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Inborn error of metabolism

Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic diseases, and these terms are considered synonymous. more...

ICF syndrome
Ichthyosis vulgaris
Imperforate anus
Inborn error of metabolism
Incontinentia pigmenti
Infant respiratory...
Infantile spinal muscular...
Infective endocarditis
Inflammatory breast cancer
Inguinal hernia
Interstitial cystitis
Iodine deficiency
Irritable bowel syndrome

The term inborn error of metabolism was coined by a British physician, Archibald Garrod (1857-1936), in the early 20th century. He is known for the "one gene, one enzyme" hypothesis, which arose from his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism was published in 1923.

Major categories of inherited metabolic diseases

Traditionally the inherited metabolic diseases were categorized as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class. Many others do not fall into these categories. ICD-10 codes are provided where available.

  • Disorders of carbohydrate metabolism
    • E.g., glycogen storage disease (E74.0)
  • Disorders of amino acid metabolism
    • E.g., phenylketonuria (E70.0), maple syrup urine disease (E71.0)
  • Disorders of organic acid metabolism
    • E.g., alcaptonuria (E70.2)
  • Disorders of fatty acid oxidation and mitochondrial metabolism
    • E.g., medium chain acyl dehydrogenase deficiency
  • Disorders of porphyrin metabolism
    • E.g., acute intermittent porphyria (E80.2)
  • Disorders of purine or pyrimidine metabolism
    • E.g., Lesch-Nyhan syndrome (E79.1)
  • Disorders of steroid metabolism
    • E.g., congenital adrenal hyperplasia (E25.0)
  • Disorders of mitochondrial function
    • E.g., Kearns-Sayre syndrome (H49.8)
  • Disorders of peroxisomal function
    • E.g., Zellweger syndrome (Q87.8)
  • Lysosomal storage disorders
    • E.g., Gaucher's disease (E75.22)

Manifestations and presentations

Because of the enormous number of these diseases and wide range of systems affected, nearly every "presenting complaint" to a doctor may have a congenital metabolic disease as a possible cause, especially in childhood. The following are examples of potential manifestations affecting each of the major organ systems:

  • Growth failure, failure to thrive, weight loss
  • Ambiguous genitalia, delayed puberty, precocious puberty
  • Developmental delay, seizures, dementia, encephalopathy, stroke
  • Deafness, blindness, pain agnosia
  • Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps
  • Dental abnormalities
  • Immunodeficiency, thrombocytopenia, anemia, enlarged spleen, enlarged lymph nodes
  • Many forms of cancer
  • Recurrent vomiting, diarrhea, abdominal pain
  • Excessive urination, renal failure, dehydration, edema
  • Hypotension, heart failure, enlarged heart, hypertension, myocardial infarction
  • Hepatomegaly, jaundice, liver failure
  • Unusual facial features, congenital malformations
  • Excessive breathing (hyperventilation), respiratory failure
  • Abnormal behavior, depression, psychosis
  • Joint pain, muscle weakness, cramps
  • Hypothyroidism, adrenal insufficiency, hypogonadism, diabetes mellitus


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Allogeneic cell therapy for the treatment of liver disease
From Progress in Transplantation, 6/1/05 by Ludlow, John W

The scarcity of human organs available for transplantation is clearly evident. Efforts to maximize the use of available organs and to increase the number of donors have increased the number of transplantations performed, but at a rate that remains far behind the rate of growth of the waiting list. Thus, the likelihood of a patient with severe liver disease receiving a liver replacement is decreasing. In order to offer treatment to most patients with liver disease, alternatives to whole-organ replacement must be found. Cell-based treatments, in which suspensions of liver cells are injected into patients with liver failure and reconstitute the patient's liver functions, may be that alternative. Here, we report on a regulatory-compliant process for the production of a cryopreserved cell therapy product that yields viable, metabolically active hepatocytes that can be infused directly into patients with the goal of reconstituting liver function. (Progress in Transplantation. 2005;15:178-184)

Liver failure is a serious health problem in the United States and the world. Each year in the United States, an estimated 300000 hospitalizations and 30000 deaths due to chronic liver diseases occur, and severe liver disease affects approximately 100000 people.1 Treatment for patients who have end-stage liver failure has been confined to whole-organ replacement via an organ transplant from a deceased donor or a lobar transplant from a living donor. Although highly successful, liver transplantation will never meet the needs of most people with liver failure because of the great disparity between the number of organs donated and the number needed. According to the Organ Procurement and Transplantation Network, 17504 patients were waiting for a liver transplant in the United States as of June 25, 2004.2 Unfortunately, only 5671 people, approximately one third of those on the waiting list, received a liver transplant in 2003/ In addition, the incidence of chronic liver failure is expected to increase markedly in the next 10 years as a result of hepatitis C. As many as 4 million people are infected with this virus, and estimates sugggest that cirrhosis will develop in 15% of them in the next 10 to 20 years.4

Conceptually, liver cell therapies are an ideal alternative to organ transplantation, because each donated liver can be used to treat many patients, and the surgical procedures are much safer and easier for patients, as well as being much more economical than whole-organ transplantation.4-7 University-based, investigator-sponsored experimental attempts at liver cell therapies are ongoing in about 50 patients. These experiments have made use of adult liver cells as a possible treatment for patients with inborn errors of metabolism,8 patients with fulminant hepatic failure,9 or patients who need a temporary bridge to transplantation.10 The results of these experimental attempts are highly promising. For example, comatose patients with cirrhosis have awakened following infusion of adult liver cells. The effectiveness of the cells was proportional to the number of cells transplanted, because little evidence of growth of transplanted cells was seen.9,11 In another case, a 10-year-old girl with an inborn error of metabolism resulting in Crigler-Najjar syndrome8 received transplanted liver cells that dramatically reduced, but did not eliminate, her need for phototherapy to maintain normal levels of unconjugated bilirubin. Unfortunately, as the patient grew during puberty, the plasma levels of unconjugated bilirubin increased, suggesting that the donor cells did not grow at the same rate as the patient's endogenous liver cells. This resulted in gradual diminution of the contribution of the donor cells.8 Patients with cirrhosis who received transplanted liver cells as a bridge to liver transplantation were more likely to survive until they received an organ transplant than were patients with cirrhosis who were managed with standard medical treatments.7,12 Taken together, these examples clearly demonstrate that liver cell therapies have a promising future in helping to manage patients with liver failure due to any of a number of causes. Although cell therapies are promising, making such therapy available to the greater population of patients is probably not feasible for university-based investigators because the Food and Drug Administration regulates this therapy as a biologic. Under an extensive list in the Code of Federal Regulations, such therapeutic material must be manufactured in a manner compliant with good manufacturing practices. These regulations are in addition to the rules governing the eligibility determination for donors of human cells, tissue, and cellular and tissue-based products.13

Success for cell therapy programs is critically dependent upon the ability to cryopreserve the cells. The difficulty in cryopreserving and recovering viable and functional mature liver cells14-16 is one of the biggest barriers to establishment of programs capable of providing cells for therapy in a timely manner. If the cells cannot be successfully cryopreserved, on a consistent basis, the logistics for obtaining, processing, and delivering cells to recipient patients are at least as difficult as those for organ transplantation. Inability to successfully cryopreserve cellular therapeutic products on a consistent basis will force cell therapy programs to be located only at major medical centers, where cell processing can be done in a setting where the cell product can be delivered shortly after the completion of the isolation process. By contrast, if cells can be cryopreserved, then the cell therapy programs can be expanded to both tertiary medical care centers and to private, small hospitals and the cells can be held in a cryopreserved state until needed and be available on demand. Moreover, the cells can be evaluated with considerable rigor for diseases and quality, and they can be tissue typed and genotyped, if required, for optimal matching of the cells from donors to recipients. With this in mind, the purpose of this study was to develop a method whereby livers rejected for whole-organ transplantation could be processed in a regulatory-compliant manner suitable for the manufacture of human cell therapy products. We report on a regulatory-compliant process resulting in a cryopreserved product that yields a viable population of functional hepatocytes that can be infused directly into patients with the goal of reconstituting liver function.


Isolation of Human Liver Cells

Donated livers not suitable for orthotopic liver transplantation were obtained from federally designated organ procurement organizations. Informed consent was obtained from next of kin for use of the livers for research purposes. All manipulations were performed within a clean-room barrier. The portal vein and/or the hepatic artery are cannulated and the organ perfused with buffer containing ethylene glycol-bis (β-aminoethyl ether) N,N,N',N'-tetraacetic acid for 15 min, followed by digestion with 125 mg/L Liberase (Roche Diagnostics, Indianapolis, Ind), a highly purified form of collagenase, for 30 min at 34°C. Following enzymatic digestion of the organ, the Glisson capsule is serrated and the cells are mechanically separated from the vascular tree. The resulting cell suspension is then passed through filters of pore size 1000, 500, and 150 µm and collected. Live cells are fractionated from dead cells and debris by using density gradient centrifugation in a Cobe 2991 cell washer (Gambro BCT, Lakewood, Colo).

Determination of Viability

An aliquot of the cell suspension is mixed 1:1 with a 0.4% solution of trypan blue prepared in phosphate-buffered isotonic sodium chloride solution (PBS). Cell density is then quantified by counting at least 200 cells on a hemacytometer. Cell viability is then expressed as the percentage of cells excluding trypan blue relative to the total number of cells.


Liver cells are washed 3 times with ice-cold serum-free Dulbecco's Modified Eagle's Medium, pelleted by centrifugation, then resuspended at a concentration of 30 × 10^sup 6^ cells/mL in Cryopreservation solution composed of 80% hypothermosol, 10% human pooled AB serum, and 10% dimethylsulfoxide. The cell suspension is then delivered to 1.5-mL cryovials or cryobags and then immediately placed into the controlled-rate freezer. Our Cryopreservation process uses a computerized controlled-rate freezing device that lowers the temperature 1°C/min to -4°C, then 25°C/min to -40°C, then raises the temperature 15°C/min to -12°C so as to reduce formation of ice crystals, then lowers the temperature 1 °C/min to -40°C, then 10°C/min to -90°C, at which time the frozen cells are transferred to vapor-phase liquid nitrogen storage.

Conversion of Ammonia to Urea

Urea production was measured by using the method of Ostrowska et al.17 Briefly, hepatocytes are incubated at 37°C under an atmosphere of 5% carbon dioxide in air in hormonally defined medium consisting of serum-free Dulbecco's Modified Eagle's Medium, bovine serum albumin, transferrin, free-fatty acids (linoleic acid, palmitic acid, oleic acid, stearic acid), nicotinomide, selenium, 2-mercaptoethanol, L-glutamine, insulin, and hydrocortisone, supplemented with ammonum chloride. Aliquots of the incubation mixtures are removed at 1, 2, 3, and 4 hours, and the cells are pelleted by centrifugation at 4°C. The supernatant medium is assayed for urea nitrogen content by using a commercially available test kit, and the results are reported in nanomoles per 10^sup 6^ cells per hour.

7-Ethoxycoumarin Metabolism Activity

To determine cytochrome P^sub 450^-dependent metabolic function, cells were incubated in hormonally defined medium (37°C, 5% carbon dioxide in air) in the presence of 7-ethoxycoumarin. Aliquots were removed at 0, 0.5, 1, and 2 hours and centrifuged to pellet the cells. The incubation medium (supernatant) was assayed for 7-hydroxycoumarin, 7-hydroxycoumarin glucuronide, and 7-hydroxycoumarin sulfate by using high-performance liquid chromatography.18 Deethylation of 7-cthoxycoumarin is widely used as a substrate to measure cytochrome P^sub 450^, glucuronosyltransferase, and sulfotransferase activities in in vitro liver models. This assay can thus be used to assess coupled phase 1 and phase 2 biotransformation activity. Values are reported as nanomoles per 106 cells per hour.

Flow Cytometric Analyses for Antigenic Markers

For cell surface markers, 1 × 10^sup 6^ cells were pelleted by centrifugation and resuspended in PBS containing fetal bovine serum and sodium azide. The monoclonal antibody of interest directly conjugated with either fluorescein or phycoerythrin was then added, and the cells were incubated for 30 minutes on ice in the dark. Cells were washed twice with PBS, and the final cell pellet was resuspended in paraformaldehyde. As a negative control for each monoclonal antibody, cells were incubated in parallel with an isotype-matched irrelevant monoclonal antibody conjugated with the same fluorochrome. For cytoplasmic markers, cells were pelleted and then fixed in paraformaldehyde in PBS. The cells are then permeabilized by using permeabilization/blocking buffer (PBS containing Triton X-100, goat serum, and teleostean fish gel) for 30 to 60 minutes, pelleted, and resuspended in permeabilization/blocking buffer containing primary antibody. After an overnight incubation, the cells are pelleted, washed twice with Triton buffer (Triton X-100 in PBS), resuspended in secondary antibody in permeabilization/blocking buffer, and incubated for an additional 3 hours. Cells were washed and resuspended in PBS for analysis with the fluorescence-activated cell sorter and FloJo software (TreeStar, San Carlos, Calif).


Cell Viabilities and Yields

Figure 1, left panel, shows a picture of the cell suspension after organ digestion and filtration. In this example, the majority of the recovered cells (74%) are dead, as determined by their uptake of the trypan blue dye. Thus, only 26% of the recovered cells were viable. Fractionation of the live from the dead cells and debris by density gradient centrifugation is performed before sampling for any analyses and cryopreservation. The advantage of using the Cobe 2991 cell washer for such fractionation is that it permits processing of large volumes (600 mL) in a closed environment, which is crucial for maintaining sterility of the cell therapy product. Figure 1, right panel, shows this same cell suspension after fractionation of the live from the dead cells and debris by density gradient centrifugation. Here, 78% of the cells are viable, an approximate 3-fold enrichment in the population of live cells compared with the starting population. Although the majority of the cell population is large hepatocytes, there is a minority of smaller cell types, most likely Kupffer, stellate, and T cells.

Table 1 illustrates the viabilities and yields for 31 livers from different age donors and represents all livers for which all data in the table were obtained. As shown by the column titled total cell number recovered, we can isolate tens of billions of cells from 1 donor organ. Although viabilities vary from organ to organ, in nearly all cases, we are able to enrich the population for viable cells.


Cryopreservation methods have been developed by using adult human liver cells isolated as just described, and these methods have been tested on donor livers experiencing both cold and warm ischemia. The key aspects of these conditions thus resulting in success are the use of a cryopreservative (eg, dimethyl sulfoxide), a medium previously demonstrated to preserve viability of human liver cells at 4°C for extended periods (HypoThermosol, BioLife Solutions, Inc, Binghamton, NY), an exogenous protein source (human AB serum), a controlled-rate freezing process, and storage in a vapor-phase, liquid nitrogen freezer. Table 1 summarizes some of the data on cell viability before and after cryopreservation. Although we can achieve more consistent increases in viabilities after fractionation but before cryopreservation, we observe greater variability in viabilities of donor organs after cryopreservation and thawing. The latter observation is most likely related to a combination of variables, including cold and warm ischemia times, donor age, cause of death, and hospital course of the patient before organ procurement.

Antigenic Characterization

Commercially available monoclonal or polyclonal antibodies and fluorochrome-conjugated secondary antibodies have been used to determine cell phenotypes in our isolated cell population. Analysis was performed by using a fluorescence-activated cell sorter. Further details on the procedure have been described previously.10-12,14 The population of cells that we are recovering from our preparations is made up predominantly of hepatocytes, as defined by reaction with an antibody to albumin, as well as small amounts of macrophages, granulocytes, T cells, and monocytes (Figure 2).

Functional Integrity of Cryopreserved Hepatocytes

A viability determination by trypan blue exclusion is the currently accepted "biological" activity measurement of the hepatocytes used to make a go/no-go decision on whether our cell therapy product can be administered to patients during the currently allowed phase 1 clinical trial. This end point is indicative only of irreversible cell damage and fails to give any indication of the metabolic state of the cells with an intact plasma membrane. More rigorous analyses are needed to more fully evaluate the robustness of the hepatocytes in our product. As such, we have chosen to analyze urea production and 7-ethoxycoumarin metabolism, parameters routinely used to assess hepatic cell function.17-20

Assays yielding the data in Table 2 were performed by using cryopreserved hepatocytes from the 5 livers that were processed entirely in a manner compliant with good manufacturing practices. Urea production results from the metabolism of ammonia and is an inherent function of these cultured liver cells. 7-Ethoxycoumarin, when added to cultured liver cells, induces cytochrome P450 activity, which metabolizes this substrate to 7-hydroxycoumarin, 7-hydroxycoumarin sulfate, and 7-hydroxycoumarin glucuronide. The presence of these metabolites indicates that the cells are metabolically active. At this time, it is not clear if one of these metabolites alone, or in combination, is a better indicator of cell function. Threshold levels of these metabolites have also not yet been established, thus it is not yet possible to do quantitative functional comparisons among different lots. Nonetheless, rates similar to these have been reported elsewhere.17-20 As such, we may conclude from these data that our processing method does indeed result in the production of a cryopreserved cell therapy product that yields viable, metabolically active hepatocytes.


We report on a regulatory-compliant process for the production of a cryopreserved cell therapy product that yields viable, metabolically active hepatocytes that can be infused directly into patients with the goal of reconstituting liver function. The Food and Drug Administration has allowed the initiation of phase 1 clinical trials with this cryopreserved hepatocyte product. It is anticipated that several patients can be treated with the mature hepatocytes processed from just 1 donated organ. The product is a sterile, cryopreserved, dissociated liver cell suspension derived from adult or pediatric human livers from deceased donors.

The manufacturing process does not involve immunoselection or cell expansion. Because the phase 1 portion of the allowed investigational new drug filing has the recipients of this therapy receiving immune suppressors, minor populations of macrophages, granulocytes, T-cells, and monocytes found in the cell product should not increase risk to the patient. Cells will be shipped to the clinical site in qualified vapor-phase liquid nitrogen shippers that maintain a temperature less than -120°C. Before use, the product is removed from the shipper, quickly thawed at 37°C, and using standard, aseptic hospital procedures, diluted 10-fold with cold isotonic sodium chloride solution in the cryobag before administration to the patient. This process precludes the need to wash the cells before infusion and minimizes the risk of compromising sterility. All release testing on the final product, including sterility, will be conducted after thawing. The product will be released on the basis of its viability and cell concentration, characterization by flow cytometry, functionality as reflected in conversion of ammonia to urea, and 7-ethoxycoumarin metabolism.

Second- and third-generation liver cell therapy products that use tissue that is not suitable for whole organ transplantation are already in development. One of these potential therapeutic agents focuses on in vitro expansion of the mature hepatocyte population. Increasing the absolute number of hepatocytes several-fold from the number that is initially recovered would further increase the number of patients who may be treated from a single organ. In preliminary studies, in vitro culturing has resulted in 4 to 6 doublings of the mature hepatocytes, with the expanded cells retaining the morphological and functional characteristics of the original cells. Along this same line of thought, the other potential treatment is centered on expansion and differentiation of hepatic progenitor cells. Having recently identified a marker for these cells and developed the method of isolating these cells (A.T. Bruce, J. W. Ludlow, M. J. Kulik, S. O. Meheux, T. M. Asfeldt, N. Moss, L. M. Reid, M. E. Furth, unpublished data), hepatic progenitor cells are hypothesized to have a much greater expansion potential than mature hepatocytes. In preliminary experiments, in vitro culturing has resulted in at least 7 doublings, with the expanded cells retaining the morphological characteristics of the original cells. Differentiation of these cells into mature hepatocytes would also further increase the number of patients who may be treated from a single organ.


We hold in the highest regard the organ donor families who provided the human livers through which this research was made possible. We thank many organ procurement organizations across the United States and the National Disease Research Interchange for submitting these donated human organs to Vesta Therapeutics. We also thank Drs Lola Reid and Ed LeCluyse for many helpful discussions.

Author Disclosure

All authors are supported by Vesta Therapeutics, Durham, NC, as employees.


1. Digestive Diseases Statistics [National Digestive Diseases Information Clearinghouse Web site]. Available at: Accessed December 2, 2003

2. Organ Procurement and Transplantation Network. Current U.S. Waiting List. June 25, 2004. Available at: http:// Accessed June 29, 2004.

3. Organ Procurement and Transplantation Network. Transplants by Donor Type. June 25, 2004. Available at: Accessed June 29, 2004.

4. Viral Hepatitis C [Centers for Disease Control and Prevention, National Center for Infectious Disease Web site]. Available at: http://www.cdc.goV/ncidod/diseases/hepatitis/c/plan/HCV_infection.htm. Accessed December 2, 2003.

5. Chowdhury J, Chowdhury N, Strom S, Kaufman S, Horslen S, Fox I. Human hepatocyte transplantation:gene therapy and more? Pediatrics. 1997;102:647-648.

6. Runge D, Fleig W, Michalopoulos G, Strom SC, Runge D. Hepatocyte transplantation: possibilities for use and examples of practical clinical application. Dtsch Med Wochenschr. 2000;125:397-400.

7. Strom SC, Chowdhury JR, Fox IJ. Hepatocyte transplantation for the treatment of human disease (review). Semin Liver Dis. 1999;19:39-48.

8. Fox IJ, Chowdhury JR, Kaufman SS, et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med. 1998;338:1422-1426.

9. Bilir BM, Guinette D, Karrer F, et al. Hepatocyte transplantation in acute liver failure. Liver Transplant. 2000;6:41-43.

10. Griffith LG, Wu B, Cima MJ, Powers MJ, Chaignaud B, Vacant! JP. In vitro organogenesis of liver tissue. Ann N Y Acad Sci. 1997;831:382-397.

11. Bilir B, Kumpe D, Krysl J, et al. Hepatocyte transplantation in patients with liver cirrhosis. Digestive Diseases (published conference abstracts). Presented at: American Association for the Study of Liver Diseases, May 16-22. 1998; New Orleans, La. Abstract #LOO56.

12. Strom S, Fisher RA, Thompson MT, et al. Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation. 1997;63:559-569.

13. 69 Federal Register 29785 (2004) (codified at 21 CFR §1271).

14. Ek S, Ringden O, Markling L, et al. Effects of cryopreservation on subsets of fetal liver cells. Bone Marrow Transplant. 1993;11:395-398.

15. Watts P, Grant MH. Cryopreservation of rat hepatocyte monolayer cultures. Hum Exp Toxicol. 1996;15:30-37.

16. Guyomard C, Rialland L, Fremond B, Chesne C, Guillouzo A. Influence of alginate gel entrapment and Cryopreservation on survival and xenobiotic metabolism capacity of rat hepatocyles. Toxicol Appl Pharmacol. 1996;141:349-356.

17. Ostrowska A, Bode DC, Pruss J, Bilir B, Smith GD, Zeisloft S. Investigation of functional and morphological integrity of freshly isolated and cryopreserved hepatocytes. Cell Tissue Bank. 2000;1:55-68.

18. Walsh JS, Patanella JE, Halm KA, Facchine KL. An improved HPLC assay for the assessment of liver slice metabolic viability using 7-ethoxycoumarin. Drug Mefab Dispos. 1995;23:869-874.

19. Sigal SH, Rajvanshi P, Gorla GR, et al. Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events. Am J Physiol. 1999;276:G1260-G1272.

20. Olinga P, Merema M, Hof IH, et al. Effect of human liver source on the functionality of isolated hepatocytes and liver slices. Drug Metab Dispos. 1998;26:5-11.

John W. Ludlow, Andrew T. Bruce, Michael J. Kulik, Sonya O. Meheux, Darell W. McCoy, Thomas M. Asfeldt

Vesta Therapeutics, Durham, NC

Copyright North American Transplant Coordinators Organization Jun 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

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