Common femoral arterial access and arteriography in infants: Principles, pearls, and pitfalls.

Infant femoral arterial access is an essential part of interventional procedures, hemodynamic monitoring, and support of critically ill patients. Due to small luminal diameter, superficial location, mobility, and increased risk of vasospasm, dissection, and thrombosis, femoral artery access in the infant is a technically demanding procedure. The purpose of this manuscript is to describe an approach to successful common femoral arterial access and arteriography in infants including common pearls and pitfalls.

Semi-automatic segmentation and surface reconstruction of computed tomography images by using rotoscoping and warping techniques.

BACKGROUND: Quick and large-scale segmentation along with three-dimensional (3D) reconstruction is necessary to make precise 3D musculoskeletal models for surface anatomy education, palpation training, medical communication, morphology research, and virtual surgery simulation. However, automatic segmentation of the skin and muscles remain undeveloped. MATERIALS AND METHODS: Therefore, in this study, we developed workflows for semi-automatic segmentation and surface reconstruction, using rotoscoping and warping techniques. RESULTS: The techniques were applied to multi detector computed tomography images, which were optimised to quickly generate surface models of the skin and the anatomical structures underlying the fat tissue. CONCLUSIONS: The workflows developed in this study are expected to enable researchers to create segmented images and optimised surface models from any set of serially sectioned images quickly and conveniently. Moreover, these optimised surface models can easily be modified for further application or educational use.

Sectioned images and surface models of a cadaver head with reference to botulinum neurotoxin injection.

BACKGROUND: The aim of this study is to elucidate the anatomical considerations with reference to botulinum neurotoxin type A (BTX) injection, on sectioned images and surface models, using Visible Korean. These can be used for medical education and clinical training in the field of facial surgery. MATERIALS AND METHODS: Serially sectioned images of the head were obtained from a cadaver. Significant anatomic structures in the sectioned images were outlined and assembled to create a surface model. RESULTS: The PDF file (27.8 MB) of the stacked models can be accessed for free. The file can also be obtained from the authors by email. Using this file, important anatomical structures associated with the BTX injection can be investigated in the sectioned images. All surface models and stereoscopic structures related with the BTX injection are described in real time. CONCLUSIONS: We hope that these state-of-the-art sectioned images, outlined images, and surface models will assist students and trainees in acquiring a better understanding of the anatomy associated with the BTX injection.

Sectioned images and surface models of a cadaver for understanding the free vascularised anterior rib flap.

BACKGROUND: The purpose of this study is to describe the vascularised anterior rib flap on sectioned images and surface models using Visible Korean for medical education and clinical training in the field of mandibular reconstructive surgery. MATERIALS AND METHODS: Serially sectioned images of the thorax were obtained from a cadaver. Significant structures in the sectioned images were outlined and stacked to create a surface model. RESULTS: The PDF file (8.45 MB) of the assembled models can be downloaded for free from our website (http://vkh.ajou.ac.kr/Products/PDF/Vascularized_anterior_rib_flap.zip). In this file, important anatomical structures related to the vascularised anterior rib flap can be examined in the sectioned images. All surface models and stereoscopic structures of the vascularised anterior rib flap are expressed in real time. CONCLUSIONS: We hope that these state-of-the-art sectioned images, outlined images, and surface models will help students and trainees gain a better understanding of the anatomy of the vascularised anterior rib flap.

Accessible and informative sectioned images and surface models of the maxillofacial area for orthognathic surgery.

BACKGROUND: The aim of this study was to describe sectioned images and stereoscopic anatomic models of the maxillofacial area by using Visible Korean which are beneficial for medical education and clinical training in the field of orthognathic surgery. MATERIALS AND METHODS: Serially sectioned images of the maxillofacial area of a cadaver were created. Significant structures in the sectioned images were outlined and stacked to build surface models. RESULTS: Browsing software (95.1 MB) and portable document format (PDF) file (142 MB) that were constructed are freely downloadable from our website (http://anatomy.co.kr). In the browsing software, the names of structures associated with malocclusion and orthognathic surgery could be viewed on the sectioned images. In the PDF file, surface models and stereoscopic maxillofacial structures were displayed in real-time. CONCLUSIONS: The state-of-the-art sectioned images, outlined images, and surface models that were arranged and systematised in this study, may help students and trainees investigate the anatomy of the maxillofacial area for orthognathic surgery.

Segmentation and surface reconstruction of a cadaver heart on Mimics software.

The Visible Korean research team used Mimics software (Materialise, Leuven, Belgium) for the segmentation and subsequent surface reconstruction of heart structures using information obtained from sectioned images of a cadaver. Twenty-six heart components were outlined in advance on Photoshop (Adobe Systems, San Jose, CA, USA). By use of the Mimics, the outlined images were then browsed along with the vertical planes as well as the 3-dimensional surface models, which were immediately built by piling the images. Erroneous delineation was readily detected and revised until satisfactory heart models were acquired. The surface models and the selected sectioned images in horizontal, coronal, and sagittal planes were inputted into a PDF file, where any combinations of reconstructed constituents could be displayed and rotated by the user. Mimics software accelerated the segmentation and surface reconstruction of heart anatomical structures. Similar benefits hopefully result from various serial images of other organs. The PDF file, and plane and stereoscopic image data are being distributed to others, and should prove valuable for medical students and clinicians.

Investigation of bioequivalence of a new fixed-dose combination of acarbose and metformin with the corresponding loose combination as well as the drug-drug interaction potential between both drugs in healthy adult male subjects.

WHAT IS KNOWN AND OBJECTIVE: Both metformin and acarbose are recommended monotherapy and add-on therapy in type 2 diabetes mellitus (T2DM). A fixed-dose combination (FDC) of acarbose and metformin has been developed to reduce pill burden and potentially improve compliance. The current study investigated the bioequivalence of the acarbose/metformin FDC compared with the individual agents administered simultaneously (loose combination). Secondary endpoints were the safety and tolerability of the FDC and the potential for drug-drug interactions between acarbose and metformin. METHODS: A single-centre, randomized, open-label, four-period crossover study was conducted in healthy male Korean subjects aged 18-45 years. Following one-period balanced Williams design, participants were randomized to receive four single oral treatments on different study days separated by ≥7 days' washout. Treatments were as follows: (i) acarbose/metformin 50/500 mg FDC (test); (ii) acarbose 50 mg and metformin 500 mg as loose combination (reference); (iii) acarbose 50 mg; and (iv) metformin 500 mg. Serial blood samples were taken for glucose and insulin levels for 4 h after a sucrose load on the day before and day of study drug administration. Additionally, serial blood samples were taken for analysis of metformin levels for 24 h after each drug containing metformin. The area under the curve for 4 h post-test (AUC0-4 h ) and the maximal serum concentration (Cmax ) of plasma glucose and serum insulin were primary pharmacodynamic (PD) parameters, and Cmax , AUC0-last and AUC for metformin levels were primary pharmacokinetic (PK) parameters. The bioequivalence of the FDC to the loose combination was considered established if the 90% confidence intervals (CIs) of the baseline-adjusted PD parameter ratios (test vs. reference) for plasma glucose and the PK parameter ratios for metformin fell completely within current acceptance limits (0·8-1·25). RESULTS AND DISCUSSION: Thirty-three of 40 randomized subjects completed the study; five withdrew consent and two discontinued because of adverse events (AEs). The 24-h plasma concentration-time curves of metformin and the 4-h plasma glucose-time curves after acarbose/metformin FDC (test) and acarbose + metformin loose combination (reference) were almost superimposable. The geometric least squares (LS) mean of the RatioAUC and RatioCmax for plasma glucose after the FDC vs. loose combination, and the LS mean of the ratios in metformin AUC, AUC0-last and Cmax were close to unity, and the 90% CI of all these parameters fell within the predefined equivalence range of 0·8-1·25, confirming bioequivalence. The metformin AUC was reduced by 26% and Cmax by 34% after acarbose + metformin compared with metformin alone. Eight subjects (20·0%) reported AEs, but all were mild, and most were gastrointestinal, as expected for these agents. The incidence of AEs was not higher with the combinations vs. monotherapy. WHAT IS NEW AND CONCLUSION: These data demonstrate that the acarbose/metformin FDC is bioequivalent to the loose combination of these agents. Although acarbose slightly reduced the bioavailability of metformin, the accumulated evidence of the efficacy of this combination implies that this is clinically irrelevant. The observed AE profile was consistent with the established knowledge on the safety of the two drugs.

The structural biochemistry of the superoxide dismutases.

The discovery of superoxide dismutases (SODs), which convert superoxide radicals to molecular oxygen and hydrogen peroxide, has been termed the most important discovery of modern biology never to win a Nobel Prize. Here, we review the reasons this discovery has been underappreciated, as well as discuss the robust results supporting its premier biological importance and utility for current research. We highlight our understanding of SOD function gained through structural biology analyses, which reveal important hydrogen-bonding schemes and metal-binding motifs. These structural features create remarkable enzymes that promote catalysis at faster than diffusion-limited rates by using electrostatic guidance. These architectures additionally alter the redox potential of the active site metal center to a range suitable for the superoxide disproportionation reaction and protect against inhibition of catalysis by molecules such as phosphate. SOD structures may also control their enzymatic activity through product inhibition; manipulation of these product inhibition levels has the potential to generate therapeutic forms of SOD. Markedly, structural destabilization of the SOD architecture can lead to disease, as mutations in Cu,ZnSOD may result in familial amyotrophic lateral sclerosis, a relatively common, rapidly progressing and fatal neurodegenerative disorder. We describe our current understanding of how these Cu,ZnSOD mutations may lead to aggregation/fibril formation, as a detailed understanding of these mechanisms provides new avenues for the development of therapeutics against this so far untreatable neurodegenerative pathology.

Differentiation between malignant and benign pathologic fractures with F-18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography.

OBJECTIVE: To evaluate the efficacy of F-18-fluoro-2-deoxy-D: -glucose positron emission tomography/computed tomography (FDG PET/CT) in differentiating malignant from benign pathologic fractures. MATERIALS AND METHODS: F-18 FDG PET/CT was performed on 34 patients with pathologic fractures between May 2004 and June 2007. Fractures were located in tubular bones (26), in the pelvis (six), in the spine (one) and in a rib (one). The FDG uptake pattern at the fracture site was described, whether FDG uptake occurred in the marrow or cortex and soft tissue. Maximum standardized uptake values (SUVmax, the largest value at the region of interest) were measured at the fracture site, including cortical bone, bone marrow and soft tissue. As a reference standard, biopsy was used for 12 patients and clinical follow-up for 22 patients. Sensitivity, specificity and diagnostic accuracy of PET/CT were calculated. RESULTS: There were 19 malignant and 15 benign fractures. In the malignant fractures, PET/CT demonstrated high (mean SUVmax 12.0, range 4.3 to 45.7) F-18 FDG uptake in bone marrow in most cases (17 of 19). In benign fractures, there was low FDG uptake (mean SUVmax 2.9, range 0.6 to 5.5) within cortical bone or adjacent soft tissue around the fracture, rarely in the marrow. There were significant differences in the pattern of intramedullary FDG uptake (P < 0.001) and in the mean SUVmax (P < 0.01) between malignant and benign fractures. The sensitivity, specificity and diagnostic accuracy of F-18 FDG PET/CT were 89.5%, 86.7% and 88.2%, respectively, with a cut-off SUVmax set at 4.7. The time interval between fracture and PET/CT did not significantly influence FDG uptake at the fracture site. CONCLUSION: F-18 FDG PET/CT reliably differentiated between malignant and benign fractures based on the SUVmax and based on medullary uptake, which was characteristic for malignant fractures.

Enhanced Ih depresses rat entopeduncular nucleus neuronal activity from high-frequency stimulation or raised Ke+.

High-frequency stimulation (HFS) is used to treat a variety of neurological diseases, yet its underlying therapeutic action is not fully elucidated. Previously, we reported that HFS-induced elevation in [K(+)](e) or bath perfusion of raised K(e)(+) depressed rat entopeduncular nucleus (EP) neuronal activity via an enhancement of an ionic conductance leading to marked depolarization. Herein, we show that the hyperpolarization-activated (I(h)) channel mediates the HFS- or K(+)-induced depression of EP neuronal activity. The perfusion of an I(h) channel inhibitor, 50 microM ZD7288 or 2 mM CsCl, increased input resistance by 23.5 +/- 7% (ZD7288) or 35 +/- 10% (CsCl), hyperpolarized cells by 3.4 +/- 1.7 mV (ZD7288) or 2.3 +/- 0.9 mV (CsCl), and decreased spontaneous action potential (AP) frequency by 51.5 +/- 12.5% (ZD7288) or 80 +/- 13.5% (CsCl). The I(h) sag was absent with either treatment, suggesting a block of I(h) channel activity. Inhibition of the I(h) channel prior to HFS or 6 mM K(+) perfusion not only prevented the previously observed decrease in AP frequency, but increased neuronal activity. Under voltage-clamp conditions, I(h) currents were enhanced in the presence of 6 mM K(+). Calcium is also involved in the depression of EP neuronal activity, since its removal during raised K(e)(+) application prevented this attenuation and blocked the I(h) sag. We conclude that the enhancement of I(h) channel activity initiates the HFS- and K(+)-induced depression of EP neuronal activity. This mechanism could underlie the inhibitory effects of HFS used in deep brain stimulation in output basal ganglia nuclei.

Transition to seizures in the isolated immature mouse hippocampus: a switch from dominant phasic inhibition to dominant phasic excitation.

The neural dynamics and mechanisms responsible for the transition from the interictal to the ictal state (seizures) are unresolved questions in epilepsy. It has been suggested that a shift from inhibitory to excitatory GABAergic drive can promote seizure generation. In this study, we utilized an experimental model of temporal lobe epilepsy which produces recurrent seizure-like events in the isolated immature mouse hippocampus (P8-16), perfused with low magnesium ACSF, to investigate the cellular dynamics of seizure transition. Whole-cell and perforated patch recordings from CA1 pyramidal cells and from fast- and non-fast-spiking interneurons in the CA1 stratum oriens hippocampal region showed a change in intracellular signal integration during the transition period, starting with dominant phasic inhibitory synaptic input, followed by dominant phasic excitation prior to a seizure. Efflux of bicarbonate ions through the GABA A receptor did not fully account for this excitation and GABAergic excitation via reversed IPSPs was also excluded as the prime mechanism generating the dominant excitation, since somatic and dendritic GABA A responses to externally applied muscimol remained hyperpolarizing throughout the transition period. In addition, abolishing EPSPs in a single neuron by intracellularly injected QX222, revealed that inhibitory synaptic drive was maintained throughout the entire transition period. We suggest that rather than a major shift from inhibitory to excitatory GABAergic drive prior to seizure onset, there is a change in the interaction between afferent synaptic inhibition, and afferent and intrinsic excitatory processes in pyramidal neurons and interneurons, with maintained inhibition and increasing, entrained 'overpowering' excitation during the transition to seizure.

High frequency stimulation or elevated K+ depresses neuronal activity in the rat entopeduncular nucleus.

High frequency stimulation (HFS) is applied to many brain regions to treat a variety of neurological disorders/diseases, yet the mechanism(s) underlying its effects remains unclear. While some studies showed that HFS inhibits the stimulated nucleus, others report excitation. In this in vitro study, we stimulated the rat globus pallidus interna (entopeduncular nucleus, EP), a commonly stimulated area for Parkinson's disease, to investigate the effect of HFS-induced elevation of extracellular potassium (K(+)(e)) on rat EP neuronal activity. Whole-cell patch-clamp recordings and [K(+)](e) measurements were obtained in rat EP brain slices before, during and after HFS. After HFS (150 Hz, 10 s), [K(+)](e) increased from 2.5-9.6+/-1.4 mM, the resting membrane potential of EP neurons depolarized by 11.1+/-2.5 mV, spiking activity was significantly depressed, and input resistance decreased by 25+/-6%. The GABA(A) receptor blocker, gabazine, did not prevent these effects. The bath perfusion of 6 or 10 mM K(+), with or without synaptic blockers, mimicked the HFS-mediated effects: inhibition of spike activity, a 20+/-9% decrease in input resistance and a 17.4+/-3.0 mV depolarization. This depolarization exceeded predicted values of elevated [K(+)](e) on the resting membrane potential. A depolarization block did not fully account for the K(+)-induced inhibition of EP neuronal activity. Taken together, our results show that HFS-induced elevation of [K(+)](e) decreased EP neuronal activity by the activation of an ion conductance resulting in membrane depolarization, independent of synaptic involvement. These findings could explain the inhibitory effects of HFS on neurons of the stimulated nucleus.

Primary clear cell sarcoma of bone.

Clear cell sarcoma is a rare soft tissue sarcoma of young adults with melanocytic differentiation. It occurs predominantly in the soft tissue of extremities, typically involving tendons and aponeuroses. Primary clear cell sarcoma of bone is extremely rare. We report a case of primary clear cell sarcoma of the right first metatarsal in a 48-year-old woman and provide a literature review of the entity.

Fibrosarcoma in bizarre parosteal osteochondromatous proliferation.

Bizarre parosteal osteochondromatous proliferation (BPOP) is a rare benign lesion predominantly involving the small bones of the hands and feet. Malignant transformation in BPOP has not been documented in the English literature. This report presents the coexistence of fibrosarcoma with BPOP in the right distal fibula of an 18-year-old woman.

Surface modification of polyhydroxyalkanoate films and their interaction with human fibroblasts.

A poly(3-hydroxybutylate-co-hydroxyvalerate) (PHA) film containing 34 mol.% 3-hydroxyvalerate (Biopol D600P) was prepared by the solvent cast method using a 10 wt.% chloroform solution of PHA. The PHA film was exposed to an oxygen plasma glow discharge to produce peroxides on its surfaces. These peroxides were then used as catalysts for the polymerization of acrylic acid (AA) in order to prepare carboxyl group-introduced PHA (PHA-C). Insulin-immobilized PHA was prepared using the coupling reaction of PU-C with insulin. The surface-modified PHAs were then characterized by attenuated total reflection Fourier transform infrared spectroscopy, electron spectroscopy for chemical analysis, and a contact angle goniometer. The amounts of insulin directly coupled to the carboxyl groups on PHA-C and coupled to the terminus amino groups of the grafted polyethylene oxide were 2.9 and 0.8 microg cm(-2), respectively. The PHA water contact angle (75 degrees ) decreased with AA grafting (33 degrees ) and insulin immobilization (31 degrees ), thereby exhibiting the increased hydrophilicity of the modified PHAs. When compared with PHA and PHA-C, the proliferation of human fibroblasts in the presence of serum was significantly accelerated on the insulin-immobilized PHAs.

Large tumor endoprostheses and extracortical bone-bridging: 28 patients followed 10-20 years.

Aseptic loosening is a common cause of failure in large tumor endoprostheses. The concept of extracortical bone-bridging was developed to tackle the problem of loosening. New bone which forms across the junction of the bone-prosthesis junction is believed to improve fixation by controlling the transfer of stresses across the junction as well as by giving additional stability to the prosthesis. We present the long-term experience with this concept following major reconstruction after tumor and non-tumor conditions in 31 patients. The overall function was good for upper and lower limb prostheses. Most patients had extracortical bone bridging which was maintained for over 10 years. In 1/3 of patients this involved over 75% of the prosthetic circumference. Prosthetic survival was best with intercalary devices, followed by proximal femoral and distal femoral prostheses. Survival of prostheses in young active patients was similar to that reported in older patients undergoing primary joint replacement.

Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily.

To clarify the key role of Rad50 in DNA double-strand break repair (DSBR), we biochemically and structurally characterized ATP-bound and ATP-free Rad50 catalytic domain (Rad50cd) from Pyrococcus furiosus. Rad50cd displays ATPase activity plus ATP-controlled dimerization and DNA binding activities. Rad50cd crystal structures identify probable protein and DNA interfaces and reveal an ABC-ATPase fold, linking Rad50 molecular mechanisms to ABC transporters, including P glycoprotein and cystic fibrosis transmembrane conductance regulator. Binding of ATP gamma-phosphates to conserved signature motifs in two opposing Rad50cd molecules promotes dimerization that likely couples ATP hydrolysis to dimer dissociation and DNA release. These results, validated by mutations, suggest unified molecular mechanisms for ATP-driven cooperativity and allosteric control of ABC-ATPases in DSBR, membrane transport, and chromosome condensation by SMC proteins.

Computerized stereochronoscopy and alternation flicker to detect optic nerve head contour change.

PURPOSE/BACKGROUND: Stereochronoscopy, a technique previously explored but abandoned for glaucoma diagnosis, viewed optic nerve images acquired at separate points in time as if a stereo pair. Prior efforts to exploit this technique were impaired by a lack of superimposability for sequential optic nerve images. We investigated computerized registration techniques for aligning sequential, monoscopic optic disc images to facilitate sensitive detection of optic nerve head contour changes in glaucoma. DESIGN: Algorithm and software development. Comparisons with standard techniques. MATERIALS: Existing patient records from the Glaucoma Service, Scheie Eye Institute, University of Pennsylvania. METHODS: Two sets of optic disc photographs, separated in time by 1 to 18 years, of 25 eyes with and without glaucomatous optic disc progression were digitized. We developed custom software for accurate image alignment. Change in disc morphology was then judged by digital stereochronoscopy and user-controlled alternation flicker of superimposed, time-separated images on a computer monitor. Comparisons were made with standard stereoscopic comparison. MAIN OUTCOME MEASURE: Identification of change or no change in optic nerve head contour for images acquired at separate points in time. RESULTS: Image processing and registration permits accurate alignment of optic disc photographs. Alternation flicker of superimposed, sequential images facilitates image comparison and detection of change as indicated by change in vessel position, color, and other cues for contour change. A high concordance was found between standard stereoscopic comparison and alternation flicker. In several cases, reinspection of stereo comparison led to a revised judgment on the basis of disc changes rendered more obvious with alternation flicker. Digital stereochronoscopy was less concordant with standard techniques. CONCLUSIONS: Digital image processing techniques and alternation flicker provide a simple, sensitive, software-based method for detecting glaucomatous optic disc change.

Grading, image analysis, and stereopsis of digitally compressed fundus images.

PURPOSE: To investigate the effects of image digitization and compression on the ability to identify and quantify features in color fundus photographs. METHODS: Color fundus photographs were digitized as tagged image file format (TIFF) and high-compression (80:1) and low-compression (30:1) joint photographic experts group (JPEG) images. Rerendered images were subjected to standard grading protocols developed for a clinical trial, and digitized images were subjected to image analysis software for drusen identification and quantitation. Re-created stereoscopic images were compared subjectively with originals. RESULTS: Original, TIFF, and low-compression (30:1) JPEG images were virtually indistinguishable when subjected to close scrutiny with magnification. The overall quality of high-compression (80:1) JPEG images and images digitized at 500 dots per inch was markedly reduced. Protocol grading of original and digitized images was highly concordant within the repeatability of multiple grading of original images. The area subtended by drusen differed by less than 1.0% for all uncompressed and compressed image pairs quantified. Stereoscopic information was accurately preserved when compared with originals for TIFF and low-compression JPEG images. CONCLUSIONS: Fundus images can be digitized and stored with significant compression while preserving stereopsis and image quality suitable for quantitative image analysis and semiquantitative grading. Low-compression (30:1) JPEG images may be suitable for archiving and telemedical applications.

Structure of the major peanut allergen Ara h 1 may protect IgE-binding epitopes from degradation.

In the past decade, there has been an increase in allergic reactions to peanut proteins, sometimes resulting in fatal anaphylaxis. The development of improved methods for diagnosis and treatment of peanut allergies requires a better understanding of the structure of the allergens. Ara h 1, a major peanut allergen belonging to the vicilin family of seed storage proteins, is recognized by serum IgE from >90% of peanut-allergic patients. In this communication, Ara h 1 was shown to form a highly stable homotrimer. Hydrophobic interactions were determined to be the main molecular force holding monomers together. A molecular model of the Ara h 1 trimer was constructed to view the stabilizing hydrophobic residues in the three dimensional structure. Hydrophobic amino acids that contribute to trimer formation are at the distal ends of the three dimensional structure where monomer-monomer contacts occur. Coincidentally, the majority of the IgE-binding epitopes are also located in this region, suggesting that they may be protected from digestion by the monomer-monomer contacts. On incubation of Ara h 1 with digestive enzymes, various protease-resistant fragments containing IgE-binding sites were identified. The highly stable nature of the Ara h 1 trimer, the presence of digestion resistant fragments, and the strategic location of the IgE-binding epitopes indicate that the quaternary structure of a protein may play a significant role in overall allergenicity.