By B. Dolok. Prescott College.
Platelet granule secretion continuously prevents intratumor hemorrhage finasteride 5mg, Cancer Res Vol 1mg finasteride. Iannacone 5 mg finasteride, Sitia finasteride 1 mg, Isogawa finasteride 5 mg, Marchese 5mg finasteride, Castro 1 mg finasteride, Lowenstein finasteride 1mg, Chisari , Ruggeri , & Guidotti (2005). Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released, Blood Vol. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin, J Clin Invest Vol. Circulating platelet-neutrophil complexes are important for subsequent neutrophil activation and migration, J Appl Physiol Vol. Platelets enhance neutrophil transendothelial migration via P-selectin glycoprotein ligand-1, Am J Physiol Heart Circ Physiol Vol. Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury, J Clin Invest Vol. Inflammation, Chronic Diseases and Cancer – 118 Cell and Molecular Biology, Immunology and Clinical Bases MacKenzie, Creevy, & Heh (1971). Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases, Nat Med Vol. Platelets: inflammatory firebugs of vascular walls, Arterioscler Thromb Vasc Biol Vol. Haemostasis, blood platelets and coagulation, Anaesthesia & Intensive Care Medicine Vol. The non-classical functions of the classical complement pathway recognition subcomponent C1q, Immunol Lett Vol. Complement activation on platelets: implications for vascular inflammation and thrombosis, Mol Immunol Vol. Platelet P-selectin is required for pulmonary eosinophil and lymphocyte recruitment in a murine model of allergic inflammation, Blood Vol. The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases, Can J Cardiol Vol. Complement: a key system for immune surveillance and homeostasis, Nat Immunol Vol. The Platelet as an Immunomodulator: The Old Thespian with New Roles in Atherosclerosis, Sepsis and Autoimmune Disease 119 Rivera, Lozano, Navarro-Nunez, & Vicente (2009). Platelet receptors and signaling in the dynamics of thrombus formation, Haematologica Vol. An updated concept of coagulation with clinical implications, J Am Dent Assoc Vol. Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function, Blood Vol. Neutrophil killing of bacteria by oxygen-independent mechanisms: a historical summary, Rev Infect Dis Vol. Stahl, Vaziri-Sani, Heinen, Kristoffersson, Gydell, Raafat, Gutierrez, Beringer, Zipfel, & Karpman (2008). Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation, Blood Vol. Thrombotic microangiopathy in anti-glomerular basement membrane glomerulonephritis, Arch Pathol Lab Med Vol. Role of complement in lethal bacterial lipopolysaccharide- induced hypotensive and coagulative changes, Infect Immun Vol. Evidence that platelet alpha-granules are a major determinant of platelet density: studies in storage pool deficiency, Thromb Haemost Vol. Washington, Gibot, Acevedo, Gattis, Quigley, Feltz, De La Mota, Schubert, Gomez- Rodriguez, Cheng, Dutra, Pak, Chertov, Rivera, M orales, Lubkowski, Hunter, Schwartzberg, & McVicar (2009). Inflammation, Chronic Diseases and Cancer – 120 Cell and Molecular Biology, Immunology and Clinical Bases Washington, Schubert, Quigley, Disipio, Feltz, Cho, & McVicar (2004). Calpain functions in a caspase-independent manner to promote apoptosis-like events during platelet activation, Blood Vol. Yamaguchi, Yu, Kumamoto, Sugawara, Kawamura, Takada, Yokochi, Sugawara, & Endo (2006). Involvement of Kupffer cells in lipopolysaccharide-induced rapid accumulation of platelets in the liver and the ensuing anaphylaxis-like shock in mice, Biochim Biophys Acta Vol. Classical pathway complement activation on human endothelial cells, Mol Immunol Vol. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation, J Clin Invest Vol. Introduction The mammalian immune system has the ability to distinguish self from non-self-antigens, a phenomenon which begins in the thymus during T cell development. Because of this mechanism, T cells in the periphery are primarily specific for non-self-antigens. However, this process is somewhat inefficient, because some self-reactive cells escape deletion therefore additional mechanisms are required to maintain peripheral immune tolerance. Regulatory T cells (Tregs) are a distinct subset of T cells that are critical for maintaining both immune homeostasis and peripheral immune tolerance. Tregs are typically identified by expression of the forkhead box 3 (FoxP3) transcription factor. Interestingly, Th3 cells suppress the activation of both Th1 and Th2 cell clones while other subsets primarily inhibit Th1 cells and have no effect on Th2 cells (Beissert S, 2006). The ability of viruses to induce proliferation and activation of regulatory T cells likely contributes to delayed clearance and persistence in the host. The best characterized are Th1 and Th2 subsets that have been associated with cell-mediated (Th1) and humoral (Th2) immunity (reviewed in (Sakaguchi S, 2010). In addition to T cells, B cells, and plasma cells are vital in development of humoral immunity. The role of plasma cells in antibody development is beyond the scope of this discussion. Recently, additional subsets have been described, including Th9, Th17, Th22, T-follicular helper cells (Tfh), and regulatory T cells. The effector cells secrete large amounts of cytokines, chemokines, and other proteins that can produce cytotoxicity to host tissues, or induce autoimmunity. Until recently, control of Treg function was believed to have primarily been through cytokine signaling. Regulatory T cells can be divided into two groups – natural Tregs develop in the thymus, while inducible Tregs are generated in the periphery from conventional T cells in response to different stimuli. The natural Tregs are the best characterized of the two groups and make up approximately 5-10% of circulating T lymphocytes in mice and humans (Gückel E, 2011). Regulatory T cells are primarily characterized by the expression of the transcription factor FoxP3. FoxP3 maintains Regulatory T Cells and Viral Disease 123 Treg gene expression induced by other transcription factors rather than actually driving Treg development. Humans express two isoforms of FoxP3 (A and B), either of which has regulatory function. In humans, FoxP3 expression on Tregs is transient, and downregulation of FoxP3 expression decreases the ability of these cells to suppress. Both natural and induced Treg cells have unique surface markers that differentiate them from conventional T cells. Natural regulatory T cells develop in the thymus through interactions between the high-affinity T cell receptor and cognate antigens on thymic epithelial cells. Inflammation, Chronic Diseases and Cancer – 124 Cell and Molecular Biology, Immunology and Clinical Bases Fig. Activation induces differentiation into either conventional or regulatory T cells. Treg cells have not yet been shown to produce memory cells, but they do differentiate into terminal effector Tregs. Treg-like cells are induced from conventional T cells depending on cytokine stimulation. These converted Treg-like cells have cell surface markers similar to those expressed by natural Tregs. Early after iTregs are stimulated, they express high levels of cell-cycle progression and T cell activation-associated genes (Prots I, 2011), mimicking genes that are upregulated in activated effector T cells. As iTregs mature, expression of these genes diminishes while they remain high in mature effector T cells. By 10 days after differentiation into iTregs, most cell cycle progression and T Regulatory T Cells and Viral Disease 125 cell activation genes are expressed at levels approximately 3 times lower than in effector T cells. In addition, genes in the FoxO family of transcription factors are over-expressed in iTregs compared to overexpression of the FoxM1 family in effector cells (Prots I, 2011). The reason for the dual function of Tregs in infection is unclear; however Dai et. A robust anti-inflammatory response is necessary to prevent overwhelming inflammation in septic individuals. On the other hand, viruses do not cause sepsis, and an adaptive immune response is necessary for protective immunity. Inflammation, Chronic Diseases and Cancer – 126 Cell and Molecular Biology, Immunology and Clinical Bases 2. These cells are derived from a common progenitor cell, and develop in response to the cytokine milieu. Tregs and Th17 cells even share common chemokine receptors and homing properties (Kanwar B, 2010). The balance between these subsets is important in many immune disorders related to host-pathogen interaction, inflammatory syndromes, autoimmune disease, and immunodeficiency. The differentiation of naïve T cells into effector T cells is mediated by cytokines in the microenviroment. The resulting cytokine profiles, responses to chemokines, and interactions with other cells promote different types of inflammatory responses. However; the mechanism of suppression has been studied both in vivo and in vitro in mice and may provide clues as to what occurs in humans. Even though conventional T cells in mice can be induced to express high levels of FoxP3 and have suppressive activity (unlike humans), mice nevertheless provide a valuable animal model to study the overall mechanism of Treg-mediated immune suppression. From mouse studies, we know that several mechanisms may be involved, including cytokine expression, metabolic disruption of the target cell, the alteration of the ability of dendritic cell to activate conventional T cells, and cytolysis (Sakaguchi S, 2010). Surprisingly, even paraformaldehyde-fixed Tregs retain their suppressive function. Those effector T cells that receive strong co- stimulatory signals remain refractory to Treg-mediated suppression. This suggests that inflammatory responses cannot be modulated in conditions where strong pro-inflammatory signals predominate (Sakaguchi S, 2010). Regulatory T cells in cancer Tregs play a dual role in preventing and enhancing disease in cancer. A correlation between greater numbers of FoxP3+ T cells and larger invasive breast ductal carcinomas Inflammation, Chronic Diseases and Cancer – 128 Cell and Molecular Biology, Immunology and Clinical Bases was found in sentinel lymph nodes of patients (Gupta R, 2011). In these examples, strategies to prevent Treg activation would be needed to enhance anti-tumor immunity. On the other hand, chronic inflammation can promote the development of cancers such as feline vaccine associated sarcomas, feline post-traumatic ocular sarcomas, and colon and hepatocellular carcinomas in humans. In these cases, activating Tregs may be necessary to prevent the progression to cancer. Anti-tumor immunity or immunosurveillance is necessary to prevent the development and progression of cancers, through the recognition and elimination of tumor cells. It is well established that immunosuppression results in an increase in viral-associated neoplasia. Higher numbers of Tregs are associated with a shorter time to treatment in patients with chronic lymphocytic leukemia (Weiss L, 2011). Paradoxically, in humans, hepatocellular carcinoma is often associated with chronic hepatitis B or C infection. Interestingly, Tregs within the tumor microenvironment of most cancers are associated with a poor prognosis; however, high Treg infiltration in colon cancer is associated with a favorable prognosis (Ladoire S, 2011). Importantly, this favorable prognosis is not associated with inactivation or loss of function of mismatch repair genes (reviewed in Ladoire, et al, 2011 (Ladoire S, 2011)). Although strategies to block Treg function in the treatment of cancer to enhance tumor immunity may be effective for some cancers, they cannot be used as widespread treatments because of the dual role of Tregs in the development and progression of cancer. Viral-mediated regulatory T cell induction Regulatory T cells typically increase late in chronic viral disease to prevent a persistent inflammatory response and viral-mediated immunopathology. In fact, tissue-protective effects of Treg were shown in models of respiratory syncytial virus, Friend virus, and West Nile Virus infection. Additionally, Treg responses to viruses (and bacteria) form the basis of the “hygiene hypothesis. Additionally, regulatory T cells responses to Regulatory T Cells and Viral Disease 129 Mycobacterium spp. However, some viruses have exploited the regulatory immune response, and trigger Treg activation early in the course of disease, leading to immune suppression and viral persistence. Surprisingly, the loss of Th17 cells was associated with increased immune activation. Investigators found that because Th17 cells were responsible for maintaining the integrity of the mucosal barrier in the intestine, loss of Th17 cells resulted in increased microbial translocation across the gut (reviewed in (Kanwar B, 2010). However, it is not known if the Treg expansion is involved in establishing chronic infection in this model.
Intestinal schistosomiasis due to Schistosoma intercalatum may be endemic in the tropical rain-forest areas of the subregion finasteride 1 mg. Case defnition Urinary schistosomiasis Endemic areas (moderate or high prevalence) Suspected case: Not applicable 5 mg finasteride. Communicable disease epidemiological profle 175 Confrmed case: A person with: visible haematuria; or positive reagent strip for haematuria; or S 1 mg finasteride. Non-endemic areas and areas of low prevalence Suspected case: A person with: Visible haematuria; or Positive reagent strip for haematuria; and Possible contact with infective water finasteride 1mg. Intestinal schistosomiasis Endemic areas (moderate or high prevalence) Suspected case: A person with nonspecifc abdominal symptoms finasteride 5mg, blood in stool 5mg finasteride, hepato(spleno)megaly finasteride 5 mg. Probable case: A person who meets the criteria for presumptive treatment 1mg finasteride, I according to the locally-applicable diagnostic algorithms . The cercariae emerge from the snail and pen- etrate human skin , usually while the person is swimming, working or wading in water (mainly among people engaged in agriculture and fshing). Bulinus snails live mainly along the grassy riverbanks away from the main current and the Biomphalaria snails more particularly in the swampy lateral pools. Transmission is focal in endemic areas and most intense in poor rural areas with inadequate sanitation and water supplies. Incubation period In primary infections: Within 4 days: localized dermatitis at the site of cercarial penetration. Any infected (acute and chronic) patient may discharge eggs via faeces or urine thereby contaminating water sources. In endemic areas, most persons have a low worm burden with only a small proportion (usually children aged 5–14 years) having heavy infections. The former has been found at Buona in the north-east, at Boundiali and Odienne in the north-west, at Danané in the Ouest region, at Kossou in the central region, at San Pedro in the south-west and at Adzopé in the south-east. The latter has been found mainly in the central region, the north region and the north-east (least humid regions). Communicable disease epidemiological profle 177 Epidemiology Disease burden An estimated 200 million people in 74 countries have schistosomiasis, 85% of these people live in sub-Saharan Africa. The most intense transmission occurs where populations concentrate around water sources. Such patterns of disease may be mirrored and amplifed among internally displaced persons and refugee populations who also congregate around water sources, as demonstrated in 2007 when infected Somali populations moved to Kenya. As schistosomiasis may be co-endemic with soil-transmitted helminthiasis, coordinated treatment for both may be appropriate. Tere is no available data on current rates but small parasi- tological surveys in selected areas of Côte d’Ivoire suggest that about one third of school-aged children are infected with schistosomiasis eggs. Higher prevalence is seen along major waterways, dams and irrigated rice-cultivation zones. Geographical distribution I Figures 11 and 12 show the geographical distribution of S. In certain condi- tions, dry periods tend to increase transmission of the disease as a result of higher cercarial densities in bodies of water and of drying of wells, with consequent increased use of infested water. Changes in ecology, such as the building of dams, lead to marked increase in the prevalence of schistosomiasis. Risk factors for increased burden Population movement Can lead to the introduction of S. Overcrowding Higher human population densities lead to increased discharge of schistosome eggs in water bodies, increasing the risk of transmission. Poor access to health services Regular preventive treatment (preventive chemotherapy) and treatment of cases has proved efective in reducing egg discharge, thus limiting introduction of Schistosoma spp. Reduced egg discharge also prevents late-stage complications of schistosomiasis in infected individuals. Food shortages Malnutrition and schistosomiasis have a synergic role in causing iron-defciency anaemia. Lack of safe water, poor hygienic practices and poor sanitation Contamination of water by urination/defecation and use of surface water infested by cercariae are essential for the transmission of schistosomiasis. Communicable disease epidemiological profle 181 Prevention and control measures Case management Praziquantel is the drug of choice against all schistosome parasites. A single oral dose of 40 mg/kg is generally sufcient to produce cure rates of between 80% and 90% and dramatic reductions in the average number of eggs excreted. Praziquantel treatment for one person requires, on average, three tablets of 600 mg in one dose. A dose pole (for calculating dosage according to height) is available to facilitate the delivery of praziquantel in schools or in community-based programmes. Drug costs decrease when the entire population is included in prevention programmes. Prevention Control of helminths occurs as coordinated mass drug administration, generally for children and women of childbearing age. In addition to preventive chemotherapy, other recommended interventions are: Community diagnosis (through primary school surveys) and regular treat- ment of endemic populations according to community-prevalence categories (see below). Creation of alternative, safe water sources to reduce contact with infective I water. Proper disposal of faeces and urine to prevent viable eggs from reaching bodies of water containing snail hosts. Reduction of snail habitats and snail contact (through irrigation and agricul- tural practices, and environmental management). Recommended treatment strategy for preventive chemotherapy of schistosomiasis Community category Prevalence among Action to be taken school-age children High-risk community ≥ 50% by parasitological Treat all school-age children Also treat adults considered methods (intestinal and (enrolled and not enrolled) to be at risk (from special urinary tract schistosomiasis) once per year groups to entire communi- or ties living in endemic areas) ≥ 30% by questionnaire for visible haematuria (urinary schistosomiasis) Moderate-risk community ≥ 10% but < 50% by Treat all school-age children Also treat adults considered parasitological methods (enrolled and not enrolled) to be at risk (special risk (intestinal and urinary once every 2 years groups only) schistosomiasis) or < 30% by questionnaire for visible haematuria (urinary schistosomiasis) Low-risk community < 10% by parasitological Treat all school-age children Praziquantel should be methods (intestinal and (enrolled and not enrolled) available in dispensaries urinary schistosomiasis) twice during their primary and clinics for treatment of schooling age (e. Epidemic control Examine for schistosomiasis and treat all who are infected (particularly those with disease), those who are heavily infected and children. Overt infection may produce a wide range of symptoms, including intestinal manifes- tations (diarrhoea, abdominal pain), general malaise and weakness, which may afect working and learning capacities and impair physical growth. Ascaris infection exacerbates vitamin A defciency; elimination of ascarids may result in rapid clinical improvement in night blindness and dryness around the eye. Persons acquiring hookworm infections may develop an itchy maculo-papular rash at the site of larval penetration. Transient pneumonitis, epigastric pain, anorexia, diarrhoea and eosinophilia may occur, complicated by iron-defciency anaemia caused by chronic intestinal blood loss. In endemic regions, typically only 10% have heavy worm burdens and tend to be I the ones who sufer from the disease. Tose with a heavy burden of worms have a friable intestinal mucosa leading to tenesmus and bloody mucoid stools. Recurrent rectal prolapse, iron-defciency anaemia, malnutrition, and growth retardation may be seen. Hookworms – Ancyclostoma duodenale and Necator americanus (small, cylin- drical, grayish-white nematodes measuring 7–13 mm in length). Communicable disease epidemiological profle 184 Case defnition Ascariasis Suspected case: Abdominal (mild abdominal discomfort, dyspepsia, loss of appetite, nausea, malnutrition) or respiratory symptoms (non-productive cough, chest discomfort, eosinophilic pneumonitis) and history of passing worms. Hookworm infection (Ancyclostoma duodenale and Necator americanus) Suspected case: Severe anaemia for which there is no other obvious cause. Confrmed case: Suspected case and presence of hookworm eggs in stools (microscopic examination). Ascaris eggs can remain viable for up to 6 years in moist loose soil and can survive freezing winter temperatures and short periods of desiccation. Infected people can contaminate soil as long as mature fertilized female worms live in the intestine (lifespan of adult worms can be 12–24 months). As larvae, they become infective in soil afer 7–10 days and can remain infective for several weeks. Communicable disease epidemiological profle 185 Infected people can contaminate soil for several years (3–5 years for Necator, and about 1 year for Ancyclostoma). In some instances, the prevalence of Ascaris infection is actu- ally greater in urban environments. In contrast, high rates of hookworm infection are typically restricted to areas where rural poverty predominates. Communicable disease epidemiological profle 186 Seasonality Distribution is infuenced by environmental parameters, especially temperature, humidity and soil dryness, factors that infuence the survival of eggs and larvae in the environment. Transmission is most intense immediately afer rainy seasons and is lowest during prolonged dry seasons. Risk factors for increased burden Population movement Population displacement for extended periods leading to living conditions with unsatisfactory sanitary facilities increases the risk of infection. Populations must remain in the same place for long enough for eggs to be discharged by an infected person and to become infective themselves. Overcrowding Overcrowding may facilitate transmission as a result of poor sanitation and poor hygienic practices, related to the number of people defecating in one area and unsafe disposal of faeces. Food shortages May lead to consumption of unsafe food and water, increasing the risk of infection. Lack of safe water, poor hygienic practices and poor sanitation The proportion of people using sanitation facilities efectively is the most impor- tant factor. Levamisole and pyrantel are less commonly used because they are less easy to administer in large-scale drug-distribution interventions. Implementing and sus- taining universal treatment twice annually is recommended for high-risk com- munities. Health education regarding safety of food and water, and proper sanitation is important. Neonatal tetanus occurs when tetanus occurs in a neonate at 3–28 days afer birth, usually when unclean instruments are used to cut the umbilical cord or, when contaminated materials are used to cover the umbilical stump. Maternal tetanus occurs during pregnancy or within 6 weeks post partum, usually as a consequence of unclean delivery or induced abortion. Overall case fatality is high (10–80%) without hospitalization and intensive care; fatality approaches 100% at extremes of age (infancy and elderly). Infectious agent Bacterium: Clostridium tetani Case defnition for neonatal tetanus Suspected case: Any neonatal death at age 3–28 days in which the cause of death is unknown; or any neonate reported as having sufered from neonatal tetanus at age 3–28 days and not investigated. Confrmed case: Any neonate with a normal ability to suck and cry during the frst 2 days of life, and who, between the age of 3 and 28 days, cannot suck normally, and becomes stif or has spasms (i. Note: The basis for case classifcation is purely clinical and does not depend on laboratory confrmation. Cases have resulted from infection of wounds considered too trivial for medical attention. Neonatal tetanus usually occurs through the introduction of spores via the um- bilical cord (e. Incubation period Usually 3–21 days; 10 days on average (may range from 1 day to several months). Shorter incubation periods have been shown to be associated with heavily con- taminated wounds, more severe disease and poor prognosis. Tetanus spores are ubiquitous in the environment and can enter the body through any type of wound via soil or objects contaminated with animal or human faeces. Côte d’Ivoire is one of 46 countries that, as of April 2009, have not eliminated neonatal tetanus. Cases of neonatal tetanus and tetanus reported in Côte d’Ivoire, 2003–2007 Year Annual number of reported cases Total annual number of reported of neonatal tetanus cases of tetanus 2007 31 Not available 2006 32 Not available 2005 2 2 2004 14 Not available 2003 12 12 Source: Tetanus (neonatal) reported cases. Côte d’Ivoire has joined other countries in implementing supplementary immunization activity with tetanus toxoid targeting all women of childbearing age (usually aged between 15 and 45 years), living in high-risk areas, in order to achieve the goal of elimination of maternal and neonatal tetanus. Geographical distribution Worldwide, although it is more common in agricultural areas where contact with animal excreta is more frequent and immunization coverage is inadequate. Risk factors for increased burden Population movement Mass population displacement may put the displaced population at risk of acci- dental injuries, while inadequate wound-care in such settings may increase the risk of tetanus infection. Communicable disease epidemiological profle 193 Overcrowding Not relevant Poor access to health services In settings where access to health services is poor, it is likely that there will be: Inadequate wound management and treatment; Poor provision of protection through immunization; Inadequate care during childbirth (thereby increasing the risk of neonatal and maternal tetanus). Food shortages Not relevant Lack of safe water, poor hygienic practices and poor sanitation Poor wound care allows tetanus spores to settle on open wounds. Poor sanitation practices allow for increased contamination of formites with spores. Prevention of maternal and neonatal tetanus requires maternal immunization with tetanus toxoid and use of hygienic delivery practices (e. Immunization Neonatal tetanus can be prevented by vaccinating women of child-bearing age either during pregnancy or outside of pregnancy (3 doses of tetanus toxoid with an interval of at least 4 weeks between the frst and second dose and at least 6 months interval between the second and third dose. If more time lapses, the schedule should not be re-started, but the next due dose should be given). Importantly, recovery from clinical tetanus does not result in protection against the disease in the future and hence immunization is required. Epidemic control Outbreaks are rare, but when they occur, a thorough case-investigation and search for a common source (e. Other symptoms include haemoptysis, sig- nifcant weight loss, chest pain, breathlessness, fever, night sweats, tiredness, and loss of appetite. The best sputum yield is obtained in the early morning, therefore at least one sample should be from an early-morning collection. This group also includes cases without a smear result, which should be exceptional in adults but relatively more frequent in children. Some cases will be easy to diagnose such as; peripheral lymphadenitis, with swelling of cervical or axial lymph nodes, chronic evolution and/or produc- tion of caseous discharge. Communicable disease epidemiological profle 200 A hospital referral for X-ray and special examinations (e. Incubation period About 2–10 weeks from infection to demonstrable primary lesion or signifcant tuberculin reaction.
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