Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M-2 muscarinic receptors

Several N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, omega-alkanediamine tetrahydrochlorides were synthesized and evaluated for their blocking activity on muscarinic receptors in guinea pig atria and rat ileum and bladder. The results were compared with those obtained for the classical nonselective muscarinic antagonist atropine. It was discovered that optimum activity is associated with an eight-carbon chain (compound 4) in guinea pig atria whereas, in both rat ileum and bladder, the 12-carbon analogue 7 had the highest activity. In addition, polymethylene tetraamines 1-6 displayed high selectivity toward guinea pig atria muscarinic receptors. The discriminatory power of 1-6 was not shared by 7. All the tetraamines were shown to be competitive antagonists of muscarinic receptors. N,N'-Bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine was the most potent and selective toward muscarinic receptors in atria, with a pA2 value of 8.13 and a selectivity ratio (atria vs. ileum or bladder) of ca. 270. At a concentration of 10 microM, tetraamine 4 did not affect histamine and 5-hydroxytryptamine receptors of guinea pig ileum or alpha-adrenoreceptors of guinea pig atria whereas it inhibited postsynaptic alpha-adrenoreceptors of rat vas deferens with a -log K value of 5.23 and nicotinic receptors of frog rectus abdominis with an IC50 value of 0.23 microM. It is concluded that 4 is a novel, powerful, and selective tool in the characterization of muscarinic receptor subtypes.     

Prospective clinical outcomes of revision fusion surgery in patients with pseudarthrosis after posterior lumbar interbody fusions using stand-alone metallic cages.

BACKGROUND CONTEXT: Posterior lumbar interbody fusion (PLIF) is a popular method of arthrodesis for surgical treatment of instabilities and degenerative conditions of the spine. With the introduction of threaded titanium cage devices, surgeons began performing PLIF procedures using these cages as stand-alone devices. Complications have been reported, however, including pseudarthrosis with persistent pain. Outcomes after revision surgical treatment for these patients with failed PLIF are not known. PURPOSE: To prospectively evaluate clinical outcomes of revision fusion surgery in patients who previously underwent posterior lumbar interbody fusion with stand-alone metallic cages resulting in pseudarthrosis. STUDY DESIGN/SETTING: Prospective case series. METHODS: Nineteen patients referred to the senior author were evaluated and diagnosed with pseudoarthrosis having previously undergone a PLIF procedure with stand-alone metallic cages. History, physical exam, and imaging studies were performed preoperatively and postoperatively. All underwent revision posterolateral fusion with iliac crest graft and pedicle screw instrumentation. Patient demographics, SF-36, and Oswestry Disability Index (ODI) data were collected prior to surgery and two years postoperatively. RESULTS: Patients undergoing revision fusion surgery were found to have had extensive facetectomies and pseudarthrosis intraoperatively. Outcomes data was collected on eighteen of nineteen patients (95%). Mean clinical follow up was 3.2 years (range 2.5-3.5 years). Seventeen patients (94%) achieved a solid fusion. Improvement was noted in seven of eight SF-36 sub-categories, but was significant only in two (Physical Function and Role Emotional). There was no significant difference in ODI scores. CONCLUSIONS: Pseudarthrosis should be considered in the differential diagnosis if severe symptoms persist in patients who undergo PLIF with stand-alone metallic cages. Successful revision fusion did not always correlate with improved clinical outcomes in these challenging patients undergoing further surgery. Performing PLIF using stand-alone metallic cages, especially after total resection of the facet joints, is not advocated unless supplemental instrumentation is utilized.     

Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene

Rearrangements of the RET receptor tyrosine kinase gene generating RET/PTC oncogenes are specific to papillary thyroid carcinoma (PTC), the most frequent thyroid tumor. Here, we show that the RET/PTC1 oncogene, when exogenously expressed in primary normal human thyrocytes, induces the expression of a large set of genes involved in inflammation and tumor invasion, including those encoding chemokines (CCL2, CCL20, CXCL8, and CXCL12), chemokine receptors (CXCR4), cytokines (IL1B, CSF-1, GM-CSF, and G-CSF), matrix-degrading enzymes (metalloproteases and urokinase-type plasminogen activator and its receptor), and adhesion molecules (L-selectin). This effect is strictly dependent on the presence of the RET/PTC1 Tyr-451 (corresponding to RET Tyr-1062 multidocking site). Selected relevant genes (CCL20, CCL2, CXCL8, CXCR4, L-selectin, GM-CSF, IL1B, MMP9, UPA, and SPP1/OPN) were found up-regulated also in clinical samples of PTC, particularly those characterized by RET/PTC activation, local extrathyroid spread, and lymph node metastases, when compared with normal thyroid tissue or follicular thyroid carcinoma. These results, demonstrating that the RET/PTC1 oncogene activates a proinflammatory program, provide a direct link between a transforming human oncogene, inflammation, and malignant behavior.     

Primary gastric lymphoma: a case report

In this case report the Authors describe a case of primary gastric lymphoma in a 62 years old patient who presented with dyspepsia and weigh loss. Primary gastric lymphoma is a rare neoplasm which of 1-10% of the malignant gastric neoplasms in the gastroenteric tract. The clinic presentation is usually aspecific. The infection by H. pylori is a factor of predisposition for this kind of disease. The diagnostic pathway consists in x-ray examination of the gastrointestinal tract, the endoscopy with biopsies, the computerized tomography and the echo-endoscopy. However obtaining a preoperative diagnosis is often difficult because of the submucosal localization of the lymphoma. There is not a common strategy among the Authors for the treatment of the disease, which can be surgical, radiotherapic or chemotherapic.     

Gastrointestinal stromal tumors: report of a clinical case and review of the literature

In this case report, the Authors describe a case of stromal gastric tumour, in a male 65 years old, who presented gastrointestinal bleeding. Gastro-Intestinal Stromal Tumors (GISTs) are neoplasm with an incidence of 1-3 per cent of the digestive tract malignant neoplasms. The rarity of this disease, its visceral wall localization, the histopathological characteristics make the diagnosis difficult. Moreover there is no correlation between the behaviour of these neoplasms and the histologic features. Surgery represents the main treatment for GISTs based on complete resection, followed by a long-term follow-up. Chemotherapy and radiotherapy don't seem to play a crucial role in the treatment of these neoplasms. A new treatment with inhibitors of the tyrosinekinase is under discussion. Follow-up represents the only way to evaluate the effective behaviour of the disease, due to the lack of classic prognostic factors impact.     

Cellular bases of the antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer.

Taxane-based therapies appear to have a significant efficacy in clinical trials on hormone-refractory prostate carcinoma. In the present study, we investigated the cellular response of androgen-independent prostate carcinoma cell lines to the novel taxane IDN 5109 (BAY 59-8862) and evaluated its antitumor activity. In previous preclinical studies, this new paclitaxel (PTX) analogue was characterized by high tolerability and antitumor efficacy, ability to overcome multidrug resistance, and activity by oral administration. Upon treatment, DU145 and PC3 prostate carcinoma cell lines underwent a transient mitotic arrest. This was followed by G1 arrest and rapid occurrence of apoptosis in DU145 cells, whereas in PC3 cells, which are defective for the postmitotic checkpoint, a slow cell death was preceded by DNA endoreduplication. At the biochemical level, such events were associated with tubulin polymerization, activation of the mitosis-promoting factor, and phosphorylation of Bcl-X(L)/Bcl-2/Raf-1. In addition, IDN 5109 shared with PTX the ability to down-regulate the expression of the two potent angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor. These findings indicated that IDN 5109 affected the same pathways involved in the cellular response to PTX and suggested that an antiangiogenic effect mediated by inhibition of paracrine stimulation of endothelial cells might contribute to the antitumor effect of both drugs. In in vivo experiments, the new taxane displayed a superior and more persistent effect compared with PTX against DU145 tumor xenografts. Such an effect was associated with pronounced reduction of the tumor microvessel density, superior to that achieved by PTX. These results support a potential therapeutic advantage of IDN 5109 over PTX against hormone-refractory prostate carcinoma.     

Surface engineering of titanium by collagen immobilization. Surface characterization and in vitro and in vivo studies

Collagen was covalently linked to the surface of Titanium (Ti) by a surface modification process involving deposition of a thin film from hydrocarbon plasma followed by acrylic acid grafting. The composition and properties of surface-modified Ti were investigated by a number of surface sensitive techniques: XPS, ATR-IR, atomic force microscopy and AFM force-separation curves. In vitro tests were performed to check samples cytotoxicity and the behavior of osteoblast-like SaOS-2 cells. In vivo experiments involved 12 weeks implants in rabbit muscle as general biocompatibility assessment and 1-month implants in rabbit bone to evaluate the effect of surface modification on osteointegration rate. Results of XPS measurements show how surface chemistry is affected throughout each step of the surface modification process, finally leading to a complete and homogeneous collagen overlayer on top of the Ti samples. AFM data clearly display the modification of the surface topography and of the surface area of the samples as a consequence of the grafting and coupling process. AFM force-distance curves show that the interfacial structure responds by shrinking or swelling to variations of ionic force of the surrounding aqueous environment, suggesting that the aqueous interface of the biochemically modified Ti samples has enhanced degrees of freedom as compared to the inorganic surface of plain Ti. As to biological evaluations, the biochemically modified Ti samples are safe in terms of cytotoxicity and in vivo biocompatibility assessment. SaOS-2 cells growth rate is lower on collagen modified surfaces, and no significant difference is detected in terms of alkaline phosphatase production as compared to control Ti. Importantly, implants in rabbit femur show a significant increase of bone growth and bone-to-implant contact in the case of the collagen modified samples, confirming that biochemical modifications of Ti surface can enhance the rate of bone healing as compared to plain Ti.     

Appendiceal carcinoid: report of 3 clinical cases and review of the literature

The Authors report three cases of appendiceal carcinoids, found during appendectomy for acute appendicitis during the last 15 years. Appendiceal carcinoid is a rare neoplasm, more frequent in females age ranging between 20 and 29 years. Lack of symptoms explains the occasional diagnosis of this disease. The prognosis is related mostly to the size of the tumor, local and lymphatic invasion, presence of metastases, localization inside the appendix, histological type and age of the patient. Therapy is mainly surgical and consists of appendectomy and right colectomy according to different criteria which are being discussed in this article.