Katarzyna Jadwiga Macura, M.D., Ph.D.

• Assistant Director ICTR Imaging Translational Program
• Professor of Radiology and Radiological Science

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0015445/katarzyna-macura

Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution erectile dysfunction medicine from dabur 20 mg cialis professional order with mastercard. The fusion glycoprotein shell of Semliki Forest virus: an icosahedral assembly primed for fusogenic activation at endosomal pH erectile dysfunction treatment tablets 20 mg cialis professional fast delivery. Cryo-electron microscopy reveals the functional organization of an enveloped virus erectile dysfunction over the counter medication discount cialis professional 40 mg free shipping, Semliki Forest virus erectile dysfunction pills generic order cialis professional overnight delivery. Proteomic and biochemical analysis of purified human immunodeficiency virus type 1 produced from infected monocyte-derived macrophages erectile dysfunction caused by low blood pressure best buy for cialis professional. The physical properties of the virion are obstacles to this seemingly simple goal. Furthermore, the viral genome is encapsidated in a stable coat that shields the nucleic acid as it travels through the harsh extracellular environment. These impediments must all be overcome during the process of viral entry into cells. Encounter of a virus particle with the surface of a susceptible host cell induces a series of events that lead to entry of the viral genome into the cytoplasm or nucleus. The first step in entry is adherence of virus particles to the plasma membrane, an interaction mediated by binding to a specific receptor molecule on the cell surface. The receptor plays an important role in uncoating, the process by which the viral genome is exposed, so that gene expression and genome replication can begin. Interaction of the virus particle with its receptor may initiate conformational changes that prime the capsid for uncoating. Alternatively, the receptor may direct the virus particle into endocytic pathways, where uncoating may be triggered by low pH or by the action of proteases. The genomes of viruses that replicate in the nucleus are moved to that location by cellular transport pathways. Virus entry into cells is not a passive process but relies on viral usurpation of normal cellular processes, including endocytosis, membrane fusion, vesicular trafficking, and transport into the nucleus. Because of the limited functions encoded by viral genomes, virus entry into cells depends absolutely on cellular processes. Attachment of Virus Particles to Cells General Principles Infection of cells by many, but not all, viruses requires binding to a receptor on the cell surface. Exceptions include viruses of yeasts and fungi, which have no extracellular phases, and plant viruses, which are thought to enter cells in which the cell wall has been physically damaged, for example by insects or farm machinery. A receptor is a cell surface molecule that binds the virus particle and participates in entry. It may induce conformational changes in the virus particle that lead to membrane fusion or penetration, and it may also transmit signals that cause uptake. Receptors for viruses comprise a variety of cell surface proteins, carbohydrates, and lipids, all with functions in the cell unrelated to virus entry. Many virus receptors have been identified in the past 30 years and include immunoglobulin-like proteins, ligand-binding receptors, glycoproteins, ion channels, gangliosides, carbohydrates, proteoglycans, and integrins. The receptor may be the only cell surface molecule required for entry into cells, or an additional cell surface molecule, or coreceptor, may be needed (Box 5. Different receptors may serve for virus entry in diverse cell types, and unrelated viruses may bind to the same receptor. For example, poliovirus infects primates and primate cell cultures but not mice or mouse cell cultures. Many viruses enter host cells by the same cellular pathways used to take up macromolecules. The entry mechanism used by a particular virus may differ depending on the nature of the target cell. Viral particles and subviral particles depend on the cytoskeleton to move within an infected cell. Binding of virions to cell receptors may activate signaling pathways that facilitate virus entry and movement, or produce cellular responses that enhance virus propagation and/or affect pathogenesis. For viruses that undergo replication in the nucleus, import can occur either through use of the nuclear pore complex or during cell division, when the nuclear membrane breaks down. Virus particles are too large to diffuse across the plasma membrane, and thus entry must be an active process. Viruses may bind multiple distinct receptors, and individual cellular proteins may be receptors for multiple viruses. Enveloped virus particles bind via their transmembrane glycoproteins; nonenveloped virus particles bind via the capsid surface or projections from the capsid. Attachment proteins may not lead to internalization and viral reproduction but may still be important for dissemination in the host. When binding to another cell surface molecule is needed, that protein is called a coreceptor. A particular cell surface molecule that is a coreceptor for one virus may be a receptor for another. Distinguishing receptors and coreceptors by the order in which they are bound is difficult to determine experimentally and is likely to be influenced by cell type and multiplicity of infection. Furthermore, as is the case for the human immunodeficiency viruses, binding only to the coreceptor may be sufficient for entry of some members. Usage of the terms "receptor" and "coreceptor" is convenient when describing virus entry, but the appellations may not be entirely precise. Our understanding of the earliest interactions of virus particles with cells comes almost exclusively from analysis of synchronously infected cells in culture. The initial association with cells is probably via electrostatic forces, as it is sensitive to low pH or high concentrations of salt, but higher affinity binding relies mainly on hydrophobic and other short-range forces between the viral and cellular surfaces. Although the affinity of a receptor for a single virus particle is low, the presence of multiple receptor-binding sites on the virion and the fluid nature of the plasma membrane allow engagement of multiple receptors. Consequently, the avidity (the strength conferred by multiple interactions) of virus particle binding to cells is usually very high. Binding can usually occur at 4°C (even though entry does not) as well as at body temperature. Infection of cultured cells can therefore be synchronized by allowing binding to take place at a low temperature and then shifting the cells to a physiological temperature to allow the initiation of subsequent steps. The first steps in virus attachment are governed largely by the probability that a virus particle and a cell will collide, and therefore by the concentrations of free particles and host cells. In this example, the poliovirus receptor is the determinant of poliovirus host range. However, production of the receptor in a particular cell type does not ensure that virus reproduction will occur. Some primate cell cultures produce the poliovirus receptor but cannot be infected. The restriction of viral reproduction in these cells is most probably due to a block in viral reproduction beyond the attachment step. Receptors can also be determinants of tissue tropism, the predilection of a virus to invade and reproduce in a particular cell type. For example, the sialic acid residues on membrane glycoproteins or glycolipids, which are receptors for influenza where A is attachment, t is time, and [V] and [H] are the concentrations of virus particles and host cells, respectively, and k is a constant that defines the rate of the reaction. It can be seen from this equation that if a mixture of viruses and cells is diluted after an adsorption period, subsequent binding of particles is greatly reduced. For example, a 100-fold dilution of the virus and cell mixture reduces the attachment rate 10,000-fold. Dilution can be used to prevent subsequent virus adsorption and hence to synchronize an infection. Many receptor molecules can move in the plasma membrane, leading to the formation of microdomains that differ in composition. Bound virus may therefore localize to specialized areas of the membrane such as lipid rafts, caveolae, or coated pits. Localization of virus particle-receptor complexes can also cause transmembrane signaling, changes in the cytoskeleton, and recruitment of clathrin. Identification of Receptors for Virus Particles the development of three crucial technologies in the past 30 years has enabled identification of many receptors for viruses. Production of monoclonal antibodies provided a powerful means of isolating and characterizing individual cell surface proteins. Hybridoma cell lines that secrete monoclonal antibodies that block virus attachment are Attachment and Entry 125 obtained after immunizing mice with intact cells. Such antibodies can be used to purify the receptor protein by affinity chromatography. Clones of such cells are recognized and selected, for example, by the binding of receptor-specific monoclonal antibodies. The receptor genes can then be isolated from these selected cells by using a third technology, molecular cloning. The power of these different technologies can lead to rapid progress: the receptor for a newly identified Middle Eastern respiratory syndrome coronavirus was identified just 4 months after the first description of the virus (Box 5. Although these technologies have led to the identification of many cell receptors for viruses, each method has associated uncertainties (Box 5. The availability of receptor genes has made it possible to investigate the details of receptor interaction with viruses by site-directed mutagenesis. Receptor proteins can be synthesized in heterologous systems and purified, and their properties can be studied in vitro, while animal cells producing altered receptor proteins can be used to test the effects of alterations on virus attachment. Because of their hydrophobic membrane-spanning domains, many of these cell surface proteins are relatively insoluble and difficult to work with. Three different strategies for identifying such rare receptor-expressing cells are outlined. Cells that make the correct receptor and become infected with such viruses can be distinguished by a color change, such as green in the case of green fluorescent protein. The fusion protein was produced in cells and incubated with lysates of cells known to be susceptible to the virus, and the resulting complexes were fractionated by native polyacrylamide gel electrophoresis. This polypeptide was excised from the polyacrylamide gel, and its amino acid sequence was determined by mass spectrometric analysis, identifying it as dipeptidyl peptidase 4. That a single protein was identified by this procedure is remarkable: typically, this approach identifies many nonspecific binding proteins. Soluble extracellular protein domains (with the virus binding sites) have been essential for structural studies of receptor-virus interactions. Receptor genes have also been used to produce transgenic mice that synthesize receptor proteins. Such transgenic animals can serve as useful models in the study of human viral diseases. Virus-Receptor Interactions Animal viruses have multiple receptor-binding sites on their surfaces. Of necessity, one or more of the capsid proteins of nonenveloped viruses specifically interact with the cell receptor. Receptor-binding sites for enveloped viruses are provided by oligomeric type 1 integral membrane glycoproteins encoded by the viral genome that have been incorporated into the cell-derived membranes of virus particles. Although the details vary among viruses, most virus-receptor interactions follow one of several mechanisms illustrated by the best-studied examples described below. Nonenveloped Viruses Bind via the Capsid Surface or Projections Attachment via surface features: canyons and loops. Members of the enterovirus genus of the Picornaviridae include human polioviruses, coxsackieviruses, echoviruses, enteroviruses, and rhinoviruses. It was known that mouse cells cannot be infected with poliovirus, because they do not produce the receptor. Consequently, it was possible to develop a small-animal model for poliomyelitis by producing transgenic mice that synthesize this receptor. Similar approaches have subsequently led to animal models for viral diseases caused by measles virus and echoviruses. Rhinoviruses multiply primarily in the upper respiratory tract and are responsible for causing up to 50% of all common colds. Over 150 rhinovirus genotypes have been identified and classified on the basis of genome sequence into three species, A, B, and C. A monoclonal antibody that blocks virus attachment might recognize not the receptor but a closely associated membrane protein. However, the encoded protein might not be a receptor but may modify another cellular protein so that it can bind virus particles. For some viruses, synthesis of the receptor on cells leads to binding but not infection. In such cases a coreceptor is required, either for internalization or for membrane fusion. The cell surface receptor bound by most A and B species rhinoviruses was identified by using a monoclonal antibody that blocks rhinovirus infection and that recognizes a cell surface protein. This monoclonal antibody was used to isolate a 95-kDa cell surface glycoprotein by affinity chromatography. Amino acid sequence analysis of the purified protein, which bound to rhinovirus in vitro, identified it as the integral membrane protein intercellular adhesion molecule 1 (Icam-1). Cell receptors for other rhinoviruses are the low-density lipoprotein receptor and cadherin-related family member 3. The canyons in the capsids of some rhinoviruses and enteroviruses are the sites of interaction with cell surface receptors. Amino acids that line the canyons are more highly conserved than any others on the viral surface, and their substitution can alter the affinity of binding to cells. Although canyons are present in the capsid of rhinovirus type 2, they are not the binding sites for the receptor, low-density lipoprotein receptor. Sequence and structural comparisons have revealed why different rhinovirus serotypes bind distinct receptors. The results of competition experiments indicated that members of two different virus families, group B coxsackieviruses and most human adenoviruses, share a cell receptor. This receptor is a 46-kDa member of the Ig superfamily called Car (coxsackievirus and adenovirus receptor).

More importantly generic erectile dysfunction drugs online cialis professional 40 mg low cost, Beijerinck made the conceptual leap that this must be a distinctive agent causes of erectile dysfunction in 40 year old purchase 40 mg cialis professional overnight delivery, because it was so small that it could pass through filters that trapped all known bacteria homeopathic remedy for erectile dysfunction causes 40 mg cialis professional order mastercard. It was two former students and assistants of Koch erectile dysfunction herbal remedies purchase cialis professional 40 mg without a prescription, Friedrich Loeffler and Paul Frosch erectile dysfunction naturopathic treatment cialis professional 20 mg buy with visa, who in the same year (1898) deduced that such infectious filterable agents comprised small particles: they observed that while the causative agent of footand-mouth disease (Box 1. Not only were the tobacco mosaic and foot-and-mouth disease pathogens much smaller than any previously recognized microorganism, but also they were replicated only in their host organisms. For example, extracts of an infected tobacco plant diluted into sterile solution produced no additional infectious agents until introduced into leaves of healthy plants, which subsequently developed tobacco mosaic disease. The serial transmission of infection by diluted extracts established that these diseases were not caused by a bacterial toxin present in the original preparations derived from infected tobacco plants or cattle. The failure of both pathogens to multiply in solutions that readily supported the growth of bacteria, as well as their dependence on host organisms for reproduction, further distinguished these new agents from pathogenic bacteria. Beijerinck termed the submicroscopic agent responsible for tobacco mosaic disease contagium vivum fluidum to emphasize its infectious nature and distinctive reproductive and physical properties. Agents passing through filters that retain bacteria came to be called ultrafilterable viruses, appropriating the term "virus" from the Latin for "poison. However, he did not identify the tobacco mosaic disease pathogen as a distinctive agent, nor was he convinced that its passage through bacterial filters was not the result of some technical failure. It may be more appropriate to attribute the founding of the field of virology to the astute insights of Beijerinck, Loeffler, and Frosch, who recognized the distinctive nature of the plant and animal pathogens they were studying more than 100 years ago. The pioneering work on tobacco mosaic and foot-andmouth disease viruses was followed by the identification of viruses associated with specific diseases in many other organisms. Important landmarks from this early period include the identification of viruses that cause leukemias or solid tumors in chickens by Vilhelm Ellerman and Olaf Bang in 1908 and Peyton Rous in 1911, respectively. The study of viruses associated with cancers in chickens, particularly Rous 12 Chapter 1 A Bacteria + virus B Berkefeld filters have three grades of porosities, two of which hold back all bacteria. It was a "candle"-style filter comprising diatomaceous earth, or Kieselguhr, pressed into the shape of a hollow candle. The white candle is in the upper chamber of the apparatus, which is open at the top to receive the liquid to be filtered into the suction flask. The smallest pore size retained bacteria and allowed virus particles to pass through. Such filters were probably used by Ivanovsky, Loeffler, and Frosch to isolate the first plant and animal viruses. Such modern-day filter systems are disposable plastic laboratory items in which the upper and lower chambers are separated by a biologically inert membrane, available in a variety of pore sizes. In an interesting twist of serendipity, Twort made his discovery of bacterial viruses while testing the smallpox vaccine virus to see if it would grow on simple media. He found bacterial contaminants, some of them appearing more transparent, which proved to be the result of lysis by a bacteriophage. Investigation of bacteriophages established the foundations for the field of molecular biology, as well as fundamental insights into how viruses interact with their host cells. The Definitive Properties of Viruses Throughout the early period of virology when many viruses of plants, animals, and bacteria were cataloged, ideas about the origin and nature of these distinctive infectious agents were quite controversial. Arguments centered on whether viruses originated from parts of a cell or were built from unique components. Little progress was made toward resolving these issues and establishing the definitive properties of viruses until the development of new techniques that allowed their visualization or propagation in cultured cells. The Structural Simplicity of Virus Particles Dramatic confirmation of the structural simplicity of virus particles came in 1935, when Wendell Stanley obtained crystals of tobacco mosaic virus. The ability to obtain an infectious agent in crystalline form, a state that is more generally associated with inorganic material, created much wonder and speculation about whether a virus is truly a life form. In retrospect, it is obvious that the relative ease with which tobacco mosaic virus could be crystallized was a direct result of both its structural simplicity and the ability of many particles to associate in regular arrays. The 1930s saw the introduction of the instrument that rapidly revolutionized virology: the electron microscope. The great magnifying power of this instrument (eventually more than 100,000-fold) allowed direct visualization of virus particles for the first time. Viruses span a broad range from that equal to some small bacteria to just under ribosome size. The units commonly used in descriptions of virus particles or their components are the nanometer (nm [10 9 m]) and the angstrom (Å [10 10 m]). The description of the morphology of virus particles made possible by electron microscopy also opened the way for the first rational classification of viruses. The Intracellular Parasitism of Viruses Organisms as Hosts the defining characteristic of viruses is their absolute dependence on a living host for reproduction: they are obligate parasites. Transmission of plant viruses such as tobacco mosaic virus can be achieved readily, for example, by applying extracts of an infected plant to a scratch made on the leaf of a healthy plant. Some viruses of humans and other species could also be propagated in laboratory animals, and methods were developed to quantify them by determining the lethal dose. The transmission of yellow fever virus to mice by Max Theiler in 1930 was an achievement that led to the isolation of an attenuated strain, still considered one of the safest and most effective ever produced for the vaccination of humans. After specific viruses and host organisms were identified, it became possible to produce sufficient quantities of virus particles for study of their physical and chemical properties and the consequences of infection for the host. Features such as the incubation period, symptoms of infection, and effects on specific tissues and organs were investigated. In 1886, Adolph Mayer first described the characteristic patterns of light and dark green areas on the leaves of tobacco plants infected with tobacco mosaic virus. He demonstrated that the mosaic lesions could be transmitted from an infected plant to a healthy plant by aqueous extracts derived from infected plants. The number of local necrotic lesions that result is directly proportional to the number of infectious particles in the preparation. However, real progress toward understanding the mechanisms of virus reproduction was made only with the development of cell culture systems. Among the simplest, but crucial to both virology and molecular biology, were cultures of bacterial cells. Lessons from Bacteriophages In the late 1930s and early 1940s, bacteriophages, or "phages," received increased attention as a result of controversy centering on how they were formed. On the other hand, Max Delbrück, in his work with Emory Ellis and later with Luria, regarded phages as autonomous, stable, self-replicating entities characterized by heritable traits. According to this paradigm, phages were seen as ideal tools with which to investigate the nature of genes and heredity. Probably the most critical early contribution of Delbrück and Ellis was the perfection of the one-step growth method for synchronization of the reproduction of phages, an achievement that allowed analysis of a single cycle of phage reproduction in a population of bacteria. This approach introduced highly quantitative methods to virology, as well as an unprecedented rigor of analysis. The first experiments showed that phages indeed multiplied in the bacterial host and were liberated in a "burst" by lysis of the cell. Delbrück was a zealot for phage research and recruited talented scientists to pursue the fundamental issues of what is now known as the field of molecular biology. This group of scientists, working together in what came to be called the "phage school," focused their attention on specific phages of the bacterium Escherichia coli. Progress was rapid, primarily because of the simplicity of the phage infectious cycle. Phages reproduce in bacterial hosts, which can be obtained in large numbers by overnight culture. By the mid-1950s, it was evident that viruses from bacteria, animals, and plants share many fundamental properties. One critical lesson came from a definitive experiment that established that viral nucleic acid carries genetic information. It was known from studies of the "transforming principle" of pneumococcus by Oswald Avery, Colin MacLeod, and Maclyn McCarty (1944) that nucleic acid was both necessary and sufficient for the transfer of genetic traits of bacteria. However, in the early 1950s, protein was still suspected to be an important component of viral heredity. In a brilliantly simple experiment that included the use of a common kitchen food blender, Alfred Hershey and Martha Chase showed that this hypothesis was incorrect (Box 1. In the early 1920s, a previously unknown interaction was discovered, in which the host cell not only survived the infection but also stably inherited the genetic information of the virus. It was also observed that certain bacterial strains could lyse spontaneously and produce bacteriophages after a period of growth in culture. Studies of lysogeny uncovered many previously unrecognized features of virus-host cell interactions (Box 1. Recognition of this phenomenon came from the work of many scientists, but it began with the elegant experiments of André Lwoff and colleagues at the Institut Pasteur in Paris. Lwoff showed that a viral genome exists in lysogenic cells in the form of a silent genetic element called the prophage. This element determined the ability of lysogenic bacteria to produce infectious bacteriophages. Bacteriophages became inextricably associated with the new field of molecular biology (Table 1. Their study established many fundamental principles: for example, control of the decision to enter a lysogenic or a lytic pathway is encoded in the genome of the virus. The first mechanisms discovered for the control of gene expression, exemplified by the elegant operon theory of Nobel laureates François Jacob and Jacques Monod, were deduced in part from studies of lysogeny by phage lambda. The biology of phage lambda provided a fertile ground for work on gene regulation, but study of virulent T phages (T1 to T7, where T stands for "type") of E. In a lysogenic bacterial cell, viral genetic information persists but viral gene expression is repressed. Insertional Mutagenesis Bacteriophage Mu inserts its genome into many random locations on the host chromosome, causing numerous mutations. This process is called insertional mutagenesis and is a phenomenon observed with retroviruses. Gene Repression and Induction Prophage gene expression in lysogens is turned off by the action of viral proteins called repressors. Expression can be turned on when repressors are inactivated (a process called induction). Elucidation of the mechanisms of these processes set the stage for later investigation of the control of gene expression in experiments with other viruses and their host cells. Transduction of Host Genes Bacteriophage genomes can pick up cellular genes and deliver them to new cells (a process known as transduction). The process can be generalized, with the acquisition by the virus of any segment from the host chromosome, or specialized, as is the case for viruses that integrate into specific sites in the host chromosome. These cancer-inducing cellular genes are then transduced along with viral genes during subsequent infection. Pioneers in the study of lysogeny: Nobel laureates François Jacob, Jacques Monod, and André Lwoff. Animal Cells as Hosts the culture of animal cells in the laboratory was initially more of an art than a science, restricted to cells that grew out of organs or tissues maintained in nutrient solutions under sterile conditions. The finite life span of such primary cells; their dependence for growth on natural components in their media such as lymph, plasma, or chicken embryo extracts; and the technical demands of sterile culture prior to the discovery of antibiotics made reproducible experimentation very difficult. However, by 1955, the work of many investigators had led to a series of important methodological advances. These included the development of defined media optimal for growth of mammalian cells, incorporation of antibiotics into cell culture media, and development of immortal cell lines such as the mouse L and human HeLa cells that are still in widespread use. These advances allowed growth of animal cells in culture to become a routine, reproducible exercise. The availability of well-characterized cell cultures had several important consequences for virology. It allowed the discovery of new human viruses, such as adenovirus, measles virus, and rubella virus, for which animal hosts were not available. In 1949, John Enders and colleagues used cell cultures to propagate poliovirus, a feat that led to the development of polio vaccines a few years later. Cell culture technology revolutionized the ability to investigate the reproduction of viruses. While viruses lack the complex energy-generating and biosynthetic systems necessary for independent existence (Box 1. The episome In 1958, François Jacob and Elie Wollman realized that lambda prophage and the E. An episome is an exogenous genetic element that is not necessary for cell survival. Its defining characteristic is the ability to reproduce in two alternative states: while integrated in the host chromosome or autonomously. F Integrated F Cataloging Animal Viruses under precisely controlled conditions by employing the analog of the one-step growth cycle of bacteriophages and simple methods for quantification of infectious particles described in Chapter 2. Our current understanding of the molecular basis of viral parasitism, the focus of this volume, is based almost entirely on analyses of one-step growth cycles in cultured cells. Rather, the infecting genome contains the information necessary to redirect cellular systems to the production of many copies of all the components needed for the de novo assembly of new virus particles. Virus classification was at one time a subject of colorful and quite heated controversy (Box 1. One camp pointed to the inability to infer, from the known properties of viruses, anything about their evolutionary origin or their relationships to one another-the major goal of classical taxonomy. The other camp maintained that despite such limitations, there were significant practical advantages in grouping isolates with similar properties. A major sticking point, however, was finding agreement on which properties should be considered most important in constructing a scheme for virus classification. Viruses Defined Advances in knowledge of the structure of virus particles and the mechanisms by which they are produced in their host cells have been accompanied by increasingly accurate definitions of these unique agents. The earliest pathogenic agents, distinguished by their small size and dependence on a host organism for reproduction, emphasized the importance of viruses as agents of disease. We can now provide a much more precise definition, elaborating their relationship with the host cell and the important features of virus particles. The Classical System Lwoff, Robert Horne, and Paul Tournier, in 1962, advanced a comprehensive scheme for the classification of all viruses (bacterial, plant, and animal) under the classical Linnaean hierarchical system consisting of phylum, class, order, family, genus, and species.

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However erectile dysfunction protocol scam buy generic cialis professional 20 mg on line, hemorrhage may be seen in a variety of other settings erectile dysfunction injections australia cheap cialis professional 20 mg fast delivery, both as a manifestation of primary vascular injury erectile dysfunction statistics in canada generic cialis professional 20 mg buy line, such as due to vasculitis erectile dysfunction treatment definition cheap cialis professional online amex, pulmonary thromboembolism erectile dysfunction unable to ejaculate cialis professional 20 mg order otc, and pulmonary hypertensive changes, and as a secondary injury to a process affecting another compartment of the lung. Clues are often present in the tissue, which may point to the cause of the bleeding, and typically the pathologist can discriminate between acute procedural hemorrhage and physiologic bleeding based on the absence or presence of hemosiderin deposition in the lung. In small biopsies and/or in patients with acute symptom onset, however, this may not always be possible and clinical correlation may be required. Sholl Hemorrhage in the absence of other histologic abnormalities may be seen most commonly in the setting of surgical or other interventional procedures (transthoracic or transbronchial core biopsies or fine needle aspirations). The findings here will be largely indistinguishable from other settings in which the lung is traumatized. Patients with a coagulopathy will be more prone to pulmonary hemorrhage when undergoing a surgical procedure. Those with a preexisting coagulopathy will typically have hemosiderin-laden macrophages visible in the alveolar spaces; these are evidence for chronic bleeding and can help to discriminate between purely procedural hemorrhage and chronic or subacute hemorrhage. Blood from sources in the upper airways/sinonasal structures may track/be aspirated into the lungs, leading to a similar appearance of histologically normal lung with blood and hemosiderin-laden macrophages filling the airspaces. Histologic Features Intra-alveolar or perivascular hemorrhage; fibrin and leukocytes may be visible. The hemorrhage in this case is tracking through the adventitia of a pulmonary vessel and has discrete boundaries. Local injury to the capillaries and small pulmonary vessels may result in focal alveolar hemorrhage, whereas erosion into a large pulmonary vessel may lead to massive, fatal hemorrhage (as in tuberculosis, squamous-cell carcinoma). Diffuse alveolar hemorrhage may be associated with a number of infectious etiologies that cause alveolar capillary injury. In immunocompromised patients, diffuse alveolar hemorrhage is most often associated with Aspergillus, cytomegalovirus, adenovirus, legionella, and mycoplasma. In immunocompetent hosts, it is most commonly seen with Staphylococcus aureus and influenza A infections, as well as dengue, malaria, and leptospirosis. Increasing red blood cell content in sequential bronchoalveolar lavage specimens can confirm a clinical or radiographic suspicion of diffuse alveolar hemorrhage. Histologic Features Intra-alveolar red blood cells and fibrin will be adjacent to a mass lesion when present as a focal finding or throughout the sample airspaces when present as a diffuse process. Hemosiderin-laden macrophages should be identifiable in the setting of subacute to chronic disease. Hyaline membranes may be identified in the context of diffuse alveolar hemorrhage due to infectious causes (see Chapter 93). Sholl Intra-alveolar hemorrhage occurs in the exudative phase of diffuse alveolar damage, defined as the first 1 to 7 days following injury, and is accompanied by edema, neutrophilic infiltrates, and hyaline membrane formation. During the proliferative and organizing phases of diffuse alveolar damage, the red cells will be consumed by macrophages and the resulting hemosiderin-laden macrophages will serve as evidence of earlier hemorrhage. However, patients with iterative injury to the lung, as is common in diffuse alveolar damage, may show a combination of fresh hemorrhage and organizing lung injury. Identification of hemorrhage in the context of diffuse alveolar damage does not point to a specific etiology. Histologic Features Hyaline membranes line the surfaces of the alveolar ducts and sacs. Alveolar septa are widened by proliferating fibroblasts/myofibroblasts in the organizing phase of diffuse alveolar damage, and hemosiderin-laden macrophages may be prominent. Hyaline membranes are visible (arrowhead) along with abundant intra-alveolar red blood cells. Organization of the diffuse alveolar damage is evident in the right half of the image. Sholl Passive congestion in the lung is most commonly a manifestation of chronic pulmonary venous hypertension. This results from 721 aberrations of the left side of the heart, pulmonary veins or aorta that obstruct blood flow. Changes can be seen across the pulmonary vascular bed as a result of the elevated pressures (see Section 10: Pulmonary Hypertension and Emboli). Alveolar hemorrhage results from increased pressure ("stress failure") at the level of the pulmonary capillaries. The capillaries will appear distended and may become displaced deeper into the wall of the alveolar septum in the context of long-standing venous hypertension. Acute right-sided heart failure in the setting of congenital heart disease, pulmonary hypertension, thromboembolic disease, or cardiac surgery can lead to pulmonary hemorrhage and hemoptysis. Echocardiography or autopsy studies will demonstrate enlargement of the right ventricle and pulmonary artery. Histologic Features Pulmonary alveolar capillaries appear distended and may or may not appear engorged. Capillaries appear displaced into the center of the alveolar structures, and increased collagen deposition leads to a widened septal profile. Hemosiderosis manifests as intra-alveolar pigmented macrophages and iron encrustation of elastic fibers. Hemosiderosis may not be apparent in the setting of acute rightsided heart failure. Prominent iron deposition can be seen, decorating the elastic fibers of a small vessel at the top left. Kerr 725 the most common malformations of the pulmonary vasculature occur as communications between the pulmonary arterial and venous systems. More than half of the patients with pulmonary arteriovenous malformations have the autosomal-dominant disorder hereditary hemorrhagic telangiectasia, also known as Rendu­Osler­Weber disease. The lesions are found in the subpleura of the lower lobes and are most commonly unifocal. The vast majority are considered to be "simple," with a single feeding artery and draining vein. Physiologically, these create an extracardiac right-to-left shunt, leading to dyspnea and cyanosis. Acquired pulmonary arteriovenous malformations may result from surgery to repair congenital cardiac defects and have been reported rarely in adults secondary to cancer, cirrhosis, or trauma. Histologic Features Arteriovenous malformations show aneurysmal dilatation of thin-walled vessels containing blood or organized thrombus. Vessel walls show variable admixtures of collagen, elastic tissue, and smooth muscle. B: Aneurysmal dilatation of a subpleural vessel with variable thickening of the wall by collagen and smooth muscle and containing blood. Feeding/draining vessels are evident at the top and at the left of the dilated vessel. Sholl Idiopathic pulmonary hemosiderosis is a form of diffuse pulmonary hemorrhage; about 80% of cases are reported in the pediatric population. It is a diagnosis of exclusion, made only after known causes of upper and lower respiratory tract bleeding have been ruled out. Idiopathic pulmonary hemosiderosis is excluded in the setting of a more specific cause of diffuse pulmonary hemorrhage, such as capillaritis (associated with connective tissue disease, drug reaction, and other immune and idiopathic causes), granulomatosis with polyangiitis, cardiovascular disease (such as pulmonary arterial hypertension, pulmonary venoocclusive disease, and mitral valve disease), bone marrow transplantation, and others. Patients present with hemoptysis, iron-deficiency anemia, and 727 pulmonary opacities on chest imaging. Detection of hemosiderinladen macrophages in bronchoalveolar lavage fluid is helpful in confirming the diagnosis; in many settings, lung biopsy can be useful to exclude histologically evident causes of hemorrhage. Of note, capillaritis in particular can be difficult to confirm in a lung biopsy because active capillaritis can be exquisitely localized and healed capillaritis can be unrecognizable as such. Pediatric patients tend to have more severe disease and worse clinical outcomes, including pulmonary fibrosis and death. Histologic Features Red blood cells seen in the interstitium and alveolar spaces may be difficult to distinguish from procedural artifact. Hemosiderin-laden macrophages are visible in the airspaces; they may be numerous or sparse. Capillaritis/vasculitis, vasculopathy, infection, tumor, infarct, or other known cause of hemorrhage and hemosiderosis are absent. Bronchoalveolar lavage fluid (A) demonstrated numerous hemosiderin-laden macrophages. Lung biopsy (B), including an iron stain (C), confirmed the hemosiderosis and helped to rule out more specific causes of pulmonary bleeding. The vasculitides are characterized by the nature of the inflammation affecting the vessels, the caliber of the affected vessels, and the associated serologic markers. The nature of the clinical presentation similarly reflects the types of vessels affected, including the vessels in extrapulmonary organs. In this context, diffuse alveolar hemorrhage results from pulmonary capillaritis and is most commonly associated with microscopic polyangiitis and granulomatosis with polyangiitis (formerly Wegener granulomatosis). Clinically, patients present with progressive dyspnea and declining hemoglobin in the absence of other sources of hemorrhage or hemolysis; hemoptysis is often absent. Treatment should be aimed at the underlying etiology and typically involves immunosuppression. A variety of distinctive clinical presentations can be seen in vasculitides lacking an alveolar hemorrhage component. Alveolar hemorrhage, likely resulting from pulmonary capillaritis, is reported in a variety of other connective tissue and autoimmune disorders, including rheumatoid arthritis, Behçet disease, Sjogren syndrome, and mixed connective tissue disease. In the absence of aggressive immunosuppressive therapy (glucocorticoids and cytotoxic agents), alveolar hemorrhage can lead to respiratory failure and rapid death in this context. Histologic Features Red blood cells and hemosiderin-laden macrophages are visible 731 in the alveolar spaces. Scattered interstitial neutrophils are visible suggestive of partially treated capillaritis. It clinically manifests as rapidly progressive crescentic glomerulonephritis with acute renal failure, pulmonary hemorrhage, and autoimmune inner ear disease. Immunofluorescence studies reveal linear deposition of IgG along the alveolar basement membrane. Immunosuppression is the mainstay of therapy; plasmapheresis has been suggested in patients with alveolar hemorrhage, but controlled trials demonstrating a benefit to this approach are lacking. Histologic Features Alveolar spaces are filled with red blood cells and hemosiderinladen macrophages. Focal fibroblastic proliferation and myxoid matrix deposition is consistent with organizing pneumonia. The alveolar septa are uniformly thickened by increased collagen deposition, and hemosiderin-laden macrophages are prominent in the airspaces. Patients may initially present with granulomatous inflammation limited to the respiratory tract or lung; the clinical and radiographic differential in this latter setting may be broad and include infection or malignancy. Histologic Features "Geographic necrosis" characterized by serpiginous bands and islands of basophilic necrotic debris. The clinical manifestations overlap with a variety of other processes, including Toxocara or Strongyloides infections, allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, and hypereosinophilic syndrome. Histologic Features Extravascular tissue infiltration by eosinophils, including eosinophilic abscesses. Inflammatory involvement of small- to medium-sized vessels, including by eosinophils. Pronounced extravascular eosinophil-rich infiltrates can be seen around the vessel in association with scar formation and airspace obliteration. Sholl Antiphospholipid syndrome is a thrombotic microangiopathy characterized by arterial, venous, or small-vessel thrombosis and 743 evidence for serum anticardiolipin, anti­beta 2 microglobulin, or lupus anticoagulant antibodies. In the classic clinical syndrome, a young woman presents with recurrent miscarriages; however, men and older individuals, particularly those with a history of lupus, are also affected. Antiphospholipid syndrome is commonly implicated in venous thromboses and stroke episodes in individuals below the ages of 70 and 50 years, respectively. Antiphospholipid syndrome is associated with elevated plasma levels of oxidized beta 2 microglobulin, and this is proposed to serve as a nidus for endothelial cell injury and thrombosis. Pulmonary hemorrhage is a rare complication of antiphospholipid syndrome and can occur without evidence of coexisting pulmonary vessel thrombosis. Although antiphospholipid antibody­mediated neutrophil recruitment and capillaritis has been implicated as the cause of hemorrhage in these cases, the hemorrhage is commonly bland and its etiology only determined based on clinical and serologic correlation. Alveolar hemorrhage in the setting of antiphospholipid syndrome is consider a rheumatologic emergency and may be refractory to immunosuppressive therapies. In cases with evident capillaritis, neutrophils decorate the alveolar interstitium. Vascular thrombosis is typically not evident in the context of alveolar hemorrhage. Diffuse airspace filling by fresh blood and hemosiderin-laden macrophages can be seen. Rather, alveolar hemorrhage is the principle manifestation in the lung, occurring in about a third to half of patients. Clinically, patients present with nonspecific complaints, including fever and weight loss, and the diagnosis may not become evident before the kidney, lungs, or other organs suffer irreversible damage. Significant alveolar hemorrhage is a major contributor to disease morbidity and mortality. Neutrophils decorating the interstitial capillaries with fibrinoid necrosis of capillary walls. The airspaces are filled with fresh red blood cells and frequent hemosiderin-laden macrophages. These hemodynamic differences stem in part from the portion of the vascular bed involved, the size of the vascular channel involved, and the mechanism of the occlusion. Although this is a definition that is both useful and reproducibly measurable, the set of diseases that can result in pulmonary vascular changes are quite diverse. For a pathologist, these associated vascular changes can be quite distinctive, but when encountered they are not invariably associated with hemodynamic changes. This may be due to the extent and distribution of the pathologic changes within the lung. The consequence of this observation is that pulmonary hypertension, while potentially suggested by vascular findings, is generally classified by a combination of hemodynamic findings and clinical scenarios than by specific pathologic findings.

Eventually the template is unable to move erectile dysfunction va disability rating purchase cheap cialis professional line, leading to reiterative copying of the U residues creatine causes erectile dysfunction cheap 20 mg cialis professional with amex. This protein is thought to bind nascent strand transcripts and block poly(A) addition by a mechanism analogous to that described for vesicular stomatitis virus N protein erectile dysfunction drugs list purchase cialis professional 40 mg without a prescription. This requirement erectile dysfunction protocol real reviews cheapest generic cialis professional uk, called the rule of six erectile dysfunction medicine reviews generic 20 mg cialis professional amex, is probably a consequence of the association of each N monomer with exactly six nucleotides. If the genome length is not a multiple of 6, then the 3 end of the genome will not be precisely aligned with the last N monomer. The genome is shown as a dark green line at the top, and the N, P, M, G, and L genes and their relative sizes are indicated. The transition from reiterative copying and termination to initiation is not perfect, and only about 70 to 80% of the polymerase molecules accomplish this transition at each intergenic region. Attachment of the 5 cap to the polymerase facilitates insertion of the 3 end of the strand into the template channel. The delta antigen bound to the rodlike Why Are and Strands Made in Unequal Quantities Such replication complexes are morphologically diverse, and the membranes originate from various cellular compartments (Chapter 14). Different viral proteins have been implicated in the formation of these viral replicative organelles. The membrane vesicles observed early in poliovirusinfected cells are thought to originate from two sources. The vesicles produced later during poliovirus infection bear several hallmarks of autophagosomes, including a double membrane and colocalization with protein markers of these vesicles. These vesicles are connected to the cytoplasm through a pore and are often near sites of virus assembly. During semiconservative replication, both strands of nucleic acid serve as templates for the synthesis of new strands (shown in red). The interactions of viral and cellular proteins with the polioviral 5 -untranslated region might determine whether the genome is translated or replicated. In this model, binding of cellular poly(rC)-binding protein 2 within the 5 -untranslated region initially stimulates translation. Once the viral protease has been synthesized, it cleaves poly(rC)-binding protein; consequently, binding of the cellular protein is reduced. The polymerase passes the poly(A) signal (purple box) and the self-cleavage domain (red circle). Similar results were obtained when the antigenome of hepatitis delta satellite virus was used in the reaction. The first ribozyme discovered was the group I intron of the ciliate Tetrahymena thermophila. Only an 85-nucleotide sequence is required for activity of this ribozyme, and can cleave optimally with as little as a single nucleotide 5 to the site of cleavage. The two helical stacks are shown in red and blue, and unpaired nucleotides are gray. The surfaces of membranous replication complexes isolated from poliovirus-infected cells appear to be coated with two-dimensional arrays of polymerase. These arrays are formed by interaction of 3Dpol molecules in a head-to-tail fashion. Surface catalysis is known to confer several advantages, including a higher probability of collision among reactants, an increase in substrate affinity from clustering of multiple binding sites, and retention of reaction products. The cluster of large and small double-membrane vesicles (outer membrane, gold; inner membrane, silver) are connected to a vesicle packet and convoluted membrane structure (bronze). Many of these polymerization errors cause lethal amino acid changes, while other mutations may appear in the genomes of infectious virus particles. For example, live attenuated poliovirus vaccine strains are viral mutants that were isolated from an unmutagenized stock of wild-type virus. The increased fidelity of this enzyme, which has a single amino acid substitution in the fingers domain, is the result of a change in the equilibrium constant for the conformational transition. These studies also provide mechanistic information on how ribavirin, an antiviral compound, causes lethal mutagenesis. The ribose of ribavirin is bound in the pocket, indicating that it has bypassed the fidelity checkpoint and induced the conformational change that holds the analog in a position ready for catalysis. Inactivation of this enzyme does not impair viral replication, but leads to 15- to 20-fold increases in mutation rates. Viruses lacking the ExoN gene display attenuated virulence in mice, and are being considered as vaccine candidates. In cells coinfected with two different influenza viruses, the eight genome segments of each virus replicate. Recombinant polioviruses are readily isolated from the feces of individuals immunized with the three serotypes of Sabin vaccine. The genome of such viruses, which are recombinants of the vaccine strains with other enteroviruses found in the human intestine, may possess an improved ability to reproduce in the human alimentary tract and have a selective advantage over the parental viruses. Polioviral recombination is predominantly base pairing dependent: it occurs between nucleotide sequences that have a high percentage of nucleotide identity. Other viral genomes undergo base-pairing-independent recombination between very different nucleotide sequences. Template exchange in poliovirus-infected cells occurs predominantly during strand synthesis, presumably because the concentration of strands is 100-fold higher than that of strands. The exact mechanism of template exchange is not known, but it might be triggered by pausing of the polymerase during chain elongation or damage to the template. This recombination event provides a selective advantage, because pathogenic viruses outgrow nonpathogenic ones. Production of these particles requires either a high multiplicity of infection or serial passaging, conditions that are achieved readily in the laboratory but rarely in nature. It is not known whether defective interfering viruses generally play a role in viral pathogenesis. The importance of polymerase errors is underscored by the dramatic decrease in poliovirus fitness caused by a single amino acid change in the polymerase that decreases error rate. This structure should be the basis for an understanding at the atomic level of the different functions of this enzyme. Distinct conformations of a putative translocation element in poliovirus polymerase. The pathways that led to this unexpected finding were quite different in the two laboratories. However, it was a difficult hypothesis to test with the technology available at the time, and attempts by Temin and others to demonstrate the existence of such a phenomenon in infected cells were generally met with skepticism. In the years following this revision of dogma, many additional reverse transcription reactions were discovered. For such reasons, we devote an entire chapter to these very important reactions (see interview with Dr. Retroviruses are the only animal viruses with genomes that encode integrase proteins. Such intracellular transposable elements are present in the genomes of most, if not all, members of the tree of life. The model was deduced from the fact that different linkage maps could be constructed for viral genomes at different stages in its life cycle. One linkage map, that of the integrated prophage, was obtained from the study of lysogenic bacteria. A different linkage map was obtained by measuring recombination frequencies of phage progeny (see part A of figure). Subsequent recombination between a specific, internal sequence in the phage genome (called attP) and a specific sequence in the bacterial chromosome (called attB) would produce an integrated viral genome, with a linkage map that was a circular permutation of that of the linear phage genome, as had been observed (see part B of figure). Other predictions of the model were also validated in several laboratories, and viral and cellular proteins that catalyzed integration were identified. The bacterial insertion site, attB (orange box), is shown below the circle, flanked by genes that encode enzymes required for galactose metabolism (gal) and biosynthesis of the vitamin biotin (bio). Consequently, it is not surprising that these enzymes employ similar catalytic mechanisms for nucleic acid polymerization reactions. It should be noted that even as arcane and distinct as the viral systems may appear, they do not exhaust the repertoire for reverse transcription reactions that exist in nature. Much of what has been learned about reverse transcription in retroviruses comes from the identification of intermediates in the reaction pathway that are formed in infected cells. The fidelity and robustness of the endogenous reaction suggests that the reverse transcription system is poised for action as soon as the virus particle enters the cell. However, as the reactions that take place inside cells are more efficient than those observed in either endogenous or reconstituted systems, it is unlikely that all of the significant molecular interactions have been reproduced in vitro. At least parts of both genomes can be, and typically are, used as templates during the reverse transcription process, accounting for the high rates of genetic recombination in these viruses. Therefore, all of the known steps in reverse transcription can take place on a single genome. It seems possible that a similar mechanism promotes primer binding on other retroviral genomes, but the generality of this process has not yet been tested. However, the number of molecules that are actually engaged in reverse transcription in each virus particle is not known. Enzymes of the three retroviruses that have been studied most extensively, avian sarcoma/leukosis virus, murine leukemia virus, and human immunodeficiency virus type 1, are used as examples throughout this chapter. Not only are specific nucleotides important, but numerous regions of base pairing mediate formation of particular structures that are also critical for function. Formation of two minor (normally 1%), circular products is shown in the shaded box on the right. Such strains are called xenotropic because they can infect foreign cells, such as human cells, in culture but are unable to reinfect mouse cells. Such internal template exchanges (known to occur even in the absence of breaks) probably proceed at regions of homology via the same steps outlined for the first template exchange. Virtually all retroviral recombination occurs between coencapsidated genomes at the time of reverse transcription. The two mechanisms are not mutually exclusive, and while copy choice is most frequent, there is experimental support for both. Viral genetic markers, arbitrarily labeled a, b, and c, are indicated to illustrate recombination. While multiple crossovers are frequently observed, single recombination events are shown for simplicity, focusing on the hypothetical a allele, with the mutant form in red. It is difficult to gauge the significance of this structural diversity, which may simply be the result of different evolutionary histories. These properties contribute to the high mutation rate of retroviruses in infected cells. Open red arrows indicate partial (asymmetric) processing, and solid red arrows indicate complete processing. Both deletions and insertions are also known to occur during reverse transcription within an infected cell, apparently because template exchanges can take place within short sequence repeats. As retroviral genomes are 104 nucleotides in length, 1 lesion per retroviral genome per replication cycle can be expected, simply by misincorporation. The avian sarcoma/ leukosis and human immunodeficiency virus enzymes are both proficient at extending mismatched terminal base pairs, such as those that result from nontemplated addition (A). A certain type of slippage within homopolymeric runs in which one or more bases are extruded on the template strand can also happen during reverse transcription (B, C); mispairing occurs after the next deoxyribonucleotide is added and the product strands attempt to realign with the template. Slippage and dislocations are assumed to be mediated by looping out of nucleotides in the template. Only single-nucleotide dislocations are shown here, but large dislocations leading to deletions are also possible. These residues coordinate the required metal ions and contribute to binding deoxyribonucleoside triphosphates and subsequent catalysis. The p61p51 heterodimer is shown at the top, with subdomains in the catalytic subunit, p66, identified. The p61 and p51 subunits are shown separated at the bottom to emphasize the distinct organization of subdomains in each. Production of two protein subunits that possess identical amino acid sequences, but have structures and functions that are distinct, is an excellent example of viral genetic economy. In actuality, such enzyme movement is quite improbable, and use of this terminology can cloud thinking about these processes. In almost all cases, these polymerases are components of large assemblies with architecture designed to bring different parts of the template, or different templates, close to each other. Consequently, it is likely that most of the "movement" is made by the flexible nucleic acid templates. The assay made use of surface-immobilized template-primer oligonucleotide substrate molecules: the protein and a nucleic acid end were labeled with donor and acceptor fluorophores. The position of the enzyme relative to the substrate was then measured by fluorescence resonance energy transfer. Such proviruses are often replication defective, a property that may facilitate coexistence with their hosts. While many of these proviruses were established in the primate lineage millions of years ago, a present-day example of this phenomenon can be observed in another mammalian species (Box 7. Processed pseudogenes comprise a less abundant group of such non-autonomously transposed retroelements. They have no introns (hence "processed"), and their sequences are related to exons in functional genes that map elsewhere in the genome. The percentage of the human genome that each element represents and the total number of retroelements in each major class are indicated in the boxes. The percentage of the human genome that is represented by each type of element is shown beneath the boxes. The koala retrovirus recently isolated from wild and captive animals in Australia, and in koala populations in zoos in other countries, appears to be a contemporary exception. The koala virus is a gammaretrovirus, related to the gibbon ape leukemia and feline leukemia viruses.

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