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Keywords:

  • osteomalacia;
  • bone mineralization;
  • vitamin D

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. Acknowledgements
  7. References

We diagnosed Fanconi's syndrome (phosphate depletion and dysfunction of the renal tubules) in three HIV+ patients. This was temporally related to their HIV treatment. Physicians caring for patients with HIV should recognize the association of this rare syndrome with antiretroviral medications and monitor their patients carefully.

Introduction: Fanconi's syndrome is caused by increased excretion of phosphate, glucose, amino acids, and other intermediary metabolites, and can result in osteomalacia.

Materials and Methods: We diagnosed this syndrome in three HIV+ patients.

Results: The first was a 43-year-old woman referred for multiple painful stress fractures. She demonstrated hypophosphatemia, metabolic acidosis, phosphaturia, glucosuria, and generalized aminoaciduria. These abnormalities resolved with oral phosphate replacement and discontinuation of the antiretroviral medication tenofovir. The second patient was a 39-year-old man with hypophosphatemia and bone pain. His symptoms improved with discontinuation of adefovir and supplementation of phosphate, potassium, and calcitriol. The third patient was a 48-year-old man who presented with symptomatic tetany caused by hypocalcemia (total serum calcium of 6.5 mg/dl [8.5–10.5 mg/dl]). Nine months before presentation, he had been treated with cidofovir for retinitis caused by cytomegalovirus. With calcium, phosphate, potassium, and calcitriol therapy, his laboratory abnormalities improved substantially, although he continues to require daily electrolyte replacement.

Conclusions: Each patient demonstrated generalized renal tubular dysfunction temporally related to treatment with antiretroviral drugs. The mechanism responsible for these abnormalities is not known; however, physicians caring for patients with HIV disease should recognize the association of Fanconi's syndrome with antiretroviral medications and monitor susceptible patients to prevent potential skeletal and neuromuscular complications.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. Acknowledgements
  7. References

Fanconi's syndrome results from generalized dysfunction of the proximal renal tubule leading to impaired reabsorption of amino acids, glucose, urate, bicarbonate, and phosphate and increased excretion of these solutes into the urine. The chronic loss of phosphate and the inadequate synthesis of 1,25(OH)2 vitamin D together produce phosphate depletion and failure to mineralize bone properly.(1) The classic clinical features of Fanconi's syndrome include polyuria, dehydration, hypokalemia, hypophosphatemia, metabolic acidosis, and rickets in children or osteomalacia in adults. The electrolyte abnormalities and osteomalacia cause the symptoms of muscle weakness, fatigue, bone pain, and pseudofractures.

Fanconi's syndrome can either be inherited or acquired. Inherited forms occur in a number of genetic disorders such as cystinosis, hereditary fructose intolerance,(2) hepatorenal tyrosinemia,(3) galactosemia,(4) Wilson's disease,(5) Lowe syndrome,(6) and glycogen storage disease type 1.(7) Most of these patients present in childhood. The classic syndrome can also be acquired because of heavy metal exposure,(8) multiple myeloma,(9) and immunologic disorders such as light-chain nephropathy(9) or interstitial nephritis. Acquired Fanconi's syndrome has also been associated with the use of a number of medications including aminoglycosides,(10) valproate,(11) methyl-3-chromone,(12) paraquat,(13)l-lysine,(14) and outdated tetracycline.(15,16) There have been several cases recently reported of Fanconi's syndrome in HIV+ patients treated with antinucleoside antiretrovirals.(17–21)

We report three cases of Fanconi's syndrome in HIV+ individuals without any features of the inherited forms of disease. Interestingly, these patients were treated with different combinations of antiretroviral medications. The first case occurred in a patient treated with the nucleoside analog tenofovir, which has recently been reported to cause Fanconi's syndrome by several different groups.(20,22-24) The second case occurred in a patient treated with adefovir, a closely related compound, which has also been associated with Fanconi's syndrome.(18,19) Although this medication was previously approved for treatment of HIV infection, it is no longer approved for this indication because of the potential for this adverse outcome. The etiology of the last case may be related to prior use of cidofovir, another nucleoside analog associated with Fanconi's syndrome,(17) or secondary to chronic interstitial nephritis. Clearly, an awareness of this complication of antiretroviral medications is critical because the skeletal and metabolic consequences can be severe. Early recognition and aggressive management of Fanconi's syndrome, including discontinuation of the offending medication, should prevent the bone pain, pathological fractures, and symptomatic tetany that can occur in these patients.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. Acknowledgements
  7. References

Patient 1

A 43-year-old HIV+ woman presented to the University of California, San Francisco Endocrinology Clinic for evaluation of osteoporosis and multiple stress fractures. Her past medical history was notable for AIDS, which was diagnosed 9 years before presentation after an episode of pneumonia caused by Pneumocystis carinii. She had also been diagnosed with lymphoma of the left hip 4 years prior and was status postexploratory surgery. She underwent menopause 4 years before presentation with osteoporosis. She had not taken hormone replacement therapy. At the time of evaluation, her antiretroviral treatment included tenofovir, ritonavir, lopinavir, and lamivudine, and she had a stable CD4 count of 360 cells/mm3 (normal range, 517-1677 cells/mm3). Her other medications included acylovir, trimethoprim/sulfamethoxazole, and morphine for the severe bone pain. In the 5 months before presentation, she developed increasingly severe bone pain involving her left foot, left knee, and right hip. The pain had increased such that she could only ambulate with the assistance of a cane. Physical examination revealed tenderness to palpation over the right hip, left knee, and left foot, with mild pitting edema of the left lower extremity. She had no bony deformities, and Chvostek's and Trousseau's signs were negative.

Laboratory data on presentation are shown in Table 1. She demonstrated persistent hypophosphatemia with a phosphate level of 1.8 mg/dl (normal range, 2.2-5.1 mg/dl). In addition, she had a significantly elevated level of alkaline phosphatase (ALP) activity (ALP = 341 U/liter; normal range, 31-110 U/liter), low normal potassium (K+ = 3.6 mM; normal range, 3.4-5.4 mM), and a low normal bicarbonate, suggestive of a mild metabolic acidosis (HCO3 = 22.5 mM; normal range, 17.0-30.6 mM). She had a baseline creatinine level of 1.1 mg/dl (normal range, 0.4-1.1 mg/dl). She had normal calcium (Ca2+ = 9.6 mg/dl; normal range, 8.4-10.3 mg/dl), normal parathyroid hormone (PTH; PTH = 45 pg/ml; normal range, 18-73 pg/ml), and normal vitamin D levels [25(OH) vitamin D = 19 ng/ml; normal range, 9-52 ng/ml; 1,25(OH)2 vitamin D = 41 pg/ml; normal range, 15-60 pg/ml]. Although many patients with Fanconi's syndrome have altered vitamin D metabolism, her 1,25(OH)2 vitamin D level was normal without supplementation. Urinalysis and 24-h urine collections confirmed normoglycemic glucosuria, proteinuria (1.6 g/24 h), phosphate wasting (441 mg/24 h), and generalized aminoaciduria. Her calculated creatinine clearance was reduced at 33 ml/minute. Serum and urine protein electrophoreses were normal.

Table Table 1.. Comparison of Laboratory Values for the Three Patients
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Radiological evaluation included determination of BMD by DXA (Table 2). Lumbar spine BMD (L1-L4) was 0.899 g/cm2 (T-score = −2.3), whereas total hip BMD was 0.631 g/cm2 (T-score = −3.1). MRI of the left foot showed bone marrow edema in the second and third metatarsals. A technetium pertechnetate bone scan showed increased uptake in the left ankle, right femur, and left knee. This was interpreted as compatible with stress fractures. No pseudofractures were seen. An MRI of the hip demonstrated a nondisplaced trabecular fracture of the right femoral head with bone marrow edema. An MRI of the left knee demonstrated stress fractures of the inferior, anterior, and lateral femoral condyles.

Table Table 2.. Comparison of BMD Measurement for the Three Patients
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She was initially treated with potassium and neutral phosphate supplementation and experienced mild improvement in biochemical parameters (see Fig. 1). After discontinuation of tenofovir, several laboratory parameters improved, including phosphorus and potassium. Her bone pain also decreased so that she no longer needed a cane for ambulation, and pain medication requirements decreased dramatically. She was maintained on phosphate replacement for a total of 4 months. She then discontinued her replacement, and her phosphate levels have remained stable over a 6-month period.

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Figure FIG. 1. Changes in laboratory parameters with evaluation and treatment of patient 1. The time of presentation is indicated with vertical dotted line. The time that the tenofovir was discontinued is indicated with a bold arrow. The normal reference range for each laboratory value is indicated with shading.

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Patient 2

A 39-year-old man with a 14-year history of HIV infection was referred to St Luke's Medical Center (Milwaukee, WI, USA) for evaluation of hypophosphatemia and bone pain. He reported severe bone pain in the proximal tibias and ankles over the previous 3 months, which was exacerbated with weight bearing. Medications at the time of evaluation included efavirenz, abacavir, trimethoprim/sulfamethoxazole, nabumetone, paroxetine, neutraphos, and potassium replacement. He had previously been taking adefovir for ∼6 months, but this medication was discontinued 3 months before evaluation. Approximately 2 months before our evaluation, he was started on Neutraphos and KCl for electrolyte abnormalities. In addition, he was treated with calcitriol (0.25 mg/day) for a total of 10 days at 2 months before presentation and again at 1 month before presentation. On physical examination, he had normal muscle strength and tenderness to palpation over the distal femurs, proximal tibias, and dorsal surfaces of his feet.

Analysis of his laboratory data revealed a progressive decline in serum phosphate to a minimum value of 1.6 mg/dl (normal range, 2.5-4.5 mg/dl) and rise in ALP activity from within the normal range to a peak of 201 U/liter (normal range, 38-126 U/liter) over a 6-month period (see Fig. 2). This was accompanied by metabolic acidosis (HCO3 at presentation = 21 mM, with a minimum value of 17 mM; normal range, 23-32 mM) and mild hypokalemia (K+ = 3.1 mM; normal range, 3.5-5.0 mM). Serum calcium was low normal (Ca2+ = 8.6 mg/dl; normal range, 8.4-10.2 mg/dl), and he had a mildly elevated creatinine level of 1.5 mg/dl (normal range, 0.7-1.3 mg/dl; see Table 1). Glucosuria, in the absence of hyperglycemia, was noted after adefovir was discontinued, but urinary amino acid determinations were negative. Initial evaluation included a PTH level that was low normal (PTH = 12 pg/ml; normal range, 10-65 pg/ml). Vitamin D levels were obtained 4 days after stopping calcitriol supplements (0.25 μg/day) and were as follows: 25(OH) vitamin D level was 25 ng/ml (normal range, 9-52 ng/ml) and 1,25(OH)2 vitamin D level was elevated at 72 pg/ml (normal range, 15-60 pg/ml).

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Figure FIG. 2. Laboratory values before presentation for patient 2. The normal reference range is shaded. The time of discontinuation of adefovir is indicated with a bold arrow. The two short courses of calcitriol treatment are indicated with horizontal lines.

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Radiological evaluation included a technetium pertechnetate bone scan that showed increased uptake in both proximal tibias, distal femurs, ankles, and feet compatible with osteomalacia. X-rays of these same areas were negative for bony abnormalities. DXA showed an average lumbar spine BMD of 1.108 g/cm2 (T-score = −0.9) and total hip BMD of 0.952 g/cm2 (T-score = −1.1; see Table 2).

As shown in Fig. 2, his phosphorus and potassium increased, ALP activity decreased, and the metabolic acidosis resolved. He experienced significant improvement in bony symptoms. The phosphate and potassium were tapered and ultimately discontinued 4.5 months after the adefovir was stopped.

Patient 3

The third patient was a 48-year old man who presented to the Emergency Room of the San Francisco Department of Veterans Affairs Medical Center with tetany and muscle cramping. A few days before presentation, he had noted progressive thirst, polyuria, and fatigue. At admission, he complained of perioral numbness, distal upper and lower extremity paresthesias, diffuse muscle pain, and muscle cramping. His past medical history was significant for HIV infection diagnosed 3 years prior, recurrent calcium oxalate stones, an episode of thrombotic thrombocytopenic purpura 2 years prior, which required splenectomy, recurrent deep venous thromboses, and recent onset of renal insufficiency. He had a history of cytomegalovirus retinitis, which was initially treated with cidofovir and then was switched to ganciclovir 9 months before presentation. His medications on admission included didanosine, ritonavir, saquinavir, nevirapine, ganciclovir, and trimethoprim/sulfamethoxazole.

Physical examination revealed a positive Trousseau's and negative Chvostek's sign. He did not have proximal muscle weakness, bone pain, or bony deformities on exam. Laboratory testing showed severe hypocalcemia (Ca2+ = 6.5 mg/day on presentation, with his lowest Ca2+ = 5.7 mg/dl; normal range, 8.5-10.5 mg/dl), with an albumin of 3.2 g/dl (normal range, 3.3-5.2 g/dl) and an ionized Ca2+ of 0.83 mM (normal range, 1.12-1.32 mM). He also had hypophosphatemia (phosphate = 1.8 mg/dl on presentation, with the lowest phosphate = 0.8 mg/dl; normal range, 2.5-4.5 mg/dl), hypokalemia (K+ = 3.1 mg/dl; normal range, 3.5-5.0 mg/dl), and transiently elevated creatinine (creatinine = 1.3 mg/dl on presentation, with a peak creatinine 3 weeks before hospitalization of 3.6 mg/dl; normal range, 0.6-1.4 mg/dl; Table 1; Fig. 3). His urine studies revealed polyuria (>4 liters of urine in 24 h), florid glucosuria with normoglycemia (24.1 g/24 h), and proteinuria (2.6 g/24 h) with normal serum and urine electrophoreses. His creatinine clearance was 74 ml/minute during hospitalization, although his serum creatinine had normalized to 1.1 mg/dl at the time this test was performed. Evaluation included a skeletal survey that revealed no osteopenia, fractures, or pseudofractures. DXA showed an average lumbar spine BMD of 0.946 g/cm2 (T-score = −1.3) and a total hip BMD of 0.866 g/cm2 (T-score = −1.1; Table 2).

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Figure FIG. 3. Laboratory values before, during, and after hospitalization for patient 3. As seen in the middle panel, the time period during hospitalization has been expanded to show the dramatic changes in laboratories during that time period. The pre- and post-hospitalization periods are marked in 100-day increments and time during hospital admission is marked in 5-day increments. Again, the shaded area indicates the normal reference range.

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This patient developed bilateral deep venous thromboses secondary to the antiphospholipid antibody syndrome and required anticoagulation. This prevented renal biopsy so that the cause of his renal insufficiency could not be definitively established. It was thought to be caused by interstitial nephritis secondary to antiretroviral medications; therefore, these therapies were withheld on hospital admission. His severe hypocalcemia was thought to be caused by impaired conversion of 25(OH) vitamin D to 1,25(OH)2 vitamin D, with a subsequent reduction in intestinal calcium absorption. Twenty-four-hour urinary calcium levels were low (<81 mg/24 h), confirming reduced gastrointestinal absorption and/or low dietary intake. Low serum phosphate levels were thought to be caused by reduced 1,25(OH)2 vitamin D levels and renal phosphate wasting. A 24-h urinary phosphate level of 1.64 g, in the presence of hypophosphatemia, indicated a renal phosphate leak. He received aggressive therapy with calcium, potassium, phosphate, and 1,25(OH)2 vitamin D, and his symptoms of tetany and muscle cramping began to improve within the first day of treatment. As shown in Fig. 3, levels of these electrolytes normalized within 1 week of treatment.

His renal failure improved steadily, and serum creatinine returned to the normal range. Antiretroviral medications were restarted, and his CD4 count remained stable. Once his electrolytes normalized with treatment, phosphate and potassium replacement were briefly discontinued. The electrolyte abnormalities returned, and he is currently maintained on daily potassium phosphate and potassium chloride supplements.

RESULTS AND DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. Acknowledgements
  7. References

We report three cases of Fanconi's syndrome in HIV+ patients that likely reflect diverse etiologies. Each patient demonstrated several features of the acquired Fanconi's syndrome including bone pain, stress fractures, electrolyte and mineral abnormalities, and evidence of renal tubular dysfunction. All three patients also had osteopenia at either cortical or trabecular sites. Other than antiretrovirals, none of the patients were taking medications known to cause this syndrome.

Each patient was taking a different combination of antiretroviral medications at the time of presentation. Given the resolution of biochemical abnormalities after discontinuation of tenofovir in the first patient, this agent is the likely cause of her Fanconi's syndrome. Her presentation is similar to that of other recently reported patients who developed Fanconi's syndrome because of tenofovir.(20,22-24) In addition, patient 1 was taking lopinavir and ritonavir, which can increase plasma levels of tenofovir and therefore increase susceptibility to dose-related adverse events.(24) The onset of metabolic abnormalities and skeletal pain in the second patient was temporally related to therapy with adefovir, suggesting that this drug induced his Fanconi's syndrome. The third patient's dramatic metabolic abnormalities did not temporally coincide with changes in his antiretroviral medications. We hypothesize that his metabolic disturbances were secondary either to prior therapy with cidofovir or from renal damage caused by other antiretroviral therapy. Interestingly, two of the three cases had complete reversal of electrolyte abnormalities after the antiretroviral medications were changed; however, the reversal occurred more quickly in the first patient than the second. In contrast, the third patient seems to have permanent Fanconi's syndrome and continues to require electrolyte supplementation 4 years after presentation.

Fanconi's syndrome is characterized by excessive excretion of key solutes leading to multiple electrolyte abnormalities. Our patients all had marked hypophosphatemia and hypokalemia (or low normal serum potassium levels in patient 1). The potassium values are particularly impressive given all patients were on chronic trimethoprim/sulfamethoxazole therapy, which typically raises serum potassium. Only the third patient had symptomatic hypocalcemia that progressed to tetany, indicating a chronic severe form of the syndrome. The low urinary calcium value in this patient suggests poor gastrointestinal absorption caused by insufficient vitamin D, although renal insufficiency and low calcium intake could certainly have contributed to this abnormality. Two of three patients had marked aminoaciduria, and all three had normoglycemic glucosuria. These abnormalities are classically seen in Fanconi's syndrome and are indicative of the underlying renal tubular dysfunction.

Osteomalacia is common in Fanconi's syndrome. Chronic phosphate depletion, acidosis, impaired conversion of 25(OH) vitamin D to 1,25(OH)2 vitamin D, and reductions in intestinal calcium and phosphate absorption are contributors to osteomalacia. These abnormalities result in inadequate mineralization of osteoid.(25) Because our patients did not undergo bone biopsy, we cannot diagnose osteomalacia. It is likely, however, that they had varying degrees of skeletal demineralization. None of our patients had low 1,25(OH)2 vitamin D levels, but all three had elevated ALP activity levels (1.5- to 3-fold above normal). This enzyme is a marker of osteoblastic activity, and levels fell concomitantly with treatment and resolution of phosphate deficiency. The first and second patients presented with bone pain and stress fractures that dominated their presentations, which is typical of osteomalacia. Interestingly, our third patient did not have bony complaints despite his severe hypocalcemia and hypophosphatemia. Finally, DXA confirmed reduced BMD values in all three patients. While this may be because of the accumulation of unmineralized osteoid, one cannot determine this without a biopsy. Patient 1 was postmenopausal; therefore, estrogen deficiency could also be contributing to her osteopenia/osteoporosis.

Patients with Fanconi's syndrome often have underlying renal dysfunction.(26) It is noteworthy that creatinine clearances in patients with proximal tubular dysfunction may not accurately reflect glomerular filtration rates. Patient 3 had renal disease that preceded his development of Fanconi's syndrome and that was likely caused by a drug-induced interstitial nephritis. The renal manifestations of Fanconi's syndrome are distinct from HIV-associated nephropathy, which is characterized by proteinuria and rapidly progressive azotemia.

The pathophysiology of the proximal tubular dysfunction in Fanconi's syndrome has been addressed in studies of experimentally induced maleate or cadmium toxicity. When toxic doses of these agents are administered to rats, their renal tubules show ultrastructural changes caused by the concentration of these drugs in the mitochondria. Mitochondrial ATP levels fall, and Na/K ATPase activity decreases.(25) ATP depletion may alter the activities of several critical transporters causing increased loss of solutes into the urine. Mitochondrial toxicity can manifest clinically with lactic acidosis (caused by hepatic dysfunction) and diabetic ketoacidosis (secondary to pancreatic insufficiency).(27,28) Certain inherited forms of hypoparathyroidism are caused by abnormalities in mitochondrial DNA.(29) Our second patient had an inappropriately low serum PTH value with a low normal total calcium, suggesting parathyroid insufficiency. The PTH level in patient 3 was elevated in response to his severe hypocalcemia, and we hypothesize that his vitamin D insufficiency plus skeletal resistance to PTH and underlying osteomalacia led to an inadequate calcemic response. In other cases of Fanconi's syndrome, PTH levels are reported to be normal or slightly elevated.(21)

The patients in our series were treated with acyclic nucleoside phosphonates (ANPs; cidofovir, adefovir, and tenofovir). These drugs enter the renal proximal tubule through the human renal organic anion transporter 1 (hOAT1).(30,31) When evaluated in Chinese hamster ovary cells expressing hOAT1, all three drugs were transported with similar efficacy into the cells. Expression of hOAT1 enhanced cytotoxicity in the cells treated with cidofovir and adefovir. When the three drugs were compared for cytotoxicity in human renal proximal tubule epithelial cells (RPTECs), the concentrations at which 50% cytotoxicity occurred was 260 μM (cidofovir) and 500 μM (adefovir), yet no signs of inhibition of cell growth were seen with tenofovir with concentrations up to 2 mM.(30) There is evidence that the cause of Fanconi's syndrome due to cidofovir and adefovir is mitochondrial cytopathology.(32,33) However, human hepatoblastoma cells, skeletal muscle cells, and RPTECs treated with tenofovir (3-300 μM) for up to 3 weeks did not show any changes in mitochondrial DNA levels.(34)

We believe the etiology for Fanconi's syndrome in our patients relates to their antiretroviral regimens—tenofovir and adefovir—in the first 2 patients. The third patient's metabolic disturbances could be because of the combination of chronic renal disease and nephrotoxicity, possibly secondary to HIV medications. It is unclear why, if all patients accumulate the drug in the proximal tubule, that only a small percentage of patients experience the renal complications seen in these cases. One possibility is that patients with underlying mitochondiral DNA mutations or polymorphisms are more susceptible to drug-induced mitochondrial toxicity. Fanconi's syndrome is a potential adverse effect of antiretroviral medications, and patients should be monitored for this potential outcome. We propose that patients on these medications undergo regular laboratory testing including serum phosphorus and potassium levels. Urinary studies should include glucose and protein determinations. By regularly monitoring patients for early signs of disease with these simple laboratory evaluations, the devastating outcomes of Fanconi's syndrome may be prevented.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. Acknowledgements
  7. References

This study was supported by National Institutes of Health Institutional National Research Service Award DK07418 and a Department of Veterans Affairs Merit Review. We appreciate Dr Ian Gilson's referral of patient 2.

References

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  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. Acknowledgements
  7. References
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