Temporary inhibition of the plasminogen activator inhibits periosteal chondrogenesis and promotes periosteal osteogenesis during appendicular bone fracture healing.

INTRODUCTION: Aminocaproic acid is approved as an anti-fibrinolytic for use in joint replacement and spinal fusion surgeries to limit perioperative blood loss. Previous animal studies have demonstrated a pro-osteogenic effect of aminocaproic acid in spine fusion models. Here, we tested if aminocaproic acid enhances appendicular bone healing and we sought to uncover the effect of aminocaproic acid on osteoprogenitor cells (OPCs) during bone regeneration. METHODS: We employed a well-established murine femur fracture model in adult C57BL/6J mice after receiving two peri-operative injections of aminocaproic acid. Routine histological assays, biomechanical testing and micro-CT analyses were utilized to assess callus volume, and strength, progenitor cell proliferation, differentiation, and remodeling in vivo. Two disparate ectopic transplantation models were used to study the effect of the growth factor milieu within the early fracture hematoma on osteoprogenitor cell fate decisions. RESULTS: Aminocaproic acid treated femur fractures healed with a significantly smaller cartilaginous callus, and this effect was also observed in the ectopic transplantation assays. We hypothesized that aminocaproic acid treatment resulted in a stabilization of the early fracture hematoma, leading to a change in the growth factor milieu created by the early hematoma. Gene and protein expression analysis confirmed that aminocaproic acid treatment resulted in an increase in Wnt and BMP signaling and a decrease in TGF-ß-signaling, resulting in a shift from chondrogenic to osteogenic differentiation in this model of endochondral bone formation. CONCLUSION: These experiments demonstrate for the first time that inhibition of the plasminogen activator during fracture healing using aminocaproic acid leads to a change in cell fate decision of periosteal osteoprogenitor cells, with a predominance of osteogenic differentiation, resulting in a larger and stronger bony callus. These findings may offer a promising new use of aminocaproic acid, which is already FDA-approved and offers a very safe risk profile.

Incidence and Clinical Significance of Acute Reocclusion after Emergent Angioplasty or Stenting for Underlying Intracranial Stenosis in Patients with Acute Stroke.

BACKGROUND AND PURPOSE: A major concern after emergent intracranial angioplasty in cases of acute stroke with underlying intracranial stenosis is the acute reocclusion of the treated arteries. This study reports the incidence and clinical outcomes of acute reocclusion of arteries following emergent intracranial angioplasty with or without stent placement for the management of patients with acute stroke with underlying intracranial atherosclerotic stenosis. MATERIALS AND METHODS: Forty-six patients with acute stroke received emergent intracranial angioplasty with or without stent placement for intracranial atherosclerotic stenosis and underwent follow-up head CTA. Acute reocclusion was defined as "hypoattenuation" within an arterial segment with discrete discontinuation of the arterial contrast column, both proximal and distal to the hypoattenuated lesion, on CTA performed before discharge. Angioplasty was defined as "suboptimal" if a residual stenosis of ≥50% was detected on the postprocedural angiography. Clinical and radiologic data of patients with and without reocclusion were compared. RESULTS: Of the 46 patients, 29 and 17 underwent angioplasty with and without stent placement, respectively. Acute reocclusion was observed in 6 patients (13%) and was more frequent among those with suboptimal angioplasty than among those without it (71.4% versus 2.6%, P < .001). The relative risk of acute reocclusion in patients with suboptimal angioplasty was 27.857 (95% confidence interval, 3.806-203.911). Furthermore, a good outcome was significantly less frequent in patients with acute reocclusion than in those without it (16.7% versus 67.5%, P = .028). CONCLUSIONS: Acute reocclusion of treated arteries was common after emergent intracranial angioplasty with or without stent placement in patients with acute stroke with intracranial atherosclerotic stenosis and was associated with a poor outcome. Suboptimal results of angioplasty appear to be associated with acute reocclusion, irrespective of whether stent placement was performed.

Effect of dentin desensitizers and cementing agents on retention of full crowns using standardized crown preparations.

STATEMENT OF PROBLEM: Past research has not controlled preparation surface area when examining the influence of dentin desensitizers on the retentive strength of cemented cast crowns, leading to inconsistent results. PURPOSE: This research controlled crown preparation surface area and evaluated the effect of various dentin desensitizers and conventional cementing agents on the in vitro retentive strength of cast crowns. METHODS AND MATERIAL: Freshly extracted human molars were prepared for a standardized crown preparation (26 degrees total convergence, 4 mm axial height) with a custom-made pantograph. Dentin desensitizers included none (control), a polymerizable material (All-Bond 2), and a nonpolymerizable desensitizer (Gluma Desensitizer). Cementing agents included zinc phosphate (Fleck's), glass ionomer (Ketac-Cem), resin-modified glass ionomer (Fuji II), and resin cement (Panavia 21). Twelve teeth were prepared for each test condition (144 teeth total). Individual castings were made from a base metal alloy (Rexillium III). Crowns were removed after storage at 26 degrees C for 48 hours at 100% relative humidity using a universal testing machine at a crosshead speed of 1.27 mm/min. The proportion of cement retained on the tooth and casting after debonding was quantified according to treatment. Statistical treatment included 1- and 2-way ANOVAs, followed by the Tukey-Kramer post hoc test at a preset alpha of 0.05.Results. Resin cement exhibited the highest retentive strength and all dentin treatments resulted in significantly different retentive values (All-Bond 2 (5.68 +/- 0.70 MPa) > control (4.67 +/- 0.48 MPa) > Gluma (4.12 +/- 0.37 MPa)). Retention of resin-modified glass ionomer was between the resin cement and glass ionomer groups: All-Bond 2 (3.46 +/- 0.26 MPa) > Gluma (2.81 +/- 0.15 MPa) = control (2.96 +/- 0.18 MPa). Conventional glass ionomer values were between those of Fuji Plus and zinc phosphate groups: All Bond 2 (2.23 +/- 0. 20 MPa) = control (2.36 +/- 0.20 MPa) > Gluma (1.98 +/- 0.23 MPa). Zinc phosphate had the lowest retention values: control (1.68 +/- 0. 08 MPa) > Gluma (0.81 +/- 0.11 MPa) > All-Bond 2 (0.67 +/- 0.14 MPa). The majority of cement was retained on the debonded tooth surface versus the casting, with the exception of zinc phosphate when used with dentin pretreatments. CONCLUSION: Controlled crown surface areas reduced the variation in strength values permitting high discrimination among retention values of desensitizer/cement combinations. In all but 1 combination, Gluma desensitizer significantly decreased crown retention. With resin cement and resin-modified glass ionomer, use of All-Bond 2 desensitizer significantly increased crown retention values.

Synthesis and renal vasodilator activity of some dopamine agonist 1-aryl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diols: halogen and methyl analogues of fenoldopam.

Certain 6-halo-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines were found to be potent D-1 dopamine agonists. The 1-(4-hydroxyphenyl) analogues did not have central nervous system activity because their high polarity inhibited entry into the brain. However, these compounds were potent renal vasodilators. Fenoldopam, the 6-chloro analogue, is an especially significant member of the series, and its synthesis, pharmacology, and clinical properties have been studied extensively. The 6-methyl and 6-iodo congeners were potent renal vasodilators, but nonpotent partial D-1 agonists as measured by stimulation of rat caudate adenylate cyclase. A possible rationalization suggests different receptor reserves for these activities. The 9-substituted benzazepines were either inactive or of low potency as dopamine agonists, while the N-methyl analogues had significant antagonist potency as measured by inhibition of dopamine stimulation of rat caudate adenylate cyclase.

A facile synthesis of beta-(S-benzylmercapto)-beta, beta-cyclopentamethylene-propionic acid.

The title compound is a key intermediate for the preparation of oxytocin and vasopressin antagonists. Using sodium benzylmercaptide instead of boron trifluoride etherate as catalyst gives a better than four fold overall improvement in yield of the title compound from ethyl cyclohexylideneacetate and benzylmercaptan. The preparation of the corresponding acid labile S-p-methylbenzylmercapto and S-p-methoxybenzylmercapto analogs is also described.

Orally active 7-phenylglycyl cephalosporins. Structure-activity studies related to cefatrizine (SK&F 60771).

The synthesis of a series of related broad-spectrum 7-phenylglycyl cephalosporins with 3-heterocyclicthiomethyl substituents is described. The effects of benzene-ring hydroxylation and 3-substituent variation on the in vitro antibacterial activity, height and duration of mouse serum levels, and effectiveness in protecting against bacterial infection in the mouse are examined. Included for comparison are cephalexin, cephaloglycin and their ortho-, meta- and para-hydroxy derivatives. The biological properties examined were influenced by the position of the hydroxyl group and by the nature of the 3-substituent. The 7-(p-hydroxyphenylglycyl)-3-heterocyclicthiomethyl analogs were found to produce significantly higher serum levels on oral administration to mice than their unhydroxylated counterparts. This effect was not observed with the 7-(m-hydroxyphenylglycyl)-3-heterocyclicthiomethyl cephalosporins, nor with the p-hydroxyphenylglycyl analog of cephalexin. While m- and p-hydroxylation had little effect on in vitro activity and o-hydroxyphenylglycyl cephalosporins tested had very low antibacterial activities and were not examined further. One derivative, 7-[R-2-amino-2-(4-hydroxyphenyl)acetamido]-3-(1H-1, 2, 3-triazole-4(5)-ylthiomethyl)-3-cephem-4-carboxylic acid (SK&F 60771) was found to have outstanding in vitro and in vivo activities along with oral and subcutaneous serum levels in the mouse that were significantly higher than those obtained with cephalexin. This derivative which has been given the generic name cefatrizine was selected for extensive additional biological evaluation.