REPORT: LOW-DOSE NALTREXONE (LDN)
EFFECT OF LOW-DOSE NALTREXONE (LDN) ON LABORATORY IMMUNE VALUES AND SELF-ASSESSMENT TRACK-SHEETS FOR PHYSIOLOGICAL AND MOOD EFFECTS
PERIOD OF STUDY: 16 WEEKS MARCH – AUGUST 2006
PARTICIPANTS: (20) ASD CHILDREN AND (38) ADULTS (PRIMARILY PARENTS OR OLDER SIBLINGS OF ASD CHILDREN), MARCH – AUGUST 2006
PRIMARY INVESTIGATOR: JAQUELYN McCANDLESS, M.D., PRIVATE PRACTICE, CANOGA PARK, CA AND HONOKAA, HI
CONSULTANT: ARISTO VOJDANI, PHD, DIRECTOR, IMMUNOSCIENCES LAB, BEVERLY HILLS, CA
EARLY INFORMAL ADVISORS ON THE STUDY:
JAAK PANKSEPP, PHD
PAUL SHATTOCK, PHD
STATISTICAL ANALYSIS PROVIDED BY DAVID GAYLOR, PhD,
ASSISTED BY JACK ZIMMERMAN, PhD
SOURCES OF SUPPORT FOR THIS STUDY
LDN TRANSDERMAL CREAM FOR CHILDREN AND CAPSULES FOR ADULTS WERE DONATED BY COASTAL COMPOUNDING PHARMACY, SAVANNAH, GA
PARTICIPANTS PAID FOR DISCOUNTED LAB SERVICES FOR THE IMMUNE TESTING DONATED BY IMMUNOSCIENCES LAB, BEVERLY HILLS, CA
OTHER SOURCES OF SUPPORT: NONE
TABLE OF CONTENTS:
COVER PAGE 1
TABLE OF CONTENTS 2
HISTORY OF NALTREXONE AND AUTISM 3
USE OF LOW-DOSE NALTREXONE (LDN) IN AUTISM 4
DESCRIPTION IMMUNE TESTS 4-6
ADDITIONAL NOTES RE TESTING: MOLLOY’S WORK 6
STATISTICAL APPROACH AND REGULATORY MARKERS 7
AND REGULATORY MARKERS
16-WEEK IMMUNE TEST RESULTS CHILDREN 8-9
SUMMARY IMMUNE TESTS FOR CHILDREN 9-10
16-WEEK TEST RESULTS, IMMUNE TESTING ADULTS 10
SUMMARY IMMUNE TESTS FOR ADULTS 11
DISCUSSION OF LDN STUDY 11
REFERENCES 13
HISTORY OF NALTREXONE AND AUTISM:
NALTREXONE IS AN FDA-APPROVED MEDICATION, A PURE OPIOID ANTAGONIST, AVAILABLE AS THE BRAND NAME RE VIA AS WELL AS IN GENERIC FORM AND USED PRIMARILY FOR TREATING OPIATE AND ALCOHOL ADDICTION SINCE THE 1970’S.
SINCE THE 1970’S, STUDIES HAVE CONSISTENTLY SHOWN A VARIETY OF IMMUNE SYSTEM DISORDERS IN AUTISTIC CHILDREN. (1) INFECTIOUS AGENTS, TOXIC CHEMICALS AND DIETARY PEPTIDES HAVE BEEN SHOWN TO BE TRIGGERS FOR IMMUNE DYSREGULATION AND AUTOIMMUNITY. (2) THE HYPERSENSITIVITY REACTIONS TO THE LARGE PEPTIDES FOUND IN CASEIN AND GLUTEN PRODUCTS BY AUTISTIC CHILDREN INSPIRED RESEARCH INTO THE OPIOID ANTAGONIST NALTREXONE IN HOPES OF AVOIDING RESTRICTIVE DIETS TO PREVENT CASEO-OPIOID AND GLUTEO-OPIOID COMPOUNDS IN THE BRAIN FROM CREATING DELETERIOUS EFFECTS COGNITIVELY AND BEHAVIORALLY. (3a, 3b, 3c) AN ITALIAN STUDY DONE IN 1996 WITH VARYING NALTREXONE DOSING SHOWED SIGNIFICANT REDUCTION OF AUTISTIC BEHAVIORS IN 7 OUT OF 12 CHILDREN. (4) BEHAVIORAL IMPROVEMENT WAS ACCOMPANIED BY ALTERATIONS IN THE DISTRIBUTION OF THE MAJOR LYMPHOCYTE SUBSETS WITH INCREASE IN NORMALIZATION OF THE CD4/CD8 (T/1) RATIO. (5)
NO SIMILAR IMMUNE STUDIES HAVE SINCE BEEN REPORTED ON THE USE OF NALTREXONE IN AUTISM, WHILE A LARGE BODY OF RESEARCH HAS POINTED REPEATEDLY TO ENDOGENOUS OPIOID SECRETIONS AS PLAYING THE CENTRAL ROLE IN THE BENEFICIAL ORCHESTRATION OF THE IMMUNE SYSTEM. (6) OPIOIDS ARE ENDORPHINS AND OPERATE AS CYTOKINES, THE PRINCIPAL COMMUNICATION SIGNALERS OF THE IMMUNE SYSTEM. (7) STUDIES AT UC DAVIS MIND INSTITUTE SHOW THAT CYTOKINE RESPONSES ELICITED BY THE T-CELLS, B-CELLS, AND MACROPHAGE CELL POPULATONS FOLLOWING THEIR ACTIVATION DIFFERS MARKEDLY IN CHILDREN WITH AUTISM COMPARED TO AGE-MATCHED CHILDREN IN THE GENERAL POPULATION. (8)
STUDIES WITH NALTREXONE FOR AUTISM HAVE BEEN EQUIVOCAL, AND SUBJECT TO NON-COMPLIANCE DUE TO THE BITTERNESS OF THE DRUG WHICH HAS POSED A PROBLEM FOR AUTISTIC CHILDREN, MOST OF WHOM COULD NOT SWALLOW CAPSULES.
BERNARD BIHARI, MD, A NEW YORK PHYSICIAN STUDYING THE IMMUNE RESPONSES IN ADDICTED HIV AIDS PATIENTS IN 1985, DISCOVERED THAT AN ULTRA-LOW DOSE OF NALTREXONE BOOSTS THE IMMMUNE SYSTEM WITHOUT SIDE EFFECTS OR TOXICITY. HE FOUND THAT WHEN GIVEN BETWEEN 9PM AND 2 AM THE PITUITARY IS ALERTED AND THE BODY ATTEMPTS TO OVERCOME THE OPIOID BLOCK WITH AN ENDORPHIN ELEVATION, STAYING ELEVATED THROUGHOUT THE NEXT 18 HOURS. (9) RESTORATION OF THE BODY’S NORMAL PRODUCTION OF ENDORPHINS IN THOSE WITH CANCER OR AUTOIMMUNE DISEASES OR ANY DISEASE CHARACTERIZED BY INADEQUATE OR DISORDERED IMMUNITY IS THE MAJOR THERAPEUTIC ACTION OF LDN, WHICH WAS SHOWN TO BE NEEDED ONLY ONCE DAILY AT BEDTIME FOR IMMUNE OPTIMIZATION.
USE OF LOW-DOSE NALTREXONE (LDN) IN AUTISM
I (DR JM) STARTED USING LDN IN A GROUP OF AUTISTIC CHILDREN PLUS A FEW ADULTS WITH OTHER AUTOIMMUNE CONDITIONS IN EARLY 2005 AFTER AN EFFECTIVE TRANSDERMAL CREAM WAS CREATED WHICH COULD BE APPLIED TO THE CHILDREN AT THEIR BEDTIME OR AFTER. DOSES WERE 3MG OF LDN CREAM FOR CHILDREN AND 4.5MG CAPSULES FOR ADULTS PER DR. BIHARI’S DISCOVERY OF THIS WINDOW OF DOSING FOR OPTIMUM IMMUNE BENEFITS.
POSITIVE RESULTS IN THIS PIONEER GROUP AND THE LACK OF SIGNIFICANT SIDE EFFECTS LED ME TO DO A LARGER INFORMAL 16-WEEK STUDY FROM MAR – AUG 2006 WITH 20 AUTISTIC CHILDREN AND 38 ADULTS (ALMOST ALL PARENTS OF ASD CHILDREN).
A PLASMA IMMUNE PANEL WAS PERFORMED AT THE START AND FINISH OF THE STUDY INCLUDING TOTAL WBC’S, T-CELLS, B-CELLS, NATURAL KILLER CELL ACTIVITY, LYMPHOCYTE SUB-POPULATION, AND BRAIN AUTO-ANTIBODIES.
WEEKLY PHYSIOLOGICAL AND MOOD CHILD ASSESSMENTS AND PARENTAL SELF-ASSESSMENTS WERE ALSO NOTED ON TRACKSHEETS THROUGHOUT THE 16-WEEK STUDY PERIOD WITH A NUMBERING SYSTEM FROM 1-10, NEGATIVE EFFECT TO POSITIVE EFFECT, 5 BEING NEUTRAL OR NOT/APPLICABLE.
DESCRIPTION:
IMMUNE TESTS PERFORMED FOR 16-WEEK LDN STUDY, MAR – AUG 06
LAB VALUES LDN STUDY:
TOTAL WHITE COUNT (WBC): THERE ARE 5 KINDS OF WHITE CELLS: NEUTROPHILS, LYMPHOCYTES, MONOCYTES, EOSINOPHILS, AND BASOPHILS. COUNT CAN BE AFFECTED BY GENERAL HEALTH, INFECTIONS (BACTERIAL RAISE THE NEUTROPHIL COUNT, VIRUSES GENERALLY LOWER NEUTROPHILS AND CAN RAISE LYMPHOCYTE COUNT AND STIMULATE IT TO PUT OUT CYTOKINES)
TOTAL T-CELLS: LYMPH CELLS THAT MATURE IN THE THYMUS, CONTROL INNATE CELL-MEDIATED IMMUNE RESPONSES AND ACTIVATE RESPONSES TO MOST ANTIGENS. T-CELLS DEAL WITH VIRUSES AND PATHOGENS THAT REPLICATE INSIDE CELLS WHERE THEY CANNOT BE REACHED BY ANTIBODIES.
TOTAL T-HELPER (CD4+): RECOGNIZE ANTIGENS, PRODUCE CYTOKINES (CHEMICAL MESSENGERS) AND ACTIVATE OTHER T & B CELLS, CONTROL INTRACELLULAR BACTERIAL INFECTIONS BY ATTRACTING MACROPHAGES, LEAD ATTACKS AGAINST INFECTION, CONTROL OTHER CELLS, COUNT DETERMINES PRESENCE OF IMMUNE DEFICIENCIES AND AUTOIMMUNITY; COUNT HELPS GUIDE TREATMENT FOR HIV+AIDS. (STUDIES SHOW ANTI-AIDS DRUGS POTENTIATED BY NALTREXONE). (10)
TOTAL SUPPRESSOR (CD8+) IMMUNITY “BRAKES”, STOP IMMUNE RESPONSE AFTER INVADING PATHOGENS ARE DESTROYED, “KILLER” CELLS SUPPRESSE IMMUNE RESPONSE, ANTI-INFLAMMATORY, CYTOTOXIC (KILLS VIRUSES & CANCER CELLS)
T-HELPER/T-SUPPRESSOR THE RATIO OF CD4+ AND CD8+ SHOULD BE 1-2.5. OVER 2.5 RELATES TO IMMUNE ACTIVATION OR AUTOIMUNITY, LESS THAN ONE RELATES TO IMMUNE SUPPRESSION OR DEFICIENCY. HEAVY METALS AND MYCOTOXINS CAN ALSO SUPPRESS IMMUNE ACTIVITY.
TOTAL NATURAL KILLER LYMPHOCYTES IN INNATE IMMUNE SYSTEM, PROVIDE AGGRESSIVE DEFENSE AGAINST CELLS INFECTED BY MICROORGANISMS, ESP VIRUSES AND CANCER CELLS, TARGET INFECTIONS BOTH INSIDE AND OUTSIDE THE CELL INNATELY WITHOUT HAVING TO BE DIRECTED BY THE CD4+ “HELPER” CELLS; WHEN HIGH USUALLY MEANS VIRUSES.
INCLUDES TOTAL IMMUNOCOMPETENT CELLS (+ CELLS) AND TOTAL NKHT3 (-CELLS).
TOTAL CD3+ CD 26+: MEMORY LYMPHOCYTES, IMPORTANT CELLS, FIGHT TOXIC CHEMICALS, HEAVY METALS, MOLDS AND RELATED MYCOTOXINS, “POLICEMEN”. (THIS IS DPP-1V PEPDIDASE)
IMMUNOREGULATORY CELLS: MAINTAIN HOMEOSTASIS AND
SELF-TOLERANCE
TOTAL CD4+ CD25 (11) : CD4+CD25+ T-REGULATORY CELLS ARE IMPORTANT IN THE MAINTENANCE OF IMMUNOLOGICAL SELF TOLERANCE AND IN THE PREVENTION OF AUTOIMMUNE DISEASE, FIGHT AUTOIMMUNITY, NEED TGF-B & IL-10 CONTACT TO BECOME POTENT SUPPRESSOR CELLS
IL-10 UNSTIMULATED (11): NEUTRALIZE INFLAMMATION, CREATE ANTI-INFLAMMATORY CYTOKINES
IL-10 STIMULATED (11): ANTI-INFLAMMATORY IN RESPONSE TO ANTIGENIC STIMULATION
TGF-BETA 1 UNSTIMULATED (12): IMMUNOSUPPRESSIVE , CREATE
SUPPRESSIVE CYTOKINES
TGF-BETA 1 STIMULATED (12): SUPPRESSIVE TO ANTIGEN
ADDITIONAL NOTES RE CYTOKINES AND DR. CYNTHIA MOLLOY’S RECENT WORK ON IMMUNE SYSTEMS OF AUTISTIC CHILDREN (PLEASE SEE REFERENCE #13, MARCH 06 JOURNAL OF NEUROIMMUNOLOGY)
MOLLOY’S STUDY FOUND THAT IMMUNE CELLS OF CHILDREN WITH
AUTISM PRODUCED HIGHER LEVELS OF BOTH THE TH1 AND TH2
CYTOKINES THAN IN CONTROLS, DEMONSTRATING POTENTIAL
UNDERLYING HYPERSENSITIVITY TO EXPOSURES IN THE GENERAL
ENVIRONMENT FOR ASD CHILDREN. THE MORE HIGHLY ACTIVATED
T1 AND T2 CYTOKINES CONFIRM THE IMMUNE DYSREGULATION
FOUND IN MANY OTHER STUDIES OF ASD CHILDREN, AND CONFIRM
THAT THESE CHILDREN EXHIBIT HYPER SENSITIVITY IN BOTH INNATE
AND ADAPTIVE SYSTEMS. THE EXCEPTION SHE FOUND WAS IN
RELATIVELY LOWER LEVELS OF THE CRITICAL REGULATORY
CYTOKINE, IL-10. DR. MOLLOY SAYS: “MANY PARADOXICAL FINDINGS
THAT HAVE BEEN REPORTED ABOUT IMMUNE RESPONSES IN AUTISM
COULD POSSIBLY BE EXPLAINED BY THE GENERAL DYSFUNCTION OF
IL-10.” SHE IS PLANNING FURTHER STUDIES ON IL-10.
TEST RESULTS FOR 16 WEEK STUDY OF CHILDREN’S IMMUNE SYSTEMS
STATISTICAL APPROACH: THE DATA FROM THE STUDY WAS SUBJECTED TO TWO DIFFERENT KINDS OF ANALYSES: QUANTITATIVE AND QUALITATIVE. THE FORMER INVOLVED TAKING THE RATIOS OF FINAL TO ORIGINAL VALUES USING THE CONVENTIONAL t-TESTS TO SEE IF THESE RATIOS WERE SIGNIFICANTLY GREATER THAN ONE.( WHEN THE DATA EXHIBITED WIDE VARIATIONS, THE LOGS OF THESE RATIOS WERE USED.) THESE QUANTITATIVE TESTS ASSUME THAT INCREASES IN THE MARKERS ARE ALWAYS “GOOD,” WHICH IS OBVIOUSLY NOT THE CASE IF THE MARKER VALUES EXCEEDED THE UPPER LIMIT OF THE NORMAL RANGE.
FOR THIS REASON—AND ALSO BECAUSE THE SCATTER OF THE MARKER DATA WAS USUALLY GREAT FOR THE CHILDREN (MUCH LESS SO FOR THE ADULTS)—WE ALSO USED A SIMPLE BINARY TEST FOR EACH MARKER BASED ON WHETHER IT MOVED IN A “GOOD” OR “BAD” DIRECTION OR MOVED WITHIN OR OUTSIDE OF NORMAL RANGE.. BECAUSE OF THE SMALL SAMPLE SIZE FOR THE CHILDREN AND THE TENDENCY FOR THE DATA TO SCATTER DUE TO ONE OR MORE UNCONTROLLED VARIABLES (INFECTIONS DURING THE SIXTEEN WEEKS, DIETARY INCONSISTENCIES, ETC.), THESE LATTER TESTS ARE TO BE TAKEN AS SUGGESTIVE EVEN WHEN THE SIGNIFICANCE LEVEL WAS 95% OR GREATER. A LARGER SAMPLE SIZE (AT LEAST EQUAL OR GREATER THAN THAT OF THE PARENTS IN THE STUDY) AND GREATER CONTROL OF OTHER VARIABLES AFFECTING THE POPULATION OF CHILDREN ARE CLEARLY NEEDED IN FUTURE STUDIES.
IN WHAT FOLLOWS WE SPEAK OF A MARKER GOING UP OR DOWN OR STAYING ESSENTIALLY THE SAME. THE CRITERION FOR THESE STATEMENTS IS BASED ON THE AMOUNT OF CHANGE RELATIVE TO THE STANDARD DEVIATION OF THE DATA.
REGULATORY MARKERS:
IL-10: IN OUR NON-PLACEBO (AND NON-CONTROLLED) STUDY - THIS MARKER VARIED WIDELY FROM CHILD TO CHILD AND SEVERAL INDIVIDUAL CHILDREN SHOWED WIDE CHANGES DURING THE STUDY, WITH AS MANY CHILDREN RAISING THEIR VALUES AS LOWERING THEM. THE AVERAGE VALUES WERE RATHER LOW RELATIVE TO THE NORMAL IL-10 RANGE, AGREEING WITH MOLLOY’S WORK. THUS IN 16 WEEKS LDN DID NOT SEEM TO HELP THIS IMPORTANT REGULATOR CYTOKINE TO INCREASE; WE AS YET HAVE NO UNDERSTANDING OF THIS. NONE OF THESE CHANGES WERE STATISTICALLY SIGNIFICANT.
TGF-B: THE TGF-B BEGINNING AVERAGE WAS QUITE A LOT HIGHER THAN THE MEDIAN OF THE NORMAL RANGE AND THE AVERAGE FINAL AVERAGE WAS LOWER THAN THE MEDIAN VALUE (ALTHOUGH, AGAIN, THIS CHANGE WAS NOT STATISTICALLY SIGNIFICANT). THIS MAY MEAN THE IMMUNOSUPPRESSIVE EFFECT OF TGF-B WAS LOWERED ON THE AVERAGE BY THE LDN, WHICH COULD BE AN INDICATION THAT AUTOIMMUNITY WAS IMPROVED IN SPITE OF THE IL-10 FINDING, PROBABLY POINTING TO INFLAMMATION STILL BEING SIGNIFICANT IN THIS GROUP. THEIR RELATIONSHIP IS AS YET UNCLEAR.
THE SIGNIFICANCE OF THESE VALUES RELATIVE TO THE USE OF LDN IS DIFFICULT TO UNDERSTAND EXCEPT IN VERY GENERAL TERMS, OTHER THAN TO SAY THAT LDN IN THIS STUDY DID NOT SEEM TO STABILIZE THE LEVEL OF IL-10 REGULATORY BENEFIT FOR INFLAMMATORY ISSUES. 16 WEEKS MAY NOT BE LONG ENOUGH FOR THIS VALUE TO CHANGE – IT IS ALSO DIFFICULT IN ANY CIRCUMSTANCE TO DETERMINE AT WHAT PHASE THE INFLAMMATION REACTION IS IN – THIS WOULD HELP DETERMINE WHETHER IT WOULD BE PREFERABLE FOR INFLAMMATORY MARKERS TO BE INCREASING OR DECREASING.
TOTAL WBC: IN REGARD TO THIS MARKER MOST CHILDREN WERE WITHIN NORMAL RANGE BOTH BEFORE AND AFTER THE TEST. THREE (3) STARTED BELOW RANGE AND FOUR (4) ENDED UP BELOW RANGE, THIS RESULT WAS CLEARLY NOT STATISTICALLY SIGNIFICANT.
TOTAL LYMPHS: MOST CHILDREN WERE WITHIN THE NORMAL RANGE FOR THIS MARKER BOTH BEFORE AND AFTER THE TEST; ONE CHILD STARTED WITH AN ELEVATED VALUE AND ENDED UP WITHIN NORMAL LIMITS; ONE CHILD STARTED WITH NORMAL VALUE AND ENDED UP WITH ELEVATED VALUE. OBVIOUSLY THESE RESULTS WERE NOT STATISTICALLY SIGNIFICANT.
TOTAL NATURAL KILLER CELL LEVEL: FIFTEEN (15) CHILDREN MOVED IN A POSITIVE DIRECTION, THREE (3) IN A NEGATIVE DIRECTION, AND ONE (1) STAYED THE SAME. ALTHOUGH THE t-TESTS FOR THIS MARKER WERE NOT SIGNIFICANT, A SIMPLE BINARY TEST SUGGESTS THAT THE CHILDREN AS A GROUP MOVED IN A POSITIVE DIRECTION WITH A SIGNIFICANCE OF 95%. THE AMOUNT OF MOVEMENT VARIED CONSIDERABLY.
CD3+CD26: RELATIVE TO THE MEDIAN OF THE NORMAL RANGE, ELEVEN (11) CHILDREN MOVED TOWARD A BETTER SCORE, TWO (2) STAYED ESSENTIALLY THE SAME, AND SEVEN (7) MOVED TO A WORSE SCORE. . ALTHOUGH THE QUALITATIVE TEST WAS NOT QUITE SIGNIFICANT FOR THIS MARKER, THE SCATTER OF THE DATA WAS SMALL ENOUGH AND THE IMPROVEMENTS OUTWEIGHED THE LESSENING SCORES QUANTITATIVELY FOR A t-TEST SIGNIFICANCE ON THE 95% LEVEL—THE ONLY SUCH QUANTITATIVE RESULT FOR THE GROUP OF CHILDREN. THIS MEANS WE CAN SAY THAT LDN SIGNIFICANTLY INCREASES THIS MARKER AT THE 95% CONFIDENCE LEVEL. THE AVERAGE INCREASE WAS 23%.
TOTAL T3: ALL CHILDREN REMAINED WITHIN THE NORMAL RANGE BOTH BEFORE AND AFTER THE TEST, WITH ELEVEN (11) INCREASING AND NINE (9) DECREASING (CLEARLY NOT SIGNIFICANT).
TOTAL SUPPRESSOR (CD8+): A MEDIAN OF 900 IS CONSIDERED GOOD; FOURTEEN (14) CHILDREN MOVED IN THE POSITIVE DIRECTION, TWO (2) REMAINED ESSENTIALLY THE SAME, AND FOUR (4 ) MOVED IN A NEGATIVE DIRECTION. ALTHOUGH THE t-TESTS SHOWED NO SIGNIFICANCE, USING A BINARY TEST, THE DIRECTION OF MOVEMENT OR “IMPROVEMENT” FOR THIS MARKER WAS STATISTICALLY SIGNIFICANT ON THE 95% LEVEL.
TOTAL T HELPER (CD4+): THIS MARKER IS A KEY MEASURE OF IMMUNE SYSTEM HEALTH. DR. VOJDANI SAYS THAT IF VALUES STAY WITHIN NORMAL RANGE, THE HIGHER THE BETTER. WE FOUND THAT EIGHTEEN (18) OF THE TWENTY (20) MOVED HIGHER, ONE MOVED LOWER, AND ONE STAYED ESSENTIALLY THE SAME., WE CONCLUDED FROM THE BINARY TEST THAT LDN HAD A SIGNIFICANT POSITIVE EFFECT ON A 99% CONFIDENCE LEVEL. (NOTE: THIS BODES WELL FOR THE UPCOMING HIV+ AIDS STUDY ON LDN IN AFRICA).
CD4/CD8 RATIO (T-HELPER/T-SUPPRESSOR): THE AVERAGE RATIO OF EIGHTEEN (18) POSITIVE CD4+ TO THE 14 POSITIVE CD8+ GAVE A VALUE OF 1.28 FOR THE CD4+CD8+ RATIO, WHICH SHOULD BE BETWEEN 1-2.5. FOUR (4) CD4+CD8+ RATIOS WERE ABNORMAL IN THE BEGINNING (TWO TOO HIGH, TWO TOO LOW); ALL OF THE CD4+/CD8+ RATIOS WERE WITHIN NORMAL LIMITS EXCEPT ONE (TOO HIGH) AT THE END OF THE STUDY; ALTHOUGH THIS RESULT IS ENCOURAGING IT IS NOT SIGNIFICANT ON THE 95% LEVEL.
SUMMARY, CHILDREN: THOSE TESTS SHOWING THE BENEFIT OF LDN WITH STATISTICAL SIGNIFICANCE AT LEAST AT THE 95% LEVEL FOR THE POPULATION OF CHILDREN WERE: