Scholarly Works, Virginia Tech Carilion School of Medicine (VTCSOM)

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Research articles, presentations, and other scholarship

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The alleged existence of partially oxidized Mg[Pt(CN)4]Cl0.28.7H2O and the attempted preparation of the analogous beryllium(2+) and barium(2+) derivatives. A caveat
Koch, Timothy R.; Gebert, E.; Williams, Jack M. (American Chemical Society, 1976-06)
X-ray diffuse scattering of one-dimensional tetracyanoplatinate salts
Schultz, A. J.; Stucky, G. D.; Williams, Jack M.; Koch, Timothy R.; Maffly, R. L. (Elsevier, 1977-01)
Structural studies of precursor and partially oxidized conducting complexes. II. A neutron diffraction study of disodium dibromotetracyanoplatinate dihydrate
Maffly, Robert L.; Johnson, Paul L.; Koch, Timothy R.; Williams, Jack M. (International Union of Crystallography, 1977-02-01)
Structural studies of precursor and partially oxidized conducting complexes. VI. A neutron diffraction study of dicesium tetracyanoplatinate(II) monohydrate
Johnson, Paul L.; Koch, Timothy R.; Williams, Jack M. (International Union of Crystallography, 1977-04-15)
Structural studies of precursor and partially oxidized conducting complexes. VII. A neutron diffraction study of disodium tetracyanoplatinate(II) trihydrate
Johnson, Paul L.; Koch, Timothy R.; Williams, Jack M. (International Union of Crystallography, 1977-06-01)
Structural studies of precursor and partially oxidized conducting complexes. XI. A neutron diffraction study of barium dibromotetracyanoplatinate(IV) hydrate
Koch, Timothy R.; Johnson, Paul L.; Washecheck, Donald M.; Cornish, Thomas L.; Williams, Jack M. (International Union of Crystallography, 1977-10-01)
Neural computations underlying social risk sensitivity
Lauharatanahirun, Nina; Christopoulos, George I.; Casas, Brooks (Frontiers, 2012-08-02)
Under standard models of expected utility, preferences over stochastic events are assumed to be independent of the source of uncertainty. Thus, in decision-making, an agent should exhibit consistent preferences, regardless of whether the uncertainty derives from the unpredictability of a random process or the unpredictability of a social partner. However, when a social partner is the source of uncertainty, social preferences can influence decisions over and above pure risk attitudes (RA). Here, we compared risk-related hemodynamic activity and individual preferences for two sets of options that differ only in the social or non-social nature of the risk. Risk preferences in social and non-social contexts were systematically related to neural activity during decision and outcome phases of each choice. Individuals who were more risk averse in the social context exhibited decreased risk-related activity in the amygdala during non-social decisions, while individuals who were more risk averse in the non-social context exhibited the opposite pattern. Differential risk preferences were similarly associated with hemodynamic activity in ventral striatum at the outcome of these decisions. These findings suggest that social preferences, including aversion to betrayal or exploitation by social partners, may be associated with variability in the response of these subcortical regions to social risk.
Biology and Physics Competencies for Pre-Health and Other Life Sciences Students
Hillborn, Robert C.; Friedlander, Michael J. (The American Society for Cell Biology, 2013-02-12)
The recent report on the Scientific Foundations for Future Physicians (SFFP) and the revised Medical College Admissions Test (MCAT) reframe the preparation for medical school (and other health professional schools) in terms of competencies: what students should know and be able to do with that knowledge, with a strong emphasis on scientific inquiry and research skills. In this article, we will describe the thinking that went into the SFFP report and what it says about scientific and quantitative reasoning, focusing on biology and physics and the overlap between those fields. We then discuss how the SFFP report set the stage for the discussion of the recommendations for the revised MCAT, which will be implemented in 2015, again focusing the discussion on biology and physics. Based on that framework, we discuss the implications for undergraduate biology and physics education if students are to be prepared to demonstrate these competencies.
Anastomotic Stricture Formation after Roux-En-Y Gastric Bypass Surgery: A Single Center Retrospective Cohort Study
Vanga, Rohini R.; Majithia, Raj; Finelli, Frederick C.; Shope, Timothy R.; Koch, Timothy R. (ACT Publishing, 2013-12-21)
AIM: Roux-en-Y gastric bypass is used for treating medically-complicated obesity. Gastrojejunal anastomotic stricture is a common complication reported in 3% to 27% of these patients. The pathogenesis of postoperative strictures is not well understood, but ischemia has been hypothesized as a major cause. The aim of this study was to evaluate potential factors that could increase the risk of a post-operative anastomotic stricture. METHODS: The records of 165 patients who had gastric bypass from June 2006 to March 2011 were reviewed. Demographics, co-morbidities, smoking status, surgical approach, medication use, and H. pylori status were noted, as well as a diagnosis of gastrojejunal stricture and/or marginal ulceration. RESULTS: Thirty-four symptomatic patients (21%) developed gastrojejunal stricture, while 26 patients (16%) developed marginal ulceration. The majority were women (89%) with a mean age of 43 years and mean body mass index of 51 kg/m2. Caucasians were at a higher risk for developing a stricture. Proton pump inhibitor use and marginal ulceration were significantly associated with risk of stricture, and there was a strong trend in patients with obstructive sleep apnea. Post-operative strictures were successfully treated with an average of two dilation sessions using an endoscopic through-the-scope balloon dilator. CONCLUSION: After gastric bypass, proton pump inhibitor use and marginal ulceration were associated with anastomotic stricture formation. Strictures were more common in Caucasians. A trend towards an increased risk of strictures in patients with sleep apnea was observed, supporting the role of ischemia. Endoscopic balloon dilation relieved symptoms in all patients.
An Acoustic Sensor for Airflow in Pediatric Artificial Airways
Gooty, Vasu; Harris, Charles; Muelenaer, Andre A.; Watson, Brian; Safford, Shawn D. (Elsevier, 2015-01-06)
Pulmonary hyalinizing granuloma (PHG) is a rare benign pulmonary nodular lesion of unknown etiology. We present a case of a 5-year-old boy who was found to have a chest mass while being evaluated for abdominal pain. He underwent a CXR and CT scan that showed popcorn calcifications in the right posterior mediastinum and within the hilum of right lung. These lesions were suspicious for benign calcified lymph nodes and follow-up chest CT after 3.5 months showed no interval changes in the calcified mediastinal masses. Extensive testing ruled out infectious diseases and malignancies. Given the unknown etiology of the lesions, he underwent VATS biopsy that demonstrated a nodular lesion characterized by a peripheral rim of fibrous tissue and central zone of necrosis and calcification, findings consistent with hyalinizing granuloma. PHG is extremely rare in pediatric age group. Although diagnosis of this condition is made by radiological and histopathological findings, it is important to rule out other causes of chest masses. Most of the patients usually have good prognosis with this rare disorder.
A Sustainable Engineering Solution for Paediatric Dehydration in Low-Resource Clinical Environments
Taylor, Ashley R.; Turovskiy, Jeffrey; Drew, Benjamin; Muelenaer, Andre A.; Redican, Kerry J.; Kochersberger, Kevin B.; Bickford, Lissett R. (Engineers Without Borders Australia, 2016)
Engineering efforts in low resource environments pose a unique set of challenges, requiring an in-depth understanding of local needs, comprehensive mapping of community resources, and extensive collaboration with local expertise. The importance of these principles is demonstrated in this paper by detailing the novel design and field demonstration of an affordable, locally manufactured intravenous fluid regulation device. Collaboration with clinical personnel in Uganda and Malawi guided device design. In-country physicians emphasised the need to regulate volume of intravenous (IV) fluid delivered to a paediatric patient without use of electricity. The proposed device regulates IV fluid delivery within ±20 mL of total prescribed dosage, providing a method of reducing fatalities caused by over-hydration in low resource environments; the feasibility of building the device from local resources was demonstrated by a field research team in Malawi. The device was successfully constructed entirely from local resources for a total cost of $46.21 (USD). Additionally, the device was demonstrated in rural clinics where 89 % of surveyed clinical staff reported that they would use the device to regulate IV fluid delivery. This paper emphasises the importance of collaborating with communities for community-based engineering solutions. Mapping community assets and collaborating with local expertise are crucial to success of engineering efforts. Long-term, community-based efforts are likely to sustainably improve health outcomes and strengthen economies of communities worldwide.
The Lung Point Sign, not Pathognomonic of a Pneumothorax
Aziz, Sameh G.; Patel, Brijesh B.; Ie, Susanti R.; Rubio, Edmundo R. (Ultrasound Quarterly, 2016-09-01)
Since the development of portable ultrasonography equipment, this technology has provided clinicians the ability to evaluate a variety of lung pathology at the bedside, but we are still learning how to accurately interpret the acquired images. Adequate interpretation and recognition of certain signs is crucial to diagnosing pathological processes. In addition, such signs must be adequately correlated with the patient's medical condition. For instance, the "lung point sign" has been traditionally considered to be pathognomonic for the presence of a pneumothorax, yet such finding may be present in patients with bullous lung disease without a pneumothorax. We present a case of an 83-year-old man with underlying chronic obstructive pulmonary disease. Bedside ultrasonography identified a "lung point sign" initially suggesting a possible pneumothorax. Further evaluation demonstrated absence of pneumothorax, with the patient having a large bulla. To our knowledge, this is the first case reported demonstrating that the "lung point sign" is not always indicative of a pneumothorax. We discuss the importance of both clinical correlation and understanding of the underlying pathophysiology when reviewing ultrasound images to accurately interpret ultrasound findings.
Noncanonical NF-κB signaling and the essential kinase NIK modulate crucial features associated with eosinophilic esophagitis pathogenesis
Eden, Kristin; Rothschild, Daniel E.; McDaniel, Dylan K.; Heid, Bettina; Allen, Irving C. (The Company of Biologists, 2017)
Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus driven by T cell and eosinophil responses to dietary allergens, resulting in chronic mucosal inflammation. Few spontaneous animal models of esophageal eosinophilia exist, with most studies relying on artificial sensitization procedures. NF-κBinducing kinase (NIK; MAP3K14) is a key signaling molecule of the noncanonical NF-κB (NFKB1) pathway, an alternative signaling cascade producing chemokines involved in lymphoid stroma development and leukocyte trafficking. Nik−/− mice have been shown to develop a hypereosinophilic syndrome in peripheral blood and major filtering organs; however, the gastrointestinal mucosa of these mice has not been well characterized. We show that Nik−/− mice develop significant, localized eosinophilic esophagitis that mimics human EoE, including features such as severe eosinophil accumulation, degranulation, mucosal thickening, fibrosis and basal cell hyperplasia. The remainder of the GI tract, including the caudal stomach, small intestine and colon, in mice with active EoE are unaffected, also similar to human patients. Gene expression patterns in esophageal tissue of Nik−/− mice mimics human EoE, with thymic stromal lymphopoetin (TSLP) in particular also elevated at the protein level. In gene expression data sets from human biopsy specimens, we further show that many genes associated with noncanonical NF- κB signaling are significantly dysregulated in EoE patients, most notably a paradoxical upregulation of NIK itself with concurrent upregulation of powerful protein-level destabilizers of NIK. These findings suggest that Nik−/− mice could be useful as a spontaneous model of specific features of EoE and highlight a novel role for noncanonical NF-κB signaling in human patients.
PI3K pathway mutations are associated with longer time to local progression after radioembolization of colorectal liver metastases
Ziv, Etay; Bergen, Michael; Yarmohammadi, Hooman; Boas, F. Ed; Petre, E. Nadia; Sofocleous, Constantinos T.; Yaeger, Rona; Solit, David B.; Solomon, Stephen B.; Erinjeri, Joseph P. (Oncotarget, 2017-04-04)
Purpose: To establish the relationship between common mutations in the MAPK and PI3K signaling pathways and local progression after radioembolization. Materials and methods: Retrospective review of a HIPAA-compliant institutional review-board approved database identified 40 patients with chemo-refractory colorectal liver metastases treated with radioembolization who underwent tumor genotyping for hotspot mutations in 6 key genes in the MAPK/PI3K pathways (KRAS, NRAS, BRAF, MEK1, PIK3CA, and AKT1). Mutation status as well as clinical, tumor, and treatment variables were recorded. These factors were evaluated in relation to time to local progression (TTLP), which was calculated from time of radioembolization to first radiographic evidence of local progression. Predictors of outcome were identified using a proportional hazards model for both univariate and multivariate analysis with death as a competing risk. Results: Sixteen patients (40%) had no mutations in either pathway, eighteen patients (45%) had mutations in the MAPK pathway, ten patients (25%) had mutations in the PI3K pathway and four patients (10%) had mutations in both pathways. The cumulative incidence of progression at 6 and 12 months was 33% and 55% for the PI3K mutated group compared with 76% and 92% in the PI3K wild type group. Mutation in the PI3K pathway was a significant predictor of longer TTLP in both univariate (p=0.031, sHR 0.31, 95% CI: 0.11-0.90) and multivariate (p=0.015, sHR=0.27, 95% CI: 0.096-0.77) analysis. MAPK pathway alterations were not associated with TTLP. Conclusions: PI3K pathway mutation predicts longer time to local progression after radioembolization of colorectal liver metastases.
Plant-Produced Asialo-Erythropoietin Restores Pancreatic Beta-Cell Function by Suppressing Mammalian Sterile-20-like Kinase (MST1) and Caspase-3 Activation
Arthur, Elena; Kittur, Farooqahmed S.; Lin, Yuan; Hung, Chiu-Yueh; Sane, David C.; Xie, Jiahua (Frontiers, 2017-04-19)
Pancreatic beta-cell death adversely contributes to the progression of both type I and II diabetes by undermining beta-cell mass and subsequently diminishing endogenous insulin production. Therapeutics to impede or even reverse the apoptosis and dysfunction of beta-cells are urgently needed. Asialo-rhuEPO, an enzymatically desialylated form of recombinant human erythropoietin (rhuEPO), has been shown to have cardioprotective and neuroprotective functions but with no adverse effects like that of sialylated rhuEPO. Heretofore, the anti-apoptotic effect of asialo-rhuEPO on pancreatic beta-cells has not been reported. In the current study, we investigated the cytoprotective properties of plant-produced asialo-rhuEPO (asialo-rhuEPO(P)) against staurosporine-induced cell death in the pancreatic beta-cell line RIN-m5F. Our results showed that 60 IU/ml asialo-rhuEPO(P) provided 41% cytoprotection while 60 IU/ml rhuEPO yielded no effect. Western blotting results showed that asialo-rhuEPO(P) treatment inhibited both MST1 and caspase-3 activation with the retention of PDX1 and insulin levels close to untreated control cells. Our study provides the first evidence indicating that asialo-rhuEPO(P)-mediated protection involves the reduction of MST1 activation, which is considered a key mediator of apoptotic signaling in beta-cells. Considering the many advantages its plant-based expression, asialo-rhuEPO(P) could be potentially developed as a novel and inexpensive agent to treat or prevent diabetes after further performing studies in cell-based and animal models of diabetes.
Providing successful faculty development to graduate medical education program directors
Nagler, Alisa; Andolsek, Kathryn M.; Rudd, Mariah J.; Kuhn, Catherine M. (2017-09-11)
Graduate Medical Education (GME) is the portion of the medical education continuum that spans the period follow-ing graduation from medical school to independent prac-tice. In the United States, successful completion of GME is essential for board certification in one of over 140 recog-nized specialties. The Accreditation Council for Graduate Medical Education (ACGME) is the accreditor for over 10,000 programs. Each program is required to have a single physician program director responsible for the program’s administrative and educational oversight. Virtually all program directors remain clinically and academically productive.
Organization of future training in bariatric gastroenterology
Koch, Timothy R.; Shope, Timothy R.; Gostout, Christopher J. (Baishideng, 2017-09-21)
A world-wide rise in the prevalence of obesity continues. This rise increases the occurrence of, risks of, and costs of treating obesity-related medical conditions. Diet and activity programs are largely inadequate for the long-term treatment of medically-complicated obesity. Physicians who deliver gastrointestinal care after completing traditional training programs, including gastroenterologists and general surgeons, are not uniformly trained in or familiar with available bariatric care. It is certain that gastrointestinal physicians will incorporate new endoscopic methods into their practice for the treatment of individuals with medically-complicated obesity, although the longterm impact of these endoscopic techniques remains under investigation. It is presently unclear whether gastrointestinal physicians will be able to provide or coordinate important allied services in bariatric surgery, endocrinology, nutrition, psychological evaluation and support, and social work. Obtaining longitudinal results examining the effectiveness of this ad hoc approach will likely be difficult, based on prior experience with other endoscopic measures, such as the adenoma detection rates from screening colonoscopy. As a longterm approach, development of a specific curriculum incorporating one year of subspecialty training in bariatrics to the present training of gastrointestinal fellows needs to be reconsidered. This approach should be facilitated by gastrointestinal trainees' prior residency training in subspecialties that provide care for individuals with medical complications of obesity, including endocrinology, cardiology, nephrology, and neurology. Such training could incorporate additional rotations with collaborating providers in bariatric surgery, nutrition, and psychiatry. Since such training would be provided in accredited programs, longitudinal studies could be developed to examine the potential impact on accepted measures of care, such as complication rates, outcomes, and costs, in individuals with medically-complicated obesity.
Microbial dysbiosis in spouses of ulcerative colitis patients: any clues to disease pathogenesis?
Sorrentino, Dario (2017-10-07)
A number of alterations have been found within the gut microbial profile of patients with inflammatory bowel diseases when compared with the healthy population; however, it is unclear whether such dysbiosis is the cause or simply the consequence of the disease state. In ulcerative colitis, the environment seems to play a crucial role in disease etiology since monozygotic twins show a concordance rate of only 8%-10% though it is unclear whether it does so by acting through the microbiome. In this study, the authors investigated the influence of cohabitation on the gut microbial community in healthy partners of ulcerative colitis patients - with the intent of clarifying some of these issues. As expected, ulcerative colitis patients had a significant dysbiosis and alterations in microbial metabolism. Interestingly, these abnormal fecal microbial communities were relatively similar amongst patients and their spouses. Thus, this study shows that the microbial profile might be partially transferred from ulcerative colitis patients to healthy individuals. Whether this finding impacts on disease development or has any implication for the role of the microbiome in inflammatory bowel disease etiology remains to be determined.
Increased efficacy of metformin corresponds to differential metabolic effects in the ovarian tumors from obese versus lean mice
Han, Jianjun; Wysham, Weiya Z.; Zhong, Yan; Guo, Hui; Zhang, Lu; Malloy, Kim M.; Dickens, Hallum K.; Huh, Gene; Lee, Douglas; Makowski, Liza; Zhou, Chunxiao; Bae-Jump, Victoria L. (2017-12-19)
Obesity is a significant risk factor for ovarian cancer (OC) and associated with worse outcomes for this disease. We assessed the anti-tumorigenic effects of metformin in human OC cell lines and a genetically engineered mouse model of high grade serous OC under obese and lean conditions. Metformin potently inhibited growth in a dose-dependent manner in all four human OC cell lines through AMPK/mTOR pathways. Treatment with metformin resulted in G1 arrest, induction of apoptosis, reduction of invasion and decreased hTERT expression. In the K18-gT(121)(+/-); p53(fl/fl); Brca1(fl/fl) (KpB) mouse model, metformin inhibited tumor growth in both lean and obese mice. However, in the obese mice, metformin decreased tumor growth by 60%, whereas tumor growth was only decreased by 32% in the lean mice (p=0.003) compared to vehicle-treated mice. The ovarian tumors from obese mice had evidence of impaired mitochondrial complex 2 function and energy supplied by omega fatty acid oxidation rather than glycolysis as compared to lean mice, as assessed by metabolomic profiling. The improved efficacy of metformin in obesity corresponded with inhibition of mitochondrial complex 1 and fatty acid oxidation, and stimulation of glycolysis in only the OCs of obese versus lean mice. In conclusion, metformin had anti-tumorigenic effects in OC cell lines and the KpB OC pre-clinical mouse model, with increased efficacy in obese versus lean mice. Detected metabolic changes may underlie why ovarian tumors in obese mice have heightened susceptibility to metformin.
Prevalence of irritable bowel syndrome in morbidly obese individuals seeking bariatric surgery
Andalib, Iman; Hsueh, William; Shope, Timothy R.; Brebbia, John S.; Koch, Timothy R. (ACT Publishing, 2018-01-01)
AIM: An increased prevalence of irritable bowel syndrome has been reported in obese individuals. Factors important in weight loss after bariatric surgery are incompletely understood, and small intestinal bacterial overgrowth in individuals with type 2 diabetes mellitus is a potential risk factor. Our aims are to examine whether the increased prevalence of irritable bowel syndrome in obese individuals seeking bariatric surgery is associated with diabetes mellitus and whether weight loss after bariatric surgery is altered by irritable bowel syndrome. METHODS: This is a single-center, retrospective study performed in a large, urban community teaching hospital. Individuals seen in gastrointestinal bariatric clinic prior to bariatric surgery from 2010 to 2013 completed a Manning symptom criteria questionnaire prior to their medical evaluation; â‰¥3 Manning criteria is accepted as diagnostic of irritable bowel syndrome. Percent excess weight loss at 6-, 12-, and 24-months after bariatric surgery is recorded. RESULTS: Thirty percent of 278 individuals seeking bariatric surgery have ≥3 Manning criteria. There is no relationship between type 2 diabetes mellitus and the presence of ≥3 Manning criteria (p>.05), nor is body mass index a significant risk factor for irritable bowel syndrome (p>.05). At 6-, 12-, and 24-months after Roux-en-Y gastric bypass or vertical sleeve gastrectomy, there is no difference in percent excess weight loss in individuals with ≥3 Manning criteria compared to individuals with ≥2 Manning criteria (for both surgical procedures: p>.05). CONCLUSION: A diagnosis of diabetes mellitus or body mass index do not explain the high prevalence of irritable bowel syndrome identified in individuals with obesity seeking bariatric surgery, and irritable bowel syndrome does not alter weight loss after bariatric surgery.

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