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- Clinical Associate Professor, Department of Clinical Pharmacy, College of Pharmacy, University of Michigan
- Clinical Pharmacist, University of Michigan Health System, Ann Arbor, Michigan
https://pharmacy.umich.edu/people/reregal
Salary limitations are identified in the Title X Notice of Award prehypertension is defined by what value discount micardis 80mg amex, reflecting the current federal appropriations law hypertension 28 years old buy cheapest micardis. Sub-recipients must maintain documentation and attendance for required trainings for all staff and volunteers normal pulse pressure 60 year old discount 40mg micardis overnight delivery. Sub-recipients should maintain documentation and attendance at continuing education programs for all staff pulse pressure 27 order generic micardis line. Funds for training and continuing education should be included in each year’s operating budget. Registered nurses and mid-level practitioners should be offered appropriate educational opportunities so as to comply with requirements of the licensure/certification process. Sub-recipients are encouraged to participate in annual Family Planning Coordinator Meetings where needs for future training programs are discussed. Annual training on the agency mandated reporting policy and procedures must include the following: 1. Review of the policy, including screening to identify situations that should be reported 2. Review of the process for documenting in the medical record that a report was made, including documenting of the minor’s age. Annual training on agency policy and procedures on human trafficking should cover signs for identifying potential victims of human trafficking and agency procedures to address the concerns with clients, including assessment of danger and development of plan of care with client, resources, and required mandatory reporting if the client is a minor. Sub-recipient agencies must submit written goals and objectives (Family Planning Work Plan) for the year with their annual plans that are specific, measurable, achievable, time-framed and consistent with Title X Program requirements as part of their annual plan. Instructions for the annual plan and work plan are available in the Michigan Information in Section I of this document and are emailed to Family Planning Coordinators annually. Projects must provide for comprehensive medical, informational, educational, social, and referral services related to family planning for clients who want such services. Sub-recipients must have written policies and procedures in place to assure the following: 9. Projects must have policies and procedures in place to identify and address intimate partner violence. Projects must have policies and procedures in place to identify and address victims of human trafficking. Necessary referrals include but are not limited to emergencies that require referral. Efforts may be made to aid the client in finding potential resources for reimbursing the referral provider, but projects are not responsible for the cost of this care. A service site that offers only a single or very limited number of family planning methods may participate only as part of a project where the entire project offers a broad range of family planning services. If pregnancy options counseling beyond basic information is requested, and the project elects to provide this service, counseling must be provided by a physician or advanced practice provider using a nondirective client-centered approach. Projects must not perform, promote, refer for, or support abortion as a method of family planning, nor take any action to assist a client to secure an abortion. Projects must provide a client who is medically verified as pregnant with a referral for medically necessary prenatal health care. Grantees must have written policies in place that address these legislative mandates: A. Projects must encourage family participation in the decision of minors to seek family planning services and must provide counseling to minors on how to resist efforts to coerce the minor into engaging in sexual activities. Projects must comply with state laws requiring notification or reporting of child abuse, child molestation, sexual abuse, rape, or incest. No provider of services under Title X is exempt from any laws requiring mandatory reporting. A confidentiality assurance statement signed by all family planning project personnel. Title X projects must not require written consent of parents of guardians for the provision of services to minors; nor can Title X staff notify a parent or guardian before or after a minor has received title X family planning services. Efforts should be made to assure that written and verbal exchanges between clients and clinic/clerical staff kept private, so that other clients in the site do not know client identity or reason for the visit. The composition of the board or advisory committee must be broadly representative of the population served in the community and include persons knowledgeable about family planning. Review the agency’s program plan, assess accomplishments and suggest future program goals and objectives. Review the agency’s progress toward meeting the needs population in the service area and maintaining services and policies responsive to the needs of the community. Use of client surveys or focus groups designed to elicit what services may be seen as needed by clients but not available. Community education program(s) should be based on an assessment of the needs of the community and should contain an implementation and evaluation strategy. Family Planning Program staff may provide administrative and clinical support to the committee but may not be voting members of the advisory committee. The committee may include professionals who work directly with population groups for which materials are intended, but the priority should be to include client and community members where possible. The agency must demonstrate efforts to recruit client and community members to assure broad representation the populations served. See “Information & Education Committee Member Recruitment Tips and Resources” at. Committee review and approval process must be included in a policy statement, by-laws, or other committee documents made available to members. All new information or education materials are distributed to committee members, along with a clinic brochure review form for each item, prior to the committee meeting. Agencies should allow at least two weeks for members to review materials prior to a meeting. Committee may delegate responsibility for the review of the factual, technical, and clinical accuracy to appropriate project staff; 88 however, final responsibility for approval of the materials rests with the committee. Committee meeting, members discuss their comments and recommendations and determine if the materials are appropriate for the intended community or target audience. The educational and cultural backgrounds of the individuals the materials are intended to serve ii. The standards of the population or community the materials are intended to serve iii. Determine whether the materials are suitable for the population or community they are intended to serve E. Committee must meet at least once a year; and should meet as often as is needed to review and approve new materials prior to their use. Minutes must be kept of all meetings and must reflect the determination for each item reviewed. Completed review forms or a compiled summary of individual review forms must be maintained to document member determinations. A master listing of materials that have been reviewed and approved by the committee with dates the items were approved/reapproved must be maintained. Acknowledgement must include the following language: “This publication was supported by award no. The current Title X grant award number under which the publication was produced must be identified in the acknowledgement of Title X grant support. Sub recipients are strongly encouraged to consider clients’ access to transportation, clinic locations, hours of operation, and other factors that influence clients’ ability to access services. Statement that clients will not be asked or required to provide their own interpreter. If the client chooses to use family or friends, the client is informed of the right to free 90 interpreter services and use of family or friends occurs only after the offer is declined and documented. Staff has completed training and understands their role in an emergency or natural disaster. In addition, sub recipients must have policies and procedures in place to follow Michigan mandatory reporting requirements under the Michigan Child Protection Act and compliance with Michigan’s Human Trafficking law and must file an annual health care plan, (Section I, pages 39, 54-56, 61-62 and 63-65). Sub-recipients must reconcile reports, ensuring that disbursements equal obligations and drawdowns. Accounting for any remaining inventory, contraceptive supplies and materials purchased with Title X funds.
During the past 20 years blood pressure chart health canada purchase generic micardis on line, dermatologic research has focused on how to arteria buccinatoria generic micardis 80 mg otc deliver antioxidants success fully through topical application blood pressure classification order micardis with american express. This strategy has major rewards: higher levels of antioxidants can be delivered to pulmonary hypertension 70 mmhg purchase generic micardis pills the skin where they are most needed, and an indwelling reservoir of antioxidants that cannot be wiped, washed, or perspired away yields constant protection. They react rapidly with oxygen free-radicals to protect cells and connective tissue from direct damage. This chapter discusses the unrecognized full extent of environmental damage, the necessity of topical antioxidants for protection, and the requirements for successful formulation to achieve topical delivery of the trace mineral selenium as well as vitamins C and E. Background Cumulative Environmental Damage More than our parents and grandparents, we expose our skin to environmental damage. Our skin suffers—both with sunburn and tanning that lead to photoaging, with leathery texture, mottled pigmentation, wrinkles, and dryness and later with actinic keratoses and skin cancer. In our cities, the concentrations of these chemical pollutants are well below the toxic or tumorigenic levels. When given orally, subcutaneously, or intratrachially, BaP does produce local skin and lung tumors (skin carcinomas and lung carcinomas, respectively). Studies have demonstrated that heavy smokers (>20 cigarettes/day) are about fve times more likely to have prominent wrinkles than non-smokers, especially around the eyes and mouth. Treatments were discontinued at week 25, and mice were observed for another fve weeks before being sacrifced. Certainly sunscreens are absolutely essential for protection, but there are many limitations in their effcacy, as enumerated in Table 23. This means that each application to a bathing suit clad body requires about one and one-half 4-oz bottles, so about six bottles are needed for a 10 a. Many individuals skip application to important areas around the eyes, under the nostrils, in front of and on the ears, as well as on the fngertips, ankles, and feet, and men (as well as women) forget areas with thinning hair on the scalp. Finally, sunscreens cannot fully protect the skin from the environment: they block only about 55% of free radical production,20,21 and they do not shield from the environmental BaPs described previously. Sunscreen does not protect against other environmental free radicals Topical Vitamins E, C, and Ferulic Acid and Topical L-Selenomethionine 301 Advantages of Topical Antioxidants There are two great advantages in applying an active formulation of topical antioxidant(s) to the skin. First, the skin attains far higher levels of each antioxidant than can be achieved by only taking these supplements orally. Topical L-Selenomethionine Selenium (Se) was recognized to be an essential trace element in humans and animals in the late 1950s. Se is a specifc component of important selenoproteins and Se-dependent enzymes required for anti oxidant defense, reduction of infammation, as well as thyroid hormone production and many other metabolic functions. Particularly large decreases in prostate cancer (to 37%), colon–rectal cancer (to 42%), and lung cancer (to 55%) were observed. Topical application of SeMet increased the concentration of Se in the skin by a factor of 1. Se levels were also elevated in the liver by topical application, proving successful transdermal absorption. Because topical SeMet penetrates transdermally, both the epidermis and dermis are protected, so previous damage can be repaired. This enhancement of repair of chronic photoaging was confrmed at the cellular and molecular level by histologic and electron microscopic analysis in mice. Its role as an antioxidant was suggested when animals made ill by ingesting rancid fat could be cured with wheat germ oil concentrates containing tocopherols. The number of methyl substituents on the chromanol ring gives rise to,,, and isomers, whereas saturation of the hydrocarbon chain defnes the tocopherol form (with a saturated chain, constituting eight stereoisomers of each of the four isomers of tocopherol) or the tocotrienol form (with an unsaturated chain and two stereoisomers of each of the four tocotrienol isomers). These researchers propose that vitamin E’s sole biologic role is as an antioxidant to protect polyunsaturated fatty acids and membrane fuidity and lipid domains. It is generally believed that the tocotrienols exhibit stronger antioxidant activity when compared to the tocopherols. The synthetic isomers are esterifed (to acetates and succinates) for use in commercial vita mins and some topical formulations because the esters are far more stable. However, this ester must be hydrolyzed before any biologic activity is possible, a reaction which readily occurs in the stomach after oral ingestion or in cell and organ culture, but is very slow after topical application. The skin has only a limited capacity to cleave the esterifed forms of vitamin E to the active free tocopherol form, so the antioxidant potential of the esters is minimal. As the outermost defense of the body, the stratum corneum is frst to absorb the oxidative stress of sunlight and pollution. In one of the frst controlled experi ments in history by a surgeon of the British Royal Navy, James Lind proved in 1747 that giving sailors lime or lemon juice prevented the dreaded, lethal disease of scurvy. It took the British Royal Navy until 1795 to include lime or lemon in sailors’ rations (leading to their nicknames “limies”). Vitamin C was frst isolated from fruit in 1928 by Albert Szent-Gyorgyi, who described its extraordi nary effects in improving human health. In the 1970s, Linus Pauling recommended far larger doses than possible through nutrition alone to attain optimal health. Pauling himself took 13 g/day, since that is the amount synthesized per day by a 130-lb goat. Vitamin C (L-ascorbic acid) is the body’s major aqueous-phase antioxidant and is essential for life. We humans get vitamin C solely from our diet, but even large doses (6000 mg/day, or 80 oranges) do not increase the concentration to optimal levels in the skin. Furthermore, exposure to sunlight and environmental pollution deplete vitamin C from the center layers of the skin. Therefore, the shelf life of most formulations containing pure vitamin C is short, so esterifed forms of vitamin C are usually used for topical appli cation in lotions, creams, serums, and patches to overcome this problem. However, these more stable, esterifed derivatives (ascorbyl-6-palmitate and magnesium ascorbyl phosphate) are not well absorbed103 and are only minimally metabolized by the skin to the active, free acid form. To achieve photoprotection and other benefts to the skin with topical vitamin C, the formulation must contain L-ascorbic acid in a high enough concentration (at least 10%), be stable, and be at an acid pH—less than the pKa (4. If topical application is discontinued after skin saturation is achieved, high levels remain in the skin for more than three days. Exciting studies in vitro compared newborn with elderly (80–95-year-old) fbroblasts. However, when vitamin C was added to the culture medium, the elderly cells actually proliferated better than normal newborn fbroblasts. Even the newborn fbroblasts proliferated almost four times better when exposed to vitamin C. Newborn fbroblasts synthesize a larger percentage of collagen than elderly cells; but again, when elderly cells were exposed to vitamin C in vitro, they produced more collagen than the nor mal, newborn fbroblasts. In contrast to the increased synthesis of collagen, other in vitro studies suggested that vitamin C may inhibit elastin biosynthesis by fbroblasts. Newborn fbroblasts (isolated from circumcised skin) and elderly fbroblasts (obtained from biopsies of individuals >90 years old) were grown in vitro with and without 10% l-ascorbic acid added to the culture medium. Clinically, a sig nifcant decrease was observed in deep furrows and substantiated by silicone replicas. Vitamin C is itself an excellent depigmentating agent because it inhibits the enzyme tyrosinase required for melanin production. Signifcant lightening of melasma and of solar lentigenes was observed in 19 of 34 patients. L’Oreal Advanced Research Laboratories, Clichy and Aulnay-sous-Bois, France; personal communication). Vitamin C + E Vitamins C and E act synergistically within cells to provide antioxidant protection: vitamin E is located in the cellular membranes and vitamin C is plentiful in the neighboring aqueous cytoplasm. With a lower redox potential, vitamin C can reduce the oxidized vitamin E, thereby regenerating vitamin E activity and eliminating the need for nutritional replacement. A decrease in the number of damaged “sunburn cells” was seen histologically, as well as a decrease in thiamine dimer formation118 compared to twofold protection for either vitamin alone. One group of 15 mice was treated with vehicle serum and the other with antioxidant serum—vitamin C (15%) + vitamin E (1%). Amazingly, only one tumor was seen in the antioxidant-treated group, whereas the vehicle-treated group had a total of 195 tumors. To compare these fgures with data from a similar experiment (vitamin E), after 40 weeks of observation the group of 15 vehicle-treated mice had 67 tumors cumulatively and the 15 d -tocopherol-treated mice had 36 tumors. It also has been shown to interact synergisticly with -tocoperhol and with ascorbic acid. Zielinski and Pinnell127 tested the effectiveness of a series of low molecular weight antioxidants that are available in chemically pure form. Ferulic acid was found to provide stability of more than 90% for L-ascorbic acid and 100% for -tocopherol.
At later stages of dementia pulse pressure pda micardis 20mg otc, physical symptoms such as epileptic seizures blood pressure 50 over 20 order genuine micardis line, difficulty swallowing hypertension vitals 20mg micardis fast delivery, and gait disorder also occur pulse pressure sepsis purchase discount micardis on-line. The management of dementia must therefore aim at maintaining cognition as well as 13 Alzheimer Europe Rare Forms of Dementia Project activities of daily living and physical well-being for as long as possible, and to minimise non-cognitive symptoms, combining pharmacological and non-pharmacological treatment strategies. For family members living with a demented person means a heavy and continuous burden which significantly increases the probability of psychological and physical morbidity [1]. The loss of a loved one, a change of roles and responsibilities, and withdrawal of relatives and friends all contribute to caregiver burden. Non-cognitive symptoms are more closely associated with caregiver distress than impairment of cognition or loss of activities of daily living [2]. Hence, providing advice and support to caregivers and improving their ability to cope with disease-related problems is another essential part of dementia management [19]. Brodaty H, Luscombe G (1998) Psychological morbidity in caregivers is associated with depression in patients with dementia. Variations in definitons and evolution of nondemented persons with cognitive impairment. Rockwood K, Bowler J, Erkinjuntti T, Hachinski V, Wallin A (1999) Subtypes of vascular dementia. This information is processed in the brain by nerve cells, analysed and integrated with our own information, our knowledge and our experience. The result of the integration generates an adapted response, an action if necessary, a storage in our memory if the information is interesting or important. All this work is performed by different specialised nerve cells, also known as neurons, that are gathered in specific neuronal populations that have different and specialised roles and location. Their function is to transport and to store the information (memory), or to trigger the activity of other cells (muscle fibers for example). The information is transported along neuronal extensions of nerve cells, called the axons. Information can jump and circulate to another neuron via a “synapse”, which is located at the end of the axon. The synapse bridges the gap between each neuron and allows the next neuron in the chain to be activated. All the information, received as micro-electric currents, is processed, analysed, integrated and then the resulting information is delivered to the appropriate neuron, via a synapse, for a specific task. For example, for vision, the eyes receive the visual information through numerous and specialised photoreceptors distributed on the retina. The visual information is then transported along axons, via a subset of neuronal population (colliculus), towards the occipital cortex. The information corresponding to the image is then transported to other brain areas to be analysed. The picture of the screen on the occipital pole (which is a primary visual area) is then analysed in secondary visual areas, and recognised as a specific object such as “an apple” for example. This recognition is the result of a comparison of the shape of the object with our knowledge of objects stored in the secondary visual areas (occipital regions around the occipital pole). Then the information is processed progressively (but very rapidly) by all other brain areas, at higher intellectual levels: the apple is recognised as a “golden” apple. If you do not like apples, you will be reminded of this by other brain areas involved in feelings and emotions, namely the limbic system. If you grab 16 Alzheimer Europe Rare Forms of Dementia Project the apple, you will activate your motor brain areas located in the upper part of the frontal cortex that will activate the nerves of your arms, then the muscles to grab the apple. In fact, the functioning of the brain is logical and easy to understand in its main lines. But to work properly, the mechanisms at the molecular levels are extremely complex and well regulated. The transmission of the information from one nerve cell to the other the synapse is a specialised neuronal ending that connects one neuron to another one in order to relay information. When the micro-current arrives at the synapse level, it releases a special molecule, known as neuromediator or neurotransmitter, that activates the other neuron, which in turn transmits the information. Drugs that stimulate the production of acetyl-choline are commercialised (Aricept, Exelon, Reminyl ) for use in the treatment of Alzheimer’s disease. Brain regions and neuro-degenerative disorders Most brain diseases first affect specific vulnerable neuronal populations. If the frontal pole is affected, the patient will likely present behaviour problems, while short-term memory problems result from a pathology of the hippocampal area. But because different types of degenerative diseases can affect the fronto-temporal regions (behaviour or language impairment), the clinical diagnosis is sometimes difficult, especially during the early stages. When memory impairment is suspected, it is important to review the clinical history and course of deterioration with both the patient and a knowledgeable informant. Clinical manifestation of the symptoms the age of onset, the symptoms presentation (such as memory, language, depression,) and the impact of the symptoms on the daily life. Functional Status assessment Analysis of the basic activities (such as walking, bathing, dressing), the instrumental activities (the use of the telephone, public services, house cleaning,) and social, community and intellectual functions. Non-cognitive symptoms Non-cognitive symptoms consist of behavioural disturbances (physical or verbal aggression, agitation, wandering, sexual disinhibition, incontinence, increase eating and screaming) and psychiatric symptoms (personality change, depression, visual and auditory hallucinations, paranoid ideas, misidentifications and mania). Despite having the same causes and origins, different presentations of the disease can be described and usually both cognitive and non-cognitive symptoms are present. Memory impairment is necessary but not sufficient criterion for the diagnosis of dementia. Criteria for dementia require a person to manifest at least one additional cognitive deficit : aphasia, apraxia, agnosia or impairment of executive functioning. Moreover, these deficits must result in impairment of social or occupational functioning and represent a significant decline from a person’s previous level of functioning. Non-cognitive symptoms need to be assessed carefully as they are important for the diagnosis. They have an important impact on the quality of life and represent one of the primary outcomes of the pharmacological treatment. These symptoms can be present at the beginning of the disease and are a major cause of placement in care. They are also used to follow the progression of the disease and the efficacy of drug treatments. In a short time (10 15 minutes), it facilitates the evaluation of global cognitive abilities. It is composed of 11 items that assess several cognitive functions: time and space orientation, short and long term memory, attention and calculation, language and apraxia. The assessment of non-cognitive symptoms of dementia represents a methodological and clinical challenge. The presence of cognitive and non-cognitive symptoms in the same patient makes the observation and characterisation of the symptoms difficult. Most dementia specialists also obtain a serum vitamin B12 level, which may be low despite the absence of anemia or macrocytosis. Biochemical markers Over the past several years, there has been an intensive search for structural and biochemical markers that can serve as diagnostic tests during the earliest stage of the disease. Likewise, monitoring the rate of cerebral atrophy may provide a measure of disease activity and response to therapy. Biochemical changes that reflect the presence of disease-related pathology also have the potential to serve as diagnostic biomarkers of Alzheimer’s disease. Both are particularly relevant to the pathology of Alzheimer disease and thus may provide diagnostically useful information. A prac-tical method for grading the cognitive state of patients for the clinician. Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42. May it reassure you that up till now research has shown that only a minor part of all dementias, including the rare forms, is caused by genetic factors, so called strong genes. This means that if one has this specific genetic material, one’s susceptibility to developing dementia is heightened. Getting the disease or not in these cases is dependent on more than just hereditary factors. Genetic material the human body consists of a large number of organs, which are built up from different tissues that contain millions of cells.
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Certification Board – Patrick Gore Due to a delay in obtaining exam results, the Certification Board report was also delayed and will be given in June. Also the subcommittee made a recommendation to remove the index to the Medical Standards due to difficulties associated with revising and maintaining it. There was no motion brought forth to continue the pilot study beyond the initial period, so it will be discontinued after 4Q 2013. Subcommittee to Evaluate Contracting with Non-accredited Banks for Processing – Kevin Ross Mr. Ross presented the subcommittee’s recommended changes to the Medical Standards as follows: C3. An eye bank performing final distribution shall inform the consignee, in writing, of requirements for tracking and traceability, outcomes and adverse reaction reporting. Compliance with applicable laws, regulations and standards in eye bank functions performed after final distribution is the responsibility of the consignee. 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The product from this step (ornithine) is then hydrolyzed by ornithine aminotransferase (RocD) and -pyrroline-5-carboxylate dehydrogenase (RocA) hypertension 7th purchase micardis 80 mg fast delivery, respectively arteria bologna 8 marzo purchase micardis us, with the production of glutamate (Figure 1) blood pressure top number low purchase 40mg micardis visa. Some bacteria employ this pathway to blood pressure chart jpg 40mg micardis for sale consume arginine and function as the supplier of carbon and/or nitrogen source. For example, if the bacteria also contain the urease system, the byproduct of urea from this pathway could be further catalyzed to ammonia and used as nitrogen source [7]. The genes from the arginase pathway of bacteria and their corresponding products are summarized in Table 1. In addition, their counterparts with similar catabolic function or homologue in mammalian cells (if any) are also listed. For the arginase pathway, arginine is converted into urea and ornithine, which islight salmon). For the arginase pathway, arginine is converted into urea and ornithine, which is subsequently catalyzed into glutamate. The produced ornithine could be transported outside and 2 exchange one molecule of arginine in the cell by the arginine–ornithine antiporter (ArcD) locatedexchange one molecule of arginine in the cell by the arginine–ornithine antiporter (ArcD) located in in the bacterial membrane. Arginine may also be transported by some unknown transporters, whichArginine may also be transported by some unknown transporters, which are shown by the question mark. RocD: ornithine aminotransferase; RocF: arginase; RocA:RocD: ornithine aminotransferase; RocF: arginase; RocA: -pyrroline-5-carboxylate dehydrogenase; ArcC: carbamate kinase; ArcA: arginine deiminase; ArcB:-pyrroline-5-carboxylate dehydrogenase; ArcC: carbamate kinase; ArcA: arginine deiminase; ArcB: ornithine carbamoyltransferase; Pi: inorganic phosphate. Regulation of Arginase Pathway Gene expression can be regulated at different stages including transcription, post-transcription, translation, and post-translation. However, the most generally used mechanism of gene regulation in bacteria lies at the transcriptional level [19], and proper transcriptional regulation is crucial for bacteria to respond to varied environmental niches [20]. The transcriptional regulation occurs by binding to the promoter regions in induction or repression manner [19], which could be mediated by transcription factors, environmental stresses, and some other effectors. The expression of rocR is negatively autoregulated as the N-terminal part of RocR is an intramolecular repressor domain, and deletion of this domain makes the constitutive expression of the roc operons [11,13]. AhrC is a homologous molecule to the arginine transcriptional regulator ArgR in Escherichia coli, which usually binds to the promoter regions of target genes [11,13,22,23]. Similarly, it was shown that AhrC can bind to the promoter region of rocA in a footprinting experiment [22]. Interestingly, it was proposed in another study that AhrC should function by direct protein–protein interaction with RocR [13]. Pathogenic bacteria have developed different strategies targeting arginine for self-preservation. Proposed model for intracellular killing of bacteria by phagocyte and bacterial defenseProposed model for intracellular killing of bacteria by phagocyte and bacterial defense strategies against phagocytosis. Bacteria could be engulfed by a phagocyte into the phagosome (strategies against phagocytosis. The action of arginase on arginine can produce an intermediary spermine, with the help of ornithineThis is used by H. Arginase has also been shown to be involved in bacterial infection caused by Mycobacterium tuberculosisSalmonella-infected macrophages [34]. Arginase has also been shown to be involved in bacterial[35,36], parasitic infection caused by Trypanosoma cruzi [37], and fungal infection caused byinfection caused by Candida albicansMycobacterium tuberculosis[38], implying the critical role of arginase for other infections. Autophagy could recycle limited arginine and prevent apoptosis prevent apoptosis as a survival response in the short term. Instead, in long-term arginineprevent apoptosis as a survival response in the short term. Instead, in long-term arginine prevent apoptosis as a survival response in the short term. The dashed lines (and) means the reactions are dependent on the availability of enzymes (panelavailability of enzymes (panelthe reactions are dependent on the availability of enzymes (panelA) or the reactions have not yet con rmed by experiments (panelA) or the reactions have not yet A) or the reactions have not yetB). Another element of this pathway, an arginine–ornithine antiporter (ArcD) encoding by arcD, could transport ornithine out and exchange a molecule of arginine into the cell (Figure 1) [14,15,18]. Their counterparts with similar catabolic function or homologue in mammalian cells (if any) are also listed. ArgR could be derived from two different protein families: ArgR/AhrC [41–43] and AraC/XylS [9,44,45]. In these bacteria, the expression of arc operon genes is repressed by glucose and the repression is usually mediated by a catabolite control protein A (CcpA) or ArcR, the transcriptional regulators belonging to the Crp/Fnr family [40,56,59], by the binding of regulatory proteins to the cis-acting catabolite response elements (cre) located in the promoter regions [61]. As an important defense strategy in innate immunity, phagocytosis has always been employed by our immune system to initiate the innate immune response and destroy infectious microorganisms [67]. In the process of phagocytosis, bacteria are enclosed in the phagosome [68,69], which would undergo maturation and fuse with the lysosome, to form the phagolysosome [70], where the pH drops as low as 4. Bacteria ingested by phagocytes can be degraded in phagolysosomes in different ways, including proteolytic enzymes like lysozymes, cationic proteins, and production of antimicrobial products [17,75]. Similar strategies have been employed by many pathogenic bacteria to survive within acidi ed phagosomes [80–83]. Arginine Metabolism and Cancer Therapy Disorder of cellular metabolism has been accepted as one of the critical marks for cancer production and expansion [3,4]; this has stimulated research on cancer metabolism and both the basic science and clinical treatment of cancer [3,84]. The metabolic differences between normal cells and tumor cells have provided opportunities for developing novel approaches for the diagnosis and treatment of cancer with higher speci city and lower toxicity than conventional cancer therapies like radiation and chemotherapy [4,85,86]. Of note, it is becoming clear that amino acid metabolic pathways could be chemotherapeutic targets for cancer therapy, as cancer cells need abnormal quantities of varied amino acids for their distinct metabolism to maintain high proliferative rates and resist some cell death signals [87]. Consequently, the deprivation of amino acids needed by cancer cells to survive has been recognized in the eld of cancer therapy for a long time [5], especially for some cancers that are auxotrophic for speci c non-essential amino acids [4,6]. Arginine Deprivation and Cancer Therapy the relationship between arginine and cancer has been recognized for many years [88]. Consequently, arginine deprivation by arginine-degrading enzymes has been used as a therapy for selective tumor cell death while not harming normal cells [89]. This is because the other arginine-degrading enzymes have limitations, such as low af nity with arginine, higher optimal pH, and poor stability [6,85,88]. Arginase I is mainly found in the liver and is considered the more ef cient subtype and used more commonly in research [6]. Compared with the arginase of bacteria, the arginase from human sources has the advantage of low immunogenicity for use in vivo. However, it has been observed to have a low af nity with arginine in vitro [4] and requires a higher pH than physiological conditions for optimal activity (up to 9. In addition, the replacement of Mn2+ with Co2+ in the active site of arginase can reduce the optimal pH of recombinant human arginase (rhArg1) to as low as 7. Recently, other recombinant human arginase (rhArg1-Fc) has been produced by ligating Fc fragment of human IgG1 to arginase I; this greatly increases the half-life, inhibits cell proliferation, and impairs cellular migration of different tumor cell lines both in vitro and in vivo [6,119]. This has been observed to have signi cantly reduced antigenicity, increased half-life [123], and high af nity with arginine (about 300-fold that Int. Because of its ef cacy, it has been widely used in clinical trials for anti-cancer treatment [105,106,125]. It has been demonstrated that arginine depletion in these cells causes nutritional deprivation and consequently induces autophagy, so that application of arginine deprivation enzymes has been undertaken for cancer therapy [5,85,101]. Autophagy is a highly regulated cellular pathway in which the constituents are sequestrated into double-membrane compartments (known as autophagosomes) and fused with lysosomes for degradation [129–131]. This process is the principal catabolic pathway to nutrient starvation [86,89,129,132]. This protective process is an extensively investigated pathway for activating autophagy and can be triggered by arginine depletion [5,85,101]. This is a survival strategy for cancer cells as the limited arginine can be recycled and provide protection for other cells [85]. Apart from autophagy, arginine metabolism was demonstrated to modulate chemosensitivity of cancer cells. Although the signaling pathway responsible for apoptosis is still not clear, it is recognized that the apoptosis induced by arginine deprivation could be activated via caspase-dependent and/or independent pathways [85,102]. Remarkably, the recombinant human arginase (rhArg) treatment restrains the proliferation of mammalian melanoma in vitro and in vivo and causes cell death induced by apoptosis [96]. The reason why rhArg affects cell proliferation is that the rhArg can induce the cell cycle arrest at both of G2/M and S phase. In the early stage of nutrient de ciency, autophagy will be triggered to recycle limited arginine and preserve the tumor cell and this will have an inhibitory effect on apoptosis. However, when the cells undergo arginine depletion for a longer time and autophagy cannot provide arginine anymore, the cells will undergo caspase-independent apoptosis. Conclusions Our recent ndings on the biochemical pathways of arginine metabolism and their regulation in bacteria and cancer cells have not only improved our knowledge of the pathogenesis of bacterial pathogens and cancer metabolism, but may also result in speci c anti-bacterial and anti-cancer therapies. Further work in these areas is warranted to improve our armory of strategies against these two common groups of diseases affecting human health.