Bipolar biobank helps identify at-risk patients for early intervention

Although the genetic contribution to bipolar disorder has been unequivocally demonstrated, few specific genetic risk factors have been confirmed. The factors identified explain only a small proportion of the genetic contribution to bipolar disorder. Mark A. Frye, MD, chair of the Department of Psychiatry and Psychology, discusses the Mayo Clinic Center for Individualized Medicine’s Biobank for Bipolar Disorder, a resource for the bipolar research community working to confirm those risk factors and discover additional contributors to bipolar disorder susceptibility and response to treatment.

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The biobank project is a multisite endeavor. Mayo Clinic in Rochester, Minnesota, serves as the primary location, but researchers from the University of Minnesota, Lindner Center of Hope in Cincinnati, Ohio, Mayo Clinic’s Arizona and Florida campuses, and Mayo Health System sites are contributing to the effort and will continue to collaborate following completion of infrastructure development in 2012. The large-scale biobank will collect biological samples and clinical data from 2,000 individuals between the ages of 18 and 65 years. Nearly 500 adults are currently enrolled.

Biobank to include children
Funding for an individualized medicine biobank for pediatric bipolar disorder was approved in May 2010. Several linked studies are planned. A study of children at risk for bipolar disease will include participants whose parents are included in the adult study. Additional participants will be recruited for the Pediatric Bipolar Biobank study, which focuses on children in whom bipolar disorder has already developed. Researchers will begin recruitment after the study protocol is approved.

Surgery effective for patients with aggressive prostate cancer

Stephen A. Boorjian, M.D., of the Department of Urology discusses a study of the outcomes after treatment for patients with high-risk prostate cancer. Patients with the most aggressive forms of prostate cancer who had radical prostatectomy procedures had a 10-year cancer-specific survival rate of 92 percent and an overall survival rate of 77 percent. The cancer-specific survival rate for patients who had radiation therapy alone was 88 percent and the overall survival rate was 52 percent.

ABSTRACT
Background
We compared the long-term survival of patients with high-risk prostate cancer following radical prostatectomy (RRP) and external beam radiation therapy (EBRT) with and without adjuvant androgen deprivation treatment (ADT).

Methods
We identified 1,238 patients who underwent RRP and 609 patients treated with EBRT (344 with EBRT + ADT and 265 with EBRT alone) between 1988-2004 who had a pretreatment prostate-specific antigen level (PSA) ≥ 20 ng/mL, biopsy Gleason score 8-10, or clinical stage ≥ T3. Median follow-up was 10.2, 6.0, and 7.2 years after RRP, EBRT + ADT, and EBRT alone, respectively. The impact of treatment modality on systemic progression, cancer-specific, and overall survival was evaluated using multivariable Cox proportional hazard regression analysis and a competing risk-regression model.

Results
Ten-year cancer-specific survival was 92%, 92%, and 88% following RRP, EBRT + ADT, and EBRT alone (p=0.06). After adjustment for case mix, no significant differences in the risks of systemic progression (hazard ratio, 0.78; 95% CI, 0.51 to 1.18; p=0.23) or prostate cancer death (hazard ratio 1.14; 95% CI, 0.68 to 1.91; p=0.61) were seen between patients treated with EBRT + ADT and patients who underwent RRP. The risk of all-cause mortality was, however, greater after EBRT + ADT than RRP (hazard ratio, 1.60; 95% CI, 1.25 to 2.05; p=0.0002).

Conclusions
RRP and EBRT + ADT provide similar long-term cancer control for patients with high-risk disease. Continued investigation into the differing impact of treatments on quality-of-life and non-cancer mortality are necessary to determine the optimal management approach for these patients.

E2-2 protein and Fuchs corneal dystrophy

Keith H. Baratz, M.D. of the Department of Ophthalmology discusses a genomewide association study that indicates a genetic variation in TCF4 contributes to the development of Fuchs corneal dystrophy (FCD).

 

ABSTRACT
Background
Fuchs corneal dystrophy is a leading cause of corneal transplantation. It affects 5% of persons in the United States who are over the age of 40 years.

Clinically visible deposits called guttae develop under the corneal endothelium in patients with FCD. A loss of endothelial cells and deposition of an abnormal extracellular matrix are observed microscopically. In advanced disease, the cornea swells and becomes cloudy because the remaining endothelial cells are not sufficient to keep the cornea dehydrated and clear.

Although rare genetic variation that contributes to both early-onset and typical late-onset forms of FCD has been identified, to our knowledge, no common variants have been reported.

Methods
We performed a genomewide association study and replicated the most significant observations in a second, independent group of subjects.

Results
Alleles in the transcription factor 4 gene (TCF4), encoding a member of the E-protein family (E2-2), were associated with typical FCD (P = 2.3×10−26). The association increased the odds of having FCD by a factor of 30 for persons with two copies of the disease variants (homozygotes) and discriminated between case subjects and control subjects with about 76% accuracy. At least two regions of the TCF4 locus were associated independently with FCD. Alleles in the gene encoding protein tyrosine phosphatase receptor type G (PTPRG) were associated with FCD (P = 4.0×10−7), but the association did not reach genomewide significance.

Conclusions
Genetic variation in TCF4 contributes to the development of FCD.

This study was funded by the National Eye Institute and others.

Authors
Keith H. Baratz, M.D., Nirubol Tosakulwong, B.S., Euijung Ryu, Ph.D., William L. Brown, O.D., Kari Branham, M.S., Wei Chen, Ph.D., Khoa D. Tran, Ph.D., Katharina E. Schmid-Kubista, M.D., John R. Heckenlively, M.D., Anand Swaroop, Ph.D., Goncalo Abecasis, Ph.D., Kent R. Bailey, Ph.D., and Albert O. Edwards, M.D., Ph.D.

Integrated teams increasingly treat patients with depression

More than half of behavioral medicine consultations at Mayo Clinic now occur in team-based or integrated practice settings. James R. Rundell, M.D. of the Department of Psychiatry and Psychology discusses studies that suggest the team model produces considerably better outcomes and patient satisfaction than a single-care provider approach to treatment of patients with depression.

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Good nutritional control may prevent polyneuropathy after bariatric surgery

P James B. Dyck, M.D. of the Department of Neurology discusses a study of patients who received psychiatric evaluation and attended nutritional clinics before having bariatric surgery at Mayo Clinic. The study was published in the June 2010 issue of Muscle & Nerve.

ABSTRACT
Background
Previously we showed that peripheral neuropathy occurs after bariatric surgery and was associated with malnutrition (mainly sensory polyneuropathy). This study asks whether a multidisciplinary approach to bariatric surgery lowers risk for developing peripheral neuropathy.

Methods
We performed a retrospective cohort study of all patients with bariatric surgery at Mayo Clinic between 1985 and 2002. Patients underwent intensive nutritional management before and after surgery. Potential risk factors were analyzed using life-table methods (Cox regression).

Results
Univariate analysis showed the following risk factors:

• Increased serum glycosylated hemoglobin and triglycerides
• Prolonged hospitalization
• Postoperative gastrointestinal symptoms
• Nausea and vomiting

Peripheral neuropathy occurred less frequently (7% vs. 13%, P < 0.01) and specifically the sensory polyneuropathy subtype (1% vs. 7%, P < 0.0001) than in our prior cohort.

Conclusions
A systematic, multidisciplinary approach of intensive nutritional management before and after surgery with frequent follow-up greatly decreased development of peripheral neuropathy (especially sensory polyneuropathy) in patients receiving bariatric surgery.

Authors
Pariwat Thaisetthawatkul, M.D., Maria L. Collazo-Clavell,  M.D., Michael G. Sarr, M.D., Jane E. Norrell, BS, and P James B. Dyck, M.D.

Imaging Evaluation and Treatment of Nephrolithiasis: An Update

Amy E. Krambeck, M.D. of the Mayo Clinic Department of Urology discusses advances in radiology that have led to improvements in care for patients with urinary tract stones.

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One of the most promising imaging techniques is dual-energy CT, which enables more accurate characterization of stone disease than other imaging techniques and helps direct therapy at the time of the initial imaging evaluation.

Improvements in percutaneous therapy have led to less-invasive and less-costly treatments for nephrolithiasis. This video describes some of these new approaches to diagnosing and caring for patients with renal stone disease.

Coinvestigators
Terry J. Vrtiska, M.D.,  Cynthia H. McCollough, Ph.D.,  Shuai Leng, Ph.D., M. Qu, Lifeng Yu, Ph.D.,   John C. Lieske, M.D.

23rd Annual Selected Topics in Internal Medicine Conference

John Bundrick, M.D. of the Department of General Internal Medicine discusses his presentation General Internal Medicine: Physical Exam Pearls, part of Mayo Clinic’s 23rd annual Selected Topics in Internal Medicine conference, January 24 – 28, 2011 in Koloa, Kauai, Hawaii.

COURSE DESCRIPTION
This postgraduate course designed to update general internists, internist-subspecialists, family medicine specialists, and other primary health care providers on selected internal medicine topics.  Expert faculty provide lectures that are clinically focused and relevant to the generalist practice.

COURSE LEARNING OBJECTIVES

• Summarize the management of pulmonary nodules based on radiographic features
• Summarize recent updates, clinical studies, and new guidelines that impact practice in general medicine
• Describe prevention and management strategies for kidney stones
• Choose appropriate duration of anticoagulation for patients with DVT
• Summarize the management for common dermatologic problems
• Review cases in women’s health
• Learn common clinical pearls in the areas of general internal medicine, gastroenterology, and infectious diseases
• Summarize new practice developments in oncology, Parkinson’s Disease, and complimentary medicine
• Describe common problems encountered in post-gastric bypass patients
• Review cases in crystalline arthropathy

Read more about the conference or register.

Mitochondrial Dysfunction and Susceptibility to Atrial Fibrillation in the Elderly

Dr. Arshad Jahangir of the Division of Cardiovascular Diseases at Mayo Clinic Arizona studies aging and its effect on the heart’s response to stress. Dr. Jahangir and co-investigators were recently awarded  a 4-year grant from the National Heart, Lung and Blood Institute of the National Institutes of Health to study mechanistic insights into the role of cardiac mitochondria in defining the substrate for atrial fibrillation (AF), the most common arrhythmia encountered in clinical practice.

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Summary:
With a projected 6-fold increase in the prevalence and a cost exceeding $15 billion per year, AF remains a major national health problem. Despite the recognition that aging increases susceptibility of the atria to fibrillation, with a 100-fold higher prevalence in the older-elderly compared to young adults, the molecular basis for this susceptibility remains unknown.

Changes in hemodynamic, vascular, and metabolic factors that accompany aging or associated disease contribute to functional and structural atrial remodeling, promoting cardiomyocytes loss and fibrosis that increases susceptibility to fibrillation. The molecular bases for such alterations contributing to the progression of atrial dysfunction, however, are not well defined.

In preliminary studies using human atrial tissue, a distinct transcriptional downregulation of genes regulating mitochondrial energetics and signaling pathways involved in energy production and utilization, cell loss and fibrosis was demonstrated with aging and AF.

Additionally, functional defects with impaired capacity to maintain cellular energetics and ionic homeostasis under stress were demonstrated in senescent mitochondria. The defects can be ameliorated by modulating mitochondrial membrane permeability.

Based on these findings, Dr. Jahangir and his co-investigators hypothesize that susceptibility to AF in the elderly results from diminished mitochondrial functional reserves in the atria. The diminished reserves promote cardiomyocyte loss and fibrosis due to enhanced sensitivity of the myocardium to energetic failure, calcium overload and oxidative injury during stress, facilitating development and progression of the substrate for AF.

The study proposes:

1. to identify differences in atrial structure and function, energetics and mitochondrial susceptibility to stress in patients with low or high risk for the development of AF and those with paroxysmal, persistent or permanent AF
2. to identify mechanisms underlying atrial energetic deficits and mitochondrial dysfunction predisposing to enhanced cell loss and fibrosis
3. to determine the protective role of mitochondrial modulation against mitochondrial and cellular injury during metabolic stress in patients at risk for or with AF

These aims will be achieved using atrial tissue obtained from patients undergoing coronary artery bypass surgery without or with risk factors for AF (heart failure, hypertension, or mitral regurgitation) or a history of paroxysmal, persistent or permanent AF. To assess those at risk of AF, those who develop AF following surgery and those with AF, investigators will use an  integrative approach that combines:

• clinical information
• in vivo and in vitro atrial structural and functional data obtained by imaging
• comprehensive cellular and mitochondrial studies assessing differences in ultrastructural, functional, molecular, genetic and proteomic changes in atrial tissue

The results will provide new insights into the role of mitochondria priming the substrate for AF and identify novel targets for the development of therapeutics toward prevention of AF.

Co-investigators:
Francisco A. Arabia, M.D., Louis A. Lanza, M.D., Marek Belohlavek, M.D., Ph.D.

Research improves treatment for patients with statin-associated adverse effects

Dr. Stephen Kopecky of the Department of Cardiovascular Diseases at Mayo Clinic describes statin intolerance as a condition that can be hard to diagnose and for which more research is needed.

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Statins are the most commonly used drugs in the world for the treatment of high cholesterol. Classic patient reactions to statins, however, include muscle aches, cramps and weakness. Reactions may occur within a few months or up to several years later.

To better care for these patients, Mayo Clinic established the Statin Intolerance Clinic to diagnose, risk stratify, and treat patients with statin-associated adverse effects. Related research focuses on drugs that may help patients who gave up on statins years ago and on genetic testing that will allow physicians to predict the drugs and dosages that may be most effective for each patient.

Learn more about the Mayo Clinic Statin Intolerance Clinic and Dr. Kopecky’s research.

Carotid ultrasound identifies high-risk subclinical atherosclerosis in adults with low Framingham risk scores

Dr. Robert (Todd) Hurst discusses research conducted at Mayo Clinic in Arizona that suggests that measuring the amount of artery disease an individual has may allow physicians to make more informed recommendations to patients.

Researchers  investigated whether the Carotid Intima Media Thickness (CIMT) test, a simple, safe ultrasound test to measure artery disease in the main artery in the neck, would help them better identify individuals that may be at risk. The study was published in the August 2010 issue of the  Journal of American Society of Echocardiography.

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ABSTRACT
Background
Worldwide, cardiovascular (CV) disease remains the most common cause of morbidity and mortality. Although effective in predicting CV risk in select populations, the Framingham risk score (FRS) fails to identify many young individuals who experience premature CV events. Accordingly, the aim of this study was to determine the prevalence of high-risk carotid intima-media thickness (CIMT) or plaque, a marker of atherosclerosis and predictor of CV events, in young asymptomatic individuals with low and intermediate FRS (<2% annualized event rate) using the carotid ultrasound protocol recommended by the American Society of Echocardiography and the Society of Vascular Medicine.

Methods
Individuals aged < or = 65 years not taking statins and without diabetes mellitus or histories of coronary artery disease underwent CIMT and plaque examination for primary prevention. Clinical variables including lipid values, family history of premature coronary artery disease, and FRS and subsequent pharmacotherapy recommendations were retrospectively collected for statistical analysis.

Results
Of 441 subjects (mean age, 49.7 + or – 7.9 years), 184 (42%; 95% confidence interval, 37.3%-46.5%) had high-risk carotid ultrasound findings (CIMT > or = 75th percentile adjusted for age, gender, and race or presence of plaque). Of those with the lowest FRS of < or =5% (n = 336) (mean age, 48.0 + or – 7.6 years; mean FRS, 2.5 + or – 1.5%), 127 (38%; 95% confidence interval, 32.6%-43.0%) had high-risk carotid ultrasound findings. For individuals with FRS < or = 5% and high-risk carotid ultrasound findings (n = 127; mean age, 47.3 + or – 8.1 years; mean FRS, 2.5 + or – 1.5%), lipid-lowering therapy was recommended by their treating physicians in 77 (61%).

Conclusions
Thirty-eight percent of asymptomatic young to middle-aged individuals with FRS < or = 5% have abnormal carotid ultrasound findings associated with increased risk for CV events. Pharmacologic therapy for CV prevention was recommended in the majority of these individuals. The lack of radiation exposure, relatively low cost, and ability to detect early-stage atherosclerosis suggest that carotid ultrasound for CIMT and plaque detection should continue to be explored as a primary tool for CV risk stratification in young to middle-aged adults with low FRS.

Authors
Mackram Eleid, M.D.; Steven Lester, M.D.; Troy Wiedenbeck, M.D.; Sharad Patel, M.D.; Christopher Appleton, M.D.; Matthew Nelson, M.D.; J. Humphries; Robert Hurst, M.D.