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They pose risks to muscle relaxant back pain over counter order 50 mg azathioprine fast delivery themselves because the earlier treatment begins muscle relaxant radiolab order 50mg azathioprine visa, the better the prognosis muscle relaxant drug test purchase azathioprine amex. The report stated that four previously healthy homosexual men developed pneumonia from an infection caused by Pneumocystis carinii (1) muscle relaxant lorzone generic azathioprine 50 mg visa. The men also suffered fungal infections in the mouth and had multiple viral infections. This scenario of disease in persons with a low resistance to infection was consistent with the broad picture of an acquired deficiency of the immune system. Later reports described cases involving heterosexual and homosexual transmission of infections, transmission by blood and blood products, transmission by contaminated needles of intravenous drug users and from improperly collected and stored blood, and spread by nursing. Even worse, in Africa over one of forty persons, both male and female, is infected. The incidence in Asia, India, Latin, Central and South America, the Caribbean, Eastern Europe, and Russia is not fully known but is increasing to astronomical proportions. This large number partially results from the success of antiretroviral drug therapy, which prolongs survival. As the virus hides and remains latent in certain body sites, current drugs are unable to provide eradication but are effective in suppressing viral volume. This dilemma for public health, public/government, and individual/insurance financing has led to the vigorous push to develop vaccines both to prevent the disease as well as to curtail its effects in those already infected, a so-called therapeutic vaccine. Resurrecting the function of these T lymphocytes is required to control the infection. The identification and removal of these factors resurrected T-cell functions (1523). However, one should recall that it took forty-seven years to develop a successful vaccine to protect us from poliomyelitis and forty-two years to find a vaccine that conquered measles virus infections. The outcome is a widespread systemic presence of the tuberculosis bacteria, reminiscent of the effect observed by von Pirquet with measles virus in the 1890s (see measles virus chapter). Indeed, since 2006, over 400 incidents of humans infected with drug-resistant tuberculin bugs have been found. The vaccine is a weakened live attenuated form of the Mycobacterium bovis strain, which is related to Mycobacterium tuberculosis, the disease-causing strain, and has shown significant protection for some but not all children during their first fifteen years of life. The persistent infection that results remains intact in spite of an early immune response that coexists with the virus. All the experiences with vaccines for smallpox, yellow fever, measles, and poliomyelitis have focused on using an attenuated virus that could replicate in the host initially, would not seriously harm the host, yet would provide enough stimulus for the hosts immune system to combat and clear the viral infection. For a vaccine to be successful, it should mimic the immune response elicited by the pathogen during a natural infection. Further, the vaccine must be milder and less injurious than the natural infection yet should provoke immunologic memory. Immunologic memory is the rapid and specific viral immune response programmed by previous virus infection or immunization. Thus, vaccines prime the immune system and program it to anticipate and resist future infection by that specific pathogen. To provide a robust immune response and subsequent immune memory that prevents or at least controls infection, three approaches have been used for developing successful vaccines. The first and overall the most successful is to use an attenuated or weakened virus whose composition closely resembles that of the virus to be overcome. A second way is to use a killed virus preparation as is done for the Salk poliomyelitis vaccine. A third method utilizes recombinant viral protein(s), that is, a subunit vaccine, and is represented by the one that successfully prevents hepatitis B virus infection. For example, there are nine distinct subtypes for group M and, within a subtype, the viruss envelope glycoproteins can vary by up to 35 percent. This is an irreversible process that occurs immediately after infection and lasts until the cell in which integration takes place is eliminated. This reservoir is stable over the life of the infected individual, is immunologically silent, and, if the cell becomes activated, it can produce new infectious viruses. The discovery that a viral infection can have links with a cancer has 260 Viruses, Plagues, and History a long history. Nearly 100 years ago, the search for a viral source of cancer began, and for the past forty-five years the focus has been on a specific viral group, the human retrovirus. Scientists now know that viral infections cause at least 20 percent of all cancers. Papillomaviruses were among the first viruses defined as filterable agents (40) and shown by Harold zur Hausen and colleagues in the late 1970s (41) to be associated with human epithelial cancers including human cervical cancer. For this observation and subsequent follow-ups, zur Hausen was awarded the Nobel prize in Physiology and Medicine for 2008. Further, over onequarter of the six hundred-plus known animal viruses have oncogenic potential, that is, the capacity to initiate in animals or cultured cells the kind of cellular division and growth that promotes the development of tumors. Transmission of cancers among animals had been attributed to viruses since the early part of the twentieth century. Many of these cancers arose from retroviruses, a family of viruses in which the replication of the viral nucleic acid is unique. At the close of the nineteenth century, the first virus that infected animals had been reported by Froesch and Loeffier (44). By the first decade of the twentieth century, viruses were being isolated and manipulated as physical entities through the use of Pasteur-Chamberland-Berkefeld filters and experimental animals. It was during this time that the first retroviruses were shown to be transmissible agents that could cause cancers. Vilhelm Ellermann and Oluf Bang (45), working in Copenhagen, Denmark, described the first true cell-free transmission of cancer. They showed that cancer induced by an agent smaller than a bacterium, an ultravisible [not seen by the microscope] virus, caused erythromyeloblastosis (a leukemia) in fowl. However, at that time leukemia was not considered a cancer, and so this discovery lacked impact. Three years passed and then Peyton Rous reproduced solid tumors (sarcomas) in fowl by injecting them with filtrates of a tumor obtained from a hen. Working at the Rockefeller Institute, Rous, after examining Plymouth Rock hens brought to him by farmers, identified their malignant tumors as spindle cell sarcomas (46). He then demonstrated that these tumors could be transmitted to closely related animals. He prepared a cell-free, bacteriafree filtrate of such tumors and inoculated it into a healthy chicken; as a result an identical sarcoma grew in that second chicken (46). Active research on breast cancers transmitted from the mother to her offspring via breast milk focused on determining whether the cancer came from a virus as opposed to a milk factor. The research results showed conclusively that the cancer originated from a retrovirus, later called mammary tumor virus. Despite these accumulated findings that associated cancer with viruses, the investigations failed to achieve major scientific recognition. For example, when the National Cancer Institute of the United States was created in 1937, the committee of leading scientists who advised the newly created institute on various lines of work which merit investigation came to this conclusion regarding tumor virus research (47): It has been definitely shown that the animal parasites and bacteria which may incite malignancy in other organisms play no role in the continuation of the process [in humans]. The present evidence tends to indicate that 262 Viruses, Plagues, and History the same may be true of viruses. As causes of the continuation of the malignant process, many microorganisms which may have been described as specific etiologic agents may be disregarded. In spite of this advice, fifty years later the first human retroviruses were isolated by workers at the National Cancer Institute and shown to cause cancers (48,49). From the 1950s through the 1970s, a plethora of discoveries were made regarding retroviruses. Many could cause tumors in mammals, and these could be transmitted vertically (into the fetus) as well as horizontally (from one individual to another after birth). Such infections often harm the immune system, most frequently by immunosuppression (suppressing its function). For example, a number of retroviruses can live in lymphocytes and macrophages and stop their activity as members of the immune system.

In North America muscle relaxant antagonist order azathioprine now, these changes may develop shorter life cycles and higher population densities have been attributed to muscle relaxant gas discount 50 mg azathioprine with amex an increase in awareness of tick-borne (Carcavallo and Curto de Casas muscle relaxant drug test buy azathioprine canada, 1996) muscle relaxant liquid buy cheap azathioprine online. High temperatures also diseases and increased abundance of wild tick hosts (principally accelerate development of the pathogen, Trypanosoma cruzi, in deer), as reforestation has expanded areas of suitable habitat the vector (Asin and Catala, 1995). Population density of domestic vectors also is York state, Ixodes scapularis has expanded its geographic s i gnificantly a ffected by human activities to control or eradicate d i stribution northward and westward in the past 10 years. The southern limits of Triatoma infestans and Chagas disease distributions recently have been moved significantly inside their climatically suitable limits by large-scale control campaigns 9. Lyme disease has a global d i stribution in temperate countries of North America, Europe, Plague is a bacterial disease that is transmitted by the bite of and Asia. The transmission cycle of Lyme disease involves a infected fleas (Xenopsylla cheopis), by inhaling infective range of mammalian and avian species, as well as tick species b a cteria, and, less often, by direct contact with infected animals all of which are affected by local ecology. Plague exists focally in all regions except a shift toward milder winter temperatures may enable expansion Europe. A combination is unclear whether climate change may affect the distribution of milder winters and extended spring and autumn seasons and incidence of plague. There does appear to be a correlation would be expected to prolong seasons for tick activity and between rainfall patterns and rodent populations (Parmenter et enhance endemicity, but this would not be expected to change al. Prospective field research disease activity because humans usually are infected by the studies must be conducted to confirm this. Ticks are ectoparasites; their the eastern subtype is transmitted by Ixodes persulcatus and geographical distribution depends on the distribution of suitable causes Russian spring-summer encephalitis. Species that transmit these diseases have complex the western subtype is transmitted by Ixodes ricinus and causes life cycles that require 3 years and three different hosts species central European encephalitis, a milder form of the disease. Bioclimatic threshold temperatures States and is transmitted by Ixodes scapularis. Humans usually set limits for tick distribution and are of importance for the become infected when they are exposed to ticks in habitats magnitude of disease occurrence (Table 9-3). The viruses also may be must be sufficiently high for completion of the ticks life cycle. Each has a specific in the annual number of cases of tick-borne encephalitis geographic distribution that is determined by that of the r e p o r ted within Sweden. Most transmission to humans is by p r i m ary rodent host (Schmaljohn and Hjelle, 1997). Humans the nymphal ticks, each of which feeds for a few days during are infected by aerosol exposure to infectious excreta or spring-summer before dropping to the ground and molting to o c c asionally by bites. The better known of these diseases are adult ticks, which feed primarily on deer and other larg e hemorrhagic fever with renal syndrome, caused by Hantaan m a mmals. All tick stages have well-defined seasons of feeding virus, in China and Korea and hantavirus pulmonary syndrome activity, which vary geographically and may be prolonged in in the Americas, caused by several viruses that are specific to regions with mild winters. Many this seasonal synchrony depends on a particular seasonal h a ntavirus infections occur in persons of lower socioeconomic p r ofile of land surface temperaturespecifically, a rapid rate status, where poorer housing and agricultural activities favor of cooling in the autumn (Randolph et al. Synchrony closer contact between humans and rodents (Schmaljohn and may be disrupted by climate change as patterns of overwinter Hjelle, 1997). Water-Related Infectious Diseases higher latitudes and altitudes, current foci in central Europe largely disappear as a result of disruption of the tick seasonal There are complex relationships between human health and dynamic by climate change. Thus, one model suggests that it problems of water quality, availability, sanitation, and hygiene. Rodent-Borne Diseases the risk of disease via contamination of water resources, poor hygiene, or other mechanisms. Increases in water stress are projected under climate change in Environmental factors that affect rodent population dynamics certain countries (see Chapter 4), but it is difficult to translate include unusually high rainfall, drought, and successful such indicators directly into the attributable risk for wateri n t r oduction of exotic plant species. Water scarcity may necessitate use of poorer are affected indirectly by ecological determinants of food quality sources of freshwater, such as rivers, which often are sources that affect rodent population size (Williams et al. Leptospirosis Excessive precipitation can transport terrestrial microbiological Leptospirosis is an acute febrile disease caused by the bacteria agents into drinking-water sources. Infection is caused by exposure to water, damp soil, or (Lisle and Rose, 1995; Atherholt et al. In many countries, handling of in flooding associated with climate change may affect the sewage is not separate from the drainage system for stormwaters. It is important that water resource management can adapt to 472 Human Health changes in the frequency of precipitation extremes to minimize h u m i dity can lead to increased dispersion of particulate fungal the risk of microbiological contamination of the public water spores, thereby increasing the risk of pneumonia caused by supply. Cholera is a waterand food-borne disease and has a complex mode of transmission. The seventh cholera pandemic currently is Pathogens often are found in coastal waters; transmission spreading across Asia, Africa, and South America. Higher temperatures excessive flooding caused cholera epidemics in Djibouti, encourage microorganism proliferation. Vibrio vulnificus is a naturally occurring and the risk of infection with cholera. Other Infectious Diseases e n v ironmental conditions and therefore are sensitive biological indicators of the combined influences of climate change and Wa t e rand food-borne diseases tend to show marked seasonality, environmental change (Harvell et al. Algal temperatures in Peru during the 19971998 El Nino were blooms can be harmful to fish and other aquatic life, often a s s ociated with a doubling in the number of children admitted causing severe economic damage, and are reported to have to the hospital with diarrhea (Checkley et al. Higher increased globally in the past several decades (Hallegraeff, temperatures also can trigger spore maturation. Because climate change is expected to There is no straightforward relationship between the presence entail warmer springs and summers, additional cases of foodof an algal bloom and an outbreak of poisoning. Human borne disease may occur, if current trends continue (Bentham p o isoning can occur in the absence of a bloom. In most developed countries, food-borne of biotoxin poisoning are associated with temperate climates disease incidence is increasing as a result of changes in behavior, and colder coastal waters: paralytic shellfish poisoning and consumption patterns, and commerce. If water temperatures rise as a result of climate change, shifts in the distribution of these Major epidemics of meningococcal infection usually occur d i seases could follow. Biotoxins associated with warmer every 510 years within the African meningitis belt; they waters, such as ciguatera in tropical waters, could extend their usually start in the middle of the dry season and end a few range to higher latitudes (Tester, 1994). Between February and April 1996, the disease affected some Pacific islands (Hales et al. The epidemic spread from the Recent evidence suggests that species of copepod zooplankton original meningitis belt to Kenya, Uganda, Rwanda, Zambia, provide a marine reservoir for the cholera pathogen and facilitate and Tanzania (Hart and Cuevas, 1997). One of the environmental its long-term persistence in certain regions, such as the estuaries factors that predispose to infection and epidemics is low humidity of the Ganges and Bramaputra in Bangladesh (Colwell, 1996). However, a climate-meningitis the seasonality of cholera epidemics may be linked to the association was not clear in parts of the Gulf of Guinea s e asonality of plankton (algal blooms) and the marine food (Besancenot, 1997). Decreases in further suggests a widespread environmental cause of the 1991 Human Health 473 epidemic in Peru, rather than point-source contamination (Seas half the population in countries of central, southern, and east et al. Environmental factors, including sea surfaces and cholera risk in the Bay of Bengal, but it is not natural factors and those that are a consequence of human possible to extrapolate such findings to cholera incidence activities, can limit agricultural potential. The potential impact of long-term extremely dry or cold climates, poor soil, erratic rainfall, steep climate warming on cholera incidence or risk of epidemics slopes, and severe land degradation. However, the causal link between sea intellectual development in children, low productivity in adults, t e mperature, plankton blooms, and human disease requires and susceptibility to infectious disease in everyone. Food Yields and Nutrition prices decrease, the number of undernourished people would fall, but populations in isolated areas with poor access to Background climate and annual weather patterns are key m a rkets still may be vulnerable to locally important decreases f a ctors in agricultural productivity, despite technological or disruptions in food supply. As temperature, rainfall, and soil moisture change, plant physiology is affected; so too is the much less predictable 9. Demographic and Economic Disruption risk of a change in patterns of plant pests and pathogens. There are many social, economic, and environmental influences on Health impacts associated with population displacement fall agricultural, horticultural, and livestock productivity. Climate under two general categories: health impacts resulting from the change represents an additional pressure on the world food new ecological environment and health impacts resulting from supply system. That system, which has yielded an overall the living environment in refugee camps (Prothero, 1994). When pastoralists in west falling food prices; pessimists point to falling soil fertility. Africa were forced to move because of reduced pasture and water, they were faced with new ecological conditions. They Modeling studies (reviewed in Chapter 5) indicate that, under experienced psychological stress and were more at risk of climate change, yields of cereal grains (the worlds dominant infectious diseases (Stock, 1976; Prothero, 1994). Climate food commodity) would increase at high and mid-latitudes but change may affect human security via changes in water supplies decrease at lower latitudes. Furthermore, this disparity would and/or agricultural productivity (Lonergan, 1998, 1999).

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Several of the security measures discussed in this chapter are embedded in the biosafety levels that serve as the foundation for good laboratory practices throughout the biological Principles of Laboratory Biosecurity laboratory community muscle relaxant prescription drugs azathioprine 50mg otc. Most biomedical and microbiological laboratories do not have select agents or toxins spasms throughout body buy cheap azathioprine line, yet maintain control over and account for research materials muscle relaxant neck order azathioprine 50mg amex, protect relevant sensitive information spasms under left breastbone order azathioprine 50 mg fast delivery, and work in facilities with access controls commensurate with the potential public health and economic impact of the biological agents in their collections. These measures are in place in most laboratories that apply good laboratory management practices and have appropriate biosafety programs. Biosafety programs reduce or eliminate exposure of individuals and the environment to potentially hazardous biological agents. Biosafety is achieved by implementing various degrees of laboratory control and containment, through laboratory design and access restrictions, personnel expertise and training, use of containment equipment, and safe methods of managing infectious materials in a laboratory setting. The objective of biosecurity is to prevent loss, theft or misuse of microorganisms, biological materials, and research-related information. This is accomplished by limiting access to facilities, research materials and information. While the objectives are different, biosafety and biosecurity measures are usually complementary. Both are based upon risk assessment and management methodology; personnel expertise and responsibility; control and accountability for research materials including microorganisms and culture stocks; access control elements, material transfer documentation, training, emergency planning, and program management. Biosafety and biosecurity program risk assessments are performed to determine the appropriate levels of controls within each program. Biosafety looks at appropriate laboratory procedures and practices necessary to prevent exposures and occupationallyacquired infections, while biosecurity addresses procedures and practices to ensure that biological materials and relevant sensitive information remain secure. The biosafety program ensures that staff are qualified to perform their jobs safely through training and documentation of technical expertise. Staff must exhibit the appropriate level of professional responsibility for management of research materials by adherence to appropriate materials management procedures. Biosafety practices require laboratory access to be limited when work is in progress. Biosecurity practices ensure that access to the laboratory facility and biological materials are limited and controlled as necessary. An inventory or material management process for control and tracking of biological stocks or other sensitive materials is also a component of both programs. For biosafety, the shipment of infectious biological materials must adhere to safe packaging, containment and appropriate transport procedures, while biosecurity ensures that transfers are controlled, tracked and documented commensurate with the potential risks. Both programs must engage laboratory personnel in the development of practices and procedures that fulfill the Principles of Laboratory Biosecurity biosafety and biosecurity program objectives but that do not hinder research or clinical/diagnostic activities. The success of both of these programs hinges on a laboratory culture that understands and accepts the rationale for biosafety and biosecurity programs and the corresponding management oversight. In some cases, biosecurity practices may conflict with biosafety practices, requiring personnel and management to devise policies that accommodate both sets of objectives. Standard biosafety practice requires that signage be posted on laboratory doors to alert people to the hazards that may be present within the laboratory. The biohazard sign normally includes the name of the agent, specific hazards associated with the use or handling of the agent and contact information for the investigator. Therefore, biosafety and biosecurity considerations must be balanced and proportional to the identified risks when developing institutional policies. Designing a biosecurity program that does not jeopardize laboratory operations or interfere with the conduct of research requires a familiarity with microbiology and the materials that require protection. Protecting pathogens and other sensitive biological materials while preserving the free exchange of research materials and information may present significant institutional challenges. Therefore, a combination or tiered approach to protecting biological materials, commensurate with the identified risks, often provides the best resolution to conflicts that may arise. However, in the absence of legal requirements for a biosecurity program, the health and safety of laboratory personnel and the surrounding environment should take precedence over biosecurity concerns. A risk management approach to laboratory biosecurity 1) establishes which, if any, agents require biosecurity measures to prevent loss, theft, diversion, or intentional misuse, and 2) ensures that the protective measures provided, and the costs associated with that protection, are proportional to the risk. The need for a biosecurity program should be based on the possible impact of the theft, loss, diversion, or intentional misuse of the materials, recognizing that different agents and toxins will pose different levels of risk. Biosecurity policies and procedures should not seek to protect against every conceivable risk. The risks need to be identified, prioritized and resources allocated based on that prioritization. Risk management methodology takes into consideration available institutional resources and the risk tolerance of the institution. Developing a Biosecurity Program Management, researchers and laboratory supervisors must be committed to being responsible stewards of infectious agents and toxins. Development of a biosecurity Principles of Laboratory Biosecurity program should be a collaborative process involving all stakeholders. The stakeholders include but are not be limited to: senior management, scientific staff, human resource officials, information technology staff, and safety, security and engineering officials. The involvement of organizations and/or personnel responsible for a facilitys overall security is critical because many potential biosecurity measures may already be in place as part of an existing safety or security program. This coordinated approach is critical in ensuring that the biosecurity program provides reasonable, timely and cost effective solutions addressing the identified security risks without unduly affecting the scientific or business enterprise or provision of clinical and/or diagnostic services. The need for a biosecurity program should reflect sound risk management practices based on a site-specific risk assessment. A biosecurity risk assessment should analyze the probability and consequences of loss, theft and potential misuse of pathogens 7 and toxins. Most importantly, the biosecurity risk assessment should be used as the basis for making risk management decisions. Example Guidance: A Biosecurity Risk Assessment and Management Process Different models exist regarding biosecurity risk assessment. Most models share common components such as asset identification, threat, vulnerability and mitigation. What follows is one example of how a biosecurity risk assessment may be conducted. In this example, the entire risk assessment and risk management process may be divided into five main steps, each of which can be further subdivided: 1) identify and prioritize biologicals and/or toxins; 2) identify and prioritize the adversary/threat to biologicals and/or toxins; 3) analyze the risk of specific security scenarios; 4) design and develop an overall risk management program; 5) regularly evaluate the institutions risk posture and protection objectives. Step 1: Identify and Prioritize Biological Materials Identify the biological materials that exist at the institution, form of the material, location and quantities, including non-replicating materials. At this point, an institution may find that none of its biologic materials merit the development and implementation of a separate biosecurity program or the existing security at the facility is adequate. Principles of Laboratory Biosecurity Step 2: Identify and Prioritize the Threat to Biological Materials Identify the types of Insiders who may pose a threat to the biologic materials at the institution. Step 3: Analyze the Risk of Specific Security Scenarios Develop a list of possible biosecurity scenarios, or undesired events that could occur at the institution (each scenario is a combination of an agent, an adversary, and an action). Consider: o access to the agent within your laboratory; o how the undesired event could occur; o protective measures in place to prevent occurrence; o how the existing protection measures could be breached. Assumptions include: o although a wide range of threats are possible, certain threats are more probable than others; o all agents/assets are not equally attractive to an adversary; o valid and credible threats, existing precautions, and the potential need for select enhanced precautions are considered. Step 4: Develop an Overall Risk Management Program Management commits to oversight, implementation, training and maintenance of the biosecurity program. Principles of Laboratory Biosecurity Management develops a biosecurity risk statement, documenting which biosecurity scenarios represent an unacceptable risk and must be mitigated versus those risks appropriately handled through existing protection controls. Step 5: Reevaluate the Institutions Risk Posture and Protection Objectives Management regularly reevaluates and makes necessary modifications to the: o biosecurity risk statement; o biosecurity risk assessment process; o the institutions biosecurity program/plan; o the institutions biosecurity systems. This section offers examples and suggestions for components of a biosecurity program should the risk assessment reveal that further protections may be warranted. Program components should be site-specific and based upon organizational threat/vulnerability assessment and as determined appropriate by facility management. Elements discussed below should be implemented, as needed, based upon the risk assessment process. They should not be construed as minimum requirements or minimum standards for a biosecurity program. Program Management Principles of Laboratory Biosecurity If a biosecurity plan is implemented, institutional management must support the biosecurity program. Appropriate authority must be delegated for implementation and the necessary resources provided to assure program goals are being met.

After absorption it is extensively metabolized to spasms gums azathioprine 50 mg without prescription citrulline spasm purchase azathioprine 50mg otc, arginine muscle relaxant histamine release order azathioprine canada, glutamate spasms vulva order 50mg azathioprine free shipping, and proline (Reeds and Burrin, 2001). The endogenous rate of production by the adult whole body has been estimated to be 60 to 100 g/d (van Acker et al. The two enzymes primarily responsible for glutamine metabolism are glutaminase, which converts glutamine to glutamate and ammonia, and glutamine synthetase, which synthesizes glutamine from glutamate and ammonia. Hazard Identification Ziegler and coworkers (1990) performed several individual studies to examine glutamine safety under different circumstances. In the first study, six volunteers were given a single oral dose of glutamine at three different doses (0, 0. A second study in nine volunteers was performed to investigate the effects of intravenous infusion of glutamine at three doses (0, 0. After single oral doses, plasma glutamine concentrations rose in proportion to the dose given, by approximately twofold after 1 hour for the higher dose, and returned to basal within 4 hours. Overall, there were no indications of adverse effects at any dose when glutamine was given by either the oral or intravenous route. There was no significant increase in plasma glutamine concentration, and no other adverse effects were observed, but the authors noted their concern regarding elevations in liver enzymes. After 6 days the plasma glutamine was increased by 8 percent in the treated group compared with a decrease of 15 percent in the controls. Plasma glutamine was modestly increased and nitrogen balances were improved compared with the control group. On the basis of plasma ammonia and glutamate levels and the absence of clinical signs of neurotoxicity, it was concluded that glutamine at this dose is safe in preterm infants. Also, Roig and coworkers (1996) reported no increases in the concentrations of glutamine, glutamate, and ammonia in very low birthweight infants given enteral supplements of glutamine (0. It is notable that despite the substantial number of published investigations in which glutamine has been administered to humans, very few, if any adverse effects have been reported. However, the published studies of toxicity have not fully taken account of a number of important factors, including the chronic consumption of glutamine. Glutamine is an important fuel utilized by most rapidly growing tumors (Kovacevic and Morris, 1972), which may deplete the bodys ability to provide glutamine (Chen et al. Moreover, tumor cells are dependent on a supply of glutamine for growth (Colquhoun and Newsholme, 1997), and the growth rates correlate with the activity of glutaminase (Knox et al. Therefore, although providing supplemental glutamine might restore the body glutamine pool, it is also important to examine the possibility that glutamine supplements may promote cancer. However, the evidence points to the contrary, and in vivo studies have not confirmed this suspicion (Klimberg and McClellan, 1996; Souba, 1993). Oral administration of glutamine did not enhance tumor growth in rats in vivo (Klimberg et al. It is the only amino acid that does not have an asymmetric carbon atom, and its metabolism is linked to that of L-serine. Men 19 through 30 years of age had the highest intakes at the 99th percentile of 7. Growth depression in rats and chicks has been reported after feeding diets containing as much as l0 percent glycine (Harper et al. In patients with schizophrenia, oral doses of approximately 60 g/d of glycine for several weeks failed to reveal adverse effects (Leiderman et al. There have been no chronic doseresponse studies with L-glycine in healthy humans. Further, men fed amino acid-based diets containing 10 g of nitrogen/d devoid of histidine remained in nitrogen balance for up to 2. Conversely, it has been observed that nitrogen balance becomes gradually negative over a longer period of time and nitrogen balance rapidly became positive upon the reintroduction of histidine (Kopple and Swendseid, 1975). Histidine is an important component of hemoglobin (8 percent), with the bulk being in the globin portion. In addition, the dipeptide carnosine, found in skeletal muscle, is a large store of histidine and serve as a source of histidine (Christman, 1971). Because of these large body pools of histidine it takes a prolonged period (more than 60 days) to deplete an adult of histidine. Men 51 through 70 years of age had the highest intakes at the 99th percentile of 5. Histidine given acutely by intraperitoneal injection or intravenously has been shown to result in changes in the concentration of brain amino acids (Oishi et al. Young rats (4 to 5 weeks old) treated with an inhibitor of histidinase exhibited reduced locomotor activity after an intraperitoneal injection of histidine (250 mg/kg of body weight) (Dutra-Filho et al. Pilc and coworkers (1982) reported bizarre behavior in rats dosed intraperitoneally with histidine (400 to 800 mg/kg of body weight). Feeding low-protein diets supplemented with L-histidine for 3 to 4 weeks resulted in significant body weight losses after only several days in rats. However, the effects became less as increasing levels of high-quality protein were added to the diet (Benevenga and Steele, 1984). Short-term feeding studies (7 to 46 days) in rats have shown growth retardation, hepatomegaly, and hypercholesterolemia at L-histidine levels of approximately 2 to 4 g/kg body weight/d (Harvey et al. Harvey and coworkers (1981) reported significantly reduced concentrations of copper and zinc in the plasma and reduced liver concentrations of copper after feeding diets containing 8 percent L-histidine (~4 g/kg body weight/d) for 46 days. Hypercholesterolemia was eliminated by the simultaneous feeding of an L-histidineand copper-supplemented diet, supporting the hypothesis that the histidine-induced hypercholesterolemia was a result of changes in copper status. No significant treatment-related increases in any tumors were reported when compared to matched controls. Pinals and coworkers (1977) treated 30 rheumatoid arthritis patients and 30 controls daily with capsules containing 4. It is not clear which adverse effects were examined; however, the authors concluded that no adverse effects of the histidine therapy were noted. In a similar double-blind treatment design, Blumenkrantz and coworkers (1975) treated 42 patients (16 chronic uremic and 26 undergoing maintenance dialysis) with oral doses of 4 g/d of L-histidine for 17. No adverse effects were reported; however, it was not evident from the report which adverse effects were examined. Studies on the effects of L-histidine on taste and smell acuity in humans have produced conflicting results. Henkin and coworkers (1975) reported decreased taste and smell acuity in six patients given 8 to 65 g of histidine/d for up to 24 days. In view of the increased urinary excretion of zinc and a decreased concentration of serum zinc, the authors postulated that the effects of histidine administration were due to a zinc-deficient state. In a study of eight healthy men given 4 g/d of histidine for 2 weeks, no effects on smell or taste acuity were reported (Schechter and Prakash, 1979). Similarly, Geliebter and coworkers (1981) failed to find any effect of L-histidine on taste and smell after oral dosing of L-histidine between 24 and 64 g/d for 4 weeks. Even at the lower dose (4 g/d), adverse effects such as headaches, weakness, drowsiness, and nausea were reported, while at the highest doses (24 and 64 g/d) anorexia, painful sensations in the eyes, and changes in visual acuity were reported in two females. Although the study examined parental administration, it provides further evidence that excess histidine intake in humans can lead to histidine/zinc interactions that might lead to a zinc-deficient state. DoseResponse Assessment In experimental animals, the only doseresponse study on the chronic oral administration of L-histidine was that of Ikezaki and coworkers (1996). However, this study utilized only two doses, neither of which demonstrated any adverse effects. In addition, no data were reported on the possible effect of the doses on zinc or copper metabolism, an effect reported in both humans and experimental animals. However, this evidence should be considered tentative given the few individuals studied and lack of doseresponse information. There is evidence from studies in experimental animals and humans that intakes of high levels of histidine can alter copper and zinc metabolism. However, the lack of doseresponse data precludes identifying the intake concentrations in humans required to elicit such responses. Carnitine is required for the transport of long-chain fatty acids and is synthesized from lysine and methionine in the liver and kidney (Mayes, 1990).