Birth Defects

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Birth Defects

  1. 1. Birth Defects : Protection Against Environmental Agents by Folic Acid March 29, 2004 Kelly Volcik School of Public Health Human Genetics Center
  2. 2. Birth Defects: Protection by Folic Acid <ul><li>Birth defects </li></ul><ul><ul><li>Causes, types, prevention </li></ul></ul><ul><li>Folate </li></ul><ul><ul><li>Background, biochemistry </li></ul></ul><ul><li>Studies </li></ul><ul><ul><li>Past, present, future </li></ul></ul>
  3. 3. Birth Defects <ul><li>Abnormalities of structure, function, or metabolism present at birth </li></ul><ul><li>Result in physical/mental disability, or are fatal </li></ul><ul><li>Leading cause of death within 1 st year of life </li></ul><ul><li>>4,000 known birth defects </li></ul><ul><li>Occur in 1 / 28 births </li></ul>
  4. 4. What Causes Birth Defects? <ul><li>Genetic and/or environmental factors </li></ul><ul><li>~60 - 70% of birth defects have unknown causes </li></ul>
  5. 5. Genetic Causes of Birth Defects <ul><li>Number and structure of chromosomes </li></ul><ul><li>Missing or abnormal gene </li></ul>
  6. 6. Environmental Causes of Birth Defects <ul><li>Most commonly result of mother’s health and exposure </li></ul><ul><li>Infections </li></ul><ul><ul><li>Rubella, CMV </li></ul></ul><ul><li>Medications </li></ul><ul><ul><li>Accutane, Thalidomide, AEDs </li></ul></ul><ul><li>Drugs/Alcohol </li></ul><ul><li>Chemicals, Radiation, Water contamination, Air Pollution, Heavy metals </li></ul>
  7. 7. Environmental + Genetic Causes of Birth Defects <ul><li>Multifactorial inheritance </li></ul><ul><ul><li>Neural tube defects </li></ul></ul><ul><ul><li>Cleft lip/palate </li></ul></ul><ul><ul><li>Heart defects </li></ul></ul>?
  8. 8. Common Birth Defects: Neural Tube Defects <ul><li>Failure of the neural tube to close </li></ul><ul><li>Occur within 1 st month of pregnancy </li></ul><ul><li>Spina Bifida: spinal column does not completely close around spinal cord </li></ul><ul><li>Anencephaly: incompletely developed or absent brain </li></ul><ul><li>Occur in 1 / 2,000 live births </li></ul><ul><li>Multifactorial inheritance </li></ul>
  9. 9. Common Birth Defects: Cleft Lip/Palate <ul><li>Occur in 1 / 700-1,000 births </li></ul><ul><li>Cleft lip: opening between upper lip and nose </li></ul><ul><li>Cleft palate: opening between roof of mouth and nasal cavity </li></ul><ul><li>Surgically repaired after birth </li></ul><ul><li>Multifactorial inheritance </li></ul>
  10. 10. Common Birth Defects: Heart Defects <ul><li>Abnormal develop of the heart </li></ul><ul><ul><li>Atrial & ventricular septal defects </li></ul></ul><ul><ul><li>Coarctation of the aorta </li></ul></ul><ul><li>Most common: occur in 1 / 100 births </li></ul><ul><li>Multifactorial inheritance </li></ul>
  11. 11. Common Birth Defects Multifactorial Inheritance <ul><li>Cerebral palsy </li></ul><ul><li>Clubfoot </li></ul><ul><li>Renal agenesis </li></ul><ul><li>Hypospadias </li></ul><ul><li>Congenital hernia </li></ul><ul><li>Congenital hip dislocation </li></ul><ul><li>Congenital hypothyroidism </li></ul><ul><li>Gastrointestinal defects </li></ul><ul><li>Congenital deafness </li></ul><ul><li>Musculoskeletal disorders </li></ul>
  12. 12. Can Birth Defects Be Prevented? <ul><li>Pre-pregnancy visit with health care provider </li></ul><ul><ul><li>Family history, medical problems </li></ul></ul><ul><li>Daily multivitamin use </li></ul><ul><ul><li>400 µ g folic acid </li></ul></ul><ul><li>Avoid alcohol, smoking and drugs </li></ul><ul><li>Take only doctor-approved medications </li></ul><ul><ul><li>Prescription, OTC, herbal </li></ul></ul>
  13. 13. Can Birth Defects Be Diagnosed Before Birth? <ul><li>Ultrasound </li></ul><ul><ul><li>Structural defects </li></ul></ul><ul><li>Amniocentesis and Chorionic Villus Sampling </li></ul><ul><li>(CVS) </li></ul><ul><ul><li>Chromosomal abnormalities </li></ul></ul>
  14. 14. Can Birth Defects Be Treated Before Birth? <ul><li>Prenatal therapy </li></ul><ul><ul><li>Inherited disorders of body chemistry </li></ul></ul><ul><li>Prenatal surgery </li></ul><ul><ul><li>Lung tumors, congenital diaphragmatic hernia </li></ul></ul><ul><li>Prenatal blood transfusions </li></ul><ul><ul><li>Rh disease, heart rhythm disturbances </li></ul></ul>
  15. 15. Birth Defects: Protection by Folic Acid <ul><li>Birth defects </li></ul><ul><ul><li>Causes, types, prevention </li></ul></ul><ul><li>Folate </li></ul><ul><ul><li>Background, biochemistry </li></ul></ul><ul><li>Studies </li></ul><ul><ul><li>Past, present, future </li></ul></ul>
  16. 16. What is Folate? <ul><li>Water-soluble B-complex vitamin </li></ul><ul><li>Folate </li></ul><ul><ul><li>Occurs naturally in food </li></ul></ul><ul><ul><li>Polyglutamate </li></ul></ul><ul><li>Folic acid </li></ul><ul><ul><li>Vitamin supplements </li></ul></ul><ul><ul><li>Fortified foods </li></ul></ul>50% absorbed 100% absorbed 85% absorbed
  17. 17. Folate Structure Pteridine Ring Pteroic Acid Glutamic Acid Residues
  18. 18. Folate Derivatives 10-FormylTHF 5-MethylTHF 5,10-MethyleneTHF 5,10-MethenylTHF Tetrahydofolate (THF)
  19. 19. Functions of Folate Biochemistry <ul><li>Folate derivatives carry and transfer various forms of one-carbon (1C) units </li></ul><ul><ul><li>Biosynthesis of nucleic acids and amino acids </li></ul></ul><ul><ul><li>Methylation of DNA, protein, lipids, etc. </li></ul></ul>
  20. 20. Folate Pathway
  21. 21. Folate Pathway
  22. 22. Major Points of Folate Biochemistry <ul><li>Overall effect </li></ul><ul><ul><li>Transfer of 1C units to essential biosynthesis reactions </li></ul></ul><ul><ul><li>Regenerate THF for 1C transfer </li></ul></ul><ul><li>Metabolic regulation </li></ul><ul><ul><li>Ensure appropriate distribution of </li></ul></ul><ul><ul><li>metabolites among pathways </li></ul></ul><ul><ul><li>Prevent accumulation of Hcy & other </li></ul></ul><ul><ul><li>potentially toxic intermediates </li></ul></ul>DNA Synthesis THF Methyl’n Hcy
  23. 23. Folate Transport Mechanisms <ul><li>2 mechanisms transport folates from plasma to cell interior, as well as across the placenta </li></ul><ul><ul><li>Carrier-mediated : RFC1: integral membrane protein; functions during high folate concentrations (passive diffusion) </li></ul></ul><ul><ul><li>Receptor-mediated : FR1&2: membrane-attached folate receptors; crucial for assimilation, distribution & retention of food folates; have high affinity for folate, especially 5-MTHF (active transport) </li></ul></ul>
  24. 24. How Do I Get Folate? <ul><li>Take a multivitamin </li></ul><ul><ul><li>400µg of folic acid </li></ul></ul><ul><li>Eat a healthy diet </li></ul><ul><ul><li>Fruits, green leafy vegetables, beans, corn, peas, bananas, </li></ul></ul><ul><ul><li>orange juice </li></ul></ul><ul><li>Eat fortified cereal and grain products </li></ul><ul><ul><li>Total ® , Special K ® , Product 19 ® </li></ul></ul>
  25. 25. Can You Take Too Much Folate? <ul><li>No known toxic level </li></ul><ul><li>Recommend consuming <1,000 µ g </li></ul><ul><li>May hide diagnosis of vitamin B-12 deficiency </li></ul>
  26. 26. Who is at Risk of Having Low Folate Levels? <ul><li>People with poor eating habits/dieting disorders </li></ul><ul><li>Cigarette smokers </li></ul><ul><li>Alcohol and drug abusers </li></ul><ul><li>Women who use birth control pills </li></ul><ul><li>Genetic variation </li></ul>
  27. 27. Consequences of Folate Deficiency <ul><li>Result of low dietary intake, genetic error of folate metabolism, lifestyle exposures </li></ul><ul><li>DNA Hypomethylation </li></ul><ul><ul><li>Gene overexpression, uncontrolled cell growth, genomic instability </li></ul></ul><ul><li>Hyperhomocysteinemia </li></ul><ul><ul><li>Excessive accumulation of Hcy </li></ul></ul><ul><li>Base Misincorporation </li></ul><ul><ul><li>Decrease in thymine synthesis; replaced by uracil </li></ul></ul><ul><ul><li>DNA strands prone to nicks, breaks and vulnerable to mutagen insertion </li></ul></ul>
  28. 28. Birth Defects: Protection by Folic Acid <ul><li>Birth defects </li></ul><ul><ul><li>Causes, types, prevention </li></ul></ul><ul><li>Folate </li></ul><ul><ul><li>Background, biochemistry </li></ul></ul><ul><li>Studies </li></ul><ul><ul><li>Past, present, future </li></ul></ul>
  29. 29. Folate and Birth Defect Prevention
  30. 30. History of NTDs & Folate Deficiency <ul><li>1976, 1980 : Smithells et al . suggest folic acid deficiency may predispose to NTDs; possible prevention by vitamin supplementation </li></ul><ul><li>1981-1992 : 8 / 9 studies show 50-70% reduction in NTDs with folic acid intake </li></ul><ul><li>1992 : U.S. Public Health Service and National Research Council recommend all women of child-bearing age consume 400 µ g of folate daily to reduce risk of NTDs </li></ul>
  31. 31. History of NTDs & Folate Deficiency <ul><li>March 1996 : FDA authorizes addition of synthetic folic acid to grain products </li></ul><ul><li>January 1998 : FDA makes folic acid fortification mandatory (140 µ g folic acid / 100g product) </li></ul><ul><li>1998 IOM Food and Nutrition Board Folic Acid Recommendations: </li></ul><ul><ul><ul><li>Men (14y +) 400 µ g </li></ul></ul></ul><ul><ul><ul><li>Women (14y +) 400 µg </li></ul></ul></ul><ul><ul><ul><li>Pregnancy 600 µ g </li></ul></ul></ul><ul><ul><ul><li>Previous NTD 4000 µ g </li></ul></ul></ul>
  32. 32. History of NTDs & Folate Deficiency <ul><li>NTD Surveillance and Folic Acid Intervention – Texas-Mexico Border, 1993-1998 </li></ul><ul><li>Anencephaly cluster in Cameron County, Tx </li></ul><ul><ul><li>19.7 / 10,000 live births </li></ul></ul><ul><li>Baseline NTD rate high along Texas-Mexico border </li></ul><ul><ul><li>13.4 / 10,000 live births </li></ul></ul><ul><ul><li>Reflective of large Hispanic population (91%) </li></ul></ul><ul><li>Provide folic acid to high-risk women in 14 border counties </li></ul>
  33. 33. History of NTDs & Folate Deficiency <ul><li>NTD Surveillance and Folic Acid Intervention – Texas-Mexico Border, 1993-1998 </li></ul><ul><li>360 NTD-affected births/terminations </li></ul><ul><li>Enrolled women were provided NTD risk-reduction education/counseling & vitamins/folic acid </li></ul><ul><li>Pregnancy outcomes after folate intervention: </li></ul><ul><ul><li>89% took folic acid before conception </li></ul></ul><ul><ul><li>79% of pregnancies resulted in non-NTD-affected birth </li></ul></ul><ul><ul><li>16% resulted in miscarriage, 4% in elective abortion </li></ul></ul><ul><ul><li>1% resulted in NTD-affected birth </li></ul></ul>
  34. 34. History of NTDs & Folate Deficiency <ul><li>Prevalence of NTDs during transition to mandatory folic acid fortification in the U.S. (2 independent studies) </li></ul><ul><li>Prevalence of SB decreased 23 – 31% </li></ul><ul><li>Prevalence of Anencephaly decreased 11 – 16% </li></ul>
  35. 35. NTDs (Birth Defects) & Folate Genetic Studies <ul><li>Errors of folate metabolism may be involved in the etiology of NTDs (birth defects) </li></ul><ul><li>Role of maternal and/or fetal metabolic error? </li></ul>
  36. 36. Genetic Polymorphisms & Birth Defect Risk <ul><li>Variation in genes encoding enzymes of the folate pathway </li></ul><ul><li>Variation in genes encoding folate transporters </li></ul>
  37. 37. Genetic Polymorphisms Folate Pathway Enzymes <ul><li>MTHFR (C677T) </li></ul><ul><ul><li> risk in moms (up to OR=6.1) & infants (up to OR=7.2) for NTDs </li></ul></ul><ul><ul><li> risk in moms (OR=3.3) & infants (OR=13.4) for NTDs if mom’s folate levels low </li></ul></ul><ul><ul><li> risk in infants for CL/P (OR=2.1) </li></ul></ul><ul><li>MS (A2756G) </li></ul><ul><ul><li> risk in moms (OR=3.1) & infants (OR=3.2) for SB </li></ul></ul><ul><ul><li> risk in moms (OR=3.5) & infants (OR=3.8) for DS </li></ul></ul><ul><li>TS (TSER, 6bp deletion) </li></ul><ul><ul><li> risk in infants (OR=3.6 – 4.7) for SB </li></ul></ul>
  38. 38. Genetic Polymorphisms Folate Transporters <ul><li>RFC1 (A80G) </li></ul><ul><ul><li> risk in moms (OR=2.7) & infants (OR=2.4) for NTDs </li></ul></ul><ul><ul><li> risk in infants (OR=2.1) for heart defects if mom did not take vitamins </li></ul></ul><ul><ul><li> risk in infants (OR=1.6) for heart defects if mom took vitamins </li></ul></ul><ul><li>FRs </li></ul><ul><ul><li>Variants rare </li></ul></ul><ul><ul><li>Genetic variation leading to incorrect functioning may </li></ul></ul><ul><ul><li>result in fetal death </li></ul></ul>
  39. 39. Genetic Polymorphisms Additional Associations <ul><li>Variation in folate pathway enzymes shown to be associated with increased risk of many other diseases </li></ul><ul><li>diabetes </li></ul><ul><li>breast cancer </li></ul><ul><li>colon cancer </li></ul><ul><li>renal disease </li></ul><ul><li>arthritis </li></ul><ul><li>Alzheimer’s </li></ul><ul><li>schizophrenia </li></ul><ul><li>atherosclerosis </li></ul><ul><li>stroke </li></ul><ul><li>coronary artery disease </li></ul>
  40. 40. NTDs (Birth Defects) & Folate Genetic Study Conclusions <ul><li>Cause of most NTDs (birth defects) unknown </li></ul><ul><li>Due to low folate, high homocysteine, both, or other downstream effects? </li></ul><ul><li>Studies have shown folate-related genes to contribute to NTD (birth defect) pathogenesis </li></ul><ul><li>Large-population CDC study suggests folic acid protects against all major birth defects </li></ul>
  41. 41. Environmental Agents & Birth Defect Prevention <ul><li>Obesity and diabetes </li></ul><ul><li>Maternal hyperthermia </li></ul><ul><li>Drug/Alcohol use </li></ul><ul><li>Medications </li></ul><ul><li>Smoking </li></ul><ul><li>Birth defects most commonly result from maternal </li></ul><ul><li>health and exposure </li></ul>
  42. 42. Environmental Agents Obesity & Diabetes <ul><li>Women with BMI ≥ 29 kg/m 2 </li></ul><ul><ul><li> risk for NTDs (OR=1.9) </li></ul></ul><ul><li>Women weighing more than 240 lbs </li></ul><ul><ul><li> risk for NTDs (OR=4.0) </li></ul></ul><ul><li>Women with IDDM </li></ul><ul><ul><li> risk for CNS defects (OR=15.5) </li></ul></ul><ul><ul><li> risk for cardiovascular system defects (OR=18.0) </li></ul></ul><ul><li>* Folic acid loses protective benefit in overweight/obese mothers </li></ul><ul><ul><li>- No reduced risk of NTDs in women weighing >154 lbs </li></ul></ul>
  43. 43. Environmental Agents Hyperthermia <ul><li>Women who had fevers and did not take vitamins </li></ul><ul><ul><li> risk for NTDs (OR=3.1) </li></ul></ul><ul><ul><li> risk for CL/P (OR=2.9) </li></ul></ul><ul><ul><li> risk for limb deficiency defects (OR=2.6) </li></ul></ul><ul><ul><li> risk for heart defects (OR=2.4) </li></ul></ul><ul><li>Women who had fevers and took vitamins </li></ul><ul><ul><li> risk for NTDs (OR=2.3) </li></ul></ul><ul><ul><li> risk for CL/P (OR=1.5) </li></ul></ul><ul><ul><li> risk for limb deficiency defects (OR=2.0) </li></ul></ul><ul><ul><li> risk for heart defects (OR=1.8) </li></ul></ul>
  44. 44. Environmental Agents Drugs/Alcohol <ul><li>Maternal alcohol use </li></ul><ul><ul><li> risk for CL/P, 1-3 drinks/mo (OR=1.5) </li></ul></ul><ul><ul><li> risk for CL/P, 4-10 drinks/mo (OR=3.1) </li></ul></ul><ul><ul><li> risk for CL/P, > 10 drinks/mo (OR=4.7) * vitamin use did not alter results </li></ul></ul><ul><ul><li>Well-established  risk for fetal alcohol syndrome </li></ul></ul><ul><li>Maternal drug use (cocaine, marijuana, ecstacy) </li></ul><ul><ul><li>No definitive reports </li></ul></ul><ul><ul><li> risk heart and renal malformations, stillbirth, SGA </li></ul></ul><ul><ul><li>low birth weight, microcephaly </li></ul></ul>
  45. 45. Environmental Agents Medications <ul><li>Maternal use of AEDs </li></ul><ul><ul><li>2-15x  risk for congenital malformations </li></ul></ul><ul><ul><li>Different AEDs lead to different malformations </li></ul></ul><ul><ul><li>Protective effect of folate dependent upon AEDs </li></ul></ul><ul><ul><li>Suggest women with epilepsy take more folic acid </li></ul></ul><ul><li>Maternal use of corticosteroids </li></ul><ul><ul><li> risk for CL/P (OR=1.3 – 6.6) </li></ul></ul><ul><li>Maternal use of oral contraceptives </li></ul><ul><ul><li> risk for CL/P (OR=1.0 – 1.4) </li></ul></ul><ul><ul><li> risk for congenital urinary tract anomalies (OR=4.8) </li></ul></ul>
  46. 46. Environmental Agents Smoking <ul><li>Clefts </li></ul><ul><li>NTDs </li></ul><ul><li>Clubfoot </li></ul><ul><li>Limb defects </li></ul><ul><li>Mental retardation </li></ul><ul><li>Craniostenosis </li></ul><ul><li>Congenital heart defects </li></ul><ul><li>Urogenital anomalies </li></ul><ul><li>Increased risk associated with multiple malformations </li></ul>
  47. 47. Environmental Agents Smoking <ul><li>Women who smoked and did not take vitamins </li></ul><ul><ul><li> risk for CL/P (OR=2.8) </li></ul></ul><ul><ul><li> risk for heart defects (OR=2.2) </li></ul></ul><ul><ul><li> risk for limb deficiency defects (OR=1.5) </li></ul></ul><ul><li>Women who smoked and took vitamins </li></ul><ul><ul><li> risk for CL/P (OR=1.5) </li></ul></ul><ul><ul><li> risk for heart defects (OR=1.0) </li></ul></ul><ul><ul><li> risk for limb deficiency defects (OR=0.8) </li></ul></ul>
  48. 48. Additional Environmental Agents <ul><li>Water contamination, Air pollution </li></ul><ul><ul><li>Tap water consumption: 3-fold  risk birth defects, 4-fold  risk spontaneous abortion </li></ul></ul><ul><ul><li>Carbon monoxide & ozone: 3-fold  risk heart defects </li></ul></ul><ul><li>Chemicals </li></ul><ul><ul><li>Paint, dry-cleaning chemicals, pesticides </li></ul></ul><ul><ul><li>Organic solvents </li></ul></ul><ul><ul><ul><li>Toluene – found in gasoline, sweeteners, plastics, cigarette smoke </li></ul></ul></ul>
  49. 49. Additional Environmental Agents <ul><li>Heavy metals </li></ul><ul><ul><li>Lead exposure during pregnancy – low birth weight, premature, miscarriage, stillbirth, mental retardation </li></ul></ul><ul><li>Radiation </li></ul><ul><ul><li>X-ray exposure during pregnancy – microcephaly, CL/P, spinal & eye defects, limb deformities, mental retardation </li></ul></ul><ul><ul><li>UV light – photolysis of folate by sunlight;  risk NTDs if mom exposed to UV light from tanning beds </li></ul></ul>
  50. 50. Additional Health Benefits of Folate During Pregnancy <ul><li>Gestational hypertension (preeclampsia) </li></ul><ul><ul><li>Characterized by edema; may indicate detachment of the placenta from the uterus; if untreated, can lead to coma and seizures </li></ul></ul><ul><ul><li>~50% reduction in risk </li></ul></ul><ul><li>Gestational hyperhomocysteinemia </li></ul><ul><ul><li>Increased risk for placental abruption, intrauterine </li></ul></ul><ul><ul><li>fetal death, small for gestational age </li></ul></ul><ul><ul><li>~68% reduction in homocysteine levels </li></ul></ul>
  51. 51. Additional (Potential) Health Benefits of Folate <ul><li>Lowers risk of heart disease and stroke </li></ul><ul><ul><li>Reduces homocysteine levels </li></ul></ul><ul><ul><li>Improves endothelial function & decreases BP in smokers </li></ul></ul><ul><li>Improves mind and mood conditions </li></ul><ul><ul><li>Depression, dementia, memory loss, low mental acuity </li></ul></ul><ul><li>Protects against some forms of cancer </li></ul><ul><ul><li>Colon, lung, cervical, breast </li></ul></ul>
  52. 52. Complex Questions Remain <ul><li>What are the mechanisms of folic acid protection? </li></ul><ul><li>What are the mechanisms of folic acid resistance and how can they be treated? </li></ul><ul><li>What are the downstream/alternate pathways involved in folate/homocysteine metabolism? </li></ul><ul><li>What are optimal fortification/supplement/blood levels? </li></ul><ul><li>How can these data and concepts translate into population screening for prevention? </li></ul>
  53. 53. Birth Defect Prevention Measures <ul><li>Folate supplementation </li></ul><ul><li>Healthy lifestyle </li></ul><ul><li>Genetic counseling; diagnostic testing </li></ul>
  54. 54. References <ul><li>www.modimes.org </li></ul><ul><li>www.cdc.gov </li></ul><ul><li>www.cbdmp.org </li></ul><ul><li>www.sbaa.org </li></ul><ul><li>Barber RC, et al. 1999. Molecular Genetics & Metabolism. 66:1-9. </li></ul><ul><li>Shaw GM, et al. 2002. Epidemiology. 13(6):625-630. </li></ul><ul><li>Lorente C, et al. 2000. American Journal of Public Health. 90(3):415-419. </li></ul><ul><li>Munger RG, et al. 1996. Teratology. 54:27-33. </li></ul><ul><li>Yerby MS. 2003. Neurology. 61:S23-26. </li></ul><ul><li>Shepard TH, et al. 2002. Teratology. 65:153-161. </li></ul>
  55. 55. References <ul><li>McInnes RR, et al. 2002. Clinical Genetics. 61:248-256. </li></ul><ul><li>Werler MM, et al. 1996. JAMA. 275:1089-1092. </li></ul><ul><li>Shaw GM, et al. 1996. JAMA 275:1093-1096. </li></ul><ul><li>Becerra JE, et al. 1990. Pediatrics. 85(1):1-9. </li></ul><ul><li>Shaw GM, et al. 2000. Am Journal of Medical Genetics. 93:188-193. </li></ul><ul><li>Green NS. 2002. Journal of Nutrition. 132:2356S-2360S. </li></ul><ul><li>Williams LF, et al. 2002. Teratology. 66:33-39. </li></ul><ul><li>MMWR Weekly. 2000. 49(1):1-4. </li></ul><ul><li>Plus many more! ☺ </li></ul>

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