Research Spotlight

Posted January 20th 2016

Tuberculous Pericarditis is Multibacillary and Bacterial Burden Drives High Mortality.

Jotam Pasipanodya M.D.

Jotam Pasipanodya, M.D.

Pasipanodya, J. G., M. Mubanga, M. Ntsekhe, S. Pandie, B. T. Magazi, F. Gumedze, L. Myer, T. Gumbo and B. M. Mayosi (2015). “Tuberculous Pericarditis is Multibacillary and Bacterial Burden Drives High Mortality.” Ebiomedicine 2(11): 1634-1639.

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Background: Tuberculous pericarditis is considered to be a paucibacillary process; the large pericardial fluid accumulation is attributed to an inflammatory response to tuberculoproteins. Mortality rates are high. We investigated the role of clinical and microbial factors predictive of tuberculous pericarditis mortality using the artificial intelligence algorithm termed classification and regression tree (CART) analysis. Methods: Patients were prospectively enrolled and followed in the Investigation of the Management of Pericarditis (IMPI) registry. Clinical and laboratory data of 70 patients with confirmed tuberculous pericarditis, including time-to-positive (TTP) cultures from pericardial fluid, were extracted and analyzed for mortality outcomes using CART. TTP was translated to log(10) colony forming units (CFUs) per mL, and compared to that obtained from sputum in some of our patients. Findings: Seventy patients with proven tuberculous pericarditis were enrolled. The median patient age was 35 (range: 20-71) years. The median, follow up was for 11.97 (range: 0 . 03-74.73) months. The median TTP for pericardial fluid cultures was 22 (range: 4-58) days or 3.91(range: 0 . 5-8 . 96) log(10)CFU/mL, which overlapped with the range of 3.24-7.42 log(10)CFU/mL encountered in sputum, a multi-bacillary disease. The overall mortality rate was 1.43 per 100 person-months. CART identified follow-up duration of 5 . 23 months on directly observed therapy, a CD4+ count of <= 199.5/mL, and TTP <= 14 days (bacillary load >= 5.53 log(10) CFU/mL) as predictive of mortality. TTP interacted with follow-up duration in a non-linear fashion. Interpretation: Patients with culture confirmed tuberculous pericarditis have a high bacillary burden, and this bacterial burden drivesmortality. Thus proven tuberculosis pericarditis is not a paucibacillary disease. Moreover, the severe immunosuppression suggests limited inflammation. There is a need for the design of a highly bactericidal regimen for this condition. (C) 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).


Posted January 20th 2016

Epidemiology, Traditional and Novel Risk Factors in Coronary Artery Disease.

Ambarish Gopal M.D.

Ambarish Gopal, M.D.

Mack, M. and A. Gopal (2016). “Epidemiology, Traditional and Novel Risk Factors in Coronary Artery Disease.” Heart Failure Clinics 12(1): 1-10.

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Coronary artery disease (CAD) mortality has been declining in the United States and in regions where health care systems are relatively advanced. Still, CAD remains the number one cause of death in both men and women in the United States, and coronary events have increased in women. Many traditional risk factors for CAD are related to lifestyle, and preventative treatment can be tailored to modifying specific factors. Novel risk factors also may contribute to CAD. Finally, as the risk for CAD is largely understood to be inherited, further genetic testing should play a role in preventative treatment of the disease.


Posted January 20th 2016

Hepatic Fibrinogen Storage Disease in a Patient with Hypofibrinogenemia: Report of a Case with a Missense Mutation of the FGA Gene.

Michael J. Lee M.D.

Michael J. Lee, M.D.

Lee, M. J., R. Venick, S. Bhuta, X. Li and H. L. Wang (2015). “Hepatic Fibrinogen Storage Disease in a Patient with Hypofibrinogenemia: Report of a Case with a Missense Mutation of the FGA Gene.” Seminars in Liver Disease 35(4): 439-443.

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We report a 9-year-old patient with abnormal liver tests found incidentally during routine bloodwork as part of a preoperative evaluation for excision of a benign cyst. A liver biopsy demonstrated hepatocytes to have pale and expanded cytoplasm that contained multiple vague globular eosinophilic inclusions. Electron microscopy showed fingerprint-like structures in the dilated cisternae of the rough endoplasmic reticulum, characteristic of fibrinogen. Whole exome sequencing identified a heterozygous missense mutation at codon 35 of the fibrinogen alpha (FGA) gene. No mutation was identified in the beta or gamma chains. His plasma fibrinogen levels were found to be decreased to 85 mg/dL (normal range 215-464). His family history was pertinent for his mother and maternal grandfather with hypofibrinogenemia. He had not had any significant bleeding episodes except for minor bruising over the shins. This case illustrates a rare etiology of storage disease that causes abnormal liver function tests.


Posted January 19th 2016

Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer.

Keun Hur Ph.D.

Keun Hur, Ph.D.

Hur, K., Y. Toiyama, Y. Okugawa, S. Ide, H. Imaoka, C. R. Boland and A. Goel (2015). “Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer.” Gut. 2015 Dec 23. pii: gutjnl-2014-308737. doi: 10.1136/gutjnl-2014-308737. [Epub ahead of print].

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BACKGROUND AND AIMS: Distant metastasis is a major cause of deaths in patients with colorectal cancer (CRC), which is partly due to lack of robust metastasis-predictive biomarkers. In spite of the important function of microRNA (miR)-203 in cancer metastasis, its clinical significance in CRC metastasis remains unknown. Here, we evaluated the potential role of serum miR-203 as a non-invasive biomarker for CRC metastasis. METHODS: MiR-203 expression was quantified by quantitative reverse-transcription PCR in 58 pairs of primary CRC (pCRC) and corresponding matched liver metastasis (LM), as well as 186 serum and 154 matched tissue specimens from patients with CRC in cohort 1. Next, we performed validation of miR-203 levels in serum from 144 patients with CRC in an independent cohort (cohort 2). Mouse models of CRC-associated metastases were established to identify the source of circulating miR-203. Expression patterns of miR-203 in tissues were determined by in situ hybridisation. RESULTS: MiR-203 expression was significantly upregulated in LM compared with matched pCRC tissues. Serum miR-203 levels were significantly upregulated in a stage-dependent manner, and high miR-203 expression was associated with poor survival in patients with CRC in both patient cohorts. Increased miR-203 levels in serum indicated high risk for poor prognosis (HR=2.1), as well as metastasis to lymph nodes (OR=2.5), liver (OR=6.2), peritoneum (OR=7.2) and distant organs (OR=4.4). Serum miR-203 levels were significantly higher in animals with liver or systemic metastasis compared with controls. CONCLUSIONS: High levels of serum miR-203 associate with poor survival and metastasis, suggesting it to be a promising non-invasive prognostic and metastasis-predictive biomarker in patients with CRC.


Posted January 19th 2016

Cuddling Nightmare Bacteria: Amikacin Pharmacokinetics / Pharmacodynamics in a Novel Hollow Fiber Mycobacterium abscessus Disease Model.

Shashikant Srivastava M.D.

Shashikant Srivastava, M.D.

Ferro, B. E., S. Srivastava, D. Deshpande, C. M. Sherman, J. G. Pasipanodya, D. van Soolingen, J. W. Mouton, J. van Ingen and T. Gumbo (2015). “Cuddling Nightmare Bacteria: Amikacin Pharmacokinetics / Pharmacodynamics in a Novel Hollow Fiber Mycobacterium abscessus Disease Model.” Antimicrobial Agents and Chemotherapy.

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The treatment of pulmonary Mycobacterium abscessus disease treatment is associated with very high failure rates and ease of acquired drug resistance. Amikacin is the key drug in treatment regimens, but optimal doses are unknown. No good pre-clinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments for this. We developed a hollow fiber system model of M. abscessus disease and studied amikacin exposure-effect and dose-scheduling. We mimicked amikacin human pulmonary pharmacokinetics. Both amikacin microbial kill and acquired drug resistance were linked to the peak to minimum inhibitory concentration (MIC) ratios; the peak/MIC associated with 80% of maximal kill (EC80) was 3.20. However, on day of the most extensive microbial kill, the bacillary burden did not fall below starting inoculum. We performed Monte Carlo simulations of 10,000 patients with pulmonary M. abscessus and examined the probability that patients treated with one of 6 doses from 750 mg to 4,000 mg would achieve or exceed the EC80. We also examined these doses for the ability of achieve a cumulative area under the concentration time curve of 82,232 mg*h/L x days that is associated with ototoxicity. The standard amikacin doses of 750-1,500 mg a day achieved EC80 in </=21%, while 4 grams/day achieved this in 70%, but at the cost of high rates of ototoxicity within a month or two. The susceptibility breakpoint was an MIC of 8-16 mg/L. Thus, amikacin, as currently dosed, has limited efficacy against M. abscessus. Different antibiotics should be urgently tested in our pre-clinical model and new regimens developed.