First aid step 2 clinical skills pdf,how to reduce swelling in hands and feet during pregnancy hurt,what is american education reform roadmap,best reference books for ssc cgl exam - PDF 2016

23.12.2015
First Aid™ Cases for the USMLE Step 1 features 400 well-illustrated cases to help you relate basic science concepts to clinical situations. General Principles, Behavioral Science, Biochemistry, Microbiology and Immunology, Chapter 4. What summary usmle step 2ck experiences ten successful test-takers scored 250-270, including advice preparation resources.
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Science, Technology and Medicine open access publisher.Publish, read and share novel research. Current Applications of 5–ALA in Glioma Diagnostics and TherapyLei Teng1, 2, Mitsutoshi Nakada1, Yutaka Hayashi1, Takeshi Yoneyama3, Shi-Guang Zhao2 and Jun-Ichiro Hamada1[1] Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa,, Japan[2] Department of Neurosurgery, The First Clinical College of Harbin Medical University, Harbin,, China[3] College of Science and Engineering, Kanazawa University, Kanazawa,, Japan1. H Aydin, I Sillenberg, H Von Lieven, 2001Patterns of failure following CT-based 3-D irradiation for malignant glioma.
E Blake, A Curnow, 2010The hydroxypyridinone iron chelator CP94 can enhance PpIX-induced PDT of cultured human glioma cells. E Buytaert, M Dewaele, P Agostinis, 2007Molecular effectors of multiple cell death pathways initiated by photodynamic therapy. D Coluccia, J Fandino, M Fujioka, S Cordovi, C Muroi, H Landolt, 2010Intraoperative 5-aminolevulinic-acid-induced fluorescence in meningiomas. L Guyon, M Ascencio, P Collinet, S Mordon, 2012Photodiagnosis and photodynamic therapy of peritoneal metastasis of ovarian cancer. M Hefti, I Albert, V Luginbuehl, 2012Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells. T Kuroiwa, Y Kajimoto, T Ohta, 1998Development of a fluorescein operative microscope for use during malignant glioma surgery- A technical note and preliminary report. T Kuroiwa, Y Kajimoto, T Ohta, 2001Development and clinical application of near-infrared surgical microscope: preliminary report.
F Lefranc, N Sadeghi, I Camby, T Metens, O Dewitte, R Kiss, 2006Present and potential future issues in glioblastoma treatment.
H Liao, K Shimaya, K Wang, T Maruyama, M Noguchi, Y Muragaki, E Kobayashi, H Iseki, I Sakuma, 2008Combination of intraoperative 5-aminolevulinic acid-induced fluorescence and 3-D MR imaging for guidance of robotic laser ablation for precision neurosurgery.
M Loning, H Diddens, W Kupker, K Diedrich, G Huttmann, 2004Laparoscopic fluorescence detection of ovarian carcinoma metastases using 5-aminolevulinic acid-induced protoporphyrin IX. U Pichlmeier, A Bink, G Schackert, W Stummer, 2008Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. W Stummer, S Stocker, A Novotny, A Heimann, O Sauer, O Kempski, N Plesnila, J Wietzorrek, H.
K Takahashi, N Ikeda, N Nonoguchi, Y Kajimoto, S Miyatake, Y Hagiya, S Ogura, H Nakagawa, T Ishikawa, T Kuroiwa, 2011Enhanced expression of coproporphyrinogen oxidase in malignant brain tumors: CPOX expression and 5-ALA-induced fluorescence. M Toda, 2008Intraoperative navigation and fluorescence imagings in malignant glioma surgery. S Utsuki, H Oka, S Sato, S Shimizu, S Suzuki, Y Tanizaki, K Kondo, Y Miyajima, K Fujii, 2007Histological examination of false positive tissue resection using 5-aminolevulinic acid-induced fluorescence guidance. S Utsuki, H Oka, S Sato, S Suzuki, S Shimizu, S Tanaka, K Fujii, 2006Possibility of using laser spectroscopy for the intraoperative detection of nonfluorescing brain tumors and the boundaries of brain tumor infiltrates. G Widhalm, S Wolfsberger, G Minchev, A Woehrer, M Krssak, T Czech, D Prayer, S Asenbaum, J.
Pharmacology, Organ Systems, Cardiovascular System, Endocrine System, Gastrointestinal System, Hematology and Oncology, Musculoskeletal System and Connective Tissue, Neurology and Psychiatry, Renal System, Reproductive System, Respiratory System. S Eljamel, C Goodman, H Moseley, 2008ALA and Photofrin fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre Phase III randomised controlled trial.
G Hahn, C Ell, 1998Photodynamic ablation of high-grade dysplasia and early cancer in Barrett’s esophagus by means of 5-aminolevulinic acid. A Shibata, N Miyoshi, N Ogawa, S Miyatake, Y Otsuki, T Kuroiwa, 2007Massive apoptotic cell death of human glioma cells via a mitochondrial pathway following 5-aminolevulinic acid-mediated photodynamic therapy.
I Miyatake, T Ichioka, M Miyashita, H Tanaka, M Tsuji, 2007Use of 5-aminolevulinic acid in fluorescence-guided resection of meningioma with high risk of recurrence- Case report. T Moesta, 2008Silencing of human ferrochelatase causes abundant protoporphyrin-IX accumulation in colon cancer.
E Liao, M Noguchi, T Maruyama, Y Muragaki, E Kobayashi, H Iseki, I Sakuma, 2012An integrated diagnosis and therapeutic system using intra-operative 5-aminolevulinic-acid-induced fluorescence guided robotic laser ablation for precision neurosurgery. P Panciani, M Fontanella, D Garbossa, A Agnoletti, A Ducati, M Lanotte, 2012aminolevulinic acid and neuronavigation in high-grade glioma surgery: results of a combined approach.
J Piotrowski, J Marczak, A Nawrocka, A Antczak, P Gorski, 2004Inhalations of 5-ALA in photodynamic diagnosis of bronchial cancer. J Reulen, 2000Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients.
J Reulen, 1998aTechnical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue. J Reulen, 1998bIn vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid. A Hainfellner, E Knosp, 2010Aminolevulinic Acid Is a Promising Marker for Detection of Anaplastic Foci in Diffusely Infiltrating Gliomas With Nonsignificant Contrast Enhancement. Chapters are keyed to Tao Le’s First Aid for the USMLE Step 1 allowing you to simultaneously study cases and high-yield facts. Consulta nuestras Condiciones de uso y nuestra Politica de privacidad para mas informacion.
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The figure illustrates 5-ALA is converted to PpIX in malignant gliomas via an oral-intake of exogenous 5-ALA. The first step of heme synthesis occurs in the mitochondrial matrix with the condensation of succinyl CoA and glycine by ALA synthase to generate ALA.
The infiltrative nature of malignant glioma makes complete resection difficult, as tumor margins are unclear.
H Pottier, 1992Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy.
L Morris, T Belichenko, 2002The role of apoptosis in response to photodynamic therapy: what, where, why, and how. J Reulen, 1998cIntraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence. In the presence of an appropriate light source with the specific wavelength, PpIX fluorescence acts bimodal function; fluorescence diagnostic marker and 5-ALA-PDT. Oligopeptide transporters (PEPT1 or PEPT2) are responsible for the import of exogenous ALA from the extracellular space into the cytoplasm of target cells. K Ray, 2007Aminolevulinic acid-based photodynamic therapy suppressed survival factors and activated proteases for apoptosis in human glioblastoma U87MG cells. R Glioma, 2009Five-Aminolevulinic Acid for Fluorescence-Guided Resection of Recurrent Malignant Gliomas: A Phase Ii Study. E Giercksky, K Berg, 2009Photochemical internalization (PCI) in cancer therapy: from bench towards bedside medicine. I Hamada, 2011Silencing of ferrochelatase enhances 5-aminolevulinic acid-based fluorescence and photodynamic therapy efficacy.
G Malkin, 1989Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. The use of fluorescence to delineate tumor margins intraoperatively has emerged as a safe and effective tool for increasing the extent of resection.
S Fluorescence-guided, surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Then, coproporphyrinogen III is transported back into the mitochondrial intermembrane space (IMS), possibly via ABCB6, where it is converted to protoporphyrinogen by protoporphyrinogen III oxidase. Therefore, methods that easily detect tumor margins during surgery would be extremely beneficial. The conversion of protoporphyrinogen to PpIX by protoporphyrinogen oxidase, its transport into the matrix and the addition of Fe2+ by ferrochelatase (FECH) to generate heme are coupled processes.
The transporter responsible for heme transfer across the outer mitochondrial membrane remains unidentified. Intraoperative tumor fluorescence provided by the chemical compound 5-ALA assists surgeons in identifying the true tumor margin during resection of glial neoplasms, consequently increasing the extent of the resection.
Heme formed from porphyrin is catabolized to biliverdin by the microsomal enzyme heme oxygenase 1. 5-ALA is the most studied fluorescer and has been used in many clinical trials, including a multicenter phase III randomized controlled trial. W Roberts, 2011Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker. ABCG2 transports porphyrins across the plasma membrane to maintain intracellular porphyrin homeostasis.4. Photodynamic therapy (PDT) is a treatment modality that takes advantage of the cytotoxic effects induced by a photosensitizer and light in the presence of oxygen (Norum et al., 2009). G Rainov, 2012Increased Expression of ABCB6 Enhances Protoporphyrin IX Accumulation and Photodynamic Effect in Human Glioma.
This photodamage may be due to direct cytotoxicity, vascular damage, and inflammatory and immunological responses (Castano et al., 2006).
The relative importance of these pathways to the therapeutic effects depends on the tissue oxygenation, photosensitizer formulation, distribution, and light dosimeter (Norum et al., 2009).
Activation of PpIX by red light in combination with oxygen causes cell death by apoptosis and necrosis through the release of cytotoxic singlet oxygen (Peng et al., 1997). This tool may aid in overcoming the hurdle of residual tumor cells after traditional neurosurgery.
Application of 5-ALA-PDT has been emerging as a new field and is expected to create a major breakthrough in addressing several unsolved medical issues, especially photokilling of residual neoplastic cells. Developing technologies such as fluorescence operation-systems to enhance endogenous fluorescence has fairly recently been shown to delineate brain tumor margins intraoperatively (Babu & Adamson, 2012). 5-ALA fluorescence-guided resection shows great promise for furthering our surgical abilities and will become the standard of care for patients diagnosed with malignant glioma in the foreseeable future. The following review analyzes the recent literature in an effort to describe how these modalities involving 5-ALA in glioma diagnostics and therapy can and should be used in the treatment of patients with glioma. Each cell metabolizes 5-ALA along a set pathway toward heme production, inducing the synthesis of the endogenous fluorescent molecule, PpIX, through metabolic conversion in the mitochondria (Bottomley & Muller-Eberhard, 1988).
When PpIX emits peak fluorescence at 635 nm with a peak excitation wavelength at 405 nm, it is observed as a red light through a filter that allows this wavelength to pass.
In the USA, it has been used with the approval of the Food and Drug Administration (FDA) as a therapeutic drug for solar keratosis. Its use has not yet been approved by the pharmaceutical authority in Japan, and it is only used after obtaining approval from the ethics committee of the respective institutes.
The tumor tissue concentration of the fluorescent dye peaks at 2–6 hours after oral administration and disappears by 12 hours. Administration of antacid should be avoided at the time of oral administration because the dye is easily decomposed in the presence of alkali, and use of 5-ALA is contraindicated in cases of porphyria, a genetic disease. When given orally, 5-ALA has been shown to produce fluorescence in glial neoplasms both in vitro and in vivo (Blake & Curnow, 2010). In addition, the fluorescence of PpIX is itself cytotoxic and has the potential for use as an adjuvant photodynamic therapy for neoplastic tissue that cannot be safely resected (Sherman et al., 2011).


Since the administered 5-ALA is excreted into the urine within 24 hours after oral administration and does not remain in the skin, the occurrence of photosensitivity can be adequately prevented by avoiding sun exposure for approximately 24 hours after administration.3. Heme biosynthesis consists of a series of enzyme-catalyzed steps, involving 5-aminolevulinate synthases 1 and 2, 5-aminolevulinate dehydratase, hydroxymethylbilane synthase, uroporphyrinogen III synthase, uroporphyrinogen decarboxylase, coproporphyrinogen oxidase (CPOX), protoporphyrinogen oxidase, and ferrochelatase (FECH). ABCG2 transports porphyrins across the plasma membrane to maintain intracellular porphyrin homeostasis.Porphyrins are synthesized from glycine and succinyl CoA via a series of enzymatic reactions. Because of the presence of the blood-brain barrier (BBB), 5-ALA given via the oral route does not usually enter the normal brain tissue. However, it can easily pass through the disrupted BBB found in the glioma tissue (Stummer et al., 2003). PpIX that accumulates in the intracellular compartments of tumor cells exhibits red fluorescence under excitation light of an appropriate wavelength (Takahashi et al., 2011).
PpIX-accumulating tumor cells can be visually discerned intraoperatively from the surrounding normal cells that accumulate PpIX to a much lesser extent. To date, little is known about the molecular mechanisms underlying PpIX accumulation in malignant brain tumors after administration of 5-ALA; despite this, in the past decade, studies on ALA focusing on the mechanism of 5-ALA uptake in glioma tissue have been conducted by many research groups.
Previously, our group revealed significantly greater down-regulation of FECH expression in glioblastomas than in normal brain tissues and that FECH plays a role in the metabolism of 5-ALA in glioma (Teng et al., 2011). Therefore, they assumed that both the induction of the CPOX gene and the inhibition of ABCG2 would increase 5-ALA-induced PpIX accumulation and thereby enhance the efficacy of 5-ALA-PDT in malignant brain tumors.
Further studies are required to explore the detailed mechanism of 5-ALA uptake and improve our knowledge concerning 5-ALA biology in gliomas.4.
5–ALA guided neurosurgeryMany previous reports describing prognostic factors in patients with malignant gliomas indicate that outcome is associated with the completeness of tumor removal (Stummer et al., 1998a). Improving the prognosis of glioma patients cannot be achieved without considerable effort to remove as much as of the lesion as possible. Since glioma tissue is not easily recognized intraoperatively, methods that easily detect tumor margins during surgery would be extremely beneficial. Subsequently, they performed a prospective study in 52 glioblastoma patients and identified the usefulness of 5-ALA-induced tumor fluorescence for guiding tumor resection. The marginal area containing infiltrating glioma cells shows vague fluorescence because the density of the glioma cells in these areas is low and heterogeneous, resulting in insufficient 5-ALA uptake and PpIX accumulation (Utsuki et al., 2006).
Therefore, more objective and quantitative indicators need to be established for neurosurgeons to improve intraoperative identification of tumor margins.
5–ALA mediated-PDTPDT is a tool for the treatment of certain cancerous and pre-cancerous conditions, especially in the field of dermatology (Buytaert et al., 2007).
5-ALA-PDT is a novel treatment modality for early or superficial cancers, as well as a palliative treatment to a certain extent, that triggers a photodynamic effect similar to that of light in the visible range to produce a rapid PDT response in the targeted tissue.
Recent studies have shown that 5-ALA-PDT-induced photodamage causes mitochondrial and nuclear DNA damage.
Unfortunately, current 5-ALA-PDT protocols have yet to be widely established in clinical treatment for glioma.
This may be partly due to limitations in current PDT regimens and partly due to the therapeutic efficacy of 5-ALA-PDT in preclinical settings (Teng et al., 2011). The reason for 5-ALA-PDT not being standard treatment in malignant glioma may be multifactorial, including the lack of randomized controlled trials and an optimal 5-ALA-PDT regimen.
Generally, PDT efficacy depends on parameters such as the photosensitizing agent, irradiance and timing, oxygen, photosensitizer concentration, and different pathologic grade glioma tissue sensitivity to the PDT effect (Teng et al., 2011).
The efficacy of 5-ALA-PDT may also be limited by reduced penetration of appropriate light through the target tissue and local acute phototoxicity to normal surrounding brain tissue (Norum et al., 2009).
In addition, post-treatment edema and long-lasting skin photosensitivity after PDT of brain tumors are potentially challenging side effects that neurosurgeons have to deal with.
Regarding the specificity of PDD for glioma surgery, new techniques allowing more specific accumulation of PpIX in target tumor cells need to be developed. Further studies are required for screening available and specific glioma antigens that are strongly expressed in glioma tissues, but not in normal brain tissues. 5-ALA labeled with antibodies against glioma-specific antigens may be useful in increasing the accumulation of PpIX and the specificity of PDD in glioma tissues. If the specificity and selectivity of 5-ALA-PDT could be improved in glioma tissue, 5-ALA-PDT would certainly be regarded as a promising and competitive alternative in glioma treatment.6.
PerspectiveIn this review, we focused on the 5-ALA agent as a potential treatment modality for patients with malignant glioma. 5-ALA-induced fluorescence is a useful intraoperative tool for the visualization of glioma tissue, and 5-ALA-PDT is a promising and alternative adjuvant therapy for photokilling residual neoplastic cells. Although impressive advances in the application of 5-ALA to glioma have been made from many clinical trials, this evolving field still faces important challenges. For example, single imaging in solid malignant glioma tissue with all of these features is not sufficient.
Furthermore, more objective indicators to measure quantitative PpIX concentrations intraoperatively in the brain tumor margin need to be established. In the future, laboratory and clinical studies should be devoted to 5-ALA-PDT in conjunction with the use of other therapies, which will have maximal effect on the residual tumor after resection.
This multiple adjuvant therapy should enhance specificity and allow lowering of the total PDT dose, while still increasing the therapeutic efficacy of PDT. Other proposals should adjust the current PDT treatment regimens, modify the existing photosensitizer, or develop new and more specific photosensitizers.



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