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1.  Diabetic cardiomyopathy is associated with defective myocellular copper regulation and both defects are rectified by divalent copper chelation 
Heart disease is the leading cause of death in diabetic patients, and defective copper metabolism may play important roles in the pathogenesis of diabetic cardiomyopathy (DCM). The present study sought to determine how myocardial copper status and key copper-proteins might become impaired by diabetes, and how they respond to treatment with the Cu (II)-selective chelator triethylenetetramine (TETA) in DCM.
Experiments were performed in Wistar rats with streptozotocin (STZ)-induced diabetes with or without TETA treatment. Cardiac function was analyzed in isolated-perfused working hearts, and myocardial total copper content measured by particle-induced x-ray emission spectroscopy (PIXE) coupled with Rutherford backscattering spectrometry (RBS). Quantitative expression (mRNA and protein) and/or activity of key proteins that mediate LV-tissue-copper binding and transport, were analyzed by combined RT-qPCR, western blotting, immunofluorescence microscopy, and enzyme activity assays. Statistical analysis was performed using Student’s t-tests or ANOVA and p-values of < 0.05 have been considered significant.
Left-ventricular (LV) copper levels and function were severely depressed in rats following 16-weeks’ diabetes, but both were unexpectedly normalized 8-weeks after treatment with TETA was instituted. Localized myocardial copper deficiency was accompanied by decreased expression and increased polymerization of the copper-responsive transition-metal-binding metallothionein proteins (MT1/MT2), consistent with impaired anti-oxidant defences and elevated susceptibility to pro-oxidant stress. Levels of the high-affinity copper transporter-1 (CTR1) were depressed in diabetes, consistent with impaired membrane copper uptake, and were not modified by TETA which, contrastingly, renormalized myocardial copper and increased levels and cell-membrane localization of the low-affinity copper transporter-2 (CTR2). Diabetes also lowered indexes of intracellular (IC) copper delivery via the copper chaperone for superoxide dismutase (CCS) to its target cuproenzyme, superoxide dismutase-1 (SOD1): this pathway was rectified by TETA treatment, which normalized SOD1 activity with consequent bolstering of anti-oxidant defenses. Furthermore, diabetes depressed levels of additional intracellular copper-transporting proteins, including antioxidant-protein-1 (ATOX1) and copper-transporting-ATPase-2 (ATP7B), whereas TETA elevated copper-transporting-ATPase-1 (ATP7A).
Myocardial copper deficiency and defective cellular copper transport/trafficking are revealed as key molecular defects underlying LV impairment in diabetes, and TETA-mediated restoration of copper regulation provides a potential new class of therapeutic molecules for DCM.
PMCID: PMC4070334  PMID: 24927960
Diabetic cardiomyopathy; Copper-deficiency cardiomyopathy; Left-ventricular dysfunction; Myocellular copper; Copper transporters; Superoxide dismutase 1; Copper chaperones; Cu (II)-chelation; Copper metalation; Heart failure
2.  Total Knee Arthroplasty in the Elderly: Does Age Affect Pain, Function or Complications? 
TKA is one of the most commonly performed procedures in the elderly, yet whether age influences postoperative pain, function, and complication rates is not fully understood for this group. This is because the current literature has limited followup, small sample sizes, and no comparator group.
We therefore asked if increasing age adversely affects postoperative pain, Knee Society Scores©, and complication rates.
We retrospectively reviewed all 438 patients 80 years or older who underwent primary TKA between 1995 and 2005. We established a comparator group of 2754 patients younger than 80 years. We assessed pain, the Knee Society Score© (KSS), and the Knee Society Function Score© (KSFS). The number and type of complications were recorded and those graded 2 or more using the classification of Dindo et al. were analyzed. Minimum followup was 5 years (mean, 6 years; range, 5–15.5 years).
We found no difference in pain scores at 3, 5, and 10 years between the two groups. The KSS was comparable between groups at Year 5, but the KSFS was lower in the octogenarians. Major complications rates were higher in the octogenarian group (19% versus 15%).
When compared with younger patients, octogenarians can expect comparable pain relief and KSS but lower function and more complications.
Level of Evidence
Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.
PMCID: PMC3706666  PMID: 23354464
3.  DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers 
Osorio, Ana | Milne, Roger L. | Kuchenbaecker, Karoline | Vaclová, Tereza | Pita, Guillermo | Alonso, Rosario | Peterlongo, Paolo | Blanco, Ignacio | de la Hoya, Miguel | Duran, Mercedes | Díez, Orland | Ramón y Cajal, Teresa | Konstantopoulou, Irene | Martínez-Bouzas, Cristina | Andrés Conejero, Raquel | Soucy, Penny | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | SWE-BRCA,  | Arver, Brita | Rantala, Johanna | Loman, Niklas | Ehrencrona, Hans | Olopade, Olufunmilayo I. | Beattie, Mary S. | Domchek, Susan M. | Nathanson, Katherine | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | John, Esther M. | Whittemore, Alice S. | Daly, Mary B. | Southey, Melissa | Hopper, John | Terry, Mary B. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Steele, Linda | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas v. O. | Jønson, Lars | Ejlertsen, Bent | Gerdes, Anne-Marie | Infante, Mar | Herráez, Belén | Moreno, Leticia Thais | Weitzel, Jeffrey N. | Herzog, Josef | Weeman, Kisa | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Bonanni, Bernardo | Mariette, Frederique | Volorio, Sara | Viel, Alessandra | Varesco, Liliana | Papi, Laura | Ottini, Laura | Tibiletti, Maria Grazia | Radice, Paolo | Yannoukakos, Drakoulis | Garber, Judy | Ellis, Steve | Frost, Debra | Platte, Radka | Fineberg, Elena | Evans, Gareth | Lalloo, Fiona | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Eccles, Diana | Cook, Jackie | Hodgson, Shirley | Brewer, Carole | Tischkowitz, Marc | Douglas, Fiona | Porteous, Mary | Side, Lucy | Walker, Lisa | Morrison, Patrick | Donaldson, Alan | Kennedy, John | Foo, Claire | Godwin, Andrew K. | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hans Jörg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Gehrig, Andrea | Stoppa-Lyonnet, Dominique | Sinilnikova, Olga M. | Mazoyer, Sylvie | Damiola, Francesca | Poppe, Bruce | Claes, Kathleen | Piedmonte, Marion | Tucker, Kathy | Backes, Floor | Rodríguez, Gustavo | Brewster, Wendy | Wakeley, Katie | Rutherford, Thomas | Caldés, Trinidad | Nevanlinna, Heli | Aittomäki, Kristiina | Rookus, Matti A. | van Os, Theo A. M. | van der Kolk, Lizet | de Lange, J. L. | Meijers-Heijboer, Hanne E. J. | van der Hout, A. H. | van Asperen, Christi J. | Gómez Garcia, Encarna B. | Hoogerbrugge, Nicoline | Collée, J. Margriet | van Deurzen, Carolien H. M. | van der Luijt, Rob B. | Devilee, Peter | HEBON,  | Olah, Edith | Lázaro, Conxi | Teulé, Alex | Menéndez, Mireia | Jakubowska, Anna | Cybulski, Cezary | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Johannsson, Oskar Th. | Maugard, Christine | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Healey, Sue | Investigators, kConFab | Olswold, Curtis | Guidugli, Lucia | Lindor, Noralane | Slager, Susan | Szabo, Csilla I. | Vijai, Joseph | Robson, Mark | Kauff, Noah | Zhang, Liying | Rau-Murthy, Rohini | Fink-Retter, Anneliese | Singer, Christian F. | Rappaport, Christine | Geschwantler Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Berger, Andreas | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Lejbkowicz, Flavio | Andrulis, Irene | Mulligan, Anna Marie | Glendon, Gord | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Sunde, Lone | Thomassen, Mads | Kruse, Torben A. | Jensen, Uffe Birk | Friedman, Eitan | Laitman, Yael | Shimon, Shani Paluch | Simard, Jacques | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Benitez, Javier
PLoS Genetics  2014;10(4):e1004256.
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03–1.16), p = 2.7×10−3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8×10−3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Author Summary
Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
PMCID: PMC3974638  PMID: 24698998
4.  Growth arrest lines and intra-epiphyseal silhouettes: a case series 
BMC Research Notes  2014;7:27.
Growth arrest lines can develop within the skeleton after physiological stress or trauma. They are usually evident on radiographs as transverse lines in the metaphyses and have been used in fields from palaeontology to orthopaedics. This report consists of three cases, two of which describe growth arrest lines in an intra-epiphyseal site hitherto rarely documented, and a third demonstrating their clinical application.
Case presentation
Case 1 describes a 9-year-old who suffered a knee hyperflexion injury requiring anterior cruciate ligament and posterior cruciate ligament reattachments. She subsequently developed a marked distal femoral intra-epiphyseal arrest silhouette, as well as metaphyseal arrest lines in the femur, tibia and fibula. Case 2 describes an 8-year-old who sustained a tibial spine fracture and underwent open reduction and internal fixation. Subsequent imaging shows a further example of femoral intra-epiphyseal arrest silhouette as well as tibia and fibula metaphyseal arrest lines. Case 3 describes a 10-year-old who sustained a distal tibia fracture which was managed with open reduction and internal fixation. Subsequently the metaphyseal growth arrest line was parallel to the physis, suggesting no growth arrest (a danger with such a fracture).
This case series describes two examples of rarely described intra-epiphyseal growth arrest silhouettes and demonstrates the usefulness of arrest lines when assessing for growth plate damage.
PMCID: PMC3927262  PMID: 24410952
Growth arrest lines; Orthopaedics; Physis
5.  Protection of the heart by treatment with a divalent-copper-selective chelator reveals a novel mechanism underlying cardiomyopathy in diabetic rats 
Intracellular calcium (Ca2+) coordinates the cardiac contraction cycle and is dysregulated in diabetic cardiomyopathy. Treatment with triethylenetetramine (TETA), a divalent-copper-selective chelator, improves cardiac structure and function in patients and rats with diabetic cardiomyopathy, but the molecular basis of this action is uncertain. Here, we used TETA to probe potential linkages between left-ventricular (LV) copper and Ca2+ homeostasis, and cardiac function and structure in diabetic cardiomyopathy.
We treated streptozotocin-diabetic rats with a TETA-dosage known to ameliorate LV hypertrophy in patients with diabetic cardiomyopathy. Drug treatment was begun either one (preventative protocol) or eight (restorative protocol) weeks after diabetes induction and continued thereafter for seven or eight weeks, respectively. Total copper content of the LV wall was determined, and simultaneous measurements of intracellular calcium concentrations and isometric contraction were made in LV trabeculae isolated from control, diabetic and TETA-treated diabetic rats.
Total myocardial copper levels became deficient in untreated diabetes but were normalized by TETA-treatment. Cardiac contractility was markedly depressed by diabetes but TETA prevented this effect. Neither diabetes nor TETA exerted significant effects on peak or resting [Ca2+]i. However, diabetic rats showed extensive cardiac remodelling and decreased myofibrillar calcium sensitivity, consistent with observed increases in phosphorylation of troponin I, whereas these changes were all prevented by TETA.
Diabetes causes cardiomyopathy through a copper-mediated mechanism that incorporates myocardial copper deficiency, whereas TETA treatment prevents this response and maintains the integrity of cardiac structure and myofibrillar calcium sensitivity. Altered calcium homeostasis may not be the primary defect in diabetic cardiomyopathy. Rather, a newly-described copper-mediated mechanism may cause this disease.
PMCID: PMC3848860  PMID: 23981320
Copper homeostasis; Calcium homeostasis; Anti-oxidant defence; Cardiac contraction; Cardiovascular disease; Copper deficiency; Copper excess; Cardiomyopathy; Diabetes mellitus; Essential trace nutrient; Experimental therapeutics; Left-ventricular dysfunction; Left-ventricular remodelling; Calcium responsiveness; Myocardium; Myocardial calcium sensitivity; QT interval; Triethylenetetramine; Troponin
6.  Mechanism of glucocorticoid regulation of the intestinal tight junction barrier 
A defective intestinal epithelial tight junction (TJ) barrier has been proposed as an important pathogenic factor contributing to the intestinal inflammation of Crohn's disease. Glucocorticoids are first-line therapeutic agents for the treatment of moderate to severe Crohn's disease. Glucocorticoid treatment has been shown to induce retightening of the intestinal TJ barrier defect in Crohn's disease patients. However, the mechanisms that mediate the glucocorticoid therapeutic action on intestinal TJ barrier function remain unknown. The aim of this study was to elucidate the mechanism of glucocorticoid modulation of the intestinal epithelial TJ barrier using an in vitro model system. Filter-grown Caco-2 intestinal epithelial cells were used as an in vitro model to examine the effects of glucocorticoids on basal intestinal epithelial TJ barrier function and on TNF-α-induced disruption of the TJ barrier. Glucocorticoids (prednisolone and dexamethasone) did not have a significant effect on baseline Caco-2 TJ barrier function but prevented the TNF-α-induced increase in Caco-2 TJ permeability. The glucocorticoid protective effect against the TNF-α-induced increase in Caco-2 TJ permeability required activation of the glucocorticoid receptor (GR) complex. The activation of the GR complex resulted in GR complex binding to the glucocorticoid response element (GRE) site on DNA and activation of a GR-responsive promoter. Glucocorticoids inhibited the TNF-α-induced increase in myosin light chain kinase (MLCK) protein expression, a key process mediating the TNF-α increase in intestinal TJ permeability. The glucocorticoid inhibition of the TNF-α-induced increase in MLCK protein expression was due to the binding of the GR complex to a GRE binding site on the MLCK promoter region suppressing the TNF-α-induced activation. Glucocorticoids inhibit the TNF-α-induced increase in Caco-2 TJ permeability. The prednisolone protective action was mediated by binding of activated GR complex to the GRE site on the MLCK promoter, suppressing the TNF-α-induced increase in MLCK gene activity, protein expression, and subsequent opening of the intestinal TJ barrier.
PMCID: PMC3724219  PMID: 17068119
prednisolone; inflammation; tumor necrosis factor-α; glucocorticoid receptor; glucocorticoid response element; Crohn's disease
7.  The Biology of Ewing Sarcoma 
ISRN Oncology  2013;2013:759725.
Objective. The goal of this study was to review the current literature on the biology of Ewing's sarcoma, including current treatments and the means by which an understanding of biological mechanisms could impact future treatments. Methods. A search of PubMed and The Cochrane Collaboration was performed. Both preclinical and clinical evidence was considered, but specific case reports were not. Primary research articles and reviews were analyzed with an emphasis on recent publications. Results. Ewing sarcoma is associated with specific chromosomal translocations and the resulting transcripts/proteins. Knowledge of the biology of Ewing sarcoma has been growing but has yet to significantly impact or produce new treatments. Localized cases have seen improvements in survival rates, but the same cannot be said of metastatic and recurrent cases. Standard surgical, radiation, and chemotherapy treatments are reaching their efficacy limits. Conclusion. Improving prognosis likely lies in advancing biomarkers and early diagnosis, determining a cell(s) of origin, and developing effective molecular therapeutics and antiangiogenic agents. Preclinical evidence suggests the utility of molecular therapies for Ewing sarcoma. Early clinical results also reveal potential for novel treatments but require further development and evaluation before widespread use can be advocated.
PMCID: PMC3549336  PMID: 23346417
8.  Establishing proof of concept: Platelet-rich plasma and bone marrow aspirate concentrate may improve cartilage repair following surgical treatment for osteochondral lesions of the talus 
World Journal of Orthopedics  2012;3(7):101-108.
Osteochondral lesions of the talus are common injuries in the athletic patient. They present a challenging clinical problem as cartilage has a poor potential for healing. Current surgical treatments consist of reparative (microfracture) or replacement (autologous osteochondral graft) strategies and demonstrate good clinical outcomes at the short and medium term follow-up. Radiological findings and second-look arthroscopy however, indicate possible poor cartilage repair with evidence of fibrous infill and fissuring of the regenerative tissue following microfracture. Longer-term follow-up echoes these findings as it demonstrates a decline in clinical outcome. The nature of the cartilage repair that occurs for an osteochondral graft to become integrated with the native surround tissue is also of concern. Studies have shown evidence of poor cartilage integration, with chondrocyte death at the periphery of the graft, possibly causing cyst formation due to synovial fluid ingress. Biological adjuncts, in the form of platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC), have been investigated with regard to their potential in improving cartilage repair in both in vitro and in vitro settings. The in vitro literature indicates that these biological adjuncts may increase chondrocyte proliferation as well as synthetic capability, while limiting the catabolic effects of an inflammatory joint environment. These findings have been extrapolated to in vitro animal models, with results showing that both PRP and BMAC improve cartilage repair. The basic science literature therefore establishes the proof of concept that biological adjuncts may improve cartilage repair when used in conjunction with reparative and replacement treatment strategies for osteochondral lesions of the talus.
PMCID: PMC3399015  PMID: 22816065
Osteochondral lesion; Cartilage repair; Platelet-rich plasma; Bone marrow aspirate concentrate
9.  Treatment Options to Manage Wound Biofilm 
Advances in Wound Care  2012;1(3):120-126.
Bioburden is an accepted barrier to chronic wound healing. Defining the significance, phenotype, clinical classification, and treatment guidelines has been historically lacking of evidence and based on paradigms that do not represent the scientific or clinical reality.
The Problem
Chronic wound bioburden is typically abundant, polymicrobial, and extremely diverse. These microbes naturally adopt biofilm phenotypes, which are quite often viable but not culturable, thereby going undetected. The failures of culture-based detection have led to abandonment of routine bioburden evaluation and aggressive treatment or, worse, to assume bioburden is not a significant barrier. Predictably, treatment regimens to address biofilm phenotypes lagged behind our diagnostic tools and understanding.
Basic/Clinical Science Advances
Microbial DNA-based diagnostic tools and treatment regimens have emerged, which provide and leverage objective information, resulting in a dramatic impact on outcomes.
Relevance to Clinical Care
Modern medicine demands decisions based on objective evidence. The diagnostic and treatment protocols reviewed herein empower clinicians to practice modern medicine with regard to bioburden, with DNA level certainty.
Bioburden is a significant barrier to healing for all chronic wounds. Molecular diagnostics provide the first objective means of assessing wound bioburden. The accuracy and comprehensive data from such diagnostic methodologies provide clinicians with the ability to employ patient-specific treatment options, targeted to each patient's microbial wound census. Based on current outcomes data, the most effective therapeutic options are topical (TPL) antibiofilm agents (ABF) combined with TPL antibiotics (ABX). In specific patients, systemic ABX and selective biocides are also appropriate, but not exclusive of ABF combined with TPL ABX.
PMCID: PMC3623577  PMID: 24527291
10.  A Rotational Scarf Osteotomy Decreases Troughing When Treating Hallux Valgus 
The traditional scarf osteotomy has been associated with complication rates between 1.1% and 45%. We have modified the traditional technique with a rotational osteotomy to reduce these complications.
We determined whether a modified rotational scarf osteotomy improves functional outcome scores, allows correction of a wide degree of an intermetatarsal (IM) angle deformity, has a low incidence of troughing, and maintains normal ROM postoperatively in the treatment of symptomatic hallux valgus (HV).
Patients and Methods
We retrospectively reviewed 140 patients: 38 men and 102 women with a mean age of 54 years (range, 35–66 years) who underwent surgery for HV and had a minimum followup of 24 months (mean, 41 months; range, 24–68 months). All patients had preoperative and postoperative American Orthopaedic Foot and Ankle Society (AOFAS) forefoot and Short Form (SF)-36 V2 outcome scores recorded.
The mean AOFAS score improved from 52 points preoperatively to 92 points (range, 71–96 points) at followup. The mean SF-36 V2 score improved from 69 points preoperatively to 94 points (range, 67–98 points) at followup. The IM angle improved from a preoperative mean of 18° (range, 9°–23°) to a mean of 8° (range, 6°–12°). Eleven patients experienced a complication.
The modified rotational scarf osteotomy has a low complication rate (9%) and apparently reduces the risk of troughing. This procedure can reduce a high degree of IM angle deformity while restoring function to the forefoot.
Level of Evidence
Level IV, case series. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3032838  PMID: 20976578
11.  Fracture of the Medial Tubercle of the Posterior Process of the Talus: Magnetic Resonance Imaging Appearance with Clinical Follow-Up 
HSS Journal  2009;5(2):161-164.
Fractures of the medial tubercle of the posterior process of the talus are rare injuries. They are often misdiagnosed, resulting in increased morbidity and symptoms of chronic ankle pain and instability. When undetected, these fractures may become displaced, with potential additional injuries such as to the flexor hallucis longus tendon which may become interposed between the fracture fragments. We report a case of a clinically unsuspected fracture of the medial tubercle of the posterior process of the talus seen on magnetic resonance imaging, treated conservatively, with interval satisfactory healing of the fracture at 6 weeks follow-up.
PMCID: PMC2744751  PMID: 19347408
magnetic resonance imaging; ankle; talus; fracture; trauma
12.  Formaldehyde Exposure and Asthma in Children: A Systematic Review 
Environmental Health Perspectives  2009;118(3):313-317.
Despite multiple published studies regarding the association between formaldehyde exposure and childhood asthma, a consistent association has not been identified. Here we report the results of a systematic review of published literature in order to provide a more comprehensive picture of this relationship.
Data sources
After a comprehensive literature search, we identified seven peer-reviewed studies providing quantitative results regarding the association between formaldehyde exposure and asthma in children. Studies were heterogeneous with respect to the definition of asthma (e.g., self-report, physician diagnosis). Most of the studies were cross-sectional.
Data extraction
For each study, an odds ratio (OR) and 95% confidence interval (CI) for asthma were either abstracted from published results or calculated based on the data provided. Characteristics regarding the study design and population were also abstracted.
Data synthesis
We used fixed- and random-effects models to calculate pooled ORs and 95% CIs; measures of heterogeneity were also calculated. A fixed-effects model produced an OR of 1.03 (95% CI, 1.02–1.04), and random effects model produced an OR of 1.17 (95% CI, 1.01–1.36), both reflecting an increase of 10 μg/m3 of formaldehyde. Both the Q and I2 statistics indicated a moderate amount of heterogeneity.
Results indicate a significant positive association between formaldehyde exposure and childhood asthma. Given the largely cross-sectional nature of the studies underlying this meta-analysis, further well-designed prospective epidemiologic studies are needed.
PMCID: PMC2854756  PMID: 20064771
asthma; children; epidemiology; formaldehyde; meta-analysis
13.  Mechanism of Interferon-γ–Induced Increase in T84 Intestinal Epithelial Tight Junction 
Interferon-γ (IFN-γ) is an important proinflammatory cytokine that plays a central role in the intestinal inflammatory process of inflammatory bowel disease. IFN-γ induced disturbance of the intestinal epithelial tight junction (TJ) barrier has been postulated to be an important mechanism contributing to intestinal inflammation. The intracellular mechanisms that mediate the IFN-γ induced increase in intestinal TJ permeability remain unclear. The aim of this study was to examine the role of the phosphatidylinositol 3-kinase (PI3-K) pathway in the regulation of the IFN-γ induced increase in intestinal TJ permeability using the T84 intestinal epithelial cell line. IFN-γ caused an increase in T84 intestinal epithelial TJ permeability and depletion of TJ protein, occludin. The IFN-γ induced increase in TJ permeability and alteration in occludin protein was associated with rapid activation of PI3-K; and inhibition of PI3-K activation prevented the IFN-γ induced effects. IFN-γ also caused a delayed but more prolonged activation of nuclear factor-κB (NF-κB); inhibition of NF-κB also prevented the increase in T84 TJ permeability and alteration in occludin expression. The IFN-γ induced activation of NF-κB was mediated by a cross-talk with PI3-K pathway. In conclusion, the IFN-γ induced increase in T84 TJ permeability and alteration in occludin protein expression were mediated by the PI3-K pathway. These results show for the first time that the IFN-γ modulation of TJ protein and TJ barrier function is regulated by a cross-talk between PI3-K and NF-κB pathways.
PMCID: PMC2988462  PMID: 19128033
14.  Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia 
Critical Care  2009;13(6):R200.
Aminoglycosides aerosolization might achieve better diffusion into the alveolar compartment than intravenous use. The objective of this multicenter study was to evaluate aerosol-delivered amikacin penetration into the alveolar epithelial lining fluid (ELF) using a new vibrating mesh nebulizer (Pulmonary Drug Delivery System (PDDS), Nektar Therapeutics), which delivers high doses to the lungs.
Nebulized amikacin (400 mg bid) was delivered to the lungs of 28 mechanically ventilated patients with Gram-negative VAP for 7-14 days, adjunctive to intravenous therapy. On treatment day 3, 30 minutes after completing aerosol delivery, all the patients underwent bronchoalveolar lavage in the infection-involved area and the ELF amikacin concentration was determined. The same day, urine and serum amikacin concentrations were determined at different time points.
Median (range) ELF amikacin and maximum serum amikacin concentrations were 976.1 (135.7-16127.6) and 0.9 (0.62-1.73) μg/mL, respectively. The median total amount of amikacin excreted in urine during the first and second 12-hour collection on day 3 were 19 (12.21-28) and 21.2 (14.1-29.98) μg, respectively. During the study period, daily through amikacin measurements were below the level of nephrotoxicity. Sixty-four unexpected adverse events were reported, among which 2 were deemed possibly due to nebulized amikacin: one episode of worsening renal failure, and one episode of bronchospasm.
PDDS delivery of aerosolized amikacin achieved very high aminoglycoside concentrations in ELF from radiography-controlled infection-involved zones, while maintaining safe serum amikacin concentrations. The ELF concentrations always exceeded the amikacin minimum inhibitory concentrations for Gram-negative microorganisms usually responsible for these pneumonias. The clinical impact of amikacin delivery with this system remains to be determined.
Trial Registration Identifier: NCT01021436.
PMCID: PMC2811890  PMID: 20003269
15.  Surgery for Retrocalcaneal Bursitis: A Tendon-splitting versus a Lateral Approach 
For patients with refractory retrocalcaneal bursitis (Haglund’s syndrome), the most effective surgical approach has not been defined. We asked whether patients undergoing the tendon-splitting approach and the lateral approach would have comparably effective relief of pain for both types of calcaneal ostectomies. We retrospectively reviewed 30 patients (31 feet) who underwent the tendon-splitting approach and compared their results with 32 previous patients (35 feet) who had a lateral incision. Minimum followup was 12 months (mean, 16 months; range, 12–23 months) for the tendon-splitting group and 15 months (mean, 51 months; range, 15–109 months) for the lateral group. The mean American Orthopaedic Foot and Ankle Society score improved from 43 points preoperatively to 81 points (range, 8–100 points) postoperatively in the tendon-splitting group and from 54 points to 86 points (range, 55–100 points) in the lateral group. The mean physical component score of the Short Form-36, version 2, at followup was 52 (range, 22–61) in the tendon-splitting group and 49 (range, 34–63) in the lateral group. The median return to normal function was 4.1 months (range, 3–13 months) in the tendon-splitting group and 6.4 months (range, 4–20 months) in the lateral group. Both approaches to calcaneal ostectomy provided symptomatic pain relief. However, patients in the tendon-splitting group returned to normal function quicker than patients in the lateral group.
Level of Evidence: Level III, retrospective comparative study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2505264  PMID: 18465183
16.  Fgf receptor 3 activation promotes selective growth and expansion of occipitotemporal cortex 
Neural Development  2009;4:4.
Fibroblast growth factors (Fgfs) are important regulators of cerebral cortex development. Fgf2, Fgf8 and Fgf17 promote growth and specification of rostromedial (frontoparietal) cortical areas. Recently, the function of Fgf15 in antagonizing Fgf8 in the rostral signaling center was also reported. However, regulation of caudal area formation by Fgf signaling remains unknown.
In mutant mice with constitutive activation of Fgf receptor 3 (Fgfr3) in the forebrain, surface area of the caudolateral cortex was markedly expanded at early postnatal stage, while rostromedial surface area remained normal. Cortical thickness was also increased in caudal regions. The expression domain and levels of Fgf8, as well as overall patterning, were unchanged. In contrast, the changes in caudolateral surface area were associated with accelerated cell cycle in early stages of neurogenesis without an alteration of cell cycle exit. Moreover, a marked overproduction of intermediate neuronal progenitors was observed in later stages, indicating prolongation of neurogenesis.
Activation of Fgfr3 selectively promotes growth of caudolateral (occipitotemporal) cortex. These observations support the 'radial unit' and 'radial amplification' hypotheses and may explain premature sulcation of the occipitotemporal cortex in thanatophoric dysplasia, a human FGFR3 disorder. Together with previous work, this study suggests that formation of rostral and caudal areas are differentially regulated by Fgf signaling in the cerebral cortex.
PMCID: PMC2661882  PMID: 19192266
17.  Improving Ambulatory Prescribing Safety with a Handheld Decision Support System: A Randomized Controlled Trial 
Objective: To evaluate the effectiveness of a personal digital assistant (PDA)–based clinical decision support system (CDSS) on nonsteroidal anti-inflammatory drug (NSAID) prescribing safety in the outpatient setting.
Design: The design was a randomized, controlled trial conducted in a university-based resident clinic. Internal medicine residents received a PDA-based CDSS suite. For intervention residents, the CDSS included a prediction rule for NSAID-related gastrointestinal risk assessment and treatment recommendations. Unannounced standardized patients (SPs) trained to portray musculoskeletal symptoms presented to study physicians. Safety outcomes were assessed from the prescriptions given to the SPs. Each prescription was reviewed by a committee of clinicians blinded to participant, intervention group assignment, and baseline or follow-up status.
Measurements: Prescriptions were judged as safe or unsafe. The main outcome measure was the differential change in unsafe prescribing of NSAIDs for the intervention versus the control group.
Results: At baseline, the mean proportion of cases per physician with unsafe prescriptions for the two groups was similar (0.27 vs. 0.29, p > 0.05). Controlling for baseline performance, intervention participants prescribed more safely than controls after receiving the CDSS (0.23 vs. 0.45 [F = 4.24, p < 0.05]). With the CDSS, intervention participants documented more complete assessment of patient gastrointestinal risk from NSAIDs.
Conclusion: Participants provided with a PDA-based CDSS for NSAID prescribing made fewer unsafe treatment decisions than participants without the CDSS.
PMCID: PMC1447547  PMID: 16357350
18.  Improved Image Fusion in PET/CT Using Hybrid Image Reconstruction and Super-Resolution 
Purpose. To provide PET/CT image fusion with an improved PET resolution and better contrast ratios than standard reconstructions. Method. Using a super-resolution algorithm, several PET acquisitions were combined to improve the resolution. In addition, functional PET data was smoothed with a hybrid computed tomography algorithm (HCT), in which anatomical edge information taken from the CT was employed to retain sharper edges. The combined HCT and super-resolution technique were evaluated in phantom and patient studies using a clinical PET scanner. Results. In the phantom studies, 3 mm18F-FDG sources were resolved. PET contrast ratios improved (average: 54%, range: 45%–69%) relative to the standard reconstructions. In the patient study, target-to-background ratios also improved (average: 34%, range: 17%–47%). Given corresponding anatomical borders, sharper edges were depicted. Conclusion. A new method incorporating super-resolution and HCT for fusing PET and CT images has been developed and shown to provide higher-resolution metabolic images.
PMCID: PMC1987321  PMID: 18521180
19.  Sensitivity and Specificity of the ViroSeq Human Immunodeficiency Virus Type 1 (HIV-1) Genotyping System for Detection of HIV-1 Drug Resistance Mutations by Use of an ABI PRISM 3100 Genetic Analyzer 
Journal of Clinical Microbiology  2005;43(2):813-817.
The ViroSeq human immunodeficiency virus type 1 (HIV-1) genotyping system is an integrated system for identification of drug resistance mutations in HIV-1 protease and reverse transcriptase (RT). Reagents are included for sample preparation, reverse transcription, PCR amplification, and sequencing. Software is provided to assemble and edit sequence data and to generate a drug resistance report. We determined the sensitivity and specificity of the ViroSeq system for mutation detection using an ABI PRISM 3100 genetic analyzer with a set of clinical samples and recombinant viruses. Twenty clinical plasma samples (viral loads, 1,800 to 10,500 copies/ml) were characterized by cloning and sequencing individual viral variants. Twelve recombinant-virus samples (viral loads, approximately 2,000 to 5,000 copies/ml) were also prepared. Eleven recombinant-virus samples contained drug resistance mutations as 40% mixtures. One recombinant-virus sample contained an insertion at codon 69 in RT (100% mutant). Plasma and recombinant-virus samples were analyzed using the ViroSeq system. Each sample was analyzed on three consecutive days at each of three testing laboratories. The sensitivity of mutation detection was 99.65% for the clinical plasma samples and 99.7% for the recombinant-virus preparations. The specificity of mutation detection was 99.95% for the clinical samples and 100% for the recombinant-virus mixtures. The base calling accuracy of the 3100 instrument was 99.91%. Mutations in clinical plasma samples and recombinant-virus samples were detected with high sensitivity and specificity, including mutations present as mixtures. This report supports the use of the ViroSeq system for identification of drug resistance mutations in HIV-1 protease and RT genes.
PMCID: PMC548107  PMID: 15695685
21.  Cloning and characterization of the mouse Mcoln1 gene reveals an alternatively spliced transcript not seen in humans 
BMC Genomics  2002;3:3.
Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disorder characterized by severe neurologic and ophthalmologic abnormalities. Recently the MLIV gene, MCOLN1, has been identified as a new member of the transient receptor potential (TRP) cation channel superfamily. Here we report the cloning and characterization of the mouse homologue, Mcoln1, and report a novel splice variant that is not seen in humans.
The human and mouse genes display a high degree of synteny. Mcoln1 shows 91% amino acid and 86% nucleotide identity to MCOLN1. Also, Mcoln1 maps to chromosome 8 and contains an open reading frame of 580 amino acids, with a transcript length of approximately 2 kb encoded by 14 exons, similar to its human counterpart. The transcript that results from murine specific alternative splicing encodes a 611 amino acid protein that differs at the c-terminus.
Mcoln1 is highly similar to MCOLN1, especially in the transmembrane domains and ion pore region. Also, the late endosomal/lysosomal targeting signal is conserved, supporting the hypothesis that the protein is localized to these vesicle membranes. To date, there are very few reports describing species-specific splice variants. While identification of Mcoln1 is crucial to the development of mouse models for MLIV, the fact that there are two transcripts in mice suggests an additional or alternate function of the gene that may complicate phenotypic assessment.
PMCID: PMC88885  PMID: 11897010
23.  Active Immobilized Antibiotics Based on Metal Hydroxides1 
The water-insoluble hydroxides of zirconium (IV), titanium (IV), titanium (III), iron (II), vanadium (III), and tin (II) have been used to prepare insoluble derivatives of a cyclic peptide antibiotic by a facile chelation process. Testing of the antibacterial activities of the products against two gram-positive and two gram-negative bacteria showed that in the majority of cases the water-insoluble antibiotics remained active against those bacteria susceptible to the parent antibiotic. The power of the assay system has been extended by the novel use of colored organisms to aid determinations where the growth of normal organisms could not be distinguished from the appearance of the supporting material. Insoluble derivatives of neomycin, polymyxin B, streptomycin, ampicillin, penicillin G, and chloramphenicol were prepared by chelation with zirconium hydroxide, and these derivatives similarly reflected the antibacterial activities of the parent compounds. Several of the metal hydroxides themselves possess antibacterial activity due to complex formation with the bacteria. However, the use of selected metal hydroxides can afford a simple, inexpensive, and inert matrix for antibiotic immobilization, resulting in an antibacterial product that may possess slow-release properties. The mechanisms by which the metal hydroxide-antibiotic association-dissociation may occur are discussed.
PMCID: PMC429618  PMID: 949174
The Journal of Cell Biology  1970;47(3):568-576.
Exposure of Tetrahymena pyriformis to 7,500 or 10,000 psi of hydrostatic pressure for 2, 5, or 10 min intervals results in a change in cell shape and ciliary activity. Shape changes occur concurrently with a degradation of longitudinal microtubules in a posterior to anterior direction. High pressure also causes a disruption of ciliary activity. Fine structural analysis reveals a breakdown (presumably microtubule depolymerization) of the central ciliary microtubules. The depolymerization begins at the junction of the central ciliary microtubules with the axosome and progresses distally along the ciliary shaft for a distance of about 0.5 µ.
PMCID: PMC2108149  PMID: 5497538
25.  Fine Structure of Vibrio cholerae During Toxin Production 
Journal of Bacteriology  1969;100(3):1393-1401.
The fine structural changes associated with cell growth and toxin production have been examined in Vibrio cholerae strain 569B. No morphological alterations in the cell envelope are apparent during logarithmic growth with thin-section techniques. However, internal swelling, suggesting alteration of cell envelope permeability, is evident particularly during the late logarithmic and early stationary phases of growth. Certain extracellular material demonstrable with negative-stain techniques does appear during the period of toxin production. The possible origin of this material is discussed. The effects of high temperature (37 C) and aeration on cell structure are also examined.
PMCID: PMC250350  PMID: 5361220

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