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  • Associate Professor of Medicine
  • Core Faculty Member, Duke-Margolis Center for Health Policy
  • Member in the Duke Clinical Research Institute


Herpetic Eye Disease Study: a controlled trial of oral acyclovir for herpes simplex stromal keratitis treatment of ringworm order mesalamine 400mg without a prescription. Anterior uveitis with sectoral iris atrophy in the absence of keratitis: a distinct clinical entity among herpetic eye disease treatment xanthelasma eyelid mesalamine 400mg. Herpetic Eye Disease Study: a controlled trial of topical corticosteroids for herpes simplex stromal keratitis medicine x 2016 discount mesalamine 400 mg with amex. May have pain in patients with acute retinal necrosis medications prolonged qt purchase discount mesalamine line, rare in progressive outer retinal necrosis D medications management buy 400mg mesalamine amex. Prominent inflammation in anterior chamber and vitreous treatment molluscum contagiosum purchase 400mg mesalamine visa, with or without optic nerve inflammation f. Clinical features suggestive of outer retinal or full thickness retinal necrosis involving peripheral retina with or without macular involvement and relative sparing of retinal arterioles c. Initial oral valacyclovir (1-2 grams three times daily), usually combined with intravitreal antiviral injections, followed by oral valacyclovir or acyclovir 3. Initial oral famciclovir, usually combined with intravitreal antiviral injections, followed by oral famciclovir or acyclovir 4. Duration of maintenance therapy with oral anti-viral agents to prevent involvement of second eye: 6 weeks to 3 months if normal immunity a. The duration of treatment with oral anti-viral agents to protect the second eye is not well established. Some have suggested indefinite prophylaxis especially if the agent is herpes simplex, if tolerated as second eye involvement (or retinitis after herpes encephalitis) can be delayed by many years if prolonged therapy used, monitor for bone marrow suppression and renal complications 5. Supplementary periocular corticosteroid injections may be useful to reduce inflammation after the infection is controlled B. Combination systemic antiviral therapy plus intravitreal therapy with ganciclovir and/or foscarnet at induction, then maintenance doses 4. Consider vitrectomy with demarcated laser photocoagulation in eyes with dense vitritis or media opacity preventing laser photocoagulation 3. Patients with baseline impairment in creatinine clearance require reduction in dose frequency or amount D. May be primary and related to direct optic nerve involvement, especially in post-encephalitic cases C. Risk of developing the retinitis in the contralateral eye (if disease unilateral) B. Follow-up is every one to four weeks during the first 3 months after infection and periodically thereafter Additional Resources 1. Congenital infection with vertical transmission from a mother infected during pregnancy b. Acquired infection from sexual contact, contact with other body fluids, including urine c. Congenital infection can have devastating neurologic and ocular effects, including blindness b. Acquired infection in children or adults may cause signs and symptoms similar to the infectious mononucleosis syndrome c. Retinal involvement occasionally occurs with other forms of immunosuppression such as patients undergoing solid organ transplantation iii. Organ-transplant patients and other patients with iatrogenic systemic immunosuppression c. Rarely, after local immunosuppression with intravitreal injection of triamcinolone or placement of fluocinolone acetonide implant 3. The eye is virtually always pain-free, and the patient may be entirely asymptomatic b. Peripheral disease may not produce perceived scotomata and most patients with central disease will complain of blurred vision rather than field loss d. Presentation with moderate to severe permanent vision loss in one eye is not uncommon 2. Constitutional symptoms such as fever, malaise and weight loss are common and may be related to disseminated infection in the blood c. An irregular active or advancing border with satellite lesions is highly characteristic c. Intraretinal hemorrhage is common but not invariable, and not essential to diagnosis d. Thick or fluffy, edematous retinal necrosis with hemorrhage along one of the major vascular arcades ("cottage cheese and ketchup") b. Isolated involvement of the optic nerve, having the same appearance as necrotizing retinitis, occurs is a small percentage of cases. Unilateral disease is more common, but one-third to one-half of cases are bilateral. The eye is white and there are usually not posterior synechiae, except with immune recovery E. Maintenance therapy with lower doses of anti-viral medication until there is improvement in the immune system a. Laser barrier for retinal detachment prophylaxis may be considered for patients with inactive retinitis and large (>25% retinal surface) areas of chorioretinal atrophy. Visual loss in patients with cytomegalovirus retinitis and acquired immunodeficiency syndrome before widespread availability of highly active antiretroviral therapy. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. Pathanapitoon K, Ausayakhum S, Kunavisarut P, Wattanakikorn S, et al (2007) Blindness and low vision in a tertiary ophthalmologis center in Thailand: the importance of cytomegalovirus retinitis. Incidence of cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Transmitted by sexual contact, sharing of contaminated needles and syringes, blood transfusion, as well as vertical transmission from mother to child including breast-feeding 3. Children with an infected mother (intrauterine/ peripartum transmission, breast feeding) C. Most patients with anterior uveitis or intermediate uveitis respond to therapy with corticosteroids a. Patients with retinal vasculitis typically respond to therapy with periocular or systemic corticosteroids 3. Adult T-cell leukemia/lymphoma with opportunistic eye infections or malignant cell infiltration a. Patients should be counseled about the risks of transmission and urged to practice safe sex (including the use of condoms). Additionally, infected women should be counseled about pregnancy and the avoidance of breastfeeding Additional Resources 1. Ocular histoplasmosis syndrome is believed to be due to exposure to Histoplasma capsulatum via the respiratory tract a. The organism may then spread through the bloodstream from the lungs to the choroid 2. This condition occurs most frequently in patients who live near the Ohio River and Mississippi River valley areas and watershed areas 2. Atrophic "punched-out" round or streak-shaped scars often prominent in retinal periphery 2. Absence of vitreous cells although choroidal inflammation without vitreous cells or choroidal neovascularization may occur (in primarily acquired disease) and cause vision loss in immunocompetent patients 5. In rare cases immunocompromised patients exposed to the fungal pathogen may develop a. Bevacizumab (Avastin), pegaptanib sodium (Macugen), ranibizumab (Lucentis) intravitreal injection b. Rarely large lesions with poor vision and extrafoveal vascular ingrowth sites may be amenable to subfoveal surgery V. Intravitreal triamcinolone: glaucoma, cataract, endophthalmitis (infectious, sterile) C. Ocular photodynamic therapy with verteporfin for choroidal neovascularization secondary to ocular histoplasmosis syndrome. Presumed ocular histoplasmosis syndrome: update on epidemiology, pathogenesis, and photodynamic antiangiogenic, and surgical therapies. Differentiation between presumed ocular histoplasmosis syndrome and multifocal choroiditis with panuveitis based on morphology of photographed fundus lesions and fluorescein angiography. Submacular surgery for subfoveal choroidal neovascular membranes in patients with presumed ocular histoplasmosis. Managing recurrent neovascularization after subfoveal surgery in presumed ocular histoplasmosis syndrome. Exists as inactive scars, latent infection encysted in host cells at borders of scars, or active replicating infection 3. Infective forms are oocysts (soil forms which are ingested) and tachyzoites (metabolically active and antigenic organism) a. Acquired disease in postnatal period is more common than previously appreciated c. Thought to occur only if mother acquires infection for the first time while pregnant 5. Exposure to undercooked meats from infected animals, which in turn were exposed to material fecally contaminated by cats 3. Atypical forms of extensive chorioretinitis can occur in immunocompromised individuals. Active chorioretinitis is yellow-white, slightly elevated, with a relatively well-defined border 2. Variably present i) Often arteritis, but also periphlebitis ii) May be remote from the chorioretinitis d. Intracellular cysts containing bradyzoites are found at the border of healed lesions b. Retinal necrosis ensues from active disease with granulomatous inflammation in the choroid. Healed lesions show destruction of retina, retinal pigment epithelium, and choroid with variable hyperpigmentation E. High sensitivity and low specificity because of high prevalence of positive antibody titers in general population (a positive serology does not make the diagnosis but only confirms exposure) b. Immunoglobulin (Ig) M antibody determinations helpful in the diagnosis of acquired toxoplasmosis 3. Determination of toxoplasmosis IgG or IgA antibody titers in aqueous humor useful in cases with atypical features 4. Intraocular surgery such as cataract surgery or instrumentation of glaucoma filtering blebs 2. Decision to treat based on proximity to macula and optic nerve, amount of inflammation, and vision 1. Antibiotic treatment there are no studies to suggest that one therapy is more effective than another 1. Can be combined with sulfadiazine or triple-sulfa, azithromycin, or clindamycin ii. Duration of Therapy There are no specific guidelines on duration of antibiotic therapy but duration is tailored to response and requires a minimum of 4-6 weeks of systemic antibiotics C. Topical corticosteroids in patients with significant anterior chamber reaction 2. Not given alone because of risk of worsened infection without antibiotic coverage d. Periocular corticosteroids felt to be contraindicated by many experts because of reports of uncontrolled infection after injection. Discoloration of tooth enamel in children < 11 years or in babies of treated mothers E. If infection was acquired, try to prevent infection in family and neighbors by finding the source C. If pregnant and the infection is newly acquired, take antibiotic treatment to reduce risk of severe fetal effects D. If pregnant and chorioretinitis is recurrent from prior disease, treatment is for maternal indications only E. Take all medications as instructed for the length of time indicated Additional Resources 1. The effect of long-term intermittent trimethoprim/sulfamethoxazole treatment on recurrences of toxoplasmic retinochoroiditis. Infestation of the retina/choroid/vitreous with a second stage larva of Toxocara canis or Toxocara catis 2. Infestation is presumed to occur after ingestion or cutaneous infection with hematogenous spread to the eye B. More common in subtropical or tropical climates where the ground does not freeze 6. Focal, elevated, white, peripheral nodule with variable degrees of surrounding peripheral membranes and pigmentary scarring ii. Focal, elevated, white nodule, usually < 1-disc diameter, with variable pigmentation ii. Ascribed to death of the parasite with a secondary exuberant inflammatory reaction E. Contact with soil or food contaminated with feces from infected animals (dogs and cats) E. Pars planitis (peripheral granuloma or endophthalmitic forms of ocular toxocariasis) D. Parasite is assumed to be dead when the patient presents with either cicatricial or acute inflammatory changes.

Optical radiation effects in pathological conditions Photodermatoses It is reasonable to treatment zinc poisoning buy mesalamine 400 mg otc believe that patients diagnosed with a known photosensitivity disorder will avoid the radiation responsible for their symptoms medicine ball exercises mesalamine 400 mg without prescription. Below top medicine buy 400mg mesalamine fast delivery, only a few of the most commonly occurring diseases/conditions are mentioned medicine 3605 buy mesalamine 400mg line. Diseases induced by optical radiation the wavelength dependency of some optical radiation-induced photodermatoses is presented in Table 6 medicine ethics order 400 mg mesalamine. The prevalence Figures presented below for the various diseases were found at medicine journal impact factor generic mesalamine 400 mg. Idiopathic or immune-based Actinic prurigo can have childhood onset or onset before 20 years of age. Hydroa vacciniforme is a rare photodermatosis with childhood onset (Rambhatla et al. Solar urticaria is an uncommon condition that affects all ages, but with a peak during the fourth and fifth decades of life (Rambhatla et al. Porphyrias Porphyrias constitute a group of disorders related to enzymatic defects in the haem synthesis (Rimington, 1985). These result in increased synthesis of porphyrins and for some of the diseases, with possible cutaneous photosensitisation. The porphyrin absorption range is about 320-600 nm with the largest absorption maximum about 400 nm and smaller maxima between about 500-700 nm. Hepatocytes and bone marrow erythroblasts are the major cell types involved in haem synthesis and thus, enzymatic defects will be manifested in these cells (Rimington, 1985; Sassa, 2006). The skin localisation of porphyrins of hepatic or erythrocyte origin is dependent on the water solubility of the porphyrins (Brun et al. Thus, knowing the type of porphyria in a patient cannot indicate safe wavelengths within the porphyria absorption spectrum by choosing appropriate penetration depths. Porphyrias are, in general, rare diseases and prevalence and incidence vary between type of porphyria and country (Table 6). Photosensitivity with exogenous origin Photosensitivity can be induced by skin exposure to plant and vegetable compounds (phytophotodermatitis), drugs, chemicals and cosmetics, all in combination with optical radiation. The most common mechanism for photosensitivity induced by drugs is phototoxicity, while a less frequent mechanism is photoallergy. Photoallergic contact dermatitis is a delayed-type hypersensitivity reaction in susceptible individuals. Photo-aggravated dermatoses this is a large and diverse group of diseases which are not primarily caused by optical radiation, but which can be exacerbated by such radiation. Susceptible groups Children in general and persons affected by photodermatoses are susceptible to excessive optical radiation exposure of their skin. Photosensitivity occurs in children for (at least) the following porphyrias: erythropoietic protoporphyria, congenital erythropoietic porphyria and hepatoerythropoietic porphyria. Theoretically, the incidence of the chemical/drug-induced types of porphyrias and induction and aggravation of any of the photodermatoses may increase with increased light exposure in general. It is distinct from radiometry, which is the science of measurement of radiant energy (including light) in terms of absolute power. Concepts such as radiance, irradiance, radiant power and radiant intensity used in radiometry can easily be defined via simple geometric relationships. Power (watts) is converted to luminous flux in lumens via the integral equation: 780 =, 380 where is the photopic response function of the human eye in day light, v = flux (lumens), Pe = power, K = constant (683 lm/W for photopic). This should not be confused with the electrical input power used historically to specify incandescent lamps. The radiant power is usually the total emission of the source and is most appropriate for sources that emit equally in all directions. If the source is directional then it is more appropriate to specify the radiant intensity (watts per steradian) and if the source is not a point source, radiance (watts per square metre [of emitter] per steradian). These quantities are radiometric quantities and are appropriate across the optical spectrum (for ultraviolet, visible and infrared emissions). It may also be appropriate to specify a spectral quantity to show how the contributions to the above quantities vary with wavelength the emission spectrum. With the spectral information, it is possible to weight the emission for a range of factors to take into account human (or other) responses. The response of the eye to optical radiation at different wavelengths has been experimentally determined and weighting with the response function, particularly for high light levels, gives the photometric quantities. Luminous flux (lumen) is equivalent to radiant power, weighted at each wavelength with the luminous efficacy function and summed across all wavelengths. The equivalent quantities for radiant intensity and radiance are luminous intensity (lumen per steradian, or candela) and luminance (lumen per metre squared per steradian, or candela per metre squared), respectively. All of these quantities are parameters associated with the actual source or a virtual source (due to the use of a diffuser or reflectors). The optical radiation incident on a surface, which could be the eye or the skin, is quantified in terms of irradiance (watts per square metre). The equivalent photometric quantity is illuminance (lumen per square metre, or lux). Spectral data for the optical radiation incident on a surface, for example in watts per square metre per nanometre, can be used to weight for a range of hazard or beneficial effects. Since the weighting function peaks at about 440 nm, decreasing by a factor of ten for wavelengths less than 400 nm and greater than 500 nm, any incident blue radiation is more significant. Most lighting sources are not directly visible to observers in order to avoid a glare source. The exceptions are indicator devices and, for example, vehicle lighting, which is in the direct field of view, and illuminated screens. A self-sustaining molecular oscillator generates the circadian rhythms at a cellular level. This oscillator comprises genes and proteins that are organized in positive and negative transcription and translation feedback loops (Takahashi, 2017). This process is influenced by post-translational modifications that affect the stability of the clock proteins and, thereby, influence the periodicity of circadian rhythms. Function of circadian rhythms Circadian rhythms most likely evolved to adapt and respond optimally to daily environmental cycles. It enables anticipation to expected events and ensures that bodily processes occur in a temporal and synchronized fashion at the most optimal timing related to the environment. A simplified example: eating when food is present and subsequently optimize metabolism processes after eating. Ranging from behaviour (sleep/wake cycles), cognition (attention, concentration), the immune system and repair mechanisms, to numerous physiological processes including endocrine functioning, metabolism, cardiovascular functioning etc. It has been shown that circadian rhythms occur in 2-10% of a tissues molecular processes and, in addition, several post transcriptional mechanisms result in circadian rhythms in protein expression (Takahashi 2017). Measuring circadian rhythms in humans To determine if circadian rhythms are influenced by external stimuli, several biomarkers for circadian rhythms are usually investigated. These include body temperature, melatonin and cortisol, of which melatonin is the most widespread used marker. Melatonin is one of the hormones with a robust circadian rhythm and its levels are easily assessed using saliva, serum or urine. Melatonin levels rise during the dark period and decrease at the end of the dark period. However, regulation of melatonin is not only via light/dark, since melatonin levels decrease towards the end of the night when no light is present and darkness during the day will not result in melatonin production. As such, melatonin levels are often used as a marker for a persons circadian phase, although this relation involves other aspects as well. Exposure to light at night reduces the production of melatonin, since norepinephrine levels drop (Schomerus and Korf 2005), but changes in circadian phase depend on other aspects as well (light during the day and other zeitgebers, such as food). Melatonin also rises at night in nocturnal animals, and, as such, it is better described as a hormone of the night, rather than a sleep hormone. Indications are obtained from association studies, circumstantial evidence and hypothesized effects based on studies investigating other types of circadian disturbance. Disturbance of the circadian system has been associated with several negative health effects. This is mainly the case for relatively severe disturbances of the circadian system that, for example, occur due to shift work or jetlag. Although the circadian disturbance observed due to evening light exposure is less severe, some underlying mechanisms and consequences might be similar. An important consequence of the circadian disturbance due to light during the evening is its effect on sleep. Furthermore, additional light during the evening has been hypothesized to phase delay circadian rhythms. This refers to the phenomenon that the circadian rhythm is delayed but the social environment requires behavioural patterns to remain at the earlier phase (Wittmann, Dinich et al. In other words, a person still has to get up early in the morning to go to work/school. This can cause several important bodily processes to occur out of sync with the biological clock, such as food consumption. This desynchronization of external and internal stimuli might be underlying some of the health effects related to disturbances of the circadian system. Social jetlag has mainly been associated with risk factors for cardio-metabolic diseases (Parsons, Moffitt et al. This disorder is characterized by late sleep and wake times and poorer sleep quality (Joo, Abbott et al. In addition to observed effects of evening light on sleep in experimental settings, it has been suggested that evening exposure to light might have a direct effect on food consumption and metabolism (Versteeg, Stenvers et al. It has been hypothesized that evening light causes increased food consumption at unfavourable moments. In addition, an association has been observed between melatonin levels and metabolic disorders. Melatonin might have a direct effect on food intake and melatonin receptors are also present on pancreatic cells. In summary, disturbances of the circadian rhythm can result in negative consequences on sleep, cognitive performance and, in the long term, on metabolic risk factors. However, most of the described experimental studies are performed in laboratory settings and using protocols that do not readily translate to normal exposures and behaviours. Furthermore, since no experimental studies have been performed with chronic exposure (multiple years) to artificial light during the evening, it is currently unknown if the disturbance of the circadian rhythm remains, increases or reduces after chronic exposure to light during the evening. The element is a human carcinogen and exposure to arsenic can result in various skin 6 diseases and can decrease nerve conduction velocity. Lead is a potent neurotoxin, and short-term exposure to high concentrations of lead can cause vomiting, diarrhoea, convulsions and damage to the kidney and reproductive system. It can also cause anaemia, increased blood pressure, and induce miscarriage for pregnant women. Children are considered to be particularly vulnerable to exposure to lead, for it can 7 damage nervous connections and cause brain disorders. The combustion of these halogenated compounds releases toxic emissions including dioxins which can cause reproductive and developmental problems, damage the immune system, interfere with hormones and also 8 cause cancer. Epidemiological data has suggested an association between indoor exposure to phtalates and asthmatic and allergic reactions in children (Bornehag et al. The search strategy used in this report was also repeated to get an update on the literature since 2014. Associate Professor in Oral Medicine and Pathology, Dental School, University of Athens. Insofar as this book Color atlas of oral diseases / George Laskaris; foreword mentions any dosage or application, readers may rest by Gerald Shklar. Published by Litsas Medical Publications, ist Italian edition 1991 Athens, Greece 1st French edition 1989 Some of the product names, patents and registered 1988,1994 Georg Thieme Verlag, RudigerstraBe 14, designs referred to in this book are in fact registered 70469 Stuttgart, Germany trademarks or proprietary names even though specific Thieme Medical Publishers, Inc. Grammlich, GmbH this book, including all parts thereof, is legally protect ed by copyright. The English text now offers a brief but ground, and wealth of experience in the disci authoritative discussion of each condition. Brackett Professor of Oral Pathology guage journals, and it is fitting that his extensive and Head of the Department of Oral Medicine experience with oral diseases is now made avail and Oral Pathology, able to the English-speaking world. Sixty-four illustrations of lesions and clinical entities affecting the oral cavity, not published in the first edition, are now included. Nineteen new illustrations of diseases pub lished in the first edition have been added to broaden the spectrum of clinical presentation of these entities. This book is not a complete reference work of When 1 first started to work in this field 20 oral medicine and should be used in conjunction years ago, I could not imagine the variety of with current textbooks and articles regarding disorders that affect the oral cavity, including recommendations on treatment and new diagnos genetic diseases, infections, cancers, blood dis tic techniques that are beyond its scope. Fortunately, the oral plates and a description of the clinical features, cavity is accessible to visual examination, and I differential diagnosis, helpful laboratory tests, and have attempted to record oral lesions in color a brief statement on treatment. During my career as a stomatologist, I have Selective bibliography and index are included. The most representative and mouth and it will find its way in the places where educationally useful illustrations have been used the battle against oral diseases is waged daily, that in this Atlas. Almost all color slides have been is dental schools, hospitals, and private practice taken by me with a Nikon-Medical camera. Their sugges dentists and physicians who have contributed by tions and criticisms have been gratefully received referring their patients to me through the years. My gratitude is extended to the late Professor Finally, I wish to thank my colleagues at the of Dermatology, John Capetanakis, and the cur Department of Oral Medicine and Pathology of rent Professor of Dermatology and Head of the the Dental School, University of Athens, with Department of Dermatology, University of whom I have worked closely for more than 25 Athens, "A. Eleana Stufi for their assistance in the prepa I am also indebted to Associate Professor of ration of the first edition of the Atlas. My sincere thanks are extended to the scientific I thank the following colleagues for permission staff of "A. Karpathios (Greece) for ling and prompt help during the 23 years of our Figure 358, Dr. Crispian Scully (England) for on the translation of the Greek edition of this Figure 278, Dr. My deepest gratitude is due to Professor Cris Last, but by no means least, I can never fully pian Scully, Department of Oral Medicine and repay all that I owe my wife and three children for Surgery, University of Bristol, England, and Pro their constant patience, support, and encourage fessor Gerald Shklar, Department of Oral ment.

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This chapter is devoted to the basic aspects of Declining autopsy rate throughout world in the recent times various such methods as are available in a modern pathology is owing to the following reasons: laboratoryranging from the basic microscopy to the most 1. Surgical pathology is the form of clinical teaching activity in medical institutions classic and time-tested method of tissue diagnosis made on worldwide. There is still no substitute for a careful postmortem As discussed already, surgical pathology made a examination which enlightens the clinician about the patho beginning from pathologic study of tissues made available at genesis of disease, reveals hazardous effects of therapy autopsy. Surgeons of old times relied solely on operative or administered, and settles the discrepancies finally between gross findings and, thereafter, discarded the excised tissues, antemortem and postmortem diagnosis. However, with technology autopsy, either of which may be followed: development and advances made in the dye industry in the 1. In conditions where multiple organs are expected to be In the beginning, this task was assigned to a surgeon involved, complete autopsy should be performed. But if a faculty member in the surgery departments who was particular organ-specific disease is suspected, a mini-autopsy appropriately called surgical pathologist. The main neuropathology, haematopathology, dermatopathology, purposes of autopsy are as under: gynaecologic pathology cytopathology, paediatric pathology, 1. Education of the entire team involved in patientcare by: Surgical pathology services in any large hospital depend i) making autopsy diagnosis of conditions which are often largely on inputs from surgeons and physicians familiar with missed clinically. Thus it is embolism, acute pancreatitis, carcinoma prostate; vital that clinician and pathologist communicate freely ii) discovery of newer diseases made at autopsy. The body of the request form must contain the entire relevant infor mation about the case and the disease (history, physical and operative findings, results of other relevant biochemical/ haematological/radiological investigations, and clinical and differential diagnosis) and reference to any preceding cytology or biopsy examination done in the pathology services. For routine tissue processing by paraffin-embedding technique, the tissue must be put in either appropriate fixative solution (most commonly 10% formol-saline or 10% buffered formalin) or received fresh-unfixed. Gross examination of the specimen received In order to avoid contamination of the laboratory with in the laboratory is the next most important step. Proper gross vapours of formalin and alcohols, vacuum tissue processors tissue cutting, gross description and selection of representative having closed system are also available. The entire process of enough and that may delay the report, or if the biopsy is small embedding of tissues and blocking can be temperature and lost in processing the entire surgical procedure for controlled for which tissue embedding centres are available biopsy may have to be done again. The blocks are then trimmed followed by sectioning stations have inbuilt system for recording gross description by microtomy, most often by rotary microtome, employing through dictaphone without the aid of an assistant to write either fixed knife or disposable blades (Fig. Some laboratories have a protocol of doing gross specimen Cryostat or frozen section eliminates all the steps of tissue photography and specimen radiography, before and after processing and paraffin-embedding. Sections are then to remove the mineral and soften the tissue by treatment with ready for staining. Frozen section is a rapid intraoperative decalcifying agents such as acids and chelating agents (most diagnostic procedure for tissues before proceeding to a major often aqueous nitric acid). Tissue cassettes along with unique number given in the gross room to the tissue sample is carried throughout laboratory procedures. Paraffin-embedded sections are routinely stained with haematoxylin and eosin (H & E). The final and the most important task of pathology laboratory is issuance of a prompt, accurate, brief, and prognostically significant report. The ideal report must contain five aspects: i) History (as available to the pathologist including patients identity). An internal quality control by mutual discussion in controversial cases and self-check on the quality of sections radical surgery. Besides, it is also used for demonstration of can be carried out informally in the set up. Presently, external certain constituents which are normally lost in processing quality control programme for the entire histopathology in alcohol or xylene. Currently, problem of allegations of negligence and malpractice in histopathology have started coming just as with other clinical disciplines. In equivocal biopsies and controversial cases, it is desirable to have internal and external consultations. Besides, the duties of sensitive reporting work should never be delegated unless the superior is confident that the delegatee has sufficient experience and ability. H & E staining is routinely used to diagnose microscopically vast majority of surgical specimens. However, in certain special circumstances when the pathologist wants to demonstrate certain specific substances or constituents of the cells to confirm etiologic, histogenic or pathogenetic components, special stains (also termed histochemical stains), are employed. The staining depends upon either physical or chemical or differential solubility of the stain with the tissues. The principles of some of the staining procedures are well known while those of others are unknown. Van Giesons Extracellular collagen Picric acid, acid Nuclei: blue/black fuchsin, celestin blue Collagen: red haemalum Other tissues: yellow 8. Massons trichrome Extracellular collagen Acid fuchsin, phospho Nuclei: blue/black molybdic acid, methyl Cytoplasm, muscle, blue, celestin blue red cells: red haemalum Collagen: blue 9. Verhoeffs elastic Elastic fibres Haematoxylin, Elastic fibres: black Ferric chloride, iodine, Other tissues: counter-stained potassium iodide 11. Gordon and Sweets Reticular fibres Silver nitrate Reticular fibres: black Nuclei: black or counterstained D. Oil red O Fats Oil red O Mineral oils: red (unfixed cryostat) Unsaturated fats, phospholipids: pink 13. Sudan black B Fats (unfixed cryostat) Sudan black B Unsaturated fats: blue black 14. Osmium tetroxide Fats Osmium tetroxide Unsaturated lipids: brown black (unfixed cryostat) Saturated lipids: unstained E. Grams Bacteria Crystal violet, Lugols Gram-positive, keratin, fibrin: blue (cocci, bacilli) iodine, neutral red Gram-negative: red 16. Ziehl-Neelsens Tubercle bacilli Carbol fuchsin, methylene Tubercle bacilli, hair (Acid-fast) blue (differentiate shaft, actinomyces: red in acid-alcohol) Background: pale blue 17. Fite-Wade Leprosy bacilli Carbol fuchsin, methy Lepra bacilli: red lene blue (decolorise in Background: blue 10% sulfuric acid) 18. Grocotts silver Fungi Sodium tetraborate, Fungi, Pneumocystis: black methanamine silver nitrate, Red cells: yellow methanamine Background: pale green 19. Luxol fast blue Myelin Luxol fast blue, Myelin: blue/green cresyl violet Cells: violet/pink 22. Perls Prussian blue Haemosiderin, iron Potassium ferrocyanide Ferric iron: blue Nuclei: red 24. Masson-Fontana Melanin, argentaffin cells Silver nitrate Melanin, argentaffin, chromaffin, lipofuscin: black Nuclei: red 25. Pigment extraction Removal of formalin pig Alcoholic picric acid Formalin pigment/malarial ment and malarial pigment pigment: removed 29. In general, there are two types of light microscopes: Enzyme histochemical techniques require fresh tissues for cryostat section and cannot be applied to paraffin-embedded Simple microscope. This has a battery of lenses which diagnostic applications and not so popular, partly due to are fitted in a complex instrument. One type of lens remains requirement of fresh tissues and complex technique, and near the object (objective lens) and another type of lens near partly due to relative lack of specificity of reaction in many the observers eye (eye piece lens). The eyepiece and objective cases, and hence have been largely superseded by immuno lenses have different magnification. The compound histochemical procedures and molecular pathology microscope can be monocular having single eyepiece or techniques. Multi-headed Presently, some of common applications of enzyme microscopes are used as an aid to teaching and for histochemistry in diagnostic pathology are in demonstration demonstration purposes. The microorganisms are illuminated by an oblique ray of light which does not pass through the microorganism. Microscope is the basic tool of the pathologist just as is the stethoscope for the physician and speculum for gynaecologist. This method is used for demonstration It is an instrument which produces greatly enlarged images of birefringence. A variety of filters are used between the source of light and objective: first, heat absorbing filter; second, red-light stop filter; and third exciter filter to allow the passage of light of only the desired wavelength. On passing through the specimen, light of both exciting and fluorescence wavelength collects. Exciter light is removed by another filter called barrier filter between the objective and the observer to protect the observers eyes so that only fluorescent light reaches the eyes of observer. Dark-ground condenser is used in fluorescence microscope so that no direct light falls into the object and instead gives dark contrast background to the fluorescence. There are two types of fluorescence techniques both of which are performed on cryostat sections of fresh unfixed tissue: direct and indirect. In the direct technique, first introduced by Coons (1941) who did the original work on immunofluorescence, antibody against antigen is directly conjugated with the fluorochrome and then examined under fluorescence microscope. In the indirect technique, also called sandwich technique, there is interaction between tissue antigen and specific anti body, followed by a step of washing and then addition of fluorochrome for completion of reaction. Two discs made up of prism are placed in the path of for the following purposes: light, one below the object known as polariser and another 1. In renal diseases for detection of deposits of immuno Immunofluorescence technique is employed to localise globulins, complement and fibrin in various types of antigenic molecules on the cells by microscopic examination. In skin diseases to detect deposits of immunoglobulin by antigenic site which is made visible by employing a frozen section, particularly at the dermo-epidermal junction fluorochrome which has the property to absorb radiation in and in upper dermis. For study of mononuclear cell surface markers using mono the immunofluorescent method has the following clonal antibodies. In renal pathology in conjunction with light microscopy used as source of light for fluorescence microscopy. Subsequently, immunoperoxidase technique employing labelled antibody method to formalin-fixed paraffin sections was 3. Semithin sections guide in making the reagent is pre-formed stable immune-complex which is linked differential diagnosis and in selecting the area to be viewed to the primary antibody by a bridging antibody. For ultrastructural examination, in which biotinylated secondary antibody serves to link the ultrathin sections are cut by use of diamond knife. In order to primary antibody to a large preformed complex of avidin, increase electron density, thin sections may be stained by biotin and peroxidase. Generally, a panel of antibodies is preferable over a single test to avoid errors. Both these tumours are about a revolution in approach to diagnosis of tumours of under the growth regulation of hormonesoestrogen and uncertain origin, primary as well as metastatic from an androgen, respectively. A panel of antibodies is chosen regulating hormones are located on respective tumour cells. Helicobacter pylori), and Tumour Immunostain parasites (Pneumocystis carinii) etc. The dividing cells are techniques employ hybridization (meaning joining together) then arrested in metaphase by the addition of colchicine or technique based on recombinant technology. Subsequently, the cells are lysed by adding is a chain of nucleotides consisting of certain number of known hypotonic solution. Probes are of different sizes and sources as under: the metaphase cells are then fixed in methanol-glacial 1. Oligonucleotide probe is a synthetic probe contrary to property of forming alternating dark and light bands. Following is a brief account of various molecular techniques c) Constitutive banding or C-banding is used to demonstrate available as diagnostic tool in surgical pathology: constitutive heterochromatin. The pairs of chromosomes are identified the end-product of hybridisation is visualised by radioactive by the arm length of chromosomes. The centromere divides labelled probe (32P, 125I), or non-radioactive-labelled probe the chromosome into a short upper arm called p arm (p for. Currently, molecular cytogenetic analysis and charac ii) In human tumours for detection of gene expression and terisation of chromosomes is possible by the revolutionary oncogenes. Southern is the name of scientist who described iii) Cancer is characterised by multiple and complex chromo Southern blot technique). In view of high degree of specificity and solid tissues homgenised to make into cell suspensions. Flow cytometric analysis finds uses in clinical techniques have widespread applications in diagnostic practice in the following ways: pathology: 1. Immunophenotyping by detailed antigenic analysis of i) In neoplasia, haematologic as well as non-haematologic. This is the oldest but still widely used and yields large accumulation of the target sequence since method in routine diagnostic pathology work. The number each newly generated product, in turn, acts as template in of cells in mitosis are counted per high power field. In this method, the proliferating cells filter hybridisation techniques and has many advantages over are labelled in vitro with thymidine and then the tissue them in being more rapid, can be automated by thermal processed for paraffin-embedding. The nuclear antigen specific for perties of cells suspended in a single moving stream. Flow cell growth and division is stained by immunohistochemical cytometry, thus, overcomes the problem of subjectivity method and then positive cells are counted under the involved in microscopic examination of cells and tissues in microscope or by an image analyser. Flow cytometer has a laser-light source for fluorescence, cell transportation system in a single stream, monochromatic 5.

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Additional prognostic factors in invasive breast cancer include: Clinical features vascular invasion by the tumour signi es a the majority of patients with invasive carcinoma poor prognosis medicine organizer box generic mesalamine 400mg, even in the absence of nodal will present with a lump in the breast medicine 1700s order mesalamine 400mg with amex. Other fea involvement; tures that warrant urgent investigation include 304 the breast altered breast contour medicine cabinet with lights buy genuine mesalamine, recent nipple inversion medicine 513 buy mesalamine 400 mg overnight delivery, Table 35 symptoms 6 days post embryo transfer generic mesalamine 400 mg without prescription. Any evidence of nipple inversion or T0 No evidence of primary tumour eczema should be noted symptoms meningitis buy discount mesalamine 400 mg. Any lump dimension should be carefully examined for evidence of T2 Tumour >2cm and <5cm in skin or muscle xation and the clinical size greatest dimension and position in relation to the nipple noted. Large, T3 Tumour >5cm in greatest dimension rm nodes in the axilla may suggest metastatic T4 Tumour of any size with skin or disease. In patients with suspected tumours, chest wall involvement liver palpation and chest auscultation should be performed. In the vast majority of N3 Metastasis to ipsilateral internal thoracic (mammary) nodes cases the diagnosis has been con rmed prior to surgery. A cylinder of breast tissue any of the four nodes are positive for tumour, is excised down to the pectoral muscle in order then further treatment is necessary by axillary to achieve complete excision (clear resection radiotherapy or surgical clearance of the margins). Postoperative radiotherapy to the axilla, removing all nodes lateral and deep to breast is routine after such a procedure. It is usually combined with reconstructive surgery to Breast reconstruction does not appear to impede restore the breast contour. Axillary surgery is the ability to detect local recurrence and may be performed at the same time. It may be performed of mastectomy and axillary clearance avoids either at the time of mastectomy or as a delayed the need for postoperative radiotherapy in procedure. The combination of skin-sparing mas most cases, although this depends on axillary tectomy and immediate breast reconstruction has node status and tumour size and grade. The possibility of immediate breast reconstruc Surgical treatment of invasive ductal or tion should be discussed with suitable patients lobular carcinoma prior to mastectomy. The choice of reconstruction for an individual patient will depend on several the aims of surgery are to remove the primary factors, including breast size, the adequacy of skin tumour and involved lymph nodes, to determine aps, whether radiotherapy is planned or has pre prognosis and to plan systemic therapy. Small viously been used, abdominal size and previous tumours (<3cm) may be suitable for breast abdominal operations, the patients concern conserving surgery (wide local excision). Typical tumours (>3cm), central tumours or multifocal reconstructions involve the use of myocutaneous tumours require mastectomy with or without aps of latissimus dorsi or rectus abdominis, aug breast reconstruction (see below). Adjuvant systemic therapy using cytotoxic agents Surgical management of the axilla and/or endocrine therapy improves survival, with greatest bene t in those women at greatest risk of Axillary node status is the most important prog relapse. As a result, axillary surgery should be per based on known prognostic factors that predict formed on all patients with invasive operable relapse and survival, including node status, histo breast cancer, but is not generally required for in logical grade and tumour size, oestrogen receptor situ disease. The 10 year survival is now 72%, with 64% of all A suggested outline for adjuvant systemic women surviving for 20 years as compared with therapy is as follows: 44% in the 1980s. These gures are likely to improve with recent advances in hormone therapy, 1 Premenopausal women. For the majority of these patients, b Intermediate/high risk disease: the initial management will be non-surgical. Following majority of these patients subsequently proceed breast-conserving surgery, such as wide local to surgery and/or radiotherapy. Radiotherapy is incision for invasive cancer, radiotherapy not recommended as sole treatment for local signi cantly reduces the risk of recurrence control of advanced disease but may be an option within the breast. In premenopausal women receiving adjuvant chemotherapy, In ammatory breast cancer postmastectomy radiotherapy may also improve survival. The factors associated In ammatory breast cancer is rare, representing with a high risk of local recurrence are only 2% of breast cancers. The breast appears tumour size, high grade, nodal involvement, swollen, red, rm and warm to touch, all cardinal lymphatic invasion and involvement of features of in ammation. After all forms of phatics in the breast, and mastectomy is usually axillary surgery, the decision as to whether the required. It is an aggressive disease associated axilla should be irradiated represents a balance with 5 and 10 year survival rates of the order of between the risks of recurrence and the risk of 50% and 30%, respectively. After axillary sampling, the axilla chemotherapy, surgery and chest wall radiother should be irradiated only if node positive or apy is accepted as achieving the highest local inadequately sampled. For advanced disseminated disease, chemotherapy can produce reasonable palliation. These will usually be elderly patients, and some may have locally advanced tumours. The princi ples of management are closer to those for meta static disease, the aim of therapy being to control Pagets disease of the primary tumour while maintaining the best the nipple quality of life. Presentation Metastatic disease Paget s 7 disease of the nipple occurs in middle aged and elderly women. It presents as a unilateral the aim of treatment is to relieve symptoms red, bleeding, eczematous lesion of the nipple and while maintaining the highest quality of life. Histologically, the epithelium patients with metastatic disease should be consid of the nipple is thickened, with multiple clear ered for some form of systemic therapy. Hormone malignant Paget cells with small dark staining therapy is less toxic than chemotherapy and is nuclei; these are hydropic malignant cells. As the disease breast carcinoma detected on clinical or radiologi progresses patients may require referral to pallia cal investigation. Surgical management includes tive care specialists for control of symptoms and mastectomy and axillary surgery for lesions asso to augment support for patients and carers. In the absence of invasive disease, or if a small central tumour lies Carcinoma of the male breast close to the nipple, cone excision of the nipple and underlying tissue followed by breast radiotherapy this accounts for less than 1% of all cases of breast may be considered. In men, breast cancer affects an older age group, with a peak incidence at 60 years. Clinically, it usually presents as a rm, painless, subareolar lump, although gynaecomastia, breast Breast screening tenderness and nipple discharge may also be present. Microscopically, it is usually a ductal car A number of trials have demonstrated a reduction cinoma, and is quite advanced at presentation. As so little skin is cancers tend to be smaller and node negative with available, it may be necessary to perform recon an increasing detection rate of in situ disease. For in situ disease, 3 yearly mammographic screening and there are simple mastectomy will suf ce. Recent evidence suggests that probably because of the sparse amount of breast the screening programme is now contributing to tissue present, which allows rapid dissemination reductions in breast cancer mortality rates in the of the growth into the regional lymphatics. He also described diseases of the bone and penis, overall survival; most tumours respond to and discovered the parasite of trichinosis in humans while a rst tamoxifen, which is therefore given as adjuvant year medical student. That a branchial cyst is a remnant of the Chapter 37, and the parathyroids in Chapter 38. A second branchial arch has been questioned, based summary of the possible causes of a lump in the on the observation that the cysts are lined with neck is given in Box 36. This countertheory suggests that the cyst arises from cystic degeneration of lymphoid tissue in the neck and is thus better termed a lateral cer Branchial cyst and sinus vical cyst. Anatomy Clinical features There are six arches and ve clefts in the branchial A branchial cyst usually presents in early adult life system (Figure 36. The rst arch forms the lower and forms a soft swelling like a half lled hot face, its external cleft the external auditory meatus, water bottle, which bulges forward from beneath and its internal cleft the eustachian tube. It second arch grows down over the third and fourth is lined by squamous epithelium and contains arches to form the skin of the neck. It there is no external cleft, while the internal cleft often presents following an upper respiratory tract forms the tonsillar fossa. Clinical diagnosis can be clinched by aspirating a few drops of this uid from the cyst Aetiology and demonstrating cholesterol crystals under the microscope. Occasionally, the cyst may become Persistence of remnants of the second branchial infected. The external cleft remnants open gland of the neck or from an acute just anterior to the sternocleidomastoid, at the lymphadenitis. A branchial sinus presents as a small ori ce, dis charging mucus, which opens over the anterior border of the sternocleidomastoid in the lower Lecture Notes: General Surgery, 12th edition. The side of the With a general decline in tuberculosis, this once neck is an excellent example of this exercise. Cervical nodes are usually secondarily involved from a tonsillar primary focus, although Lymph nodes the adenoids or even the dental roots may occa Infective sionally be the primary source of infection. The organisms may be human or bovine, and occa Malignant sionally the disease is secondary to active pulmo the lymphomas, lymphatic leukaemia (Chapter nary infection. Lymphatics Clinical features Cystic hygroma Artery At rst, the nodes are small and discrete; then, as they enlarge, they become matted together and Carotid body tumour caseate, and the abscess so formed eventually Carotid artery aneurysm bursts through the deep fascia into the subcutane ous tissues. This results in one pocket of pus deep Salivary glands to and one super cial to the deep fascia, both con Submandibular salivary tumours or sialectasis nected by a small track: a collar stud abscess. Left Tumour in the lower pole of the parotid gland untreated, this discharges onto the skin, resulting in a chronic tuberculous sinus. Pharynx Pharyngeal pouch Differential diagnosis Branchial arch remnant Solid nodes must be differentiated from acute Branchial cyst lymphadenitis, one of the lymphomas or sec ondary deposits. The breaking down abscess Bone must be differentiated from a branchial cyst (see Cervical rib above). Diagnosis may be assisted by an X-ray of the neck; usually, the chronic tuberculous nodes show ecks of calci cation. The sinus extends upwards between the internal and exter A full course of antituberculous chemotherapy is nal carotid arteries to the sidewall of the pharynx. Small nodes are treated conservatively and It may open into the tonsillar fossa (which repre the patient is kept under observation. If the patient presents with a collar stud abscess, the pus is evacuated, a search made for the hole penetrating through the deep Treatment fascia, and the underlying caseating node evacu Surgical excision is required. Carotid body tumour (chemodectoma) Special investigations Duplex ultrasound gives precise localization of Pathology the tumour and its relation to the carotid and its bifurcation. Also called carotid glomus tumours or paragangli Arteriography shows the carotid bifurcation to onomas, these are slow-growing tumours that be splayed open by the mass and the rich arise from the chemoreceptor cells in the carotid vascularity of the tumour is demonstrated. Most behave in a Magnetic resonance imaging and computed benign fashion; in a few patients, the tumour tomography show the tumour and its relation becomes locally invasive and may metastasize. Macroscopically, it is a lobulated, yellowish tumour closely adherent to the internal and exter nal carotid arteries at the bifurcation. Treatment Microscopically, it is made up of large chromaf It is often possible to dissect the tumour away n polyhedral cells in a vascular brous stroma. If the carotid vessels are rmly involved, resection can be performed with Clinical features graft replacement of the artery. In the elderly, these slow-growing tumours can the tumour presents as a slowly enlarging mass in be left untreated, or treated with local radiother a patient over the age of 30 years, which transmits apy (the Gamma knife ). The mass itself may be so 37 the thyroid Learning objectives To know the embryological course of the thyroid and related remnants. Embryology the thyroid gland forms as a diverticulum origi Thyroglossal cyst nating in the oor of the pharynx, and descends through the tongue, past the hyoid, to its position A thyroglossal cyst forms in the embryological in the neck. The diverticulum usually closes, remnants of the thyroid and presents as a uctu leaving a pit at the base of the tongue (the foramen ant swelling in or near the midline of the neck. It caecum, which lies in the midline at the junction is diagnosed by its characteristic physical signs. Failure of the thyroid to descend or 1 It moves upwards when the patient protrudes incomplete descent of the track may result in the tongue, because of its attachment to the ectopic thyroid tissue (Figure 37. In all cases of unexplained attachment to the larynx by the pretracheal midline nodules in the neck, thyroid tissue should fascia. A radioiodine scan should be per formed to ensure that there is normal thyroid Treatment tissue present in the correct place before the lump Such cysts should be removed surgically, together is removed. Such a patient presents with a lump at the foramen Thyroglossal stula caecum of the tongue. This is termed a lingual this presents as an opening onto the skin in the line of the thyroid descent, in the midline of the Lecture Notes: General Surgery, 12th edition. The track runs in close Iodine in the diet is absorbed into the blood relationship to the body of the hyoid; therefore, stream as iodide, which is taken up by the thyroid this should be removed in addition to the stula. After entering the follicle, the iodide is con Dissection is continued up to the region of the verted into organic iodine, which is then bound foramen caecum of the tongue. The colloid within the thyroid vesicles is composed of thyroglobulin, which is synthesized in the follicu Thyroid physiology lar cells, and T3 and T4. These hormones are released into the bloodstream after being sepa the thyroid gland is concerned with the synthesis rated from thyroglobulin within the follicular cells. Some follicles are lined with hyperactive epithelium and others secretion with attened atrophic cells. Some contain no the immediate control of synthesis and liberation colloid, others an excessive amount. Nodular secreted in response to the level of thyroid hor goitres may produce a normal amount of T4, but mones in the blood by a negative feedback mecha sometimes excessive T4 production results in nism. The thyroid is usually enlarged, irregular and Pharmacological control of nodular and, although one lobe often predomi secretion nates at presentation, the condition does affect the entire gland. The production of thyroid hormones can be inhib ited by the thiouracils and carbimazole, which Symptoms block the binding of iodine but do not interfere with the uptake of iodide by the gland. Although the enlarging thyroid can produce a number less T3 and T4 is produced, the thyroid gland tends of pressure symptoms including dysphagia, to become large and vascular with treatment by breathlessness, orthopnoea, hoarseness and facial these drugs. High doses of iodide given to patients with excessive thyroid hormone production result in an Investigation of multinodular goitre increase in the amount of iodine-rich colloid, and a diminished liberation of thyroid hormones; the Patients require two speci c investigations: gland also becomes less vascular. Thiocyanates prevent the thyroid gland retrosternal extension, and to identify the from taking up iodide. It includes colloid goitre forward (especially retrosternal extension) (see below) and the hyperplasia of Graves disease Orthopnoea: owing to the weight of the gland but the commonest cause is multinodular goitre. The characteristics of an enlarged thyroid are a Haemorrhage into a cyst, producing pain and mass in the neck on one or both sides of the increased swelling (which may produce trachea, which moves on swallowing, since it is sudden tracheal compression).

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