Final Report

The year 2008 resulted in 99 scans that were funded through NIH agencies. An additional 43 MRI scans were funded by industry. Over 250 scans were acquired by various investigators as �pilot� data to be used for future grant applications. While these numbers are modest in comparison to most busy research MRI Centers, they are in line with that of a newly established MRI research facility. The initial 12-18 months of operation were primarily dedicated to establishing new IRB approved research studies, and acquiring pilot data for future grant applications. During the year 2009 the MRI Center continued to show positive growth with respect to funded studies and the number of scan sessions. The number of NIH sponsored scans increased to 242 and the number of industry funded studies climbed to 81. This more than doubled our numbers of funded scans over the previous year. In addition, 398 scans were acquired as pilot data; most of which were fMRI�s. The MRI Center continued to expand with additional researchers who were interested in probing the brain�s response to chronic pain. Other studies looked at regions of brain activation in patients with impulsivity disorders; including smokers. A large majority of the imaging studies were focused on the brain; however, the MRI Center continued to accommodate the needs of various types of investigators, who studied various types of human pathology. Studies of porcine cardiac function and myocardial perfusion were performed. Another study of ultra-fast acute abdominal MRI in children was underway; eventually leading to publication in AJR. These non-neuro type research projects allowed the MRI Center to expand upon the depth and breadth of service that has now become available to researchers at UVM. The UVM MRI Center became the first clinical/research site in North America to install dual radio frequency (RF) amplifiers on a 3T MRI system. The use of dual RF amplifiers helps to eliminate standing wave artifacts that are prevalent at 3T. Standing wave artifacts often rendered spine or abdominal 3T MR images to be poor quality or unreadable prior to the availability of multi-transmit. A research collaboration agreement with Philips Healthcare, Best, Netherlands allowed our site to have first use of the technology; while at the same time giving us the opportunity to provide critical feedback to Philips Healthcare about our experiences with multi-transmit. This dramatically improved image quality for 3T MRI sites across the US and the world. Philips has stationed an onsite MRI physicist at UVM to work collaboratively with researchers at the University of Vermont on various MRI related projects. He has worked collaboratively with UVM investigators toward the design and publication of several journal articles and abstracts during his time at UVM. As the MRI Center advanced through the year 2010, an additional MRI technologist and a MRI physicist were hired to accommodate the increased demand for MRI scanning and data processing expertise. This enabled us to not only expand our hours of operation; it also helped to augment our MRI pulse programming and data processing capabilities. Studies that used state-of-the-art MRI techniques like pseudo continuous arterial spin labeling (pCASL) allowed researchers from the Department of Obstetrics and Reproductive Services to obtain non-contrast brain perfusion values of women to help them to better understand the effects of preeclampsia. At year-end 2010 the MRI Center completed 303 NIH funded and 198 industry funded scans. The number of no charge pilot scans decreased to 189

Diagnosis of Rhinocerebral Mucormycosis by Treatment of Cavernous Right Internal Carotid Artery Occlusion With Mechanical Thrombectomy: Special Case Presentation and Literature Review

Background: Mucormycosis is a rapidly progressive, angioinvasive fungal infection that has a predilection for the paranasal sinuses and adjacent mucosa. Rhinocerebral mucormycosis (RCM) is the most common form and is known to invade the skull base and its associated blood vessels—leading to mycotic aneurysms, ischemic infarcts, and intracerebral hemorrhage. There are documented cases of mechanical thrombectomy in ischemic stroke due to RCM, however, there are no known cases that were diagnosed primarily by histological and pathological analysis of the embolus. We present a case of treatment of large vessel occlusion that led to the diagnosis and treatment of RCM.Case Presentation: A 21 year-old male inmate with history of type 1 diabetes presented with generalized weakness, abdominal pain, right eye blindness, and ophthalmoplegia after an assault in prison. He underwent treatment for diabetic ketoacidosis, but subsequently developed left hemiplegia and was found to have complete occlusion of his right internal carotid artery. He underwent successful mechanical thrombectomy and pathological analysis of the embolus revealed a diagnosis of mucormycosis. He completed a course of amphotericin B, micafungin, and posaconazole. With the aid of acute rehabilitation he achieved a modified Rankin score of 2.Discussion: We review the pathogenesis, diagnosis, and treatment of RCM. A comprehensive multidisciplinary approach is critical in the management of this often-fatal disease. Early diagnosis and treatment are essential in RCM as delaying treatment by more than 6 days significantly increases mortality. Treatment includes surgical debridement and intravenous antifungal therapy (amphotericin B + micafungin or caspofungin) for a minimum of 6–8 weeks

Türk ve Amerikalı üniversite öğrencilerinde hızlı depresif belirti envanteri-özbildirim formu’nun (HDBE16-ÖF) karşılaştırmalı olarak geçerlik ve güvenirliği

Comparative validity and reliability study of the QIDS-SR16 in Turkish and American college student samples Objective: To evaluate the validity and reliability of the Quick Inventory of Depressive Symptomatology, self-reported version, in a Turkish student sample (QIDS-SR16-T) by comparing it to (a) the American version (QIDS-SR16-US) and (b) the Turkish version of the Beck Depression Inventory (BDI-II-T). Materials and Methods: Slightly modified versions of the QIDS-SR16-T, and the BDI-II-T were administered to 626 outpatients at the Uludag University campus-based family health center. The QIDS-SR16-US was administered to 584 respondents at an American university. SAS and MPlus were used to provide descriptive statistics, classical exploratory factor analysis, and item response theory analyses (in the form of a multiple group confirmatory factor analysis). Results: The internal consistency (Cronbach a) of the QIDS-SR16-T was 0.77. Both QIDS-SR16 versions were unidimensional, but the BDI-II-T was not. The mean QIDS-SR16-T and QIDS-SR16-US item-total correlations were similar. The correlation between the QIDS-SR16-T and BDI-II-T was 0.72 (.90 when disattenuated). Multiple-group confirmatory factor analysis suggested that the QIDS-SR16-T and QIDS-SR16-US had the same factor loadings but different intercepts. This reflects group differences in level of depression, perhaps because the Turkish respondents, unlike their US counterparts, were seen in a medical context where illness-related depression is more prevalent. Scores on the QIDS-SR16-T and the BDI-II-T were also equated. Discussion: The QIDS-SR16-T has good psychometric properties and convergent validity with the BDI-II-T. Its use is recommended when a self-reported instrument is appropriate

Preeclampsia and its relationship to pathological brain aging

The development of preeclampsia during pregnancy may have long-term effects on brain aging in women. Associations between preeclampsia and vascular dementia have been established, however the connection between preeclampsia and Alzheimer’s disease has not been as thoroughly explored. Both preeclampsia and Alzheimer’s disease have been associated with misfolded amyloid beta proteins and inflammation; due to these similarities, in this minireview, we examined the potential links between a history of preeclampsia and the development of dementia. We also discussed how hypertensive disorders of pregnancy may relate to both normal brain aging and dementia to highlight the need for additional research regarding the long-term cognitive effects of preeclampsia on the brain

Decision-making in percutaneous coronary intervention: a survey

<p>Abstract</p> <p>Background</p> <p>Few researchers have examined the perceptions of physicians referring cases for angiography regarding the degree to which collaboration occurs during percutaneous coronary intervention (PCI) decision-making. We sought to determine perceptions of physicians concerning their involvement in PCI decisions in cases they had referred to the cardiac catheterization laboratory at a major academic medical center.</p> <p>Methods</p> <p>An anonymous survey was mailed to internal medicine faculty members at a major academic medical center. The survey elicited whether responders perceived that they were included in decision-making regarding PCI, and whether they considered such collaboration to be the best process of decision-making.</p> <p>Results</p> <p>Of the 378 surveys mailed, 35% (133) were returned. Among responding non-cardiologists, 89% indicated that in most cases, PCI decisions were made solely by the interventionalist at the time of the angiogram. Among cardiologists, 92% indicated that they discussed the findings with the interventionalist prior to any PCI decisions. When asked what they considered the best process by which PCI decisions are made, 66% of non-cardiologists answered that they would prefer collaboration between either themselves or a non-interventional cardiologist and the interventionalist. Among cardiologists, 95% agreed that a collaborative approach is best.</p> <p>Conclusion</p> <p>Both non-cardiologists and cardiologists felt that involving another decision-maker, either the referring physician or a non-interventional cardiologist, would be the best way to make PCI decisions. Among cardiologists, there was more concordance between what they believed was the best process for making decisions regarding PCI and what they perceived to be the actual process.</p

Analysis of MRE11's function in the 5′→3′ processing of DNA double-strand breaks

The resection of DNA double-strand breaks (DSBs) into 3′ single-strand tails is the initiating step of homology-dependent repair pathways. A key player in this process is the MRE11-RAD50-NBS1 complex, but its contribution to and mechanistic role in resection are not well understood. In this study, we took advantage of the Xenopus egg extract system to address these questions. We found that depletion of MRE11 caused a dramatic inhibition of 5′-resection, even for the first nucleotide at the 5′-end. Depletion of Xenopus CtIP also inhibited 5′-strand resection, but this inhibition could be alleviated by excess MRN. Both MRE11 and CtIP could be bypassed by a DNA that carried a 3′-ss-tail. Finally, using purified proteins, we found that MRN could stimulate both the WRN-DNA2-RPA pathway and the EXO1 pathway of resection. These findings provide important insights into the function of MRE11 in 5′-strand resection

Mapping replication dynamics in Trypanosoma brucei reveals a link with telomere transcription and antigenic variation

Survival of Trypanosoma brucei depends upon switches in its protective Variant Surface Glycoprotein (VSG) coat by antigenic variation. VSG switching occurs by frequent homologous recombination, which is thought to require locus-specific initiation. Here, we show that a RecQ helicase, RECQ2, acts to repair DNA breaks, including in the telomeric site of VSG expression. Despite this, RECQ2 loss does not impair antigenic variation, but causes increased VSG switching by recombination, arguing against models for VSG switch initiation through direct generation of a DNA double strand break (DSB). Indeed, we show DSBs inefficiently direct recombination in the VSG expression site. By mapping genome replication dynamics, we reveal that the transcribed VSG expression site is the only telomeric site that is early replicating – a differential timing only seen in mammal-infective parasites. Specific association between VSG transcription and replication timing reveals a model for antigenic variation based on replication-derived DNA fragility

MRE11 complex links RECQ5 helicase to sites of DNA damage

RECQ5 DNA helicase suppresses homologous recombination (HR) possibly through disruption of RAD51 filaments. Here, we show that RECQ5 is constitutively associated with the MRE11–RAD50–NBS1 (MRN) complex, a primary sensor of DNA double-strand breaks (DSBs) that promotes DSB repair and regulates DNA damage signaling via activation of the ATM kinase. Experiments with purified proteins indicated that RECQ5 interacts with the MRN complex through both MRE11 and NBS1. Functional assays revealed that RECQ5 specifically inhibited the 3′→5′ exonuclease activity of MRE11, while MRN had no effect on the helicase activity of RECQ5. At the cellular level, we observed that the MRN complex was required for the recruitment of RECQ5 to sites of DNA damage. Accumulation of RECQ5 at DSBs was neither dependent on MDC1 that mediates binding of MRN to DSB-flanking chromatin nor on CtIP that acts in conjunction with MRN to promote resection of DSBs for repair by HR. Collectively, these data suggest that the MRN complex recruits RECQ5 to sites of DNA damage to regulate DNA repair