Recent Publications by CFE Educators

We recently developed a genetic transneuronal tracing approach that allows for the study of circuits that are altered by nerve injury. We generated transgenic (ZW-X) mice in which expression of a transneuronal tracer, wheat germ agglutinin (WGA), is induced in primary sensory neurons, but only after transection of their peripheral axon. By following the transneuronal transport of the tracer into the central nervous system (CNS) we can label the circuits that are engaged by the WGA-expressing damaged neurons. Here we used the ZW-X mouse line to analyze dorsal root ganglia (DRG) for intraganglionic connections between injured sensory neurons and their neighboring "intact" neurons. Because neuropeptide Y (NPY) expression is strongly induced in DRG neurons after peripheral axotomy, we crossed the ZW-X mouse line with a mouse that expresses Cre recombinase under the influence of the NPY promoter. As expected, sciatic nerve transection triggered WGA expression in NPY-positive DRG neurons, most of which are of large diameter. As expected, double labeling for ATF-3, a marker of cell bodies with damaged axons, showed that the tracer predominated in injured (i.e., axotomized) neurons. However, we also found the WGA tracer in DRG cell bodies of uninjured sensory neurons. Importantly, in the absence of nerve injury there was no intraganglionic transfer of WGA. Our results demonstrate that intraganglionic, cell-to-cell communication, via transfer of large molecules, occurs between the cell bodies of injured and neighboring noninjured primary afferent neurons.

Clavicle fractures are common, and it is important for primary care physicians to be familiar with basic principles of evaluation and management in order to initiate treatment as well as discuss these injuries with patients and consulting orthopedic surgeons. These injuries are almost always the result of trauma (often a direct blow to the shoulder) and occur most often in the young male population. Evaluation begins with a thorough history and physical examination and typically progresses to plain radiographs identifying the fracture site and pattern. These fractures have been classified by Allman into groups I (mid-shaft), II (lateral), and III (medial); this classification, along with fracture characteristics (eg, displacement and comminution) is used to assist with determining the strategy for management. Although nondisplaced fractures continue to be treated conservatively with a simple sling until the fracture is healed according to radiographs and clinical assessment, various forms of open reduction and internal fixation are now commonly used to treat fractures with little or no cortical contact between fragments. Open reduction and internal fixation has shown superior results compared with conservative management in recent trials of management of displaced fractures. Nonunion and malunion are rare, but may be symptomatic in a subset of patients. These complications may be addressed with open reduction and internal fixation, bone grafting, and osteotomy as needed.

STUDY OBJECTIVES

To compare the accuracy of the pharmacogenetic dosing table included in the warfarin label with two empiric dosing strategies in predicting initial therapeutic warfarin doses, and to identify factors that influence the accuracy of the table.

DESIGN

Retrospective cohort study.

DATA SOURCE

International Warfarin Pharmacogenetic Consortium database.

PATIENTS

A total of 3727 racially diverse patients receiving stable doses of warfarin who had international normalized ratios (INRs) between 2.0 and 3.0.

MEASUREMENTS AND MAIN RESULTS

Mean absolute error (MAE) and mean percentage of patients whose predicted doses were within 20% of their actual therapeutic doses (percentage within 20%) were compared between the pharmacogenetic table and two empiric dosing strategies. In the first strategy, warfarin 5 mg/day was used, and in the second strategy, dosing varied depending on the patient's race. The mean percentage of patients whose actual doses were within the ranges of the table (percentage within range) was also calculated. Warfarin dosing using the table resulted in a lower MAE (10.9 mg/wk) and a higher percentage within 20% (41.5%) than both empiric dosing strategies (MAE 12.3-12.6 mg/wk, percentage within 20% of 31.8-32.7%). In addition, using the table showed similar MAE, mean percentage within 20%, and mean percentage within range across the different racial groups. Dosing according to the table had higher mean percentage within 20% (56.4% vs 15.4%) and higher mean percentage within range (53.3% vs 19.2%) in the intermediate-dose group (> 21 but ≤ 49 mg/wk) than in the low-dose group (≤ 21 mg/wk). Being female and taking amiodarone were identified as factors that significantly increased the likelihood that the patient's predicted dose would be outside of 20% of their actual therapeutic dose or outside the range of the pharmacogenetic table.

CONCLUSION

Using the pharmacogenetic dosing table included in the warfarin label resulted in higher accuracy of dosing prediction than two empiric dosing strategies. The table had similar accuracy across racial groups and better accuracy in patients receiving an intermediate dose of warfarin. When the table is used for warfarin dosing, women and patients receiving amiodarone may require more intensive monitoring of their warfarin therapy.

OBJECTIVES

The purpose of this study was to test the lipid depletion hypothesis and to establish the time course of change in carotid plaque morphology and composition during lipid therapy using high-resolution magnetic resonance imaging (MRI).

BACKGROUND

Lipid therapy is thought to improve plaque stability and reduce cardiovascular events by targeting the plaque rupture risk features such as large lipid core, thin fibrous cap, and high level of inflammatory infiltrates. However, the plaque stabilizing process during lipid therapy has not been clearly demonstrated in humans and in vivo.

METHODS

Subjects with coronary or carotid artery disease, apolipoprotein B ≥120 mg/dl, and lipid treatment history 1 year, were randomly assigned to atorvastatin monotherapy or to atorvastatin-based combination therapies with appropriate placebos for 3 years. All subjects underwent high-resolution, multicontrast bilateral carotid MRI scans at baseline and annually for 3 years. All images were analyzed for quantification of wall area and plaque composition blinded to therapy, laboratory results, and clinical course.

RESULTS

After 3 years of lipid therapy, the 33 subjects with measurable lipid-rich necrotic core (LRNC) at baseline had a significant reduction in plaque lipid content: LRNC volume decreased from 60.4 ± 59.5 mm(3) to 37.4 ± 69.5 mm(3) (p 0.001) and %LRNC (LRNC area/wall area in the lipid-rich regions) from 14.2 ± 7.0% to 7.4 ± 8.2% (p 0.001). The time course showed that %LRNC decreased by 3.2 (p 0.001) in the first year, by 3.0 (p = 0.005) in the second year, and by 0.91 (p = 0.2) in the third year. Changes in LRNC volume followed the same pattern. Percent wall volume (100 × wall/outer wall, a ratio of volumes) in the lipid-rich regions significantly decreased from 52.3 ± 8.5% to 48.6 ± 9.7% (p = 0.002). Slices containing LRNC had significantly more percent wall volume reduction than those without (-4.7% vs. -1.4%, p = 0.02).

CONCLUSIONS

Intensive lipid therapy significantly depletes carotid plaque lipid. Statistically significant plaque lipid depletion is observed after 1 year of treatment and continues in the second year, and precedes plaque regression. (Using Magnetic Resonance Imaging to Evaluate Carotid Artery Plaque Composition in People Receiving Cholesterol-Lowering Medications [The CPC Study]; NCT00715273).

OBJECTIVE

Health outcomes in rheumatoid arthritis (RA) have improved significantly over the past 2 decades. However, research suggests that disparities exist by race/ethnicity and socioeconomic status, with certain vulnerable populations remaining understudied. Our objective was to assess disparities in disease activity and function by race/ethnicity and explore the impact of language and immigrant status at clinics serving diverse populations.

METHODS

We examined a cross-sectional study of 498 adults with confirmed RA at 2 rheumatology clinics: a university hospital clinic and a public county hospital clinic. Outcomes included the Disease Activity Score in 28 joints (DAS28) and its components, and the Health Assessment Questionnaire (HAQ), a measure of function. We estimated multivariable linear regression models including interaction terms for race/ethnicity and clinic site.

RESULTS

After adjusting for age, sex, education, disease duration, rheumatoid factor status, and medication use, clinically meaningful and statistically significant differences in DAS28 and HAQ scores were seen by race/ethnicity, language, and immigrant status. Lower disease activity and better function was observed among whites compared to nonwhites at the university hospital. This same pattern was observed for disease activity by language (English compared to non-English) and immigrant status (US-born compared to immigrant) at the university clinic. No significant differences in outcomes were found at the county clinic.

CONCLUSION

The relationship between social determinants and RA disease activity varied significantly across clinic setting with pronounced variation at the university, but not at the county clinic. These disparities may be a result of events that preceded access to subspecialty care, poor adherence, or health care delivery system differences.

UNLABELLED

Study Type--Therapy (case series). Level of Evidence 4. What's known on the subject? And what does the study add? Single-stage urethral segment replacement has historically poor outcomes and two-stage repairs are now more common. We present a novel approach to the single-stage repair with initial outcomes similar to two-stage repairs.

OBJECTIVE

• To present our experience with repairing long-segment urethral strictures in a single-stage using a combined tissue-transfer technique.

PATIENTS AND METHODS

• In all, 14 men underwent urethroplasty where a segment of urethra was completely replaced using a dorsal onlay buccal mucosa graft and a ventral onlay fasciocutaneous flap in a single stage. • Primary success was defined as an open urethra at >6 months follow-up with no need for additional surgical intervention. • Secondary success was defined as the need for a single postoperative endoscopic procedure before stricture stabilization. • Failure was the need for multiple endoscopic procedures, repeat urethroplasty, urinary diversion or intermittent dilatation.

RESULTS

• The mean (SD) stricture length was 9.75 (4.6) cm. The mean (SD) neourethral length was 5.4 (2.7) cm. Stricture location was penile/bulbar in 12 men, and bulbar alone in two. Primary success was achieved in nine of the 14 men at a median (range) follow-up of 2.5 (0.5-9.43) years. • The mean (SD) time to recurrence in the five initial failures was 340 (376) days. • Secondary success was achieved in two men after a single endoscopic procedure for an overall success in 11 of 14 men. • Patients that recurred had longer strictures (12.8 vs 8.7 cm, P= 0.04) than initial successes, but neourethral lengths were similar (6.2 vs 5.1 cm, P= 0.5). • In all, three of the 14 men failed, two of whom required a repeat urethroplasty.

CONCLUSIONS

• Our initial outcomes were favourable using the combined tissue-transfer technique for segmental urethral replacement with initial and secondary success rates similar to those reported for two-stage repairs. • This technique is not suitable for all patients as it requires healthy penile skin, but appears to be effective when a single-stage repair is desirable.

BACKGROUND

Pai You Guo is a weight loss supplement manufactured in China and adulterated with the banned pharmaceutical products sibutramine and phenolphthalein. The US Food and Drug Administration (FDA) announced a voluntary recall of Pai You Guo in 2009, yet clinicians have noted its continued use among Brazilian-born women in Massachusetts.

OBJECTIVE

To assess prevalence of Pai You Guo use, associated side effects, modes of acquisition, and impact of FDA regulatory action on these outcomes.

DESIGN

Cross-sectional study using an anonymous questionnaire.

PARTICIPANTS

Women ≤60 years of age, born in Brazil who attended one primary care clinic or one of six churches in Massachusetts.

MAIN MEASURES

Prevalence of use, how users first heard about the product, location of purchase, associated side effects, patterns of use before and after the FDA recall.

KEY RESULTS

Twenty-three percent (130/565) of respondents reported using Pai You Guo. In multivariate analysis, obesity (adj OR 3.7, p-value 0.001) and lack of insurance (adj OR 2.6, p-value 0.005) were associated with use. The majority of users (85%) reported at least one side effect. Dry mouth (59%), anxiety (29%), and insomnia (26%) were most commonly reported adverse effects. Nearly thirty-percent of users (38/130) purchased Pai You Guo from local stores and 9% (11/130) purchased it over the Internet. The majority of respondents (79/130; 61%) purchased Pai You Guo after the FDA recall. No respondent was aware of the FDA recall.

CONCLUSIONS

Use of this pharmaceutically adulterated supplement is common among Brazilian-born women in Massachusetts. The FDA alerts and recall did not appear to decrease its use.