Antithrombotic efficacy of direct oral anticoagulants on patency rate following microsurgical anastomosis in crushed rat arteries.

BACKGROUND: During the last decade direct oral anticoagulants (DOAC) have been established in various fields of medicine.Their use in microsurgery has not been evaluated yet though. This study aims to evaluate their efficacy in microsurgery and additionally compare them with a well established antithrombotic agent. MATERIALS AND METHODS: The right femoral artery of 101 rats divided into 4 groups, was crushed and anastomosed. Group A (20 rats) received placebo therapy (1 ml NaCl 0.9%, orally), while Group B (27 rats), Group C (27 rats) and Group D (27 rats) received rivaroxaban (3 mg/kg, orally), dabigatran (30 mg/kg, orally) and enoxaparin (30 mg/kg, subcutaneously) respectively. All drugs were administered 3 h preoperatively and once daily for the following postoperative days until the sacrifice of the animals. Patency was evaluated at 1st, 7th and 20th postoperative day. Following patency evaluation the rats were sacrificed and the vessels were harvested for histological examination. RESULTS: None of the rats died postoperatively. Patency rates of rivaroxaban group (78%), dabigatran group (70%) and enoxaparin group (63%) were statistically similar, but significantly higher than the placebo-treated control group (p < 0.05). Cells with morphologic features of endothelial cells were evident 7 days after the injury. CONCLUSION: The results of this study demonstrate the following: (1) rivaroxaban and dabigatran through inhibition of thrombus formation significantly enhanced the patency rate compared to placebo treatment (2) the antithrombotic efficacy of rivaroxaban and dabigatran in compromised microvessels was similar to that of enoxaparin, the most widely used antithrombotic agent.

Design and Synthesis of Novel 2-Acetamido, 6-Carboxamide Substituted Benzothiazoles as Potential BRAFV600E Inhibitors - In vitro Evaluation of their Antiproliferative Activity.

The oncogenic BRAFV600E kinase leads to abnormal activation of the MAPK signaling pathway and thus, uncontrolled cellular proliferation and cancer development. Based on our previous virtual screening studies which issued 2-acetamido-1,3 benzothiazole-6-carboxamide scaffold as active pharmacophore displaying selectivity against the mutated BRAF, eleven new substituted benzothiazole derivatives were designed and synthesized by coupling of 2-acetamidobenzo[d]thiazole-6-carboxylic acid with the appropriate amines in an effort to provide even more efficient inhibitors and tackle drug resistance often developed during cancer treatment. All derived compounds bore the benzothiazole scaffold substituted at position-2 by an acetamido moiety and at position-6 by a carboxamide functionality, the NH moiety of which was further linked through an alkylene linker to a sulfonamido (or amino) aryl (or alkyl) functionality or a phenylene linker to a sulfonamido aromatic (or non-aromatic) terminal pharmacophore in the order -C6 H4 -NHSO2 -R or reversely -C6 H4 -SO2 N(H)-R. These analogs were subsequently biologically evaluated as potential BRAFV600E inhibitors and antiproliferative agents in several colorectal cancer and melanoma cell lines. In all assays applied, one analog, namely 2-acetamido-N-[3-(pyridin-2-ylamino)propyl]benzo[d]thiazole-6-carboxamide (22), provided promising results in view of its use in drug development.

The binding of ß-d-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: A new class of inhibitors.

Glycogen phosphorylase (GP) is a promising target for the treatment of type 2 diabetes. In the process of structure based drug design for GP, a group of 15 aromatic aldehyde 4-(ß-d-glucopyranosyl)thiosemicarbazones have been synthesized and evaluated as inhibitors of rabbit muscle glycogen phosphorylase b (GPb) by kinetic studies. These compounds are competitive inhibitors of GPb with respect to α-d-glucose-1-phosphate with IC(50) values ranging from 5.7 to 524.3µM. In order to elucidate the structural basis of their inhibition, the crystal structures of these compounds in complex with GPb at 1.95-2.23Å resolution were determined. The complex structures reveal that the inhibitors are accommodated at the catalytic site with the glucopyranosyl moiety at approximately the same position as α-d-glucose and stabilize the T conformation of the 280s loop. The thiosemicarbazone part of the studied glucosyl thiosemicarbazones possess a moiety derived from substituted benzaldehydes with NO(2), F, Cl, Br, OH, OMe, CF(3), or Me at the ortho-, meta- or para-position of the aromatic ring as well as a moiety derived from 4-pyridinecarboxaldehyde. These fit tightly into the ß-pocket, a side channel from the catalytic site with no access to the bulk solvent. The differences in their inhibitory potency can be interpreted in terms of variations in the interactions of the aldehyde-derived moiety with protein residues in the ß-pocket. In addition, 14 out of the 15 studied inhibitors were found bound at the new allosteric site of the enzyme.

Outcomes with microsurgery of common peroneal nerve lesions.

OBJECTIVES: The purpose of this retrospective study is to present our results with peroneal nerve lesions, to examine the relative significance of various factors, to assess their effect on outcome, and to establish guidelines of treatment for the microsurgical management of these difficult lesions. METHODS: Over a 33-year period, a total of 62 patients were treated at McGill University and the Microsurgical Research Center, Eastern Virginia Medical School. The clinical records of all patients treated for peroneal nerve lesions were reviewed for retrospective analysis. RESULTS: Of 62 patients, 35 had microneurolysis and nerve decompression of the common peroneal nerve (CPn) as the only surgical procedure while 27 required reconstruction with nerve grafting. Postoperatively muscle power was graded from M + 4 to M - 5 in 27 patients, from M - 4 to M4 in 26 patients, from M - 3 to M + 3 in 8 patients, and from M - 2 to M + 2 in 1 patient. The behavioral video data showed a mean preoperative ankle dorsiflexion of 6.79° ± 5.6 and postoperative ankle dorsiflexion of 37.9° ± 9.3. Overall, excellent functional results were achieved in 27 of 62 patients (43%) with peroneal palsy who underwent microsurgical reconstruction, and good results were observed in 25 patients (40%). CONCLUSIONS: Despite previous widespread pessimism, the surgical repair of CPn lesion is worthwhile, yielding good to excellent results in the majority of patients, after a careful preoperative consultation, establishment of a sound strategy of reconstruction and using aggressive and atraumatic microsurgery.

Vascularized free fibular bone graft in the management of congenital tibial pseudarthrosis.

Congenital pseudarthrosis of the tibia (CPT) remains one of the most challenging problems confronting the orthopaedic surgeon. The operative results are frequently less than successful; many cases require several surgical procedures, and a significant number of them ending in amputation. The purpose of this study was to access the surgical results, complications, secondary procedures, and long-term results of free vascularized fibular graft (FVFG) in the treatment of congenital pseudarthrosis of the tibia. Between 1992 and 2007, nine patients with CPT were treated consecutively at our clinic with free fibula transfer. There were six females and three males. The mean age at the time of operation was 6.5 years (range, 1-12 years). Stability, after reconstruction with FVFG, was maintained with internal fixation in five patients, unilateral frame external fixation in three patients, and intramedullary pin in one patient. Average postoperative follow-up time was 9 years (range, 2-15 years). In seven patients, both ends of the graft healed primarily within 3.7 months (range, 1.5-6 months). In one patient, the distal end of the graft did not unit. This patient required three subsequent operations to achieve union. Stress fracture occurred in the middle of the grafted fibula in one patient, who underwent four additional operations before union, was achieved. Despite the relatively high-complication rate, FVFG remains a valid method for the treatment of CPT. However, even achieving union of pseudarthrosis is not enough for the resolution of the disease. This is only half of the problem; the other half is to maintain union. Long-term follow-up beyond skeletal maturity, if possible, is necessary to evaluate surgical results.

Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs.

Acyl ureas were discovered as a novel class of inhibitors for glycogen phosphorylase, a molecular target to control hyperglycemia in type 2 diabetics. This series is exemplified by 6-{2,6-Dichloro- 4-[3-(2-chloro-benzoyl)-ureido]-phenoxy}-hexanoic acid, which inhibits human liver glycogen phosphorylase a with an IC(50) of 2.0 microM. Here we analyze four crystal structures of acyl urea derivatives in complex with rabbit muscle glycogen phosphorylase b to elucidate the mechanism of inhibition of these inhibitors. The structures were determined and refined to 2.26 Angstroms resolution and demonstrate that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Acyl ureas induce conformational changes in the vicinity of the allosteric site. Our findings suggest that acyl ureas inhibit glycogen phosphorylase by direct inhibition of AMP binding and by indirect inhibition of substrate binding through stabilization of the T' state.

Ortho-Directed Lithiation of omega-Phenoxy Alcohols.

omega-Phenoxy alcohols, PhO(CH(2))(n)()OH (n = 2-7), have been subjected to metalation with 2 equiv of n-butyllithium in tetrahydrofuran/methylcyclohexane solvent. Reaction of the resulting lithiated compounds with carbon dioxide (n = 2-7), benzaldehyde (n = 2-6), benzophenone (n = 2, 3), dimethylformamide (n = 2), ethyl formate (n = 2), and chlorodiphenylphosphine (n = 3) afforded the corresponding ortho-substituted hydroxyalkoxybenzenes in yields ranging from 45 to 83%. The synthesis is also reported of five new bis[o-(omega-hydroxyalkoxy)phenyl]mercury compounds (n = 2-6), four crystal structures of which have been determined.

Synthesis and characterization of new aromatic aldehyde/ketone 4-(beta-D-glucopyranosyl)thiosemicarbazones.

A series of 22 aromatic aldehyde/ketone 4-(beta-D-glucopyranosyl)thiosemicarbazones have been synthesized by condensation of 4-(per-O-acetylated-beta-D-glucopyranosyl)thiosemicarbazide with an aldehyde or a ketone, and then, deacetylation of the resulting product. The compounds were fully characterized by spectroscopic techniques, elemental analysis, and for two derivatives by X-ray analysis. The data indicate the beta configuration, and the E configuration pertaining to the stereochemistry of the C=N bond. However, a partial conversion of the E-form into the Z-form is possible in solution after several hours.

Outcomes with suprascapular nerve reconstruction in obstetrical brachial plexus patients.

BACKGROUND: Restoration of shoulder abduction is very important following obstetrical brachial plexus paralysis. The purpose of this report is to present the authors' experience of suprascapular nerve reconstruction in 53 cases of obstetrical brachial plexus palsy. METHODS: From 1978 to 2002, 170 children with obstetrical brachial plexus palsy were seen at the authors' institution. One hundred nine children underwent surgical treatment, and 53 of them had suprascapular nerve reconstruction. RESULTS: The overall results were good or excellent in 96 percent of patients for the supraspinatus muscle and 75 percent for the infraspinatus muscle. The overall mean postoperative muscle grading was 3.71 +/- 0.7 for the supraspinatus muscle and 2.94 +/- 0.8 for the infraspinatus muscle (p < 0.05). By using the Mallet score, 23 patients (46 percent) achieved Mallet grade III and 24 patients (48 percent) achieved Mallet grade IV shoulder abduction function. Evaluating external rotation function, 21 patients (42 percent) achieved Mallet grade III and 20 patients (40 percent) achieved Mallet grade IV. Early surgery (<6 months) yielded significantly better results than late surgery (>6 months). CONCLUSIONS: Suprascapular nerve neurotization is a worthwhile procedure and is a high priority in upper limb reanimation for restoration of glenohumeral joint stability, shoulder abduction, and external rotation. Concomitant neurotization of the axillary nerve yields improved outcomes in shoulder abduction function. The best results are seen in patients with high severity scores, when only the upper two roots are involved, and when direct neurotization of the suprascapular nerve is performed within 6 months after the injury.

Vein grafts used as nerve conduits for obstetrical brachial plexus palsy reconstruction.

BACKGROUND: Limited availability of donor nerve grafts along with donor-site morbidity has stimulated research toward other alternatives for the repair of severe nerve injuries. The authors provide a comprehensive review of "tubulization" biology and share with the readers their experience with two cases of obstetrical brachial plexus paralysis where they used vein grafts with "minced" nerve tissue, to accomplish connectivity of proximal donors with distal targets. Usage of vascular tissue as conduits for nerve regeneration was first reported more than 100 years ago. It has been suggested that the vein's wall allows diffusion of the proper nutrients for nerve regeneration, acts as a barrier against ingrowth of scar, and prevents wastage of regenerating axons. METHODS: In this report, vein grafts of 2.4, 3.5, and 22 cm in length filled with minced peripheral nerve tissue were used as bridges in two cases of obstetrical brachial plexus paralysis. RESULTS: By filling the vein lumen with small pieces of nerve tissue suspended in a heparinized saline solution, a potential problem associated with vein collapse caused by compression was solved. CONCLUSION: The authors suggest that tubulization techniques should be kept in mind in clinical practice when autologous nerve grafts are insufficient for distal target connectivity or as an alternative to conventional nerve grafts for bridging certain nerve defects.

Suprascapular nerve reconstruction in 118 cases of adult posttraumatic brachial plexus.

BACKGROUND: Shoulder stabilization is of utmost importance in upper extremity reanimation following paralysis from devastating brachial plexus injuries. The purpose of this report is to present the authors' experience with suprascapular nerve reconstruction in 118 cases of adult brachial plexus lesions. Outcomes were analyzed in relation to various factors, including patient age, denervation time, donor nerve used, and functional restoration achieved in the supraspinatus versus the infraspinatus muscles. METHODS: The medical records of 118 adult patients operated on by a single surgeon between 1978 and 2002 who had suprascapular nerve reconstruction were reviewed; 102 patients had adequate follow-up. Direct neurotization of the suprascapular nerve was carried out in 78 patients, while in 40 patients, interposition nerve grafts were used. In 80 patients, the distal spinal accessory was used as the motor donor nerve for suprascapular nerve neurotization, while in 10 patients, other extraplexus motor donors were used. In 28 patients, intraplexus motor donors were used to reinnervate the suprascapular nerve. RESULTS: Results were good or excellent in 79 percent of the patients for the supraspinatus muscle and in 55 percent for the infraspinatus. There was a statistically significant difference between direct spinal accessory to suprascapular nerve neurotization and accessory to suprascapular via a nerve graft. Early surgery and less than 6 months of denervation time yielded significantly better results than late surgery and more than 6 months of delay in the treatment. CONCLUSIONS: Suprascapular nerve neurotization is a high priority in upper limb reanimation for restoration of glenohumeral joint stability, shoulder abduction, and external rotation. Concomitant neurotization of the axillary nerve yields improved outcomes in shoulder abduction function. The best results are seen when direct neurotization of the suprascapular nerve is performed within 6 months from the injury.

Restoration of shoulder function with nerve transfers in traumatic brachial plexus palsy patients.

Shoulder stabilization is of utmost importance in upper extremity reanimation following paralysis from devastating injuries. Although secondary procedures such as tendon and muscle transfers have been used, they never achieve a functional recovery comparable to that following successful reinnervation of the supraspinatus, deltoid, teres minor, and infraspinatus muscles. Early restoration of suprascapular and axillary nerve function through timely brachial plexus reconstruction offers a good opportunity to restore shoulder-joint stability, adequate shoulder abduction, and external rotation function. Overall, in our series, 79% of patients achieved good and excellent shoulder abduction (muscle grade, +3 or more), and 55% of patients achieved good or excellent shoulder external rotation after reinnervation of the suprascapular nerve. The best results were seen when direct neurotization of the suprascapular nerve from the distal spinal accessory nerve or neurotization by the C5 root was carried out. Concomitant neurotization of the axillary nerve yields improved outcomes in shoulder abduction and external rotation function.