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1.  The accuracy of the physical examination for the detection of lower extremity peripheral arterial disease 
The Canadian Journal of Cardiology  2010;26(10):e346-e350.
Peripheral arterial disease (PAD) is a major risk factor for adverse cardiovascular events. There has been a definite push for wider use of the ankle-brachial index (ABI) as a simple screening tool for PAD. Perhaps this has occurred to the detriment of a thorough physical examination.
To assess the accuracy of the physical examination to detect clinically significant PAD compared with the ABI.
PADfile, the PAD module of CARDIOfile (the Kingston Heart Clinic’s cardiology database [Kingston, Ontario]), was searched for all patients who underwent peripheral arterial testing. Of 1619 patients, 1236 had all of the necessary data entered. Patients’ lower limbs were divided into two groups: those with a normal ABI between 0.91 and 1.30, and those with an abnormal ABI of 0.90 or lower. Peripheral pulses were graded as either absent or present. Absent was graded as 0/3, present but reduced (1/3), normal (2/3) or bounding (3/3). Femoral bruits were graded as either present (1) or absent (0). Using the ABI as the gold standard, the sensitivity, specificity, negative predictive value (NPV), positive predictive value and overall accuracy were calculated for the dorsalis pedis pulse, the posterior tibial pulse, both pedal pulses, the presence or absence of a femoral bruit and, finally, for a combination of both pedal pulses and the presence or absence of a femoral bruit.
In 1236 patients who underwent PAD testing and who underwent a complete peripheral vascular physical examination (all dorsalis pedis and posterior tibial pulses palpated and auscultation for a femoral bruit), the sensitivity, specificity, NPV, positive predictive value and accuracy for PAD were 58.2%, 98.3%, 94.9%, 81.1% and 93.8%, respectively.
The clinical examination of the peripheral arterial foot pulses and the auscultation for a femoral bruit had a high degree of accuracy (93.8%) for the detection or exclusion of PAD compared with the ABI using the cut-off of 0.90 or lower. If both peripheral foot pulses are present in both lower limbs and there are no femoral bruits, the specificity and NPV of 98.3% and 94.9%, respectively, make the measurement of the ABI seem redundant. The emphasis in PAD detection should be redirected toward encouraging a thorough physical examination.
PMCID: PMC3006105  PMID: 21165366
Ankle-brachial index; Peripheral arterial disease; Physical examination
2.  Use of Sugar on the Healing of Diabetic Ulcers: A Review 
With the advent of several innovative wound care management tools, the choice of products and treatment modalities available to clinicians continues to expand. High costs associated with wound care, especially diabetic foot wounds, make it important for clinician scientists to research alternative therapies and optimally incorporate them into wound care protocols appropriately. This article reviews using sugar as a treatment option in diabetic foot care and provides a guide to its appropriate use in healing foot ulcers. In addition to a clinical case study, the physiological significance and advantages of sugar are discussed.
PMCID: PMC2956799  PMID: 20920433
diabetic foot ulcers; sugar; wound healing
3.  Novel Use of Platelet-Rich Plasma to Augment Curative Diabetic Foot Surgery 
Autologous platelet-rich plasma (PRP) may enhance wound healing through the formation of a platelet plug that provides both hemostasis and the secretion of biologically active proteins, including growth factors such as platelet-derived growth factor, transforming growth factor (TGF)-β, TGF-β2, and epidermal growth factor. The release of these growth factors into the wound may create an environment more conducive to tissue repair and could accelerate postoperative wound healing. To our knowledge, there are no reports of combining the use of PRP with curative diabetic foot surgery. This article provides a summary of the literature regarding PRP and wound healing and presents a case of a 49-year-old man with diabetes and a three-month history of a deep, nonhealing plantar hallux wound in which PRP was combined with a first metatarsophalangeal joint arthroplasty. Through the use of the PRP and bioengineered tissue to supplement curative diabetic foot surgery, the patient healed uneventfully at seven weeks.
PMCID: PMC2956802  PMID: 20920431
diabetic; foot surgery; platelet rich plasma; wound
4.  A one-year economic evaluation of six alternative strategies for the management of uninvestigated upper gastrointestinal symptoms in Canadian primary care 
The cost-effectiveness of initial strategies in managing Canadian patients with uninvestigated upper gastrointestinal symptoms remains controversial.
To assess the cost-effectiveness of six management approaches to uninvestigated upper gastrointestinal symptoms in the Canadian setting.
The present study analyzed data from four randomized trials assessing homogeneous and complementary populations of Canadian patients with uninvestigated upper gastrointestinal symptoms with comparable outcomes. Symptom-free months, quality-adjusted life-years (QALYs) and direct costs in Canadian dollars of two management approaches based on the Canadian Dyspepsia Working Group (CanDys) Clinical Management Tool, and four additional strategies (two empirical antisecretory agents, and two prompt endoscopy) were examined and compared. Prevalence data, probabilities, utilities and costs were included in a Markov model, while sensitivity analysis used Monte Carlo simulations. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were determined.
Empirical omeprazole cost $226 per QALY ($49 per symptom-free month) per patient. CanDys omeprazole and endoscopy approaches were more effective than empirical omeprazole, but more costly. Alternatives using H2-receptor antagonists were less effective than those using a proton pump inhibitor. No significant differences were found for most incremental cost-effectiveness ratios. As willingness to pay (WTP) thresholds rose from $226 to $24,000 per QALY, empirical antisecretory approaches were less likely to be the most cost-effective choice, with CanDys omeprazole progressively becoming a more likely option. For WTP values ranging from $24,000 to $70,000 per QALY, the most clinically relevant range, CanDys omeprazole was the most cost-effective strategy (32% to 46% of the time), with prompt endoscopy-proton pump inhibitor favoured at higher WTP values.
Although no strategy was the indisputable cost-effective option, CanDys omeprazole may be the strategy of choice over a clinically relevant range of WTP assumptions in the initial management of Canadian patients with uninvestigated dyspepsia.
PMCID: PMC2947002  PMID: 20711528
Antisecretory therapy; Cost-effectiveness; Dyspepsia; Economic modelling; Endoscopy; Helicobacter pylori
5.  Wound Inflammatory Index: A “Proof of Concept” Study to Assess Wound Healing Trajectory 
Diabetes around the globe results in one major limb amputation every 30 seconds, over 2500 limbs lost per day. The underlying pathophysiology sometimes leads to a chronic inflammatory stage, which may prevent appropriate healing, and therefore, the need for a clear strategy for assessing and classifying wounds and wound healing cannot be overstated. Temperature is a surrogate marker for inflammation. Quantitative thermography using a numerical index provides a useful way to assess wound healing. Advances in technology have afforded the availability of low-cost, high-resolution thermal imaging systems, which can be used to quantify sensitive changes on the skin surface and may be particularly useful to develop monitoring strategies for wounds. This article provides a standardized technique for calculating a thermal index (TI) supported with a case report from assessment of a diabetic foot ulcer. In this single case study, the TI/wound inflammatory index indicates a shift from negative to positive (p < .05) before it reaches zero.
PMCID: PMC2909505  PMID: 20663437
diabetic foot ulcers; thermal index; thermography; thermometry; wound healing
6.  Digital Planimetry Results in More Accurate Wound Measurements: A Comparison to Standard Ruler Measurements 
Cutaneous wound measurements are important to track the healing of a wound and direct appropriate therapy. The most commonly used method to calculate wound area is an estimation by multiplying the longest length by the widest width. Other devices can provide an accurate and precise measurement of the true area (TA). This study aim was to compare wound areas calculated by computerized planimetry with standard area estimation by multiplying the longest length by the widest width (l × w).
We reviewed the wound records of 10 patients with circular or oval wounds and estimated the area with the l × w method. We compared this with the TA obtained by a specialized planimetric camera.
Average wound size was 4.3 cm2 by l × w estimation and 3 cm2 by TA calculation. We found the l × w method overestimated wound area an average of 41%.
Standard, manual (l × w) measurement of cutaneous wounds inaccurately overestimates wound area by roughly 40%.
PMCID: PMC2909508  PMID: 20663440
planimetry; Silhouette; ulcer; wound measurement
7.  The Micrograft Concept for Wound Healing: Strategies and Applications 
The standard of care for wound coverage is to use an autologous skin graft. However, large or chronic wounds become an exceptionally challenging problem especially when donor sites are limited. It is important that the clinician be aware of various treatment modalities for wound care and incorporate those methods appropriately in the proper clinical context. This report reviews an alternative to traditional meshed skin grafting for wound coverage: micrografting. The physiological concept of micrografting, along with historical context, and the evolution of the technique are discussed, as well as studies needed for micrograft characterization and future applications of the technique.
PMCID: PMC2909510  PMID: 20663442
diabetic foot ulcers; micrografting; wound healing
8.  Novel Use of Insulin in Continuous-Instillation Negative Pressure Wound Therapy as “Wound Chemotherapy” 
Negative pressure wound therapy (NPWT) is frequently employed in the treatment of complex wounds. A variety of wound chemotherapeutic agents such as insulin, which acts as a growth factor, may prove helpful in treatment as well. We present a case report in which insulin was used as a chemotherapeutic agent in continuous-instillation NPWT. To our knowledge, this is the first report in the literature describing this method of delivery.
PMCID: PMC2909511  PMID: 20663443
diabetic foot ulcers; insulin; negative pressure wound therapy; wound chemotherapy
9.  Liquid Silicone to Mitigate Plantar Pedal Pressure: A Literature Review 
Disruption of the body’s plantar fat pad can occur as a result of one of three mechanisms: simple fat pad atrophy associated with age-related degeneration, steroid use, or collagen vascular disease. Actual or relative displacement in to the underlying osseous prominences may be seen in association with structural deformity of the foot. Disease states such as diabetes may alter the normal structural integrity of soft tissues through nonenzymatic glycation leading to increased stiffness and thus reduced attenuating capacity. Fat pad atrophy, regardless of the cause, is often associated with substantial emotional, physical, productivity, and financial losses. In situations where the patient is sensate, the resultant skin on bone situation is extremely painful, especially when walking.
PMCID: PMC2909515  PMID: 20663447
atrophy; augmentation; pressure; silicone
10.  Estimated right ventricular systolic pressure during exercise stress echocardiography in patients with suspected coronary artery disease 
To determine the normal range of estimated right ventricular systolic pressure (RVSP) at peak exercise during exercise stress echocardiography (ExECHO) in a series of consecutive patients referred for the investigation of coronary artery disease.
Of 1057 ExECHO examinations over a span of 11 months, 807 met the study criteria. A total of 250 patients were excluded, 188 for missing rest or peak RVSP measurements, 16 for a resting RVSP above 50 mmHg, 16 for nondiagnostic echocardiographic images and the remaining 30 for missing data. The maximal tricuspid regurgitant jet was recorded at rest and following acquisition of the stress images (mean [± SD] time 103.1±35.2 s). A mean right atrial pressure of 10 mmHg was used in the calculation of RVSP. All data were entered into a cardiology database (CARDIOfile; Registered trademark, Kingston Heart Clinic) for later retrieval and analysis.
There were 206 male (58.9±12.0 years of age) and 601 female patients (57.4±12.0 years of age). Patient age ranged from 18 to 90 years. The mean resting and peak exercise RVSP was 27.8±7.8 mmHg and 34.8±11.3 mmHg in men, and 27.8±7.7 mmHg and 34.6±11.7 mmHg in women, respectively. The mean increase in RVSP was 7.0±8.8 mmHg in men and 6.7±8.9 mmHg in women. The 95% CI for peak RVSP was 12.2 mmHg to 57.4 mmHg in men, and 11.2 mmHg to 58.0 mmHg in women. There was no significant difference in peak RVSP for a normal ExECHO compared with an abnormal ExECHO. RVSP at rest and at peak exercise increased with both age and left atrial size.
In individual patients, the RVSP should not increase above the resting value by more than 24.6 mmHg in men and 24.5 mmHg in women. This value was calculated as the increase in RVSP plus 2×SD of the RVSP. Peak RVSP should not exceed 57.4 mmHg in men and 58.0 mmHg in women. If either of these criteria is exceeded, the response of RVSP to exercise should be considered abnormal.
PMCID: PMC2851391  PMID: 20151058
Coronary artery disease; Right ventricular systolic pressure; Stress echocardiography
11.  Factors influencing the echocardiographic estimate of right ventricular systolic pressure in normal patients and clinically relevant ranges according to age 
Previous studies have shown that in the absence of underlying cardiac pathology, the echocardiographic estimate of right ventricular systolic pressure (RVSP) increases progressively and normally with age. There are limited data in patients older than 60 years of age.
To define the ranges of RVSP according to age and to include more elderly patients than have previously been reported.
All patients undergoing echocardiography since May 26, 1999, at the Kingston Heart Clinic (Kingston, Ontario) have had their data entered into a locally designed cardiology database (CARDIOfile; Registered trademark, Kingston Heart Clinic). RVSP was calculated from the peak tricuspid regurgitant jet velocity (V) using the modified Bernoulli equation (RVSP = 4V2 + RAP), with the mean right atrial pressure (RAP) estimated to be 10 mmHg. Of the 22,628 patients who had undergone echocardiography, 10,905 had RVSP measured. All abnormal echocardiograms were excluded, leaving 1559 echocardiograms for analysis.
Patient age ranged from 15 to 93 years. The mean age was 49 years. RVSP increased significantly only after the age of 50 years. The mean (± SD) RVSP for those younger than 50 years, 50 to 75 years, and older than 75 years of age was 27.3±5.7 mmHg, 30.2±7.6 mmHg and 34.8±8.7 mmHg, respectively (P<0.0001 among all age groups). The normal range (95% CI) of RVSP in those younger than 50 years, 50 to 75 years, and older than 75 years of age was 16 mmHg to 39 mmHg, 15 mmHg to 45 mmHg, and 17 mmHg to 52 mmHg, respectively. Multivariate analysis indicated that age, mitral diastolic early-to-late filling velocity ratio, ejection fraction, aortic size and early mitral filling velocity/early diastolic mitral annular velocity were the only significant independent variables. There were significant changes in diastolic function with increasing age, which may have been responsible for the changes in RVSP.
RVSP remains stable in both men and women until the age of 50 years. Thereafter, RVSP increases progressively in a linear manner with age and is significantly higher in patients older than 75 years of age. The changes may relate to changes in diastolic function. These ranges should be taken into account when using echocardiogram-derived RVSP for the diagnosis of pulmonary hypertension in the absence of cardiovascular disease.
PMCID: PMC2851398  PMID: 20151056
Echocardiography; Pulmonary hypertension
12.  Receipt of Cardiac Medications Upon Discharge among Men and Women with Acute Coronary Syndrome and Non-Obstructive Coronary Artery Disease 
Clinical cardiology  2010;33(1):36-41.
Management of acute coronary syndrome (ACS) patients with non-obstructive epicardial coronary artery disease (CAD) remains poorly understood.
ACS patients with non-obstructive CAD are less likely to receive effective cardiac medications upon discharge from the hospital.
We identified patients hospitalized with ACS that underwent coronary angiography and had 6-month follow-up. Patients were grouped by CAD severity: non-obstructive CAD (<50% blockage in all vessels) or obstructive CAD (≥50% blockage in ≥1 vessels). Data were collected on demographics, medications at discharge, and adverse outcomes at 6 months, for all patients.
Of the 2,264 ACS patients included in the study: 123 patients had non-obstructive CAD and 2,141 had obstructive CAD. Cardiac risk factors including hypertension and diabetes were common among patients with non-obstructive CAD. Men and women with non-obstructive CAD were less likely to receive cardiac medications compared to patients with obstructive CAD including aspirin (87.8% vs. 95.0%, p=0.001), beta-blockers (74.0% vs. 89.2%, p<0.001), or statins (69.1% vs. 81.2%, p=0.001). No gender-related differences in discharge medications were observed for patients with nonobstructive CAD. However women with non-obstructive CAD had similar rates of cardiac-related rehospitalization as men with obstructive CAD (23.3% and 25.9%, respectively).
Patients with non-obstructive CAD are less likely to receive evidence-based medications compared to patients with obstructive CAD, despite the presence of CAD risk factors and occurrence of an ACS event. Further research is warranted to determine if receipt of effective cardiac medications among patients with non-obstructive CAD would reduce cardiac related events.
PMCID: PMC2935808  PMID: 20063300
Non-obstructive coronary artery disease; Acute Coronary Syndrome; Prevention
13.  Trial Protocol: Using genotype to tailor prescribing of nicotine replacement therapy: a randomised controlled trial assessing impact of communication upon adherence 
BMC Public Health  2010;10:680.
The behavioural impact of pharmacogenomics is untested; informing smokers of genetic test results for responsiveness to smoking cessation medication may increase adherence to this medication. The objective of this trial is to estimate the impact upon adherence to nicotine replacement therapy (NRT) of informing smokers that their oral dose of NRT has been tailored to a DNA analysis. Hypotheses to be tested are as follows:
I Adherence to NRT is greater among smokers informed that their oral dose of NRT is tailored to an analysis of DNA (genotype), compared to one tailored to nicotine dependence questionnaire score (phenotype).
II Amongst smokers who fail to quit at six months, motivation to make another quit attempt is lower when informed that their oral dose of NRT was tailored to genotype rather than phenotype.
An open label, parallel groups randomised trial in which 630 adult smokers (smoking 10 or more cigarettes daily) using National Health Service (NHS) stop smoking services in primary care are randomly allocated to one of two groups:
i. NRT oral dose tailored by DNA analysis (OPRM1 gene) (genotype), or
ii. NRT oral dose tailored by nicotine dependence questionnaire score (phenotype)
The primary outcome is proportion of prescribed NRT consumed in the first 28 days following an initial quit attempt, with the secondary outcome being motivation to make another quit attempt, amongst smokers not abstinent at six months. Other outcomes include adherence to NRT in the first seven days and biochemically validated smoking abstinence at six months. The primary outcome will be collected on 630 smokers allowing sufficient power to detect a 7.5% difference in mean proportion of NRT consumed using a two-tailed test at the 5% level of significance between groups. The proportion of all NRT consumed in the first four weeks of quitting will be compared between arms using an independent samples t-test and by estimating the 95% confidence interval for observed between-arm difference in mean NRT consumption (Hypothesis I). Motivation to make another quit attempt will be compared between arms in those failing to quit by six months (Hypothesis II).
This is the first clinical trial evaluating the behavioural impact on adherence of prescribing medication using genetic rather than phenotypic information. Specific issues regarding the choice of design for trials of interventions of this kind are discussed.
Trial details
Funder: Medical Research Council (MRC)
Grant number: G0500274
ISRCTN: 14352545
Date trial stated: June 2007
Expected end date: December 2009
Expected reporting date: December 2010
PMCID: PMC2996370  PMID: 21062464
14.  Differential effects of pre and post-payment on neurologists' response rates to a postal survey 
BMC Neurology  2010;10:100.
Monetary incentives are an effective way of increasing response rates to surveys, though they are generally less effective in physicians, and are more effective when the incentive is paid up-front rather than when made conditional on completion.
In this study we examine the effectiveness of pre- and post-completion incentives on the response rates of all the neurologists in the UK to a survey about conversion disorder, using a cluster randomised controlled design. A postal survey was sent to all practicing consultant neurologists, in two rounds, including either a book token, the promise of a book token, or nothing at all.
Three hundred and fifty-one of 591 eligible neurologists completed the survey, for a response rate of 59%. While the post-completion incentive exerted no discernible influence on response rates, a pre-completion incentive did, with an odds-ratio of 2.1 (95% confidence interval 1.5 - 3.0).
We conclude that neurologists, in the UK at least, may be influenced to respond to a postal survey by a pre-payment incentive but are unaffected by a promised reward.
PMCID: PMC2984383  PMID: 20973984
15.  A diagnostic PCR assay for the detection of an Australian epidemic strain of Pseudomonas aeruginosa 
Chronic lung infection with the bacterium Pseudomonas aeruginosa is one of the hallmarks of cystic fibrosis (CF) and is associated with worsening lung function, increased hospitalisation and reduced life expectancy. A virulent clonal strain of P. aeruginosa (Australian epidemic strain I; AES-I) has been found to be widespread in CF patients in eastern Australia.
Suppression subtractive hybridization (SSH) was employed to identify genetic sequences that are present in the AES-I strain but absent from the sequenced reference strain PAO1. We used PCR to evaluate the distribution of several of the AES-I loci amongst a collection of 188 P. aeruginosa isolates which was comprised of 35 AES-I isolates (as determined by PFGE), 78 non-AES-I CF isolates including other epidemic CF strains as well as 69 P. aeruginosa isolates from other clinical and environmental sources.
We have identified a unique AES-I genetic locus that is present in all 35 AES-I isolates tested and not present in any of the other 153 P. aeruginosa strains examined. We have used this unique AES-I locus to develop a diagnostic PCR and a real-time PCR assay to detect the presence of P. aeruginosa and AES-I in patient sputum samples.
We have developed diagnostic PCR assays that are 100% sensitive and 100% specific for the P. aeruginosa strain AES-I. We have also shown that Whatman FTA® Elute cards may be used with PCR-based assays to rapidly detect the presence of P. aeruginosa strains in CF sputum.
PMCID: PMC2912777  PMID: 20637114
16.  General practitioners' perceptions of the effectiveness of medical interventions: an exploration of underlying constructs 
Many interventions shown to be effective through clinical trials are not readily implemented in clinical practice. Unfortunately, little is known regarding how clinicians construct their perceptions of the effectiveness of medical interventions. This study aims to explore general practitioners' perceptions of the nature of 'effectiveness'.
The design was qualitative in nature using the repertory grid technique to elicit the constructs underlying the perceived effectiveness of a range of medical interventions. Eight medical interventions were used as stimuli (diclophenac to reduce acute pain, cognitive behaviour therapy to treat depression, weight loss surgery to achieve weight loss, diet and exercise to prevent type 2 diabetes, statins to prevent heart disease, stopping smoking to prevent heart disease, nicotine replacement therapy to stop smoking, and stop smoking groups to stop smoking). The setting involved face-to-face interviews followed by questionnaires in London Primary Care Trusts. Participants included a random sample of 13 general practitioners.
Analysis of the ratings showed that the constructs clustered around two dimensions: low patient effort versus high patient effort (dimension one), and small impact versus large impact (dimension two). Dimension one represented constructs such as 'success requires little motivation', 'not a lifestyle intervention', and 'health-care professional led intervention'. Dimension two represented constructs such as 'weak and/or minimal evidence of effectiveness', 'small treatment effect for users', 'a small proportion of users will benefit' and 'not cost-effective'. Constructs within each dimension were closely related.
General practitioners judged the effectiveness of medical interventions by considering two broad dimensions: the extent to which interventions involve patient effort, and the size of their impact. The latter is informed by trial evidence, but the patient effort required to achieve effectiveness seems to be based on clinical judgement. Some of the failure of evidence-based medicine to be implemented may be more explicable if both dimensions were attended to.
PMCID: PMC2827366  PMID: 20158896
17.  Partial Calcanectomy in High-Risk Patients With Diabetes: Use and Utility of a “Hurricane” Incisional Approach 
Eplasty  2010;10:e17.
Introduction: Plantar heel ulcers in people with diabetes represent a difficult challenge to the treating physician. They become even more difficult with underlying osteomyelitis. When this infection is in the calcaneus it typically results in a partial or total calcanectomy or even more frequently, high-level amputation. Methods: In this article, we describe a novel serpentine incisional approach to the plantar and (if necessary) posterior heel allowing for ample exposure and facilitating closure predominantly along relaxed skin tension lines. Results: We present several representative case examples in which a hurricane incision has been used to treat and provide closure to plantar-based calcaneal ulcers. Discussion: The use of this incision, which resembles a satellite view of a hurricane, was successful in achieving a desired partial calcanectomy and wound closure. This may be an additional tool in the armamentarium of the surgeon to assist in healing and amputation prevention.
PMCID: PMC2817571  PMID: 20165545
18.  Wound Chemotherapy by the Use of Negative Pressure Wound Therapy and Infusion 
Eplasty  2010;10:e9.
Introduction: Although the use of negative pressure wound therapy (NPWT) is broadly efficacious, it may foster some potentially adverse complications. This is particularly true in patients with diabetes who have a wound colonized with aerobic organisms. Traditional antiseptics have been proven useful to combat such bacteria but require removal of some NPWT devices to be effective. Methods: In this article, we describe a method of “wound chemotherapy” by combining NPWT and a continuous infusion of Dakins' 0.5% solution either as a standardized technique in one device (ITI Sved) or as a modification of standard technique in another (KCI VAC) NPWT device. The twin goals of both techniques are to effectively reduce bacterial burden and to promote progressive wound healing. Results: We present several representative case examples of our provisional experience with continuous streaming therapy through 2 foam-based negative pressure devices. Discussion: Wound chemotherapy was successfully applied to patients with diabetes, without adverse reactions, complications, or recolonization during the course of treatment. We believe this to be a promising method to derive the benefits of NPWT without the frequent adverse sequela of wound colonization.
PMCID: PMC2806786  PMID: 20090841
19.  Structural Basis for Regioisomerization in the Alkali-Metal-Mediated Zincation (AMMZn) of Trifluoromethyl Benzene by Isolation of Kinetic and Thermodynamic Intermediates 
Performed with a desire to advance knowledge of the structures and mechanisms governing alkali-metal-mediated zincation, this study monitors the reaction between the TMP-dialkylzincate reagent [(TMEDA)Na(TMP)(tBu)Zn(tBu)] 1 and trifluoromethyl benzene C6H5CF32. A complicated mixture of products is observed at room temperature. X-ray crystallography has identified two of these products as ortho- and meta-regioisomers of heterotrianionic [(TMEDA)Na(TMP)(C6H4-CF3)Zn(tBu)], 3-ortho and 3-meta, respectively. Multinuclear NMR data of the bulk crystalline product confirm the presence of these two regioisomers as well as a third isomer, 3-para, in a respective ratio of 20:11:1, and an additional product 4, which also exhibits ortho-zincation of the aryl substrate. Repeating the reaction at 0 °C gave exclusively 4, which was crystallographically characterized as [{(TMEDA)2Na}+{Zn(C6H4-CF3)(tBu)2}−]. Mimicking the original room-temperature reaction, this kinetic product was subsequently reacted with TMP(H) to afford a complicated mixture of products, including significantly the three regioisomers of 3. Surprisingly, 4 adopts a solvent-separated ion pair arrangement in contrast to the contacted ion variants of 3-ortho and 3-meta. Aided by DFT calculations on model systems, discussion focuses on the different basicities, amido or alkyl, and steps, exhibited in these reactions, and how the structures and bonding within these isolated key metallic intermediates (prior to any electrophilic interception step), specifically the interactions involving the alkali metal, influence the regioselectivity of the Zn−H exchange process.
PMCID: PMC3660950  PMID: 20568749

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