William P. Magee

Isozyme-nonselective N-Substituted Bipiperidylcarboxamide Acetyl-CoA Carboxylase Inhibitors Reduce Tissue Malonyl-CoA Concentrations, Inhibit Fatty Acid Synthesis, and Increase Fatty Acid Oxidation in Cultured Cells and in Experimental Animals

Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect the multitude of cardiovascular risk factors associated with the metabolic syndrome. To achieve maximal effectiveness, an ACC inhibitor should inhibit both the lipogenic tissue isozyme (ACC1) and the oxidative tissue isozyme (ACC2). Herein, we describe the biochemical and acute physiological properties of CP-610431, an isozyme-nonselective ACC inhibitor identified through high throughput inhibition screening, and CP-640186, an analog with improved metabolic stability. CP-610431 inhibited ACC1 and ACC2 with IC50s of ∼50 nm. Inhibition was reversible, uncompetitive with respect to ATP, and non-competitive with respect to bicarbonate, acetyl-CoA, and citrate, indicating interaction with the enzymatic carboxyl transfer reaction. CP-610431 also inhibited fatty acid synthesis, triglyceride (TG) synthesis, TG secretion, and apolipoprotein B secretion in HepG2 cells (ACC1) with EC50s of 1.6, 1.8, 3.0, and 5.7 μm, without affecting either cholesterol synthesis or apolipoprotein CIII secretion. CP-640186, also inhibited both isozymes with IC50sof ∼55 nm but was 2–3 times more potent than CP-610431 in inhibiting HepG2 cell fatty acid and TG synthesis. CP-640186 also stimulated fatty acid oxidation in C2C12 cells (ACC2) and in rat epitrochlearis muscle strips with EC50s of 57 nm and 1.3 μm. In rats, CP-640186 lowered hepatic, soleus muscle, quadriceps muscle, and cardiac muscle malonyl-CoA with ED50s of 55, 6, 15, and 8 mg/kg. Consequently, CP-640186 inhibited fatty acid synthesis in rats, CD1 mice, and ob/ob mice with ED50s of 13, 11, and 4 mg/kg, and stimulated rat whole body fatty acid oxidation with an ED50 of ∼30 mg/kg. Taken together, These observations indicate that isozyme-nonselective ACC inhibition has the potential to favorably affect risk factors associated with the metabolic syndrome.

Selective adenosine A3 receptor stimulation reduces ischemic myocardial injury in the rabbit heart

OBJECTIVE The aim of this study was to determine whether selective activation of the adenosine A3 receptor reduces infarct size in a Langendorff model of myocardial ischemia-reperfusion injury. METHODS Buffer-perfused rabbit hearts were exposed to 30 min regional ischemia and 120 min of reperfusion. Infarct size was measured by tetrazolium staining and normalized for area-at-risk (IA/AAR). RESULTS Preconditioning by 5 min global ischemia and 10 min reperfusion reduced infarct size (IA/AAR) to 19 +/- 4% (controls: 67 +/- 5%). Replacing global ischemia with 5 min perfusion of the rabbit A3-selective agonist, IB-MECA (A3 Ki: 2 nM; A1 Ki: 30 nM) elicited a concentration-dependent reduction in infarct size; 50 nM IB-MECA reduced IA/AAR to 24 +/- 4%. The A1-selective agonist, R-PIA (25 nM) reduced IA/AAR to a similar extent (21 +/- 6%). However, while the cardioprotective effect of R-PIA was significantly inhibited (54 +/- 7% IA/AAR) by the rabbit A1-selective antagonist, BWA1433 (50 nM), the IB-MECA-dependent cardioprotection was unaffected (28 +/- 6% IA/AAR). A non-selective (A1 vs. A3) concentration of BWA1433 (5 microM) significantly attenuated the IB-MECA-dependent cardioprotection (61 +/- 7% IA/AAR). CONCLUSIONS These data clearly demonstrate that selective A3 receptor activation provides cardioprotection from ischemia-reperfusion injury in the rabbit heart. Furthermore, the degree of A3-dependent cardioprotection is similar to that provided by A1 receptor stimulation or ischemic preconditioning.

Studies of the Candidate Genes TGFB2, MSX1, TGFA, and TGFB3 in the Etiology of Cleft Lip and Palate in the Philippines

Population-based candidate-gene studies can be an effective strategy for identifying genes involved in the etiology of disorders where family-based linkage studies are compromised by lack of access to affected members, low penetrance, and/or genetic heterogeneity. We evaluated association data for four candidate genes using a population from the Philippines that is genetically separate from previously studied Caucasian populations. Case ascertainment was made possible by collaboration with Operation Smile, a volunteer medical organization, which facilitated identification of a large number of cases for study. A new allelic variant of transforming growth factor-beta 3 was identified to use in these studies. After exclusion of syndromic cases of cleft lip and palate, no evidence for association with previously reported allelic variants of transforming growth factor-beta 2 (TGFB2), homeobox 7 (MSX1), or transforming growth factor-alpha (TGFA), or with the new TGFB3 variant was detected. Previous association studies using Caucasian populations of nonsyndromic cleft lip and/or palate (CL/P) and cleft palate only (CPO) have strongly suggested a role for TGFA in the susceptibility of clefting in humans. Exclusion of significant association in a non-Caucasian population for TGFA suggests that TGFA plays less of a role than it does in Caucasians. This may be due to multiple or different genetic and/or environmental factors contributing to the etiology of this most common cranio-facial anomaly in the Philippine population.

Uses of the trapezius and sternomastoid myocutaneous flaps in head and neck reconstruction.

Both of these myocutaneous flaps can supplant forehead and deltopectoral flaps, in certain indications. They are additional arterialized flaps for the armamentarium of the reconstructive surgeon, and can be useful in many repairs in the head and neck region.

Pectoralis “paddle” myocutaneous flaps: The workhorse of head and neck reconstruction

The pectoralis paddle myocutaneous flap is extremely dependable and provides an added advantage of covering the vital structures of the neck with adequate length without excessive bulk. The donor defect is more acceptable than any we have previously encountered. The use of this skin muscle paddle in irradiated necks has distinct advantages. In addition, the ability to carry bony segments for use in mandibular reconstruction proved a distinct advantage in the two cases in which it was used.

A Novel nonpeptidic caspase-3/7 inhibitor, (S)-(+)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin reduces myocardial ischemic injury

The efficacy of a novel, nonpeptidic, caspase 3/7-selective inhibitor, (S)-(+)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (MMPSI) for reducing ischemic injury in isolated rabbit hearts or cardiomyocytes was evaluated. MMPSI (0.1-10 microM) evoked a concentration-dependent reduction in infarct size (up to 56% vs. control; IC(50)=0.2 microM). Furthermore, apoptosis (DNA laddering, soluble nucleosomes) was reduced in the ischemic area-at-risk. MMPSI inhibited recombinant human caspase-3 with an IC(50)=1.7 microM. Apoptosis in H9c2 cells after 16-h simulated ischemia and 2-h simulated reperfusion was significantly reduced by MMPSI in a concentration-dependent manner (IC(50)=0.5 microM); similar effects were observed in isolated adult rabbit cardiomyocytes (IC(50)=1.5 microM). These data support an important role for caspase-3/7 in mediating myocardial ischemic injury. Furthermore, these data indicate that cardioprotection via caspase-3/7 inhibition is attainable via a small molecule (nonpeptidic) inhibitor, a necessary step in making this approach therapeutically viable.

The Medical Mission and Modern Cultural Competency Training

BACKGROUND Culture has increasingly appreciated clinical consequences on the patient-physician relationship, and governing bodies of medical education are widely expanding educational programs to train providers in culturally competent care. A recent study demonstrated the value an international surgical mission in modern surgical training, while fulfilling the mandate of educational growth through six core competencies. This report further examines the impact of international volunteerism on surgical residents, and demonstrates that such experiences are particularly suited to education in cultural competency. METHODS Twenty-one resident physicians who participated in the inaugural Operation Smile Regan Fellowship were surveyed one year after their experiences. RESULTS One hundred percent strongly agreed that participation in an international surgical mission was a quality educational experience and 94.7% deemed the experience a valuable part of their residency training. In additional to education in each of the ACGME core competencies, results demonstrate valuable training in cultural competence. CONCLUSIONS A properly structured and proctored experience for surgical residents in international volunteerism is an effective instruction tool in the modern competency-based residency curriculum. These endeavors provide a unique understanding of the global burden of surgical disease, a deeper appreciation for global public health issues, and increased cultural sensitivity. A surgical mission experience should be widely available to surgery residents.

The role of humanitarian missions in modern surgical training.

Background: Surgical trainees have participated in international missions for decades and are now seeking out these experiences in record numbers. Resident participation in humanitarian service has been highly controversial in the academic plastic surgery community, and little evidence exists elucidating the value of these experiences. This report examines the impact of international volunteerism on surgical training. Methods: Twenty-one resident physicians who participated in the inaugural Operation Smile Regan Fellowship were surveyed 1 year after their experiences. Results: One hundred percent responded that participation in an international surgical mission had an overall positive impact on their lives, and 94.7 percent reported that they had achieved marked personal growth. Results demonstrate significant education in each of the Accreditation Council for Graduate Medical Education core competencies and insights into global health and cultural competency. One hundred percent “strongly agreed” that the Regan Fellowship was a quality educational experience, and 94.7 percent deemed the experience a valuable part of their residency training. Conclusions: Resident physicians are calling for more international health opportunities, and they should be generously supported. A properly structured and proctored experience for surgical residents in international volunteerism is an effective instruction tool in the modern competency-based residency curriculum. These endeavors provide a unique understanding of the global burden of surgical disease, a deeper appreciation for global public health issues, and increased cultural sensitivity. Plastic surgery training programs can contribute mightily to global health and improved resident education by embracing and fostering the development of international humanitarian opportunities. A surgical mission experience should be widely available to plastic surgery residents.

Application of Outcome Measures in International Humanitarian Aid: Comparing Indices through Retrospective Analysis of Corrective Surgical Care Cases

It is common for international organizations to provide surgical corrective care to vulnerable populations in developing countries. However, a current worsening of the overall surgical burden of disease in developing countries reflects an increasing lack of sufficient numbers of trained healthcare personnel, and renders outside volunteer assistance more desirable and crucial than ever. Unfortunately, program evaluation and monitoring, including outcome indices and measures of effectiveness, is not measured commonly. In 2005, Operation Smile International implemented an electronic medical record system that helps monitor a number of critical indices during surgical missions that are essential for quality assurance reviews. This record system also provided an opportunity to retrospectively evaluate cases from previous missions. Review of data sets from >8,000 cases in 2005 and 2006 has provided crucial information regarding the priority of surgery, perioperative and operative complications, and surgical program development. The most common procedure provided was unilateral cleft lip repair, followed closely by cleft palate. A majority of these interventions occurred for patients who were older than routinely provided for in the western world. The average child treated had an age:weight ratio at or below the [US] Centers for Disease Control and Prevention (CDC) 50th percentile, with a small percentage falling below the CDC 20th percentile. A majority of children had acceptable levels of hemoglobin, but the relative decreased age:weight ratio nonetheless can reflect mild malnutrition. Complications requiring medical intervention were seen in 1.2% of cases in 2005 and 1.0% in 2006. Thirty percent were reported as anesthesia complications, and 61% reported as surgical complications. One death was reported, but occurred after discharge outside the perioperative period. Complication rates are similar to rates reported in the US and UK and emphasizes the importance of standardization with uniform indices to compare quality performance and equity of care. This study offers an important example of the importance of collecting, analyzing, and reporting measures of effectiveness in all surgical settings.

Biomechanical comparison of a fully threaded, variable pitch screw and a partially threaded lag screw for internal fixation of Type II dens fractures.

Study Design. Stiffness and load to failure were studied in a human cadaver model of Type II odontoid fractures stabilized with either a single partially threaded lag screw and washer or a headless fully threaded variable pitch screw. Objective. To determine whether a headless fully threaded variable pitch screw provides biomechanically superior fixation of Type II odontoid fractures in comparison with a partially threaded, cannulated lag screw and washer. Summary of Background Data. Surgical treatment of Anderson and D’Alonzo Type II odontoid fractures is often performed using a partially threaded cannulated screw and washer. Reported clinical failure rates of this construct are as high as 20%. This technique requires perforation of the cortex of the tip of the dens, placing the brainstem and vertebrobasilar circulation at risk. A headless fully threaded variable pitch screw has not been described for this application. Methods. A transverse osteotomy was created at the base of the dens in 16 human cadaver C2 specimens and stabilized using either a headless fully threaded variable pitch screw or a partially threaded cannulated lag screw and washer. Specimens were loaded to failure under a static, posteriorly directed force applied to the surface of the dens. Stiffness and load to failure were measured and the mode of failure for each specimen was determined. Results. Stiffness and load to failure were greater for the headless, fully threaded variable pitch screw compared with the partially threaded lag screw and washer. The mode of failure for all specimens was via anterior screw cut-out at the C2 vertebral body. Conclusion. A headless, fully threaded variable pitch screw was biomechanically favorable in comparison with a partially threaded lag screw and washer in this cadaver model of Type II dens fractures. The mode of failure at the C2 vertebral body may have important implications for further improvements in construct strength.