bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of diazepam on growth hormone secretion in abstinent alcoholic men
Authors: VESCOVI P. P. , COIRO V.
Published: July 2002

The present study was performed in order to establish, with a simple and safe neuroendocrinological test, whether alcoholism is associated with alterations in sensitivity to benzodiazepines. For this purpose, we tested the stimulatory effects of diazepam on GH secretion. An intravenous bolus of 10 mg diazepam was injected in 51 (33–51‐year‐old) alcoholic men after at least 5 weeks of abstinence and in 20 age‐ and weight‐matched normal controls. On a different occasion, a control test with placebo (physiological saline) was performed in the same subjects. Diazepam but not placebo administration induced a striking increase of GH secretion in the normal controls. In contrast, neither diazepam nor placebo treatment significantly changed the basal serum GH levels in alcoholic men. These data show that alcoholism is associated with disrupted benzodiazepine activity on the hypothalamic‐pituitary control of GH secretion. The simplicity of the diazepam GH‐releasing test makes the drug suitable for clinical research in alcoholism.
Cell Cycle Regulation of the Replication Licensing System: Involvement of a Cdk-dependent Inhibitor
Authors: Mahbubani Hiro M. , Chong James P.J. , Chevalier Stephane , Thömmes Pia , Blow J. Julian
Published: July 2002

The replication licensing factor (RLF) is an essential initiation factor that is involved in preventing re-replication of chromosomal DNA in a single cell cycle. In Xenopus egg extracts, it can be separated into two components: RLF-M, a complex of MCM/P1 polypeptides, and RLF-B, which is currently unpurified. In this paper we investigate variations in RLF activity throughout the cell cycle. Total RLF activity is low in metaphase, due to a lack of RLF-B activity and the presence of an RLF inhibitor. RLF-B is rapidly activated on exit from metaphase, and then declines during interphase. The RLF inhibitor present in metaphase extracts is dependent on the activity of cyclin-dependent kinases (Cdks). Affinity depletion of Cdks from metaphase extracts removed the RLF inhibitor, while Cdc2/cyclin B directly inhibited RLF activity. In metaphase extracts treated with the protein kinase inhibitor 6-dimethylaminopurine (6-DMAP), both cyclin B and the RLF inhibitor were stabilized although the extracts morphologically entered interphase. These results are consistent with studies in other organisms that invoke a key role for Cdks in preventing re-replication of DNA in a single cell cycle.
Targeting of Chitin Synthase 3 to Polarized Growth Sites in Yeast Requires Chs5p and Myo2p
Authors: Santos Beatriz , Snyder Michael
Published: July 2002

Chitin is an essential structural component of the yeast cell wall whose deposition is regulated throughout the yeast life cycle. The temporal and spatial regulation of chitin synthesis was investigated during vegetative growth and mating of Saccharomyces cerevisiae by localization of the putative catalytic subunit of chitin synthase III, Chs3p, and its regulator, Chs5p. Immunolocalization of epitope-tagged Chs3p revealed a novel localization pattern that is cell cycledependent. Chs3p is polarized as a diffuse ring at the incipient bud site and at the neck between the mother and bud in small-budded cells; it is not found at the neck in large-budded cells containing a single nucleus. In large-budded cells undergoing cytokinesis, it reappears as a ring at the neck. In cells responding to mating pheromone, Chs3p is found throughout the projection. The appearance of Chs3p at cortical sites correlates with times that chitin synthesis is expected to occur. In addition to its localization at the incipient bud site and neck, Chs3p is also found in cytoplasmic patches in cells at different stages of the cell cycle. Epitope-tagged Chs5p also localizes to cytoplasmic patches; these patches contain Kex2p, a late Golgi-associated enzyme. Unlike Chs3p, Chs5p does not accumulate at the incipient bud site or neck. Nearly all Chs3p patches contain Chs5p, whereas some Chs5p patches lack detectable Chs3p. In the absence of Chs5p, Chs3p localizes in cytoplasmic patches, but it is no longer found at the neck or the incipient bud site, indicating that Chs5p is required for the polarization of Chs3p. Furthermore, Chs5p localization is not affected either by temperature shift or by the myo2-66 mutation, however, Chs3p polarization is affected by temperature shift and myo2-66. We suggest a model in which Chs3p polarization to cortical sites in yeast is dependent on both Chs5p and the actin cytoskeleton/Myo2p.
Targeted Disruption of Decorin Leads to Abnormal Collagen Fibril Morphology and Skin Fragility
Authors: Danielson Keith G. , Baribault Helene , Holmes David F. , Graham Helen , Kadler Karl E. , Iozzo Renato V.
Published: July 2002

Decorin is a member of the expanding group of widely distributed small leucine-rich proteoglycans that are expected to play important functions in tissue assembly. We report that mice harboring a targeted disruption of the decorin gene are viable but have fragile skin with markedly reduced tensile strength. Ultrastructural analysis revealed abnormal collagen morphology in skin and tendon, with coarser and irregular fiber outlines. Quantitative scanning transmission EM of individual collagen fibrils showed abrupt increases and decreases in mass along their axes, thereby accounting for the irregular outlines and size variability observed in cross-sections. The data indicate uncontrolled lateral fusion of collagen fibrils in the decorindeficient mice and provide an explanation for the reduced tensile strength of the skin. These findings demonstrate a fundamental role for decorin in regulating collagen fiber formation in vivo.
Involvement of the Transmembrane Protein p23 in Biosynthetic Protein Transport
Authors: Rojo Manuel , Pepperkok Rainer , Emery Gregory , Kellner Roland , Stang Espen , Parton Robert G. , Gruenberg Jean
Published: July 2002

Here, we report the localization and characterization of BHKp23, a member of the p24 family of transmembrane proteins, in mammalian cells. We find that p23 is a major component of tubulovesicular membranes at the cis side of the Golgi complex (estimated density: 12,500 copies/μm2 membrane surface area, or ≈30% of the total protein). Our data indicate that BHKp23-containing membranes are part of the cis-Golgi network/intermediate compartment . Using the G protein of vesicular stomatitis virus as a transmembrane cargo molecule, we find that p23 membranes are an obligatory station in forward biosynthetic membrane transport, but that p23 itself is absent from transport vesicles that carry the G protein to and beyond the Golgi complex. Our data show that p23 is not present to any significant extent in coat protein (COP) I-coated vesicles generated in vitro and does not colocalize with COP I buds and vesicles. Moreover, we find that p23 cytoplasmic domain is not involved in COP I membrane recruitment. Our data demonstrate that microinjected antibodies against the cytoplasmic tail of p23 inhibit G protein transport from the cis-Golgi network/ intermediate compartment to the cell surface, suggesting that p23 function is required for the transport of transmembrane cargo molecules. These observations together with the fact that p23 is a highly abundant component in the intermediate compartment, lead us to propose that p23 contributes to membrane structure, and that this contribution is necessary for efficient segregation and transport.
Location and Clonal Analysis of Stem Cells and Their Differentiated Progeny in the Human Ocular Surface
Authors: Pellegrini Graziella , Golisano Osvaldo , Paterna Patrizia , Lambiase Alessandro , Bonini Stefano , Rama Paolo , De Luca Michele
Published: July 2002

We have analyzed the proliferative and differentiation potential of human ocular keratinocytes. Holoclones, meroclones, and paraclones, previously identified in skin, constitute also the proliferative compartment of the ocular epithelium. Ocular holoclones have the expected properties of stem cells, while transient amplifying cells have variable proliferative potential. Corneal stem cells are segregated in the limbus, while conjunctival stem cells are uniformly distributed in bulbar and forniceal conjunctiva. Conjunctival keratinocytes and goblet cells derive from a common bipotent progenitor. Goblet cells were found in cultures of transient amplifying cells, suggesting that commitment for goblet cell differentiation can occur late in the life of a single conjunctival clone. We found that conjunctival keratinocytes with high proliferative capacity give rise to goblet cells at least twice in their life and, more importantly, at rather precise times of their life history, namely at 45–50 cell doublings and at ∼15 cell doublings before senescence. Thus, the decision of conjunctival keratinocytes to differentiate into goblet cells appears to be dependent upon an intrinsic “cell doubling clock.” These data open new perspectives in the surgical treatment of severe defects of the anterior ocular surface with autologous cultured conjunctival epithelium.
Apg9p/Cvt7p Is an Integral Membrane Protein Required for Transport Vesicle Formation in the Cvt and Autophagy Pathways
Authors: Noda Takeshi , Kim John , Huang Wei-Pang , Baba Misuzu , Tokunaga Chikara , Ohsumi Yoshinori , Klionsky Daniel J.
Published: July 2002

In nutrient-rich, vegetative conditions, the yeast Saccharomyces cerevisiae transports a resident protease, aminopeptidase I (API), to the vacuole by the cytoplasm to vacuole targeting (Cvt) pathway, thus contributing to the degradative capacity of this organelle. When cells subsequently encounter starvation conditions, the machinery that recruited precursor API (prAPI) also sequesters bulk cytosol for delivery, breakdown, and recycling in the vacuole by the autophagy pathway. Each of these overlapping alternative transport pathways is specifically mobilized depending on environmental cues. The basic mechanism of cargo packaging and delivery involves the formation of a double-membrane transport vesicle around prAPI and/or bulk cytosol. Upon completion, these Cvt and autophagic vesicles are targeted to the vacuole to allow delivery of their lumenal contents.

Key questions remain regarding the origin and formation of the transport vesicle. In this study, we have cloned the APG9/CVT7 gene and characterized the gene product. Apg9p/Cvt7p is the first characterized integral membrane protein required for Cvt and autophagy transport. Biochemical and morphological analyses indicate that Apg9p/Cvt7p is localized to large perivacuolar punctate structures, but does not colocalize with typical endomembrane marker proteins. Finally, we have isolated a temperature conditional allele of APG9/CVT7 and demonstrate the direct role of Apg9p/Cvt7p in the formation of the Cvt and autophagic vesicles. From these results, we propose that Apg9p/Cvt7p may serve as a marker for a specialized compartment essential for these vesicle-mediated alternative targeting pathways.
Identification and Characterization of Sa/Scc3p Subunits in the Xenopus and Human Cohesin Complexes
Authors: Losada Ana , Yokochi Tomoki , Kobayashi Ryuji , Hirano Tatsuya
Published: July 2002

A multisubunit protein complex, termed cohesin, plays an essential role in sister chromatid cohesion in yeast and in Xenopus laevis cell-free extracts. We report here that two distinct cohesin complexes exist in Xenopus egg extracts. A 14S complex (x-cohesinSA1) contains XSMC1, XSMC3, XRAD21, and a newly identified subunit, XSA1. In a second 12.5S complex (x-cohesinSA2), XSMC1, XSMC3, and XRAD21 associate with a different subunit, XSA2. Both XSA1 and XSA2 belong to the SA family of mammalian proteins and exhibit similarity to Scc3p, a recently identified component of yeast cohesin. In Xenopus egg extracts, x-cohesinSA1 is predominant, whereas x-cohesinSA2 constitutes only a very minor population. Human cells have a similar pair of cohesin complexes, but the SA2-type is the dominant form in somatic tissue culture cells. Immunolocalization experiments suggest that chromatin association of cohesinSA1 and cohesinSA2 may be differentially regulated. Dissociation of x-cohesinSA1 from chromatin correlates with phosphorylation of XSA1 in the cell-free extracts. Purified cdc2-cyclin B can phosphorylate XSA1 in vitro and reduce the ability of x-cohesinSA1 to bind to DNA or chromatin. These results shed light on the mechanism by which sister chromatid cohesion is partially dissolved in early mitosis, far before the onset of anaphase, in vertebrate cells.
Akt Regulates Cell Survival and Apoptosis at a Postmitochondrial Level
Authors: Zhou Honglin , Li Xin-Ming , Meinkoth Judy , Pittman Randall N.
Published: July 2002

Phosphoinositide 3 kinase/Akt pathway plays an essential role in neuronal survival. However, the cellular mechanisms by which Akt suppresses cell death and protects neurons from apoptosis remain unclear. We previously showed that transient expression of constitutively active Akt inhibits ceramide-induced death of hybrid motor neuron 1 cells. Here we show that stable expression of either constitutively active Akt or Bcl-2 inhibits apoptosis, but only Bcl-2 prevents the release of cytochrome c from mitochondria, suggesting that Akt regulates apoptosis at a postmitochondrial level. Consistent with this, overexpressing active Akt rescues cells from apoptosis without altering expression levels of endogenous Bcl-2, Bcl-x, or Bax. Akt inhibits apoptosis induced by microinjection of cytochrome c and lysates from cells expressing active Akt inhibit cytochrome c induced caspase activation in a cell-free assay while lysates from Bcl-2–expressing cells have no effect. Addition of cytochrome c and dATP to lysates from cells expressing active Akt do not activate caspase-9 or -3 and immunoprecipitated Akt added to control lysates blocks cytochrome c–induced activation of the caspase cascade. Taken together, these data suggest that Akt inhibits activation of caspase-9 and -3 by posttranslational modification of a cytosolic factor downstream of cytochrome c and before activation of caspase-9.
Lineage-Specific Modulation of Interleukin 4 Signaling by Interferon Regulatory Factor 4
Authors: Gupta Sanjay , Jiang Man , Anthony Alissa , Pernis Alessandra B.
Published: July 2002

Interleukin (IL)-4 is an immunoregulatory cytokine that exerts distinct biological activities on different cell types. Our studies indicate that interferon regulatory factor (IRF)-4 is both a target and a modulator of the IL-4 signaling cascade. IRF-4 expression is strongly upregulated upon costimulation of B cells with CD40 and IL-4. Furthermore, we find that IRF-4 can interact with signal transducer and activator of transcription (Stat)6 and drive the expression of IL-4–inducible genes. The transactivating ability of IRF-4 is blocked by the repressor factor BCL-6. Since expression of IRF-4 is mostly confined to lymphoid cells, these data provide a potential mechanism by which IL-4–inducible genes can be regulated in a lineage-specific manner.
An Expanded Peripheral T Cell Population to a Cytotoxic T Lymphocyte (Ctl)-Defined, Melanocyte-Specific Antigen in Metastatic Melanoma Patients Impacts on Generation of Peptide-Specific Ctls but Does Not Overcome Tumor Escape from Immune Surveillance in Metastatic Lesions
Authors: Anichini Andrea , Molla Alessandra , Mortarini Roberta , Tragni Gabrina , Bersani Ilaria , Di Nicola Massimo , Gianni Alessandro M. , Pilotti Silvana , Dunbar Rod , Cerundolo Vincenzo , Parmiani Giorgio
Published: July 2002

It is not known if immune response to T cell–defined human histocompatibility leukocyte antigen (HLA) class I–restricted melanoma antigens leads to an expanded peripheral pool of T cells in all patients, affects cytotoxic T lymphocyte (CTL) generation, and correlates with anti-tumor response in metastatic lesions. To this end, a limiting dilution analysis technique was developed that allowed us to evaluate the same frequency of peptide-specific T cells as by staining T cells with HLA–peptide tetrameric complexes. In four out of nine patients, Melan-A/Mart-127–35–specific CTL precursors (CTLp) were ≥1/2,000 peripheral blood lymphocytes and found mostly or only in the CD45RO+ memory T cell subset. In the remaining five patients, a low (<1/40,000) peptide-specific CTLp frequency was measured, and the precursors were only in the CD45RA+ naive T cell subset. Evaluation of CTL effector frequency after bulk culture indicated that peptide-specific CTLs could be activated in all patients by using professional antigen-presenting cells as dendritic cells, but CTLp frequency determined the kinetics of generation of specificity and the final number of effectors as evaluated by both limiting dilution analysis and staining with HLA-A*0201–Melan-A/Mart-1 tetrameric complexes. Immunohistochemical analysis of 26 neoplastic lesions from the nine patients indicated absence of tumor regression in most instances, even in patients with an expanded peripheral T cell pool to Melan-A/Mart-1 and whose neoplastic lesions contained a high frequency of tetramer-positive Melan-A/Mart-1–specific T cells. Furthermore, frequent lack of a “brisk” or “nonbrisk” CD3+CD8+ T cell infiltrate or reduced/absent Melan-A/Mart-1 expression in several lesions and lack of HLA class I antigens were found in some instances. Thus, expansion of peripheral immune repertoire to Melan-A/Mart-1 takes place in some metastatic patients and leads to enhanced CTL induction after antigen-presenting cell–mediated selection, but, in most metastatic lesions, it does not overcome tumor escape from immune surveillance.
CD8β Endows CD8 with Efficient Coreceptor Function by Coupling T Cell Receptor/CD3 to Raft-associated CD8/p56lck Complexes
Authors: Arcaro Alexandre , Grégoire Claude , Bakker Talitha R. , Baldi Lucia , Jordan Martin , Goffin Laurence , Boucheron Nicole , Wurm Florian , van der Merwe P. Anton , Malissen Bernard , Luescher Immanuel F.
Published: July 2002

The extraordinary sensitivity of CD8+ T cells to recognize antigen impinges to a large extent on the coreceptor CD8. While several studies have shown that the CD8β chain endows CD8 with efficient coreceptor function, the molecular basis for this is enigmatic. Here we report that cell-associated CD8αβ, but not CD8αα or soluble CD8αβ, substantially increases the avidity of T cell receptor (TCR)-ligand binding. To elucidate how the cytoplasmic and transmembrane portions of CD8β endow CD8 with efficient coreceptor function, we examined T1.4 T cell hybridomas transfected with various CD8β constructs. T1.4 hybridomas recognize a photoreactive Plasmodium berghei circumsporozoite (PbCS) peptide derivative (PbCS (4-azidobezoic acid [ABA])) in the context of H-2Kd, and permit assessment of TCR-ligand binding by TCR photoaffinity labeling. We find that the cytoplasmic portion of CD8β, mainly due to its palmitoylation, mediates partitioning of CD8 in lipid rafts, where it efficiently associates with p56lck. In addition, the cytoplasmic portion of CD8β mediates constitutive association of CD8 with TCR/CD3. The resulting TCR-CD8 adducts exhibit high affinity for major histocompatibility complex (MHC)-peptide. Importantly, because CD8αβ partitions in rafts, its interaction with TCR/CD3 promotes raft association of TCR/CD3. Engagement of these TCR/CD3-CD8/lck adducts by multimeric MHC-peptide induces activation of p56lck in rafts, which in turn phosphorylates CD3 and initiates T cell activation.
Activation of Na+-permeant Cation Channel by Stretch and Cyclic AMP-dependent Phosphorylation in Renal Epithelial A6 Cells
Authors: Marunaka Yoshinori , Shintani Yutaka , Downey Gregory P. , Niisato Naomi
Published: July 2002

It is currently believed that a nonselective cation (NSC) channel, which responds to arginine vasotocin (an antidiuretic hormone) and stretch, regulates Na+ absorption in the distal nephron. However, the mechanisms of regulation of this channel remain incompletely characterized. To study the mechanisms of regulation of this channel, we used renal epithelial cells (A6) cultured on permeable supports. The apical membrane of confluent monolayers of A6 cells expressed a 29-pS channel, which was activated by stretch or by 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterase. This channel had an identical selectivity for Na+, K+, Li+, and Cs+, but little selectivity for Ca2+ (PCa/PNa < 0.005) or Cl− (PCl/PNa < 0.01), identifying it as an NSC channel. Stretch had no additional effects on the open probability (Po) of the IBMX-activated channel. This channel had one open (“O”) and two closed (short “CS” and long “CL”) states under basal, stretch-, or IBMX-stimulated conditions. Both stretch and IBMX increased the Po of the channel without any detectable changes in the mean open or closed times. These observations led us to the conclusion that a kinetic model “CL ↔ CS ↔ O” was the most suitable among three possible linear models. According to this model, IBMX or stretch would decrease the leaving rate of the channel for CL from CS, resulting in an increase in Po. Cytochalasin D pretreatment abolished the response to stretch or IBMX without altering the basal activity. H89 (an inhibitor of cAMP-dependent protein kinase) completely abolished the response to both stretch and IBMX, but, unlike cytochalasin D, also diminished the basal activity. We conclude that: (a) the functional properties of the cAMP-activated NSC channel are similar to those of the stretch-activated one, (b) the actin cytoskeleton plays a crucial role in the activation of the NSC channel induced by stretch and cAMP, and (c) the basal activity of the NSC channel is maintained by PKA-dependent phosphorylation but is not dependent on actin microfilaments.
Conductance and Permeability of the Residual State of Connexin43 Gap Junction Channels
Authors: Bukauskas Feliksas F. , Bukauskiene Angele , Verselis Vytas K.
Published: July 2002

We used cell lines expressing wild-type connexin43 and connexin43 fused with the enhanced green fluorescent protein (Cx43-EGFP) to examine conductance and perm-selectivity of the residual state of Cx43 homotypic and Cx43/Cx43-EGFP heterotypic gap junction channels. Each hemichannel in Cx43 cell–cell channel possesses two gates: a fast gate that closes channels to the residual state and a slow gate that fully closes channels; the transjunctional voltage (Vj) closes the fast gate in the hemichannel that is on the relatively negative side. Here, we demonstrate macroscopically and at the single-channel level that the I-V relationship of the residual state rectifies, exhibiting higher conductance at higher Vjs that are negative on the side of gated hemichannel. The degree of rectification increases when Cl− is replaced by Asp− and decreases when K+ is replaced by TEA+. These data are consistent with an increased anionic selectivity of the residual state. The Vj-gated channel is not permeable to monovalent positively and negatively charged dyes, which are readily permeable through the fully open channel. These data indicate that a narrowing of the channel pore accompanies gating to the residual state. We suggest that the fast gate operates through a conformational change that introduces positive charge at the cytoplasmic vestibule of the gated hemichannel, thereby producing current rectification, increased anionic selectivity, and a narrowing of channel pore that is largely responsible for reducing channel conductance and restricting dye transfer. Consequently, the fast Vj-sensitive gating mechanism can serve as a selectivity filter, which allows electrical coupling but limits metabolic communication.
Clinical and economic evaluation of subsequent infection following intravenous ciprofloxacin or imipenem therapy in hospitalized patients with severe pneumonia
Authors: Caldwell John W. , Singh Shanny , Johnson Royce H.
Published: July 2002

A recent multicentre clinical study evaluated the safety and efficacy of iv ciprofloxacin therapy compared with imipenem- cilastatin in hospitalized patients with severe pneumonia. Monotherapy with iv ciprofloxacin was at least equivalent to imipenem in terms of bacteriological eradication and clinical response. In a single-centre, retrospective, post-therapy evaluation of persistent and subsequent infection, the incidence of Gram-negative infections and associated costs were compared. The main elements of the economic analysis included costs of additional antimicrobial therapy and hospitalization. Thirty-two patients were randomized into the study, of whom 27 were efficacy-valid. The 13 patients randomized into the ciprofloxacin group were not significantly different from the 14 patients in the imipenem group in terms of clinical parameters. Clinical cure occurred in ten of 13 patients (77%) in the ciprofloxacin group and in seven of 14 (50%) in the imipenem group. Bacteriological eradication was achieved in 11 of 13 (85%) ciprofloxacin-treated and eight of 14 (57%) imipenem-treated patients. Five of 13 (38%) patients in the ciprofloxacin group and nine of 14 (64%) in the imipenem group experienced persistent or subsequent infection requiring post-treatment antimicrobials. In these five ciprofloxacin patients, three had cultures with Gram-positive organisms only and two had cultures with both Gram-positive and Gram-negative organisms. In the nine imipenem-treated patients requiring post-study antimicrobials, all had Gram-negative bacteria and three also had Gram-positive organisms. The incidence of subsequent Gram-negative infection in the two groups (15% vs 64%) was significantly different (P < −0.05). Pseudomonas aeruginosa was isolated from seven patients in the imipenem group but only one in the ciprofloxacin group (P < 0.05). Subsequent costs for post-therapy antimicrobials and hospital stay while receiving study and post-study drug therapy were evaluated; the cost per patient cure was US$29,000 for ciprofloxacin and US$76,000 for imipenem. Initial treatment of severe pneumonia with ciprofloxacin resulted in significantly less subsequent Gram-negative infection and was associated with substantially lower curative costs.
Spatial resolution measurements in quasimonochromatic x rays with mosaic crystals for mammography application
Authors: Gambaccini Mauro , Tuffanelli Alessandra , Taibi Angelo , Del Guerra Alberto
Published: July 2002

A novel x‐ray source for mammography application is being investigated. Quasimonochromatic x rays have been produced via Bragg diffraction with a W‐anode x‐ray tube and a graphite mosaic crystal array. The system provides 18 keV x rays with an energy resolution A thorough analysis of the spatial resolution of the system has been performed in order to understand and quantify the effect of the introduction of an active optical element such as a mosaic crystal in the x‐ray path. The focal spot of the source and its emission properties have been studied by using the slit camera method. Experiments have shown that the introduction of a mosaic crystal in the optical path modifies the resolution properties of the Bragg diffraction‐based radiography system. Along the direction perpendicular to the diffraction plane the resolution properties of the imaging system mainly depend on the x‐ray tube focal spot size and position. Along the diffraction plane the focal spot size depends on mosaic characteristics and on the geometrical setup. Hence, it could be modified by setting the appropriate experimental conditions.
Dosimetric effect of source centering and residual plaque for β‐emitting catheter based intravascular brachytherapy sources
Authors: Sehgal Varun , Li Zuofeng , Palta Jatinder R. , Bolch W. E.
Published: July 2002

Catheter‐based radiation delivery systems employing both β‐particle and γ‐ray emitters are currently being investigated for their efficacy in addressing restenosis following percutaneous coronary intervention (PCI). The dosimetric consequences of source centering within the arterial lumen and presence of residual plaque are potentially important issues for the uniform delivery of dose to the arterial tissue. In this study, we have examined the effect of source centering on the resulting dose to the arterial wall from clinical intravascular brachytherapy sources containing and Monte Carlo simulations using the MCNP code were performed for these catheter‐based sources with offsets of 0.5 mm and 1 mm from the center of the arterial lumen in homogenous water medium as well as in the presence of residual plaque. Three different positions were modeled and the resulting dose values were analyzed to assess their impact on the resulting dose distribution. The results indicate a variation ranging from −40% to +70% for source and −30% to +50% for at a radial distance of 2 mm from the center of the coronary artery, relative to the dose from a centered source, for a 0.5 mm offset. The variation for a 1 mm offset ranges from −65% to +182% for source and to −50% to +140% for A concentric residual plaque layer was also modeled so as to assess the combined influence of offset and residual plaque on the dosimetry. Finally the effect of cardiac motion and its potential impact on catheter position and hence the dose distribution is also examined by considering two separate cases of catheter displacement. The results indicate that dose variations range between −28% to +91% when it is assumed that cardiac motion causes catheter movement during coronary lesion irradiation.
High energy slit aperture SPECT and simplified in vitro methods for the dosimetry of positron emitting radiotracers
Authors: Wrobel Mark Christopher
Published: July 2002

The dosimetry of new positron emitting radiopharmaceuticals is initially estimated using animal organ biodistributions assessed in vitro. This research investigated the accuracy of in vivo assessments using single photon emission computed tomography (SPECT). Measurements were performed with SPRINT, a full ring detector SPECT system using a slit aperture to obtain a 3‐to‐1 object to image magnification ratio. Acceptable resolution for 511 keV photons was achieved using a high energy parallel slice collimator and a novel technique to correct for penetration of the slit aperture by high energy photons. The resulting FWHM was approximately 4.5 mm axially and transaxially. System sensitivity was 25 cps/MBq (∼55 cpm/μCi), a consequence of high resolution collimation and poor intrinsic detector efficiency. Qualitative and quantitative high energy imaging was performed using two‐ and three‐dimensional phantoms and live rats injected with fluorodeoxyglucose. Three mm μJaszczak phantom objects were well resolved, and rat images showed good contrast of the brain and heart regions. Hot phantom regions and animal organs were quantified with an accuracy of ±8% (S.D. ±15%). Accurate determination of region activity required concentrations up to 3.7 MBq/ml (∼100 μCi/ml) and imaging times of one hour. In summary, animal biodistributions assessed with slit aperture SPECT can show good accuracy for organs with substantial uptakes, but poor sensitivity limits temporal resolution.
Studies on imaging properties of a novel medical digital radiography system and its clinical applications [In Japanese]
Authors: Ogura Toshihiro
Published: July 2002

This dissertation describes the imaging properties of a novel digital radiography (DR) system. This 2048×2048‐matrix image intensifier‐TV‐DR system was introduced in January 1990. The basic imaging properties of the system were investigated in terms of system linearity, resolution, noise, and detectability of low contrast objects. It was found that the image quality is sufficient for close fluoroscopic GI‐tract examinations. The imaging properties of this system depend on the incident exposure rate, the level of signal current from the TV image pickup tube and also the size of the iris (diaphragm) in the TV lens. To obtain high‐resolution images, the incident exposure should be adjusted to obtain a small iris diaphragm and a low level of signal current. If, on the other hand, high resolution is not required the incident exposure can be reduced by increasing the iris diaphragm. Therefore, using the knowledge of these relationships, the DR system parameters and exposure levels should be determined when acquiring clinical images and evaluating the imaging properties. We have ascertained the performance of this DR system through our extensive investigation. This novel medical digital radiography system has been used for mass screening the upper GI‐tract of more than 12 500 patients.
An analytical approximation of the Bragg curve for therapeutic proton beams
Authors: Bortfeld Thomas
Published: July 2002

The knowledge of proton depth‐dose curves, or “Bragg curves,” is a fundamental prerequisite for dose calculations in radiotherapy planning, among other applications. In various cases it is desirable to have an analytical representation of the Bragg curve, rather than using measured or numerically calculated data. This work provides an analytical approximation of the Bragg curve in closed form. The underlying model is valid for proton energies between about 10 and 200 MeV. Its main four constituents are: (i) a power‐law relationship describing the range‐energy dependency; (ii) a linear model for the fluence reduction due to nonelastic nuclear interactions, assuming local deposition of a fraction of the released energy; (iii) a Gaussian approximation of the range straggling distribution; and (iv) a representation of the energy spectrum of poly‐energetic beams by a Gaussian with a linear “tail.” Based on these assumptions the Bragg curve can be described in closed form using a simple combination of Gaussians and parabolic cylinder functions. The resulting expression can be fitted to measurements within the measurement error. Very good agreement is also found with numerically calculated Bragg curves.
Interstitial hyperthermia with PdNi thermoseeds
Authors: van Wieringen Niek
Published: July 2002

The objective of this study was to improve the temperature control of ferromagnetic seed implants aiming at a more homogeneous temperature distribution in the target volume. A metallurgical procedure was developed for the production of PdNi seeds with a sharp ferromagnetic transition at the Curie temperature. The heat production was improved by the development of seeds composed of a number of filaments with a smaller diameter. The catheters used for implantation of the seeds and possible air layers inside the catheters impair the thermal interaction between the seeds and the tissue. This interaction can be enhanced by inserting the seeds into metallic needles and by filling them with water. As an alternative, one can place tubular seeds on the outside of a catheter or brachytherapy needle. This would also enable a simultaneous application of interstitial hyperthermia and interstitial radiotherapy. A 3‐D thermal treatment planning system developed at the University Hospital Utrecht was used to model the application of different types of seeds and implantation techniques in tissue with discrete vessel structures. The simulations confirmed the importance of a sharp ferromagnetic transition and good heat transfer from the seed to the tissue. They also indicated that the use of seeds with the appropriate Curie temperature could compensate for local hot or cold spots.
Optimally weighted wavelet transform based on supervised training for detection of microcalcifications in digital mammograms
Authors: Zhang Wei , Yoshida Hiroyuki , Nishikawa Robert M. , Doi Kunio
Published: July 2002

We are developing a computer‐aided diagnosis (CAD) scheme for detection of clustered microcalcifications in digital mammograms. The use of an empirically chosen wavelet and scale combination for detection of microcalcifications as an initial step of the CAD scheme has been reported by us previously. In this study, we developed a technique for optimizing the weights at individual scales in the wavelet transform to improve the performance of our CAD scheme based on the supervised learning method. In the learning process, an error function was formulated to represent the difference between a desired output and the reconstructed image obtained from weighted wavelet coefficients for a given mammogram. The error function was then minimized by modifying the weights for wavelet coefficients by means of a conjugate gradient algorithm. The Least Asymmetric Daubechies' wavelets were optimized with 297 regions of interest (ROIs) as a training set by a jackknife method. The performance of the optimally weighted wavelets was evaluated by means of receiver‐operating characteristic (ROC) analysis by use of the above set of ROIs. The analysis yielded an average area under the ROC curve of 0.92, which outperforms the difference‐image technique used in our existing CAD scheme, as well as the partial reconstruction method used in our previous study.
The effect of phosphor persistence on image quality in digital x‐ray scanning systems
Authors: Mainprize James G. , Yaffe Martin J.
Published: July 2002

A digital x‐ray scanning system offers several advantages over conventional film–screen systems. However, there are sources of image degradation resulting from the scanning motion, such as motion blur due to the temporal response of the phosphor. This mechanism produces an asymmetrical blur, requiring the use of the complex optical transfer function (OTF) rather than the normal modulation transfer function (MTF) for correct characterization of image resolution. The luminescence response of eight phosphors was measured under pulsed x‐ray excitation. A weighted exponential model was used to represent the primary luminescence. The dominant luminescence lifetimes ranged from 2.7 μs for to 558 μs for The long term response was also measured, monitoring significant increases in a slow form of luminescence known as afterglow. Afterglow was modeled by an inverse power law equation. Afterglow was found to be strong in two of the phosphors studied (ZnCdS:Ag and ). In selecting a phosphor for a scanning system, it must satisfy several criteria, including a fast temporal response. Thus, a phosphor like which has a slow luminescence, but otherwise excellent imaging properties, may not be as useful as a more rapid phosphor like CsI:Tl.
Characterization of the output for helical delivery of intensity modulated slit beams
Authors: Balog J. P. , Mackie T. R. , Reckwerdt P. , Glass M. , Angelos L.
Published: July 2002

The UW tomotherapy workbench utilizes a convolution/superposition based dose calculation and optimization program. It specifies the energy fluence that must be delivered from each leaf for each phantom projection angle. This requires that the spectrum of the radiation emitted from the one‐dimensional MLC (multileaf collimator) attached to the linear accelerator be determined. The steps involved in that process are described. The spectrum along the central axis of the slit beam was determined, as well as the softening with off‐axis position. Moreover, the magnitude of the energy‐fluence output had to be quantified on a per MU (monitor unit) basis. This was done for a single leaf along the central axis of the beam. Factors, which modify that energy‐fluence output, were investigated. The output increases with off‐axis position due to the horns of the beam. The output for a leaf of interest will also increase if additional leaves are open due to the absence of the tongue‐and‐groove effect and penumbra blurring. The energy‐fluence increase per leaf increases by 4.9% if an adjacent leaf is open. No other factors related to the state of additional leaves were found to significantly increase the energy‐fluence output for an individual leaf.
The flatness of Siemens linear accelerator x‐ray fields
Authors: Faddegon B. A. , O'Brien P. , Mason D. L. D.
Published: July 2002

The primary definer for Siemens MXE and MDX linear accelerators projects a circular opening with a radius of 25 cm at 100 cm from the target. Our measurements of photon beam profiles, however, indicate that the photon fluence drops to 95% of the central axis value at a radius of 18 cm. The flattening filter for these machines projects a flattened field size that is much smaller than the primary definer would allow. The clinical implications of this mismatch for large rectangular fields and for fields defined by asymmetric jaws are discussed and solutions are considered. A large field flattener was designed for our Siemens MXE 6 MV beam using Monte Carlo simulation of the treatment head and water phantom. The accuracy required of source and geometry details for dose distributions calculation is presented. The key parameters are the mean energy and focal spot size of the electron beam incident on the exit window, the material composition, and thickness profile of the exit window, target, flattener, and primary collimator, and the position of the primary collimator relative to the target. Profiles were more sensitive than central axis depth doses to simulation details. The beam energy and primary collimator position were selected to achieve good agreement between measured and calculated dose distributions. The flattener we designed with Monte Carlo was machined from brass and mounted on our MXE treatment unit. Measurements demonstrate that the large field flattener extends the useful radius of the field out to 22 cm, right into the penumbra cast by the primary collimator.
Experimental determination of section sensitivity profiles and image noise in electron beam computed tomography
Authors: McCollough Cynthia H. , Kanal Kalpana M. , Lannutti Nicholas , Ryan Kelly J.
Published: July 2002

To determine the effect of continuous‐volume scanning (CVS) on z‐axis resolution, section sensitivity profiles were measured on an electron beam computed tomography (CT) scanner and compared with those obtained using the step‐volume scanning (SVS) mode. A steel bead was imaged using different scan parameters, and the mean CT number over the bead was plotted against the z‐axis position to determine section sensitivity profiles. From these profiles, full width at half maximum (FWHM), full width at tenth maximum (FWTM), and full width at tenth area (FWTA) were calculated. A uniform water phantom was imaged to measure noise. To determine the visual significance of changes in the section sensitivity profile, a section thickness and contiguity phantom was imaged. All section sensitivity profiles measured had an FWHM value within 0.5 mm of the nominal scan width. The FWTM and FWTA values increased with the CVS mode compared with the SVS mode. This broadening of the section sensitivity profiles was most significant with larger collimator widths. However, use of smaller collimator widths increased image noise. When all other parameters remained constant, increasing the exposure time to reduce image noise did not affect the section sensitivity profile. The CVS mode produced wider section sensitivity profiles than the SVS mode. This effect was minimized when the smallest collimator width was used, but at the expense of increased image noise.
Experimental verification of in‐phantom calculations for an accelerator‐ based neutron source for boron neutron capture therapy
Authors: Dobelbower M. Christian , Vest Albert , Reed Michael J. , Blue Thomas E.
Published: July 2002

In this paper we present computer calculations and measurements of the 2200 m/s neutron flux in two different phantoms irradiated in the treatment port of a prototype moderator assembly for an accelerator‐based neutron source (ABNS) for boron neutron capture therapy (BNCT). The 2200 m/s flux is a useful quantity, because it is proportional to the boron absorbed dose rate in phantom. The results of the calculations and measurements are compared at several locations in head phantoms. When cross sections for hydrogen are used, along the beam centerline, the calculations agree with measurements with average deviations of plus 7%, for a rectangular parallelepiped water phantom, and minus 6%, for a polymethylmethacrylate (PMMA) ellipsoidal phantom.
Optimal configuration of multiple‐focused ultrasound transducers for external hyperthermia
Authors: Lin Win‐Li , Chen Yung‐Yaw , Lin Shu‐Yuh , Yen Jia‐Yush , Shieh Ming‐Jium , Kuo Te‐Son
Published: July 2002

External ultrasound hyperthermia is considered to be a very flexible modality for heating deep‐seated tumors owing to its penetration and focusing ability. However, using this flexibility requires that many complicated, interacting decisions be made to obtain optimal treatment. This paper presents the feasibility of arranging multiple‐focused ultrasound transducers to produce an appropriate heating pattern for a specific treatment, based on the optimal scan parameters obtained from an optimization algorithm. The variable scan parameters of the heating system optimized are the transducer tilt and rotation angles, focal depth, scan radius, and output acoustical power. After obtaining the optimal scan parameters, multiple transducers are systematically arranged according to these scan parameters. Three‐dimensional ultrasound power deposition and temperature distribution for a specific treatment are calculated for this multiple ultrasound transducer system. A more uniform temperature distribution in the treatment region for a large, highly perfused tumor can be achieved by scanning the system with respect to the central scan axis and/or swinging the transducers inwards and outwards. The maximum heating depth of focused ultrasound transducers used in this heating system is also studied. Simulation results demonstrate that the optimal arrangement of this multiple‐focused ultrasound transducer system is highly promising for heating deep, large, and highly perfused tumors.
Experimental verification of a CT‐based Monte Carlo dose‐calculation method in heterogeneous phantoms
Authors: Wang Lu , Lovelock Michael , Chui Chen‐Shou
Published: July 2002

To further validate the Monte Carlo dose‐calculation method [Med. Phys. 25, 867–878 (1998)] developed at the Memorial Sloan‐Kettering Cancer Center, we have performed experimental verification in various inhomogeneous phantoms. The phantom geometries included simple layered slabs, a simulated bone column, a simulated missing‐tissue hemisphere, and an anthropomorphic head geometry (Alderson Rando Phantom). The densities of the inhomogeneity range from 0.14 to 1.86 g/cm3, simulating both clinically relevant lunglike and bonelike materials. The data are reported as central axis depth doses, dose profiles, dose values at points of interest, such as points at the interface of two different media and in the “nasopharynx” region of the Rando head. The dosimeters used in the measurement included dosimetry film, TLD chips, and rods. The measured data were compared to that of Monte Carlo calculations for the same geometrical configurations. In the case of the Rando head phantom, a CT scan of the phantom was used to define the calculation geometry and to locate the points of interest. The agreement between the calculation and measurement is generally within 2.5%. This work validates the accuracy of the Monte Carlo method. While Monte Carlo, at present, is still too slow for routine treatment planning, it can be used as a benchmark against which other dose calculation methods can be compared.