Bao H. Do

The Role of Selection in the Evolution of Human Mitochondrial Genomes

High mutation rate in mammalian mitochondrial DNA generates a highly divergent pool of alleles even within species that have dispersed and expanded in size recently. Phylogenetic analysis of 277 human mitochondrial genomes revealed a significant (P < 0.01) excess of rRNA and nonsynonymous base substitutions among hotspots of recurrent mutation. Most hotspots involved transitions from guanine to adenine that, with thymine-to-cytosine transitions, illustrate the asymmetric bias in codon usage at synonymous sites on the heavy-strand DNA. The mitochondrion-encoded tRNAThr varied significantly more than any other tRNA gene. Threonine and valine codons were involved in 259 of the 414 amino acid replacements observed. The ratio of nonsynonymous changes from and to threonine and valine differed significantly (P = 0.003) between populations with neutral (22/58) and populations with significantly negative Tajimas D values (70/76), independent of their geographic location. In contrast to a recent suggestion that the excess of nonsilent mutations is characteristic of Arctic populations, implying their role in cold adaptation, we demonstrate that the surplus of nonsynonymous mutations is a general feature of the young branches of the phylogenetic tree, affecting also those that are found only in Africa. We introduce a new calibration method of the mutation rate of synonymous transitions to estimate the coalescent times of mtDNA haplogroups.

Quantitative Magnetic Resonance Imaging UTE-T2* Mapping of Cartilage and Meniscus Healing After Anatomic Anterior Cruciate Ligament Reconstruction

Background: An anterior cruciate ligament (ACL) injury greatly increases the risk for premature knee osteoarthritis (OA). Improved diagnosis and staging of early disease are needed to develop strategies to delay or prevent disabling OA. Purpose: Novel magnetic resonance imaging (MRI) ultrashort echo time (UTE)–T2* mapping was evaluated against clinical metrics of cartilage health in cross-sectional and longitudinal studies of human participants before and after ACL reconstruction (ACLR) to show reversible deep subsurface cartilage and meniscus matrix changes. Study Design: Cohort study (diagnosis/prognosis); Level of evidence, 2. Methods: Forty-two participants (31 undergoing anatomic ACLR; 11 uninjured) underwent 3-T MRI inclusive of a sequence capturing short and ultrashort T2 signals. An arthroscopic examination of the medial meniscus was performed, and modified Outerbridge grades were assigned to the central and posterior medial femoral condyle (cMFC and pMFC, respectively) of ACL-reconstructed patients. Two years after ACLR, 16 patients underwent the same 3-T MRI. UTE-T2* maps were generated for the posterior medial meniscus (pMM), cMFC, pMFC, and medial tibial plateau (MTP). Cross-sectional evaluations of UTE-T2* and arthroscopic data along with longitudinal analyses of UTE-T2* changes were performed. Results: Arthroscopic grades showed that 74% (23/31) of ACL-reconstructed patients had intact cMFC cartilage (Outerbridge grade 0 and 1) and that 90% (28/31) were Outerbridge grade 0 to 2. UTE-T2* values in deep cMFC and pMFC cartilage varied significantly with injury status and arthroscopic grade (Outerbridge grade 0-2: n = 39; P = .03 and .04, respectively). Pairwise comparisons showed UTE-T2* differences between uninjured controls (n = 11) and patients with arthroscopic Outerbridge grade 0 for the cMFC (n = 12; P = .01) and arthroscopic Outerbridge grade 1 for the pMFC (n = 11; P = .01) only and not individually between arthroscopic Outerbridge grade 0, 1, and 2 of ACL-reconstructed patients (P > .05). Before ACLR, UTE-T2* values of deep cMFC and pMFC cartilage of ACL-reconstructed patients were a respective 43% and 46% higher than those of uninjured controls (14.1 ± 5.5 vs 9.9 ± 2.3 milliseconds [cMFC] and 17.4 ± 7.0 vs 11.9 ± 2.4 milliseconds [pMFC], respectively; P = .02 for both). In longitudinal analyses, preoperative elevations in UTE-T2* values in deep pMFC cartilage and the pMM in those with clinically intact menisci decreased to levels similar to those in uninjured controls (P = .02 and .005, respectively), suggestive of healing. No decrease in UTE-T2* values for the MFC and new elevation in UTE-T2* values for the submeniscus MTP were observed in those with meniscus tears. Conclusion: This study shows that novel UTE-T2* mapping demonstrates changes in cartilage deep tissue health according to joint injury status as well as a potential for articular cartilage and menisci to heal deep tissue injuries. Further clinical studies of UTE-T2* mapping are needed to determine if it can be used to identify joints at risk for rapid degeneration and to monitor effects of new treatments to delay or prevent the development of OA.

Informatics in Radiology: RADTF: A Semantic Search–enabled, Natural Language Processor–generated Radiology Teaching File

Storing and retrieving radiology cases is an important activity for education and clinical research, but this process can be time-consuming. In the process of structuring reports and images into organized teaching files, incidental pathologic conditions not pertinent to the primary teaching point can be omitted, as when a user saves images of an aortic dissection case but disregards the incidental osteoid osteoma. An alternate strategy for identifying teaching cases is text search of reports in radiology information systems (RIS), but retrieved reports are unstructured, teaching-related content is not highlighted, and patient identifying information is not removed. Furthermore, searching unstructured reports requires sophisticated retrieval methods to achieve useful results. An open-source, RadLex(®)-compatible teaching file solution called RADTF, which uses natural language processing (NLP) methods to process radiology reports, was developed to create a searchable teaching resource from the RIS and the picture archiving and communication system (PACS). The NLP system extracts and de-identifies teaching-relevant statements from full reports to generate a stand-alone database, thus converting existing RIS archives into an on-demand source of teaching material. Using RADTF, the authors generated a semantic search-enabled, Web-based radiology archive containing over 700,000 cases with millions of images. RADTF combines a compact representation of the teaching-relevant content in radiology reports and a versatile search engine with the scale of the entire RIS-PACS collection of case material.

Diagnosis of aseptic deep venous thrombosis of the upper extremity in a cancer patient using fluorine-18 fluorodeoxyglucose positron emission tomography/ computerized tomography (FDG PET/CT)

We describe a patient with a history of recurrent squamous cell carcinoma of the tongue and abnormal FDG uptake in the left arm during a re-staging FDG PET/CT. After revision of the patient’s clinical history, tests and physical exam, the abnormal FDG uptake was found to correspond to an extensive aseptic deep venous thrombosis of the upper extremity.

Childhood onset mitochondrial myopathy and lactic acidosis caused by a stop mutation in the mitochondrial cytochrome c oxidase III gene

More than 100 mitochondrial (mt) DNA mutations have been described in association with different complex neurological disorders and with respiratory chain (RC) deficiency in the past decade.1 Aside from more frequently reported mt tRNA mutations and deletions, a growing list of pathogenic mutations affecting structural genes of mtDNA encoded respiratory chain subunits, mainly cytochrome b and cytochrome c oxidase subunit genes, has now been reported in association with various mitochondrial disorders as well2 and most of these mutations are thought to be of sporadic origin. Cytochrome c oxidase (COX or complex IV), the terminal enzyme of the RC, catalyses the reduction of molecular oxygen by reduced cytochrome c. The complex is composed of 13 subunits. Three highly conserved mtDNA encoded subunits (COX I-III) form the catalytic core of the enzyme and the remaining 10 nuclear subunits are thought to modify or stabilise the complex. While the core forming subunits COX I and COX II contain the prosthetic groups and are known to play the most essential role in proton pumping and electron transfer, the function of COX III remains largely unknown. It is of interest that pathogenic mutations in mtDNA encoded subunits I-III have been identified whereas no mutations in the 10 nuclear genes are known so far. In contrast, numerous mutations in nuclear genes involved in the assembly of COX ( SURF1, SCO2, SCO1, COX10 ) have been described.3 As with most mtDNA mutations, the clinical presentation of patients harbouring mutations in mt encoded COX subunit genes is highly variable, ranging from late childhood onset myopathy4–8 to severe childhood onset multisystem disorders,9–14 and this might be explained by the variable distribution and abundance of mutant mtDNA in different tissues and by different expression thresholds.3 All mt COX subunit gene mutations reported to date …

Pattern of 18F-FDG uptake in the spinal cord in patients with non-central nervous system malignancy.

Study Design. Retrospective review. Objective. To (1) propose a standard method to quantitate 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) uptake in the spinal cord and (2) use this methodology to retrospectively characterize the pattern of uptake within the entire spinal cord using whole-body positron emission tomography/computed tomography (PET/CT) imaging. Summary of Background Data. A physiologic understanding of glucose metabolism within the spinal cord may provide insight regarding infectious, inflammatory, vascular, and neoplastic spinal cord diseases. Methods. Institutional review board approval was obtained. A total of 131 consecutive whole-body PET/CT studies from July to August 2004 were reviewed, and using exclusionary criteria of: (1) severe spinal arthropathy or curvature, (2) motion artifact, (3) canal hardware, (4) spinal tumor, and (5) marrow hyperplasia, 92 studies of neurologically intact patients (49 men and 43 women) were selected for a retrospective review of spinal cord 18F-FDG activity. The transaxial CT was used to define the canal and circular regions of interests were placed within the canal at the level of the vertebral body midpoint from C1 to L3. Region of interest total count, area, and maximum standardized uptake value (SUVmax) were recorded. Measurements at L5 served as an internal control. For comparative analysis, the cord-to-background (CTB) ratio was defined as spinal cord SUVmax to L5 SUVmax. Results. Mean CTB decreased along each spinal level from cranial to caudal (P < 0.001). Significant relative increases were observed at the T11-T12 vertebral body levels (P < 0.001). Although insignificant, a relative increase was observed at C4. No significant interactions of age or sex on CTB were observed. Conclusion. The pattern of 18F-FDG uptake within the spinal cord, observed in patients with non-central nervous system malignancy, may be helpful in understanding glucose physiology of spinal cord diseases and warrants further research.

Evaluation of negation and uncertainty detection and its impact on precision and recall in search.

Radiology reports contain information that can be mined using a search engine for teaching, research, and quality assurance purposes. Current search engines look for exact matches to the search term, but they do not differentiate between reports in which the search term appears in a positive context (i.e., being present) from those in which the search term appears in the context of negation and uncertainty. We describe RadReportMiner, a context-aware search engine, and compare its retrieval performance with a generic search engine, Google Desktop. We created a corpus of 464 radiology reports which described at least one of five findings (appendicitis, hydronephrosis, fracture, optic neuritis, and pneumonia). Each report was classified by a radiologist as positive (finding described to be present) or negative (finding described to be absent or uncertain). The same reports were then classified by RadReportMiner and Google Desktop. RadReportMiner achieved a higher precision (81%), compared with Google Desktop (27%; p < 0.0001). RadReportMiner had a lower recall (72%) compared with Google Desktop (87%; p = 0.006). We conclude that adding negation and uncertainty identification to a word-based radiology report search engine improves the precision of search results over a search engine that does not take this information into account. Our approach may be useful to adopt into current report retrieval systems to help radiologists to more accurately search for radiology reports.

Analysis of FAS (CD95) Gene Mutations in Higher-Grade Transformation of Follicle Center Lymphoma

The FAS antigen (CD95/APO-1) is suggested to be a tumor suppressor gene since mice and patients with congenital FAS mutations are prone to B cell lymphomas and somatic FAS mutations are described in hematological and solid tumors. Indeed, mutations of the FAS antigen have been found in 13% of multiple myelomas, 6% of follicle center lymphomas (FCL) and 21% of diffuse large B-cell lymphomas (DLBCL). To assess the possible role of FAS mutations in higher-grade transformation of FCL, biopsy specimens from 16 FCL patients were analyzed by denaturing high performance liquid chromatography and direct sequencing. Overall, 17 biopsy specimens obtained at the time of FCL diagnosis (2 biopsy specimens from one patient), 4 sequential biopsies obtained at the time of FCL relapse and 14 sequential biopsies from the time of morphologic transformation to DLBCL were evaluated. Ten polymorphisms were detected, only 4 of which have been reported previously. Nine of the polymorphisms occurred in non-translated regions, while one silent mutation was located in exon 7. Neither loss of heterozygosity nor occurrence of new mutations was observed upon higher-grade transformation of FCL to DLBCL.

Automatic retrieval of bone fracture knowledge using natural language processing.

Natural language processing (NLP) techniques to extract data from unstructured text into formal computer representations are valuable for creating robust, scalable methods to mine data in medical documents and radiology reports. As voice recognition (VR) becomes more prevalent in radiology practice, there is opportunity for implementing NLP in real time for decision-support applications such as context-aware information retrieval. For example, as the radiologist dictates a report, an NLP algorithm can extract concepts from the text and retrieve relevant classification or diagnosis criteria or calculate disease probability. NLP can work in parallel with VR to potentially facilitate evidence-based reporting (for example, automatically retrieving the Bosniak classification when the radiologist describes a kidney cyst). For these reasons, we developed and validated an NLP system which extracts fracture and anatomy concepts from unstructured text and retrieves relevant bone fracture knowledge. We implement our NLP in an HTML5 web application to demonstrate a proof-of-concept feedback NLP system which retrieves bone fracture knowledge in real time.

A tRNAAla mutation causing mitochondrial myopathy clinically resembling myotonic dystrophy

More than 100 pathogenic mitochondrial (mt) DNA mutations have been described in the past decade in association with different neuromuscular disorders. Apart from large scale mtDNA rearrangements and common point mutations in mt tRNA genes, pathogenic mutations affecting structural genes of mtDNA encoded respiratory chain subunits have been reported as well.1 Pathogenic tRNA mutations can affect translation of respiratory chain (RC) complexes that are partly encoded by the mtDNA, that is, complexes I, III, and IV. The most common tRNA mutation is associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and is located in the tRNALeu(UUR) gene. So far, 13 additional pathogenic mutations have been described in this gene in association with different neurodegenerative disorders. Similarly, mutations in tRNAIle , tRNALys , and tRNASer(UCN) are known to cause various mitochondrial encephalomyopathies or non-syndromic deafness (see Mitomap http://www.mitomap.org/). The remaining 18 mitochondrially encoded tRNAs are rarely reported to be mutated in mitochondrial disorders.2 In tRNAAla only one pathogenic mutation is listed in Mitomap to date. This mutation was found in an Italian patient who presented with late onset progressive external ophthalmoplegia and dysphagia.3 Another heteroplasmic G>A mutation at position 5650 of mt tRNAAla was described in addition to a Notch3 mutation in a 53 year old patient with typical symptoms of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) together with symptoms of a myopathy with numerous ragged red fibres.4 Therefore, the authors suggested a pathogenic role for both, the Notch3 and the tRNAAla G5650A mutation. However, the G5650A mutation has not been reported to any mitochondrial database. Here we report a patient suffering from a novel type of mitochondrial myopathy resembling muscular dystrophy associated with the heteroplasmic G5650A mutation in the mtDNA encoded tRNAAla …