-27a-3p and miR-222-3p, and the effect on PDE3A protein expression was analyzed by Western blotting. Only PDE3A is expressed in hCMEC/D3 cells. The in silico prediction identified 67 PDE3A-related miRNAs, of which 49 were expressed in hCMEC/D3 cells. Further analysis of the top two miRNA clusters (miR-221/miR-222 and miR-27a/miR-27b/miR-128) indicated a potential link to pathways relevant to cerebral and vascular integrity and repair. hCMEC/D3 cells transfected with miR-27a-3p and miR-222-3p mimics had reduced relative expression of PDE3A protein. PDE3A-related miRNAs miR-221/miR-222 and miR-27a/miR-27b/miR-128 are potentially linked to pathways essential for immune regulation as well as cerebral and vascular integrity/function. Furthermore, relative PDE3A protein expression was reduced by miR27a-3p and miR-222-3p.

Nasopharyngeal amyloidosis: an unusual cause of unilateral hearing loss.

Amyloidosis is typically a systemic depositional disease, diagnosed on clinical symptoms and signs in conjunction with histopathology. When occurring on a localized basis in the head and neck, the lesion is most commonly observed in the larynx. Primary localized nasal amyloidosis however is an uncommon finding, with 25 reported cases in the literature to date. We present the case of a young woman presenting with primary localized nasal amyloidosis secondary to the curious symptoms of unilateral hearing loss.

Fluorescent 7-diethylaminocoumarin pyrrolobenzodiazepine conjugates: synthesis, DNA interaction, cytotoxicity and differential cellular localization.

The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a class of DNA minor groove binding agents that react covalently with guanine bases, preferably at Pu-G-Pu sites. A series of three fluorescent PBD-coumarin conjugates with different linker architectures has been synthesized to probe correlations between DNA binding affinity, cellular localization and cytotoxicity. The results show that the linker structure plays a critical role for all three parameters.

Survival and clinical outcome of SB Charite III disc replacement for back pain.

Between January 1990 and December 2000 we carried out 226 SB Charité III disc replacements for lumbar disc degeneration in 160 patients. They were reviewed at a mean follow-up of 79 months (31 to 161) to determine the clinical and radiological outcome. The clinical results were collected by an independent observer, who was not involved in patient selection, treatment or follow-up, using a combination of outcome measures, including the Oswestry Disability Index. Pain was recorded using a visual analogue score, and the most recent radiographs were reviewed. Survival of the device was analysed by the Kaplan-Meier method and showed a cumulative survival of 35% at 156 months when radiological failure was taken as the endpoint. The mean improvement in the Oswestry disability index scores after disc replacement was 14% (6% to 21%) and the mean improvement in the pain score was 1.6 (0.46 to 2.73), both falling below the clinically significant threshold. Removal of the implant was required in 12 patients, four because of implant failure. These poor results indicate that further use of this implant is not justified.

Posterior sternoclavicular dislocation in a rugby player as a cause of silent vascular compromise: a case report.

BACKGROUND: Approximately 120 cases of posterior sternoclavicular joint (SCJ) dislocation have been documented in the medical literature since it was first described in 1824 by Sir Astley Cooper, a statistic which underlies its relative rarity. It is associated with high energy trauma, and although it may present innocently enough, it is a potentially life threatening injury. CASE AND RESULTS: We describe a case in which there was no clinical evidence of complication, although CT imaging revealed complete obstruction of the brachiocephalic vein and impingement of the aorta. This required open reduction and a novel fixation technique was employed. The reduction was stable at 8 month follow up appointment as evidenced by CT scan. CONCLUSIONS: We acknowledge that this type of complication is well recognised but emphasise that it should not be managed complacently. A high index of suspicion is required to determine the presence of serious complications in this type of injury, which may manifest insidiously.

Effect of upregulation of AMPA glutamate receptors on cerebral O(2) consumption and blood flow in rat.

AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors, in cerebral cortex, underwent upregulation (35% increase) following chronic blockade with a non-competitive AMPA receptor antagonist, GYKI 52466 (1-(aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodiazepine). Such upregulation did not alter basal cerebrocortical blood flow or O(2) consumption. There was a much higher increase in blood flow and O(2) consumption in the upregulated, agonist (AMPA) stimulated cortices of anesthetized rats.

Premalignant changes in ulcerative colitis.

Colitis-associated carcinoma is often associated with, or preceded by, noninvasive epithelial neoplastic changes termed dysplasia. Surveillance colonoscopy with biopsies looking for dysplasia is now standard practice in the management of the cancer problem in ulcerative colitis. However, this practice continues to have a number of limitations and problems that need to be understood by surgeons who may be referring such patients. A number of recent reports indicate that colitis associated carcinoma is predominantly left-sided and incorporation of this distribution in the surveillance methods merits consideration. The molecular and genetic abnormalities involved in the pathogenesis of colitis associated neoplasia are being actively investigated and may yield supplementary methods to better define individual patient risk.

Trace metals in tropical marine fish from the Bay of Bengal.

Concentrations of potassium, calcium, magnesium, manganese, iron, nickel, copper, zinc, lead, cadmium, strontium and rubidium were determined in the flesh of six marine fish species from the Bay of Bengal. Analytical quality was determined by analysis of standard reference material MA-A-2 (TM), Fish Flesh Homogenate, from IAEA (International Atomic Energy Agency). In most cases the results are similar to data published on fish from other marine environments.

Augmented histamine test--diagnostic and prognostic values.

The results of the augmented histamine test in 107 controls, 48 patients with gastric ulcer and 141 patients with duodenal ulcer are presented. The mean basal acid secretion and maximal acid output (MAO) were significantly higher in duodenal ulcer patients than in normal subjects. Ulcers of the body of the stomach were associated with lower than normal levels of secretion, whereas ulcers of the prepyloric region were associated with higher than normal levels. In this study of 141 patients with duodenal ulcer, 101 patients or 72% had an MAO above the upper limit of normal (20.4 mEq./hr.). Conversely, a patient with an MAO of less than 12.4 mEq./hr. is unlikely to have duodenal ulcer disease. The use of the ratio of MAO to actual body weight did not increase the diagnostic discrimination between normal subjects and those with duodenal ulcer. Duodenal ulcer patients with complications had a significantly higher MAO to histamine than those without complication. The finding of an MAO greater than 40 mEq./hr. is highly suggestive of the presence or the imminence of a complication.