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Appalachian Student Research Forum

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Oral Presentation

Abstracts Submitted:Oral Presentation (Medical Residents and Biomedical Post-docs only)

Methadone and QTc interval. A review of the evidence.

Said B. Iskandar, MD, B Mechleb, MD, B Abi-Saleh, MD, Stephen A. Fahrig, MD, FACC Department of cardiology, East Tennessee State University, Johnson City, TN 37614, USA.

Methadone is been prescribed daily to approximately 180 000 Americans as a component of methadone maintenance treatment. This number has been increasing dramatically over the last few years. It is a synthetic opioid, used both as an analgesic in severe pain relief and in the treatment of opioid dependence. The high dose methadone (>60 mg/day) has been shown to be more effective in reducing illicit drug in heroin-abusing patients than the lower-dose therapy (20 mg/day). The practice of administering methadone in higher doses is becoming more common for both opioid addiction and chronic pain. In a recent article there were suggestions that dose more that 700 mg per day can be used if needed and that there does not appear to be a maximum daily dose limit when determining what is adequately "enough" methadone in methadone maintenance treatment. Prolongation of the QT interval is associated with polymorphic ventricular tachycardia, or torsade de pointes. This has lead to the withdrawal or restriction of the use of many drugs that have already been marketed. The mechanism by which drugs may cause this type of arrhythmia is developing but no good predictors of this serious side effect are available. Thus, although clinicians may be able to predict that a given drug may carry some risk, they can neither assess nor quantify it accurately. High dosages of levomethadyl acetate (LAAM), a long acting derivative of methadone, have been associated with development of a prolonged corrected QT interval (QTc) Ten cases of severe cardiac arrhythmias including seven cases of TdP that occurred in patients taking LAAM have been submitted to the FDA's safety surveillance program. Based on these findings, the FDA has issued a black-box warning regarding the potential cardiac risks associated with LAAM and European regulatory agencies have halted the marketing of this product. Methadone is a long-acting narcotic analgesic that may be used orally or parenterally. It has similar side effects profile as opioids, but recent studies raised some concern about cardiac rhythm abnormalities associated with the higher dose of methadone. Mortality from methadone is not well established. In the UK, between 1993 and 2002 there were 11.2% deaths in patients who died from substance abuse where methadone was mentioned on the death certificate. In the past 30 years, death from methadone has been reported from a range of countries around the world. Respiratory depression is the most common cause of death from methadone, especially when it is used in combination with other drugs, including opiates and/or alcohol. Cardiac problems on the other hand were reported but are rare. We present a patient who was on 160 mg of methadone per day, who presented with torsades de pointes (Tdp) with long QT interval. After an electrophysiology study, it was proven that the high dose of methadone caused long QTc which was complicated by Tdp. A review of the mechanism by which methadone can induce Tdp and recommendations for therapy and prevention will be offered."


Madathilparambil V. Suresh, Sanjay K. Singh, Donald A. Ferguson Jr. and Alok Agrawal, Department of Pharmacology, East Tennessee State University, College of Medicine, Johnson City, TN 37614

C-reactive protein (CRP) is an acute phase protein in humans but not in mice. CRP binds to pneumococcal C-polysaccharide in vitro and subsequently activates classical pathway of complement in human serum. It has been shown previously that CRP protects mice from lethality following infection with Streptococcus pneumoniae, and complement activation is required for full protection. However, it is not known whether the complement-activating property of CRP per se is essential for this protection. In the current study, we investigated participation of CRP-mediated complement activation in the protection of mice from lethal infection with virulent S. pneumoniae type 3. We compared the protective capacity of wild-type CRP with that of a mutant CRP, Y175A. Like wild-type CRP, the Y175A mutant CRP binds pneumococcal C-polysaccharide, but unlike wild-type CRP, the mutant CRP does not activate complement in human serum. Passively administered mutant CRP protected mice from S. pneumoniae infection as effectively as the wild-type CRP did. Infected-mice injected with either wild-type CRP or with mutant CRP lived longer and had lower mortality compared to mice that did not receive any CRP. Increased median survival time correlated with reduced bacteremia in both cases. Thus, the protection of mice conferred by CRP was independent of its complement-activating function. Based on the assumption that CRP does not differentiate between human and mouse complement, we conclude that the complement activation by CRP is not necessary for the protection of mice from S. pneumoniae infection.


Fan Hua, Tuanzhu Ha, Jing Ma, Xiang Gao, Jim Kelley, David L. Williams, I. William Browder, Race L. Kao, and Chuanfu Li, Department of Surgery and Internal Medicine,East Tennessee State University, Johnson City, TN 37614. Animal Model Research Center, Nanjing University, China, 210093

Toll-like receptors (TLRs) play critical role in the induction of innate and adaptive immunity. Significant reduction of infarction in TLR4 deficient mice following myocardial ischemia/reperfusion (I/R) has been reported. We have previously reported that modulation of TLR4 mediated NFB activation pathway rapidly induces cardio protection. Myeloid differentiation factor 88 (MyD88) is an important adaptor protein in TLR mediated NFB activation pathway. To investigate whether blocking MyD88-dependent signaling could protect the myocardium from I/R injury we constructed double deleted adenovirus expressing dominant negative MyD888 (Ad5-dnMyD88) and transfected the Ad5-dnMyD88 into the myocardium three days before the hearts were subjected to ischemia (45 min) followed by reperfusion for 4 hrs. Ad5-GFP served as control. Myocardial infract size was determined by triphenyltetrazolium chloride (TTC) staining. NFB binding activity was examined by EMSA and phospho-IB and phosphor- Akt were examined by Western Blots with specific antibody. Cardiac myocyte apoptosis was determined by TUNEL assy. Transfection of Ad5- dnMyD88 significantly reduced infarct size by 53.6% compared with I/R group. Transfection of Ad5-GPF did not affect I/R induced myocardial injury. Transfection of Ad5-dnMyD88 significantly inhibited NFB binding activity and decreased the levels of phospho-IB following I/R while transfection of Ad5-GFP did not. In addition, transfection of Ad5-dnMyD88 significantly increased phospho-Akt levels and reduced cardiac myocyte apoptosis. Results of present study demonstrated that TLR mediated MyD88 dependent pathway plays an important role in myocardial ischemia/reperfusion injury.


Vyas H, Fitzgerald SM, Milhorn DM, Chi DS, Krishnaswamy G, Division of Allergy and Immunology, Department of Internal medicine, James H Quillen College of medicine and the James H. Quillen V.A Medical center, East Tennessee State University, Johnson City, Tennessee 37614.

Rationale: Mast cells have been shown to infiltrate the smooth muscle layer of asthmatic airways. The relationship between the two cell types is unclear. We postulated that mast cell-smooth cell interactions might influence inflammatory responses.

Methods: Human mast cells (HMC-1) were co-cultured with BSMC or NHLF. Supernatants were collected after 24 hours and assayed by enzyme-linked immunosorbent assay (ELISA) for granulocyte/macrophage colony stimulating factor (GM-CSF) and stem cell factor (SCF). Cell separation experiments were performed using a 0.4 m or 3 m track-etched membrane inset to physically separate the two cell types. Nuclear factor kappa B (NFB) p50 / p65 transcription factor was assayed by ELISA on nuclear extracts from the BSMC or NHLF following co-culture with HMC-1.

Results: Co-culturing HMC-1 with BSMC or NHLF led to a significant decrease in both GM-CSF and SCF levels as compared to BSMC or NHLF cultured alone (p<0.0005). Upon separation of cells with a 0.4 m porous membrane, the inhibition persisted albeit less prominent. In addition the p65 subunit of NFB was inhibited by cell-cell contact whereas cells separated by either membrane resulted in an increase in p65 NFB activity.

Conclusion: The direct cell-to-cell interaction between BSMC or NHLF and HMC-1 results in a significant inhibition of GM-CSF and SCF production (p<0.05) and impaired p65 NFB activity. Inhibition of hematopoietic cytokine activity may have profound influences on development and activation of eosinophils and mast cells, thereby dampening certain inflammatory responses. Our data suggests that in selected cases, cell-cell interactions may act to dampen inflammatory responses.


Bernard Abi-Saleh, MD, Said B. Iskandar, MD, Stephen Fahrig, MD, FACC, Department of Internal Medicine, East Tennessee State University, College of Medicine, Johnson City, TN 37614

A novel cardiac syndrome name Takotsubo cardiomyopathy was first described in Japan 10 years ago. The syndrome mimics ST-segment elevation myocardial infarction on electrocardiography and is characterized by a reversible left ventricular apical ballooning. It is gaining considerable worldwide interest, especially in the United States, and receiving more clinical attention over the last couple of years. We present an 82 year old woman presented to the emergency department with chest pain after sustaining a transient ischemic attack one week prior to presentation. Electrocardiography revealed ST-segment elevation in leads I, II, aVF and V3 through V6. Coronary angiography demonstrated normal coronaries, but left ventriculography showed apical akinesis and basal hyperkinesis. One month later her follow-up cardiac echocardiography showed no wall motion abnormality. Several report of "Tako-Tsubo" syndrome or "transient left ventricular apical ballooning" were described especially in Japan. the patient described herein represents a typical case of tako-tsubo cardiomayopathy after a cerebrovascular accident. The coronary angiography eliminated spasm induced left ventricular dysfunction. Although several series has been reported lately, little is known about the pathophysiology of the syndrome and the question yet to be answered is the one of the prominent predilection of the syndrome in women of advanced age.


Kasasbeh, Ehab, MD, Krishnaswamy, Guha, MD. Department of Internal Medicine, East Tennessee State University, Johnson City, Tennessee, 37614

A young female patient who was diagnosed with Systemic Lupus Erythematosis presented with recurrent sinus infections and pneumonias in the past two years. CT scan of her sinuses reveals pansinusitus and further workup revealed Common Variable Immune Deficiency. We reviewed the literature for similar cases that have variable presentation. We discuss the various hypothesis that have been discussed regarding the pathogenesis.



Myocardial infarction and unstable angina have been reported as complications in patients with hyperthyroidism, even in the setting of normal coronary arteries. The exact involved mechanisms are not clearly defined although some hypotheses have been suggested. We report the case of a 78 year old female patient who presented with seizures secondary to hyperthyroidism that was uncontrolled on maximum anti-thyroid medications. Electrocardiography showed ST-segment depression. Serial cardiac enzymes showed elevation of serum troponin-I. Cardiac catheterization showed normal coronary arteries. In this article, we review all the cases previously reported in the English literature, studying the prevalence, pathogenesis, morbidity and the suggested therapy.


Harsha Vyas MD, Mahnaz Saudian MD, Masoud Jalilvand MD, George Youngberg MD, David Chi Ph.D., F.A.A.M, Guha Krishnaswamy MD

From the Division of Allergy and Immunology, Department of Internal Medicine and the Department of pathology, James H. Quillen College of Medicine and the James H. Quillen V.A Medical Center, East Tennessee State University, Johnson City, Tennessee 37614

Introduction: Urticarial Vasculitis is characterized clinically by the persistence of urticarial lesions for more than 24 hours, and histologically by leucocytoclastic vasculitis. Hypocomplementemic urticarial vasculitis has been recognized as a rare but distinct clinical subset of patients with urticarial vasculitis that presents with rather severe multisystem disease.

Case Presentation: A 37-year-old Caucasian female, born and raised in East Tennessee, was referred to our outpatient service in June of 2001 for evaluation of a history of fever and an erythematous, pruritic eruption of six months duration. The eruption lasted for upto three to four days before it completely resolved, leaving behind a dusky pigment upon healing. There were associated migratory arthralgia, severe fatigue, loss of weight (45 pounds in six months), difficulty in swallowing and occasional nausea and vomiting. On examination, the patient was afebrile and her heart rate and blood pressure were normal. She was very cachectic with a weight 91 pounds. Multiple lymph nodes in the anterior cervical, posterior cervical, and axillary group were palpable. The patient also demonstrated indurated urticarial lesions on the skin of her trunk, neck and upper extremities. The lesions appeared erythematous, palpable and with a purplish discoloration. Laboratory evaluation demonstrated low levels of complement component 3 (C3) and undetectable levels of the C4 levels and extremely low CH 50 levels. The C-reactive protein (CRP) was elevated at 52 mg/dl. The patient had no evidence of autoimmune disease, hepatitis C or cryoglobulinemia. A 4 mm punch biopsy of the skin showed evidence of urticarial vasculitis with characteristic leukocytoclasia and nuclear dust. The diagnosis was compatible with hypocomplementemic urticarial vasculitis syndrome (HUVS). She has attained remission with the immunomodulator, dapsone.

Conclusion: HUVS is an uncommon multi-system disease, which may present to the primary care physician for its manifestations as urticarial skin. Rheumatological disease, infections, hepatitis C, cryoglobulinemia and food allergy have all been incriminated in this disease. As opposed to normocomplementemic urticarial vasculitis (NUVS), HUVS tends to be more severe with more systemic manifestations like fever, asthma, renal disease, neuropathy. Several treatment options exist including the use of nonsteroidal agents, glucocorticoids, immunosuppressives and intravenous immunoglobulin. The role of newer agents such as tumor necrosis factor antagonists is currently unknown. Rarely HUVS may evolve into a systemic necrotizing vasculitis or patients may, over time, demonstrate evidence of a connective tissue disease such as lupus. Hence these patients need to be carefully observed over time.

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