Duration of action of antispasmodic agents: novel use of a mouse model as an in vivo pharmacological assay.

OBJECTIVE: Radial arteries are increasingly used as conduits for coronary artery bypass grafts, but perioperative graft vasospasm remains a concern. In vitro testing has demonstrated the efficacy of phenoxybenzamine and verapamil/nitroglycerin as topical antispasmodic agents, but their duration of action in vivo is unknown. Using an in vivo mouse model, we measured their duration of action in functioning vascular grafts, and compared this to their in vitro duration of action in ungrafted vascular segments. METHODS: Two millimetre mouse aortic segments (C57/BL6) were incubated with phenoxybenzamine, verapamil/nitroglycerin, or buffer (controls) for 15 min in organ chambers. Isometric tension responses to phenylephrine and prostaglandin F2alpha were measured at 0, 2, 6 and 12 h post-incubation. In parallel, 36 murine infrarenal aortic interposition grafts (2 mm) were performed. Twelve grafts were pre-treated (15 min) with phenoxybenzamine, 12 with verapamil/nitroglycerin and 12 remained untreated (controls). Isometric tension responses to the same agonists were measured in grafts harvested 2, 6, 13 and 23 h after surgery. RESULTS: Phenoxybenzamine prevented alpha-adrenergic vasoconstriction for up to 16 h in vivo (grafts), and 12h in vitro (ungrafted segments). Verapamil/nitroglycerin was effective for at least 2 h in vitro, but did not prevent vasoconstriction after 2 h in vivo. CONCLUSIONS: The mouse model appears to be a useful technique for assessing the pharmacological properties of antispasmodic agents in vivo. Phenoxybenzamine has an extended action in arterial grafts in vivo. Verapamil/nitroglycerin is short-lived in vivo but lasts longer in vitro. Measurements of antispasmodic duration of action in vitro should be interpreted with caution.     

Biomaterial microarrays: rapid, microscale screening of polymer-cell interaction

The identification of biomaterials that induce optimal gene expression patterns and allow for appropriate levels of cellular attachment is of central importance in tissue engineering and cell therapy. Herein, we describe the creation of cell-compatible, biomaterial microarrays, that allow rapid, microscale testing of biomaterial interactions with cells. As proof of principle, we simultaneously characterized over 3456 human mesenchymal stem cell (hMSC)-biomaterial composite interactions, and describe preliminary studies on the utility of these arrays with a neural stem cell line (NSC), and primary articular chondrocytes.     

Pathophysiology of mild endometriosis: review of literature

Endometriosis is a puzzling condition and the literature ischaracterized by a large number of uncontrolled reports on itsaetiology and pathophysiology. In particular the relationshipbetween mild endometriosis and subfecundity is uncertain. Thispaper critically reviews the published literature on the pathogenesis,prevalence, menstrual symptomatology and natural history ofendometriosis. Furthermore, factors implicated in causing subfecundityin relation to endometriosis and the impact of various treatmentsin enhancing fertility among women with mild endometriosis havebeen assessed.     

Regulation of T-cell receptor signalling by membrane microdomains

There is now considerable evidence suggesting that the plasma membrane of mammalian cells is compartmentalized by functional lipid raft microdomains. These structures are assemblies of specialized lipids and proteins and have been implicated in diverse biological functions. Analysis of their protein content using proteomics and other methods revealed enrichment of signalling proteins, suggesting a role for these domains in intracellular signalling. In T lymphocytes, structure/function experiments and complementary pharmacological studies have shown that raft microdomains control the localization and function of proteins which are components of signalling pathways regulated by the T-cell antigen receptor (TCR). Based on these studies, a model for TCR phosphorylation in lipid rafts is presented. However, despite substantial progress in the field, critical questions remain. For example, it is unclear if membrane rafts represent a homogeneous population and if their structure is modified upon TCR stimulation. In the future, proteomics and the parallel development of complementary analytical methods will undoubtedly contribute in further delineating the role of lipid rafts in signal transduction mechanisms.     

The Safety and Efficacy of Using Drainage in Arthroscopic Rotator Cuff Repair

PurposeThis study aimed to evaluate the effects of not using a drain or placing a drain in the glenohumeral (GH) or subacromial (SA) joint spaces on fluid retention and pain in the early postoperative period and late clinical outcomes.MethodsPatients who underwent arthroscopic rotator cuff repair between 2018 and 2020 were included in the study. Before the operation, demographic data, range of motion (ROM), visual analog scale (VAS) scores, Constant–Murley scores has documented. Deltoid muscle diameter (DMD) were measured. The total amount of irrigation used during the surgery and the operation duration were recorded, and the active amount of fluid coming from the drain in patients with a drain was recorded. The first postoperative DMD measure was made in the operating room and accepted as day 0. DMD measurements repeated postoperative first and second day. VAS assessments were performed on the postoperative first and second days. At the outpatient clinic, these measurements were repeated on the first and second weeks after discharge. Functional evaluations were made with ROM and Constant–Murley scores at the final follow-up examination.ResultsThere was no difference in the amount of drainage between the two groups in which a drain was used. When the three groups were compared among themselves regarding preoperative and postoperative VAS scores, Constant–Murley scores, and DMD, no significant difference was found.ConclusionsWe do not recommend the routine use of drains after arthroscopic rotator cuff surgery in terms of cost-effectiveness.Level of evidenceLevel II: Prospective Cohort Study.     

Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy.

The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.