Roger Scott Blumenthal, M.D.

• Director of Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease
• Professor of Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0003450/roger-blumenthal

Depending on the goal of the study and the type of samples analyzed treatment 4 addiction buy generic rumalaya pills, the researcher should decide upon which is better suited to his/her purposes medicine 911 discount rumalaya 60pills without prescription. However medicine 60 rumalaya 60pills generic, if the samples to be compared come from the same or closely related sites treatment group buy rumalaya 60 pills visa, deeper sequencing may be necessary to reveal minor differences in the community composition (Lemos et al medications xyzal buy rumalaya 60pills amex. Now medications that raise blood sugar buy discount rumalaya 60pills online, the important question to be answered refers to the role of different species in the consortium. Because as-yetuncultivated bacteria make up a large proportion of most environments, studies of the physiologic and functional roles of the community members should also rely on culture-independent approaches. Physiology and function in a bacterial community can be inferred by the substances produced and released by the community members. Metagenomics is the culture-independent analysis of the collective microbial genomes (termed the metagenome) in an environmental community, using an approach based either on expression or on sequencing (Handelsman 2004). Metagenomics treats the genomes of all microorganisms present in a specific habitat as an entity. Metagenomics is different from community analysis, as the latter focuses on microbial diversity as determined by a single target gene whereas in the former theoretically all genes in the community are analyzed. Of the molecular methods discussed in this chapter, metagenomics is the only one that remains to be used in endodontic microbiology research. High specificity and accurate identification of strains with ambiguous phenotypic behavior 3. Do not require carefully controlled anaerobic conditions during sampling, transportation, and handling 7. When taking samples from endodontic infections, difficulties posed by the physical constraints of the root canal system and by the limitations of the conventional sampling technique using paper points can make it difficult to obtain a good representative sample from the main canal (Siqueira and R^ cas 2005a). It is also important to take into consideration the analytical sensitivity needed for the specific clinical sample. For example, a sensitivity of no more than 104 microbial cells per mL is required for urine, while a sensitivity of one cell may be of extreme relevance for samples from blood or cerebrospinal fluid (Boissinot and Bergeron 2002). There is no clear evidence as to the microbial load necessary for apical periodontitis to be induced. Endodontic infections are characterized by a mixed community and individual species can have different roles in the consortium or dominate various stages of the infection. Also, from an ecologic point of view, one cannot dismiss the ecologic role of the less abundant species in the consortium, exclusively on the basis of numbers, particularly if we consider that nothing is known about their functional role in the ecosystem. In other words, even less abundant species may exert a big difference in the ecosystem (Siqueira and R^ cas 2009a). Also, it remains unknown whether or not the abundance of these species changes over time and what are the consequences of such changes. Based on this, it would be glaringly prudent to use the method with the highest sensitivity to detect all species colonizing the root canal. Therefore, the analytical sensitivity of the method does not always correspond to its "clinical" sensitivity. Therefore the use of highly sensitive techniques is welcome in the study of endodontic infections, decreasing the risks for potentially important species to pass unnoticed during sample analysis. On the one hand, this allows for detection of hitherto uncultivated or fastidious bacteria that can die during sampling, transportation, or isolation procedures (Wang et al. However, the fact that some microorganisms die during the course of an infectious process does not necessarily implicate that in a determined moment these microorganisms have not participated in the pathogenesis of the disease. Viable bacteria detected in a cross-sectional study may be involved with maintenance of the disease but not necessarily with causation. Moreover, in the clinical situation, tissue fluids and exudate can seep into the canal and comprise the main sustainable source of nutrients to intraradicular bacteria. Thus, any comparisons between the use of molecular methods in palaeomicrobiology and endodontics can be considered inappropriate at best. These stains are selective in penetrating only into dead bacterial cells with compromised membrane/cell wall integrity but not into live cells with intact membranes/cell walls. Exposure to bright light for 1 minute leads to covalent binding and inactivation of the free stain. Several molecular methods have been or have the potential to be applied to the study of endodontic infections. The choice of a particular approach depends on the questions to be answered and a variety of techniques have been used to offer a better picture of the endodontic bacterial communities. Traditionally, endodontic infections have been studied by means of culture-dependent approaches (see Chapter 4). Such studies have resulted in the establishment of a set of species thought to have an important role in the pathogenesis of apical periodontitis. Over the last 15 years, not only have findings from culture-based methods been confirmed, but they have also been significantly supplemented with those from molecular diagnostic techniques (Siqueira and R^ cas 2009b). Detection of cultivable named species in higher prevalence by molecular methods can be explained on the basis of the higher sensitivity of the methods when compared to culture, the fastidious nature of the microorganisms, or even the fact that not all strains within a species can be cultivated or accurately identified. Moreover, the list of candidate pathogens has expanded to include fastidious cultivable species or even as-yet-uncultivated bacteria that have never been previously found in endodontic infections by culturing procedures. Consequently, the endodontic microbiota has been refined and redefined by molecular methods. First generation: involves studies of the endodontic microbiota using open-ended (or broad-range) culture methods, which disclosed many cultivable species in association with apical periodontitis. These methods allowed the inclusion of some difficult-to-grow species in the set of candidate endodontic pathogens. By these approaches, not only cultivable species, but also as-yet-uncultivated and uncharacterized bacteria have been identified. The choice for a particular technique will depend on the type of analysis to be performed. Further, not only have findings from culture-based methods been confirmed, but they have also been significantly supplemented with those from culture-independent molecular biology techniques, which comprise the other four generations of endodontic microbiology studies (Siqueira and R^ cas 2009b). The impact of molecular studies in endodontics is highly significant in terms of deciphering the microbial diversity in endodontic infections. Approximately 500 different microbial species (mostly bacteria) have been detected in different types of endodontic infections (Siqueira and R^ cas 2009b). Another significant contribution of molecular methods to the knowledge of endodontic infections comes from bacterial community-profiling analyses. According to the latter, the community is the unit of pathogenicity and several factors influence its virulence, with special emphasis to the presence of certain pathogenic species, their multiple interactions in a multispecies consortium, and the accumulation of virulence factors in the biofilm (Siqueira and R^ cas 2009a). The different types of endodontic infections were confirmed as being composed of multispecies bacterial communities (Siqueira et al. There is a great interindividual variability in the diversity of endodontic bacterial communities associated with the same clinical disease (R^ cas et al. The fact that the composition of the endodontic microbiome differs consistently between individuals with the same disease indicates a heterogeneous etiology for apical periodontitis, where multiple species combinations can lead to similar disease outcomes. For instance, endodontic bacterial communities associated with symptomatic lesions are more similar to each other when compared with communities present in teeth with asymptomatic lesions (Siqueira et al. Therefore, disease severity (intensity of signs and symptoms) or response to treatment may be related to the bacterial community composition. The apical portion of the root canal harbors a microbiome that is significantly different in composition than that occurring in the more coronal 104 Endodontic Microbiology aspects of the root canal (Alves et al. The apical bacterial communities are as diverse as those occurring at the middle/coronal thirds (Alves et al. A high variability is observed for both interindividual (samples from the same root canal region but from different patients) and intraindividual (samples from different root canal regions of the same tooth) comparisons (Alves et al. The number of bacterial cells in an infected canal varies from 103 to 108 (Vianna et al. Comparison of the bacterial community profiles between symptomatic (abscesses) and asymptomatic primary infections by community-profiling techniques have found marked differences between these conditions (Siqueira et al. This means that there is a significant difference in the species composition and abundance associated with symptomatic and asymptomatic infections. Symptomatic infections also harbor a significantly higher number of bacterial species (Siqueira et al. It is highly likely that these species belonging to uncommon phyla are lowabundance members of the endodontic community. Culture-independent molecular studies have also disclosed several as-yet-uncultivated phylotypes from the five other phyla that have cultivable representatives in the endodontic microbiome. Spirochetes are highly motile, spiral-shaped bacteria that have been frequently observed in samples taken from endodontic infections by microscopy, but had never been identified to the species level. The application of molecular diagnostic methods to the identification of spirochetes has demonstrated that their occurrence in infections of endodontic origin has been overlooked by technical hurdles of culture techniques. They can be classified into two groups according to the fermentation of carbohydrates: the saccharolytic species include T. Several other molecular studies confirmed that this treponeme and all the other cultivable species can take part in the microbiome of primary endodontic infections, including abscesses (Siqueira et al. Overall, 28 different taxa were identified: 9 cultivable and validly named species, 1 cultivable as-yet-uncharaterized strain and 18 as-yetuncultivated phylotypes. Dialister pneumosintes and Dialister invisus have been frequently present in the microbiome associated with asymptomatic and symptomatic primary endodontic infections (Munson et al. Black-pigmented Gram-negative anaerobic rods of the genera Prevotella and Porphyromonas have been commonly found in endodontic infections by culture (Haapasalo et al. Molecular studies have shown even higher prevalence of black-pigmented bacteria in primary infections (Siqueira et al. Other Prevotella species, such as Prevotella multissacharivorax and Prevotella baroniae, and Alloprevotella tannerae, have been detected in endodontic infections only after the advent of molecular methods (Xia et al. Fusobacterium nucleatum is one of the most commonly encountered Gram-negative species in primary endodontic infections by culturing studies (Sundqvist 1992; Debelian et al. Molecular studies have confirmed these findings and have shown even higher prevalence values for this species in primarily infected root canals, including cases of abscesses (Jung et al. Culture-dependent studies have shown that anaerobic Gram-negative bacteria are the most common microorganisms in primary endodontic infections, but some Gram-positive bacteria may also be frequent members of the endodontic microbial consortium. Culture-independent analyses of primary endodontic infections not only have supported these findings, but also have shown higher prevalence for some species and included new Gram-positive species in the set of candidate pathogens. Gram-positive species found in similar or higher prevalence by molecular techniques when compared to culture include streptococci (Siqueira et al. One of the most prevalent as-yetuncultivated phylotypes found in endodontic infections is Bacteroidaceae sp. These include bacteria that are relatively easy to cultivate on ordinary media but have, for some reason, only recently been cultivated for the first time. Findings from laboratories in different countries are often quite different regarding the prevalence of the species involved in endodontic infections. Although these differences may be attributed to variations in the identification methodologies, a geographic influence in the composition of the root canal microbiome has been suspected. Molecular approaches are the most appropriate methods to compare microbiologic findings from distinct geographic locations. Because samples from different countries should ideally be analyzed in the same laboratory, the time elapsed from collection to delivery to a distant laboratory may make samples improper for culturing analysis.

Laser Doppler flow measurements of pulpal blood flow and severity of dental injury symptoms miscarriage order cheap rumalaya online. Comparison of the efficacy of a custom-made pulse oximeter probe with digital electric pulp tester medicine jobs order 60 pills rumalaya overnight delivery, cold spray and rubber cup for assessing pulp vitality medications removed by dialysis purchase generic rumalaya pills. It is possible for a tooth exhibiting irreversible pulpitis to also show acute alveolar abscess symptoms of hiv cheap rumalaya on line. A True B False 14 Current therapy in endodontics 5 Electric pulp testing is more accurate than thermal testing in assessing pulp vitality medicine 8 discogs buy cheap rumalaya 60 pills. A True B False 6 Which of the following findings is always associated with a diagnosis of asymptomatic irreversible pulpitis A Spontaneous pain B Swelling C Recent pulpectomy procedure D Radiographic evidence of caries extending into the pulp chamber 7 Antibiotics should be prescribed to a patient who presents with swelling symptoms 7 days after conception purchase rumalaya discount, fever, and lymphadenopathy. A True B False 8 Which of the following findings negatively affects the prognosis of a tooth A A crack B Swelling C Presence of a sinus tract D Lingering pain to hot fluids 9 Percussion testing is done to identify inflammation in the periodontal ligaments of a given tooth. There have been many improvements, both in quality and in radiation hygiene, since the discovery of x-rays by Wilhelm Roentgen in 1896. Patients presenting for evaluation today have an increased level of knowledge and awareness of the harmful effects of radiation compared to two decades ago. The information (or misinformation) is readily available for the patient to acquire. An op-ed in a New York Times article is just one example of how information is accessible to the public. A concern within the medical community is that certain healthcare professionals default to obtaining the best imaging module when an inferior one with a lower radiation level would have achieved the same result. However, there is also a sense that the radiation levels are too low to be detrimental to the health of the patient. The purpose is to emphasize the importance of ordering the image with the least radiation while achieving its diagnostic purpose. Digital radiography Digital radiography has many advantages over wet film radiography. Thirdly, the ability to share pertinent findings on a large computer screen is a more effective patient education tool. There are two types of digital radiography systems on the market: the direct digital systems use an intraoral sensor to produce an instantaneous digital image on a computer monitor. The plate is then placed into a scanner, which produces a digital image within a few minutes. Advances in digital radiography have focused on making the sensors less bulky and increasing the spatial resolution of the displayed image. Wet film has a spatial resolution of 16 lp/mm, which increases to about 20 to Current Therapy in Endodontics, First Edition. With available image enhancement tools, patients can more easily visualize important findings, such as caries or a periapical radiolucency. However, the sensor with the highest spatial resolution is not always the best sensor. The human eye is only capable of identifying 10 to 13 lp/mm without any visual aids. The image is captured by the thin plate and processed using Chapter 2: Imaging technologies 17 a laser scanner. Even though the scanning process takes some time to produce the images, obtaining the image is still faster than wet film radiography. One study claims the screens become nondiagnostic after 50 uses, [6] and another study found the number to be 200. Because the technology has advanced to the point where direct and indirect digital systems are better alternatives to wet film radiography, the decision to transition should be easy. A software program, proprietary to each manufacturer, reconstructs the final images for the viewer. B, A cone-beam computed tomography scan of the area depicts a well-defined circular low-density area palatal to the root of the tooth. An overread from an oral and maxillofacial radiologist confirms a diagnosis of nasopalatine duct cyst. The axial and proximal (sagittal in anterior region, coronal in posterior region) views are of particular value because they cannot be visualized with conventional radiography. Just as a pixel is a minimum unit for a digital photo, a voxel (volumetric pixel) is a minimum unit for 3D data. B, An isotropic (symmetrical) voxel provides a highly accurate image that is free of distortion. B, An axial slice from a cone-beam computed tomography scan provides the necessary information on the type of resorption (internal or external) and the prognosis of the tooth. B, A sagittal slice of a cone-beam computed tomography scan of the same area depicts a well-defined low-density finding in the periapical region of the tooth. Sagittal (B) and coronal (C) slices from a cone-beam computed tomography scan of the same area depict the high-density mass clearly. An overread provided by an oral and maxillofacial radiologist identified the high-density mass as idiopathic osteosclerosis. B and C, Beam hardening artifacts from cone-beam computed tomography imaging can resemble bone loss or root fracture. Metallic posts, crowns, bridges, implants, and gutta-percha filling materials create artifacts that pose difficulty for the clinician in interpreting 24 Current therapy in endodontics findings. These artifacts can complicate imaging interpretation by masking the area of interest or by mimicking endodontic complications. In the head and neck region, the organs used to calculate the effective dose include the thyroid, esophagus, bone marrow, bone surface, salivary glands, skin, and other tissues, as specified by the International Commission on Radiological Protection [22]. This is due to the presence of more sensitive tissues and organs in the path of the x-ray beam in the mandibular posterior scan. Therefore, it is very difficult to compare the dosages of available units on the market [23]. However, radiation risk is best measured based on the effective dose received by the patient. Improvements in stability during patient positioning, and the overall harmonics of the machine, improve image quality by minimizing vibration or motion artifacts. Decreasing the exposure time also minimizes motion artifact and reduces radiation exposure. Lastly, improved software reconstruction filters aim to enhance image quality and reduce or eliminate artifacts. Evaluation of image quality parameters of representative intraoral digital radiographic systems. Storage phosphor plates: how durable are they as a digital dental radiographic system Joint Position Statement of the American Association of Endodontists and the American Academy of Oral and Maxillofacial Radiology. Evaluation of cone-beam computed tomography in the diagnosis of vertical root fractures: the influence of imaging modes and root canal materials. The last two decades have been witness to phenomenal growth in endodontic technology. The introduction of these new technologies has resulted in endodontics becoming easier, faster, and, most importantly, better. The technical demands and level of precision required for successful performance of endodontic procedures have always been achieved by careful manipulation of hand instruments within the root canal space and by adherence to the biological and surgical principles essential for disinfection and healing. To improve the speed and efficiency of the treatment, there has been a resurgence of mechanized and automated systems for preparing and sealing the root canal system. The clinical endodontic breakthrough has been progressing from using a series of stainless steel hand files and rotary Gates Glidden drills to integrating NiTi files for shaping canals. Use of automated NiTi instruments was an important and logical development and step to improve the efficiency of the treatment. This chapter includes pertinent information on the most recent rotary NiTi instruments as they have become widely used adjuncts in root canal treatment. Cleaning and shaping A wide spectrum of possible strategies exists for attaining the goal of removing the canal contents and eliminating infection. At one end of the spectrum is a minimally invasive approach of removing canal contents and accomplishing disinfection that does not involve the use of a file. This is the noninstrumentation technique, which consists of a pump, a hose, and a special valve that is cemented into the access cavity to provide oscillation of irrigation solutions at a reduced pressure [2]. At the other end of the spectrum is a treatment procedure that removes all intraradicular infection by extracting the tooth in question. Shaping and cleaning of the root canal system is considered a decisive link in the endodontic chain, because shaping determines the efficacy of subsequent procedures. This includes mechanical debridement, the creation of space for the delivery of medicaments, and optimized canal geometries for adequate obturation [4]. Chemomechanical preparation of the root canal includes both mechanical instrumentation and antibacterial irrigation and is principally directed toward the elimination of microorganisms from the root canal system. From a biological perspective, the goals of chemomechanical preparation are to eliminate microorganisms from the root canal system, to remove pulp tissue that may support microbial growth, and to avoid forcing debris beyond the apical foramen, which may sustain inflammation. Mechanical instrumentation is one of the important steps in reducing bacteria in the infected root canal. Clinical experience, handling properties, usage safety, and case outcomes should decide the choice of a particular design. NiTi rotary instruments have become a mainstay in clinical Current Therapy in Endodontics, First Edition. The technical goals of canal preparation are directed toward shaping the canal so as to achieve the biological objectives and to facilitate placement of a root filling. The following sections describe the instrument systems most widely used for root canal preparation. The basic strategies apply to all NiTi rotary instrument systems, regardless of the specific design or brand. These instruments can be differentiated into active and passive instruments (Box 3. The alloy was called Nitinol, an acronym for the elements from which the material was composed: ni for nickel, ti for titanium, and nol from the Naval Ordnance Laboratory. The NiTi alloy used to manufacture endodontic instruments is composed of approximately 56% nickel and 44% titanium by weight and is generically known as 55 Nitinol [5]. NiTi alloys are softer than stainless steel, are not heat treatable, have a low modulus of elasticity but a greater strength, and are tougher and more resilient. A study found that size #15 NiTi instruments were two to three times more flexible than stainless steel instruments [6]. NiTi instruments showed superior resistance to angular deflection: they fractured after 2 1/2 full revolutions (900 degrees) compared with 540 degrees for stainless steel instruments. Nitinol belongs to a category of alloys called "shape-memory alloys," which have some extraordinary qualities. NiTi behaves like two different metals, because it can exist in one of two crystalline forms. Hero, K3 Passive Instruments Passive instruments perform a scraping or burnishing action rather than a real cutting action. If the stress is released, the structure recovers to an austenitic phase and its original shape. These alloys are mainly characterized by two properties that distinguish them from other metal alloys and are of interest in endodontics: superelasticity and high resistance to cyclic fatigue. These two properties allow continuously rotating instruments to be used successfully in curved root canals. These properties can be explained by specific crystal structures of the austenite and martensite phases of the alloy [5]. Heating the metal above 212 F (100 C) can lead to a phase transition, and the shape memory property forces the instrument back to a preexisting form. When this file is placed in a curved canal, the atoms rearrange into a closely packed hexagonal array, and the alloy is transformed into the more flexible martensite crystal structure. This molecular transition enables these files to bend easily and around severe curves without permanent deformation. After release of stresses, the metal returns to the austenitic phase and the file regains its original shape. This stress-induced martensitic transformation is a unique property of NiTi alloys and makes this material one of the few alloys suitable for use in rotary endodontic instruments [5, 7]. The superelasticity of NiTi allows deformation of as much as 8% strain to be fully recoverable, in comparison to a maximum of less than 1% with alloys such as stainless steel [5]. Despite the increased flexibility of NiTi instruments, separation is still a concern. NiTi engine-driven rotary systems require that the instrument be activated before it is inserted into the canal, where it mostly operates in flexed conditions.

Cutting edge: recognition of Grampositive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2 medicine 100 years ago purchase 60 pills rumalaya with amex. Comparison of endodontic bacterial community structures in root-canal-treated teeth with or without apical periodontitis symptoms esophageal cancer cheap 60pills rumalaya amex. Herpesviruses cause disease in humans in two ways: herpesvirus infections may result at the site of entry or they may enter the circulation and infect distant organs treatment 4 ringworm buy discount rumalaya 60 pills on-line. The mode of release of the virions can determine the pattern of infection from the infected cell (Tucker and Compams 1992; Bergelson 2009; Contreras et al medicine website cheap 60 pills rumalaya otc. If the virion is released from the apical part of the cell treatment toenail fungus buy rumalaya us, the infection will become localized; however medications 377 order 60 pills rumalaya otc, if the virion is released from the basolateral side of the cell, the infection becomes a disseminating infection (Tucker and Compams 1992; Bergelson 2009; Contreras et al. The viral replication and the production of infectious virions involve activations of three sets of genes: the expression of immediate-early, early, and late classes of genes. In past two decades, new viruses have been identified that have expanded our knowledge and understanding of viral infections and their pathogenicity. Apical periodontitis and its etiopathogenesis, especially the molecular events preceding and causing Endodontic Microbiology, Second Edition. A virion initiates infection by fusion of the viral envelope with the plasma membrane after attachment to the cell surface. Viral transcription and translation occur in three phases: immediate early, early, and late. Viral glycoproteins and tegument protein patches in cellular membranes and capsids are enveloped. Virions are transported via endoplasmic reticulum and released by exocytosis or cell lysis. Pulpal and periapical infections exhibit complex microbial ecologies involving synergistic, antagonistic, and commensal interrelationships among resident microorganisms. Sundqvist (1992) found strong positive associations between Fusobacterium nucleatum and Parvimonas micra, Porphyromonas endodontalis, Selenomonas sputigena, and Campylobacter rectus, and negative or neutral associations with streptococcal species, Propionibacterium propionica, Capnocytophaga ochracea, Veillonella parvula, and other bacteria in root canals of teeth with periapical lesions. Significant relationships may also exist between endodontic Porphyromonas gingivalis and Tannerella forsythia or Treponema species (Jung et al. A marked shift toward a more anaerobic microbiota has been demonstrated during the development of experimental endodontic infections in monkeys (Fabricius et al. Varying nutritional demands and anaerobic requirements of infecting organisms are important determinants of microbial interrelationships and population changes in the endodontic microbiota (Sundqvist 1994). Differing levels of host resistance may also significantly influence the composition of the periapical microbiota. Viruses in Endodontic Pathosis 181 Current hypotheses on the pathogenesis of periapical pathosis include both bacterial and host factors, but the pathogenic events that trigger the conversion of a stable, asymptomatic endodontic lesion to a progressive or a symptomatic lesion remain obscure. A commonly held idea regarding apical pathosis as a bacterial disease could not fully explain the pathogenesis of the disease, site-specificity, and tissue tropism. The pathogenic events that trigger the conversion of a stable, asymptomatic endodontic lesion to a progressive or a symptomatic lesion remain obscure. Viral association with bacteria and apical disease is consistent with pathologic role of both infectious agents. Acute exacerbation of periapical disease may be caused from a combination of herpesviral and bacterial causes. This possibility is consistent with the majority of studies that have observed presence of active herpesvirus infections in symptomatic periapical lesions and the proinflammatory potential of herpesviruses (Mogensen and Paludan 2001). Human herpesviruses are classified into three groups (,) based upon details of tissue tropism, pathogenicity, and behavior in the laboratory (Table 8. In most individuals, primary infection by herpesviruses occurs early in life and exhibits few or no overt disease symptoms. Herpesviruses remain in infected hosts for a lifetime in a prolonged state of latency but retain their capacity for renewed or episodic Table 8. Reactivation of latent herpesviruses is involved in driving the pathologic process of some types of symptomatic periapical disease. Physical trauma, stress, immunosuppression, immune dysfunction, and radiotherapy can trigger herpesvirus activation. Herpesviral replication takes place in the nucleus of the host cell and involves the expression of immediate-early, early, and late classes of genes. Late (structural) genes are expressed during the productive (lytic) phase of herpesviral infections. After primary exposure, herpesviruses establish latency in various host cell reservoirs, from which they may reactivate periodically (Sissons et al. Herpesvirus transmission occurs by intimate contact with infected secretions including saliva, blood, and genital secretion (Gautheret-Dejean et al. Acquisition of herpesviruses takes place from an early age and sometimes in the uterus. Clinical manifestations of herpesvirus infections are highly diverse and range from mild or subclinical disease in most healthy individuals to encephalitis, pneumonia, and other potentially lethal infections, and various types of cancer including lymphoma, sarcoma, and carcinoma in immunocompromised hosts. Infected patients experience an initial primary infection followed with a period of latency. Patients with latent herpes simplex infection develop episodes of recurrent oral herpes labialis characterized by the occurrence of a cluster of vesicles and shallow ulcers localized to the lateral aspects of the lips. Symptoms of this disease included fever, lymphadenopathy, malaise, and sore throat. Oral lesions include vesicles on the lips, and the hard and soft palates (Millar and Troulis 1994; Miller 1996). It involves the trigeminal nerve and forms ulcerated lesions with prominent red borders, resembling aphthous ulcers. Lesions are unilaterally distributed along the infected nerve (Millar and Troulis 1994; Miller 1996). It has also been reported to infect a wide variety of cell types (Ablashi 184 Endodontic Microbiology et al. Viruses in Endodontic Pathosis 187 Herpes simplex virus infection demonstrated no relationship to periapical disease. However, most of the symptomatic periapical lesions studied failed to yield black-pigmented anaerobic rods. Acute exacerbation of periapical disease may be caused by unique constellations of pathogenic bacteria or, alternatively, may result from a combination of herpesviral and bacterial causes. The latter possibility is consistent with the observed uniform presence of active herpesvirus infections in most symptomatic periapical lesions and the proinflammatory potential of herpesviruses (Mogensen and Paludan 2001). Herpesviruses possess several virulence factors of potential importance for periapical pathosis, including the ability to induce immune impairment (Michelson 1999; Boeckh and Nichols 2003), and subsequent overgrowth of pathogenic microorganisms (Kimberlin 1998). Herpesviruses seem also to cooperate with pathogenic bacteria in producing a variety of medical diseases, including inflammatory bowel disease, enterocolitis, esophagitis, pulmonary infections, sinusitis, acute otitis media, dermal abscesses, and pelvic inflammatory disease (Brogden and Guthmiller 2003). Additionally, herpesviruses may give rise to periapical pathosis by inducing cytokine and chemokine release from inflammatory and noninflammatory host cells (Mogensen and Paludan 2001). Periapical sites having inadequate antiviral immune response may be particularly prone to tissue breakdown (Sabeti et al. The presence of cytomegalovirus in symptomatic periapical pathosis is consistent with the notion that inflammatory cells are the source of the virus. Also, cytomegalovirus in marginal periodontitis lesions exists in macrophages and T lymphocytes (Contreras et al. The Fas/Fas ligand system, which is an important cellular pathway mediating apoptosis (Chaudhuri et al. In fact, our findings are in agreement with other current studies that demonstrate there are various but not specific bacterial types, which indiscriminately were actively present in normal, asymptomatic, as well as symptomatic periapical lesions. On this basis, bacterial infection may serve as cofactor in lymphoid transvascular migration, and cytokine expression be involved in the pathogenesis of periapical lesions. The inhibition of apoptosis may further result in continuous inflammation and cytokine production and the establishment of a chronic inflammatory stage. The effect of which may be a failure of the host to control or eliminate the viral infection, and subsequently the bacterial infection. In conclusion, the present flow cytometric analysis and previous histopathologic and polymerase chain reaction-based findings have identified cytomegalovirus as a frequent inhabitant of symptomatic periapical lesions. As an active cytomegalovirus infection induces a multiplicity of interconnected immune reactions, incorporating cytomegalovirus and other herpesviruses into studies on infectious causes and causal mechanisms of periapical pathosis may provide important new insights into the pathogenesis of the disease. Herpesvirusmediated pathogenicity takes place through several mechanisms, operating alone or in combination, and involving both cellular and humoral host responses (2000 (Table 8. Herpesviruses can cause direct cytopathic effects on periapical fibroblasts, endothelial cells, and bone cells, the results of which are impaired tissue turnover and repair, and ultimately loss of tissue. Impairment of host defense cells can predispose to overgrowth of endodontic pathogenic bacteria. Herpesvirus activation can induce significant immunosuppressive and immunomodulatory effects in periapical sites. Herpesviruses can trigger an array of host responses that include dysregulation of macrophages and lymphocytes and downregulate the antiviral host immune response (Boeckh and Nichols 2003). Herpesvirus infections elicit proinflammatory cytokine and chemokine release from inflammatory cells. These inflammatory mediators, which are most likely produced locally by periapical macrophages (Miyauchi et al. Previous studies a have focused on lipopolysaccharide as an inducer of macrophage cytokine production (Page et al. Cytokines and chemokines have important roles in the first line of defense against human herpesvirus infections and contribute significantly to regulation of acquired immune responses. However, by a diverse array of strategies, herpesviruses are able to interfere with cytokine production or divert potent antiviral cytokine responses, which allow the viruses to survive throughout the lifetime of the host (Alcami and Koszinowski 2000; Tortorella et al. Proinflammatory activities normally serve a positive biologic goal by aiming to overcome infection or invasion by infectious agents, but can also exert detrimental effects when a challenge becomes overwhelming or with a chronic pathophysiologic stimulus. Also, viruses display great uniqueness when it comes to diverting the potent antiviral cytokine responses to their benefit (Tortorella et al. Herpesviruses can produce periapical tissue injury as result of immunopathologic responses. Th1 cells, which predominate in periapical lesions (Brogden and Guthmiller 2003), are mediators of delayed type hypersensitivity (Seymour et al. Control of herpesviral replication and prevention of pathosis depend on both innate and adaptive immune mechanisms. Antiviral antibodies can help control infectious virions and cytotoxic T lymphocytes have an important role in limiting the proliferation of herpesvirus-infected cells. However, while antiherpesviral immune responses may be able to protect from disease, they are insufficient to eliminate reservoirs of persistent viral gene expression. Herpesvirus infection of periapical sites may be important in a multistage pathogenesis by altering local host defenses. Initially, bacterial infection or mechanical trauma of the pulp cause inflammatory cells to enter pulpal and periapical tissues. Alteration between prolonged periods of herpesvirus latency interrupted by periods of activation may partly be responsible for intermittant episodes of periapical disease flareup. Frequent reactivation of periapical herpesviruses in some patients may result in rapid disease progression. Absence of herpesviral infection or reactivation and lack of endodontic pathogenic bacteria may explain why some teeth having necrotic pulp can maintain periapical health or minimal disease for extended periods of time. An abscessed tooth with swelling, pain with a large redographic lesion has a higher rate of flareup (Genet et al. An incidence of flareup in a chronic apical abscess with presence of a sinus tract is unlikely (Torabinejad et al. Viruses in Endodontic Pathosis 191 Perhaps not coincidentally, acute exacerbation of periapical disease may be caused by unique constellations of pathogenic bacteria or, alternatively, may result from a combination of herpesviral and bacterial causes. The latter possibility is consistent with the observed uniform presence of active herpesvirus infections in symptomatic periapical lesions and the proinflammatory potential of herpesviruses (Mogensen and Paludan 2001). Herpesviral activation leads to increased inflammatory mediator responses in macrophages and probably also in resident connective tissue cells within the periapical lesion. Several of the herpesvirus-associated cytokines and chemokines are prominent in periapical lesions (Nair 1997; Wang et al. Moreover, in a vicious cycle, triggering of cytokine responses may activate latent herpesviruses and in so doing further aggravate periapical disease. In conclusion, endodontic inflammation can be initiated by a variety of infectious agents and is mediated by cellular components, such as neutrophils, macrophages, and lymphocytes, as well as molecular components, including cytokines and chemokines. These responses possess pro- and/or anti-inflammatory properties, with harmful or beneficial effects. Reactivation of latent herpesviruses is involved in driving the pathologic process of cases of symptomatic periapical disease. Alteration between prolonged periods of herpesvirus latency interrupted by periods of activation may partly be responsible for intermittent episodes of exacerbation of periapical disease. Perhaps not coincidentally, herpesvirus-activating factors are also associated with acute endodontic disease (Torabinejad 1994). Intercellular junctional proteins as receptors and barriers to virus infection and spread. Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus.

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Syndromes

• Dengue hemorrhagic fever
• Swollen, red, painful nodule at site of fly bite
• Wound breaks open
• Vomiting blood
• Damage to nerves of the legs and arms (peripheral neuropathy)
• Some varnishes
• Joints (arthritis)
• Slow speaking

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Minor intraoral soft tissue infections and bony infections, for example, osteomyelitis and bisphosphonaterelated osteonecrosis of the jaw are not addressed. Dramatic changes have occurred in the management of infections since the early seventeenth century when teeth were the fifth or sixth most common cause of death. There is no accurate estimate of the frequency of deep neck space infections worldwide, but they are still associated with high rates of morbidity and mortality. Early recognition by the oral health care professional of potentially severe infections and prompt management can prevent progression of the infection, with the later need for hospitalization and life-saving surgery. If not recognized and treated at an early stage, these infections may progress to cause airway obstruction, necrotizing infections with septic shock, or fatal outcomes from complications such as brain abscess, cavernous sinus thrombosis, or mediastinitis. Although medical advances in imaging, antibiotics, and critical care have increased our ability to treat infectious diseases, the outcome remains a balance between the virulence of the infectious agent and the immune response of the host. Today, severe aggressive odontogenic infections remain an important cause of morbidity, mortality, and utilization of hospital resources. In subcategorizing odontogenic infections, 65% were secondary to caries, 22% pericoronitis, and 22% were periodontal (some patients had more than one source), with 68% of cases originating in the mandibular third molars, followed by the mandibular bicuspids and molars (Flynn et al. However, other authors have described more male patients (62%) and also a high incidence of ethnic minorities: African American 54%, Hispanic 22% (Flynn et al. There is a wide range reported in the literature for the association of a compromised immune system with severe deep space infections, from 8% (Flynn et al. However, this may reflect the patient population of the study which was set in a large urban public hospital, rather than a potential specific predilection for developing these serious infections. In one large series of head and neck infection patients with necrotizing fasciitis, 89. A comprehensive review article of necrotizing fasciitis concluded that 70% of adult cases have an underlying immune compromising disease (McGurk 2003). Pure aerobic infections are much less common comprising approximately 5%, and pure anaerobic infections comprise the remaining 25%. Cultures show mixed infections with Severe Head and Neck Infections 233 Gram-positive cocci and Gram-negative rods predominating. Other authors recommend cultures to guide antibiotic selection for extensive or rapidly spreading infections, in immunocompromised patients, recurrent infections, where there is no response to antibiotics, nosocomial infections, or necrotizing and gas-producing infections as opposed to purely empiric therapy (Jones and Cadelaria 2000). Lastly, some researchers have described the use of molecular microbiologic methods. As noted in Chapter 5, this methodology has been shown to detect uncultivable species of bacteria (Riggio et al. The clinical applicability of these types of diagnostics is questionable because the phenotypic properties of the microorganisms and their responses to antibiotics cannot be detected with certainty. Therefore, at this time it does not appear as though molecular microbiology can change the initial management of these types of cases. However, there may be some benefit in assisting with the selection of a narrow-spectrum antibiotic after surgical therapy has been implemented. Unless patients were allergic or had a necrotizing infection, all were started on intravenous penicillin G, and subsequently 19% of isolated species were found to be penicillin-resistant, and one or more of these resistant bacteria were found in 54% of cases. All six patients who failed penicillin treatment were found to have one or more penicillinresistant strains, and six out of ten (60%) patients with resistant bacteria were treatment failures. However, the authors point out that the identification of penicillinresistant organisms was often delayed up to 2 weeks, at which time clinical decisions had already been made (Flynn et al. Because of the very predictable polymicrobial mixed infections, most patients are treated empirically on hospital admission with regimens that usually include a penicillin, clindamycin, and/or metronidazole. Reported antibiotic regimes are penicillin + metronidazole, or clindamycin in 60% and 20% of 157 patients, respectively (Wang et al. In necrotizing fasciitis, most infections particularly those of the limbs, perineum, and abdomen have been attributed to group A streptococci, which appears to have an increasing incidence (Kaul et al. However, although the classic disease is seen with group A streptococci alone or in combination with Staphylococcus aureus, this disease may also be polymicrobial with prominent anaerobic species present (Brook and Frazier 1995). Because of the severe systemic compromise and high mortality rate, triple antibiotic therapy is usually mandated. Regimens recommended include a penicillin, aminoglycoside, and antianaerobe (Lin et al. An abscess is a localized collection of pus classically caused by Staphylococcus species which produce the coagulase enzyme, which "walls off" infections. Cellulitis is an infection that spreads widely through the tissues, not usually producing much pus but permeating tissue spaces, and is classically caused by streptococci that produce collagenase and hyaluronidase to break down the ground substance of connective tissue and promote spread. In necrotizing fasciitis, there is a rapid progressive liquefaction of subcutaneous fat and fascia with thrombosis of the subdermal veins. Although the underlying muscle is usually preserved, myositis can occur as can gas formation ("gas gangrene"). Extensive underlying skin necrosis may be present with comparatively little in the way of clinical signs. The patterns of spread of the cellulitic infections will determine symptoms and signs and also whether the airway is liable to be compromised. Pus and cellulitic fluid will usually follow the path of least resistance and track along fascial planes in the neck and face. The direction of spread for odontogenic infections is therefore determined by the anatomic relationships of the tooth root to the jawbone and the muscle insertions into the jaw. The majority of severe odontogenic infections are related to the mandibular third molars, followed by the other molars and premolars. It should also be appreciated by the reader that most of these spaces or potential spaces are interconnected so that many of these infections involve multiple spaces. Once pulp necrosis has occurred, periapical infection is located within the medullary bone of the jaw. This infection will eventually perforate the cortical plate to gain access to the soft tissue spaces. In the mandibular molar region, the roots tend to be situated lingually and lingual perforation is more common. If the apex of the tooth is inferior to the attachment of the mylohyoid muscle and to the mylohyoid ridge (which is usually the case), pus can directly enter the submandibular space. If the apex is superior to the mylohyoid attachment then it will enter the sublingual space. Both these spaces are connected posteriorly at the free edge of the mylohyoid muscle. If the pus perforates buccally in the mandibular molar region and it is inferior to the buccinator muscle attachment, it can involve the buccal space. If the apex of the tooth is superior to the buccinator insertion, the pus will present intraorally as a vestibular abscess. In the maxilla, buccal perforation from posterior teeth may enter the buccal space and from the canine to the canine space, which can lead to orbital or intracranial involvement. Infections perforating the palatal side of the alveolus, for example, from lateral incisors or the palatal roots of molars, are usually well confined by the thick bound down palatal mucosa of the hard palate and simply require intraoral drainage. In order to understand the presentation and management of these infections, some knowledge of the anatomy of these spaces is essential. The submandibular space lies inferior to the mandible and contains the submandibular gland, lymph nodes, the facial artery, and the anterior facial vein. The mandibular branch of the facial nerve lies superiorly and the lingual and hypoglossal nerve posteriorly and deeply. Anteriorly is the anterior belly of the digastric muscle although the submandibular space communicates freely anteriorly with the submental space. Superiorly is the lower border of the mandible and the pterygomasseteric sling and inferiorly the hyoid bone. The space communicates with the submental anteriorly, the sublingual space posterosuperiorly, and the lateral pharyngeal posteriorly. This is a bilateral infection of the submandibular, sublingual, and submental spaces; the term angina means "to constrict. Anteriorly is the oral commissure with zygomaticus major and depressor anguli oris muscle, and the infraorbital space, while posteriorly is the pterygomandibular raphe. The medial boundary is the superior and middle constrictor muscles and laterally are the medial pterygoid and parotid glands. Superiorly lies the lateral pterygoid muscle and inferior the pterygomasseteric sling. Anterior is the facial skin and posterior the maxilla, while inferiorly are the levator labii superiori, levator labii, and alaeque nasi muscles. Reconstruction for these patients can be surgically challenging, especially if the functional units of the face are involved. Many reconstructive surgeons will follow the principles of the "reconstructive ladder"; which is as follows: r Healing by secondary intention; r Skin grafting; r Local flaps; r Regional flaps; r Free tissue transfer. Important areas to cover in the history include precipitating factors (toothache or trauma), and specific symptoms that may alert the clinician to the fact that that the patient has impending airway obstruction. Symptoms that are very concerning are dysphagia and/or odynophagia, or difficulty in and/or pain with swallowing, or speaking with a muffled or "hot potato" voice quality. Patients with these symptoms represent true surgical emergencies and can quickly progress to a lifethreatening situation. A complaint of inability to fully open the mouth (trismus) is suggestive of pus causing spasm of the masticatory muscles. The examination is directed toward an overall systemic assessment of the patient and a good head and neck examination. This is the worst case scenario, with the patient leaning forward to protect his/her airway and unable to control his/her own saliva because of tongue edema. It can be predicted that even attempting to lie the patient flat to intubate him/her can precipitate complete obstruction. Fever and tachycardia may be marked especially in children, and this may exacerbate dehydration in patients with inability to swallow. These systemic manifestations of acute infection may destabilize preexisting diseases. In necrotizing fasciitis, the skin is diffusely reddened over a wide area, and with progression becomes white and then black and necrotic. Crepitus due to gas-forming microorganisms may be elicited, such as Clostridium perfringens, Clostridium novyi, and Kelbsiella pneumoniae. In abscess or cellulitis, the swelling may be obvious on initial visual examination, for example, swelling of the cheek in buccal space infections or of the submandibular region in submandibular space infections. However, in infections around the masticatory muscles severe trismus may occur, which will prevent a good intraoral examination and be a problem for airway access. Some space infections, such as the masseteric space, have trismus as the most prominent sign. The overlying skin may be shiny or reddened and in advanced cases becomes thinned prior to spontaneous drainage 10. In these infections, the presence of a "normal" white cell count is clinically abnormal and usually indicates a deficient immune response. Blood glucose and electrolytes will be essential for diabetic patients and for suspected necrotizing fasciitis to diagnose underlying systemic problems. Soft tissue lateral views of the neck have been used to visualize increased prevertebral soft tissue thickening in retropharyngeal abscess (Haug et al. If the two modalities were combined, accuracy was 89%, sensitivity 95%, and specificity 80%. Because of their negative exploration rate of 25%, these authors emphasized the importance of clinical decision-making for surgical drainage. It shows all the spaces of the head and neck to demonstrate involvement of areas that were not clinically suspected, as well as visualizing spaces that cannot be directly examined in patients with severe trismus, such as the brain and mediastinum; when extensive spread and complications need to be ruled out, clinical assessment is paramount. Despite the valuable information that can be gained from imaging, the clinician has to balance the benefits against the risk in any case where the airway is an issue. This is frequently a challenging task because of generalized fascial swelling with edema of the tongue, pharynx, and larynx, often accompanied by severe trismus. When the cords can be visualized then standard oral endotracheal intubation is a safe way to proceed, especially with the use of a Glidescope. However, in the presence of edema, inappropriate manipulation of the airway can cause further swelling and bleeding, requiring emergent surgical intervention. In addition, a retropharyngeal or peritonsillar collection of pus may be ruptured by injudicious use of the laryngoscope with aspiration of purulent material and subsequent pulmonary or mediastinal complications.