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Freitag, 27. März 2015 Dr. Ursula Jacob Medical director USA 2012.

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1 Freitag, 27. März 2015 Dr. Ursula Jacob Medical director USA 2012


3 Clinic Dr. Ursula Jacob Silberwaldstrasse 34 D 72280 Dornstetten – Hallwangen Germany Tel: +49 7443 964 240 Fax.: +49 7443 964 24 99

4 Company Overview The clinic has 17 rooms Over 7,000 patients treated, from Europe, Australia and North America. Staff of 4 doctors,12 nurses

5 Indications preventive diagnostics and treatments regenerative treatments oncological diseases hematological diseases metabolic disorders chronic neurological diseases chronic viral diseases

6 Diagnostics Electrocardiogram (at rest and stress) Sonography Pulmonary function test Bone marrow cytology with rapid diagnostic Biopsy under appropriate control

7 Diagnostics Diagnostics in cooperation: X-Ray CT and MRT Bronchoscopy Gastroscopy Colonoscopy Rectoscopy PET (positron-emission-tomography) Scintigraphy Laboratory diagnostics (standard diagnostics, tumour markers, immunology) Chemosensitivity test CTC Test (Circulating Tumour Cells) CFS Test (Chronic Fatigue Syndrome) Pathology Genetic testing

8 Therapies Hyperthermia Immunological therapy Naturopathy Psycho-oncological treatment Nutritional therapy Photopheresis Individual chemotherapy / Immune therapies Regenerative therapy Antiviral therapy Individual preventative treatments Various vaccination therapies


10 History of Cell Therapy Rufus von Ephesus98-117Detection of the human thymus gland Galen130-200Exact description of the thymus Vesalius1543Pictorial illustration of the thymus Felix Platter1536-1614First clinical correlation „thymus death“ Sir Astley Cooper1832A thymus tumor is first described Restelli1845Animal trials Friedleben1858Thymectomy Emil T. Kocher1883„Transplantation“ (1841-1919) J. Wagner-Jaureg, G. Bayer (Hrsg.) 1913Textbook on Organotherapy Elis Sandberg (THX)1938Publication of theoretical studies Aleksandrowicz Miller Neymeyer Pesic Skotnicki (THF)

11 Stem cells 1. Adult stem cells 2. Umbilical stem cells 3. Fetal stem cells 4. Early embryonic stem cells Source: Claustres M et al., Horm Res. 1988; 29: 17-22

12 Stem cells – Differentiation Source: Claustres M et al., Horm Res. 1988; 29: 17-22

13 Stem cells - Type Stem cell typeSourceTissue EmbryonalEmbryoAll cells HematopoieticBone marrow Cord blood Blood cells Brain cells Endothelium NeuronalFetal brain Cord blood Glial cells Blood cells MesenchymalBone marrow Cord blood Muscle, liver, bones, cartilage, endothelium Source: Data on file

14 Stem cells – Characteristics (I) MoleculeFunctionTypically Expressed onComments CD2 Ligand of CD58 (LFA-1) Thymocytes NK-cells, T-cells Lineage marker CD14LPS-RMonocytes, macrophagesLineage marker CD19B-cells, pre-B-cellsLineage marker CD54 ICAM-1 adhesion molecule, binds LFA-1 (CD11a) Antigen-presenting cellsLineage marker CD64FC-y Receptor IMonocytes, macrophagesLineage marker CD94NK-cellsLineage marker CD34 Bone-marrow derived hematopoietic stem cells (HSC) Key marker hematopoietic stem cells Source: Data on file

15 Stem cells – Characteristics (II) MoleculeFunctionTypically Expressed onComments CD38 Pre-B-cells, plasma cells thymocytes, dendritic cells, macrophages Absent on HSC CD45Tyrosine kinaseLeukocyte common antigenLineage marker CD71 Transferrin R, activation marker Activated and most dividing cells CD117 C-kit, stem cell factor Receptor (SCF-R) Hematopoietic stem cells (HSC), hematopoietic progenitor cells mesenchymal stem cells (MSC) CD123IL-3RHematopoietic stem cells Source: Data on file

16 Stem cells – Characteristics (III) MoleculeFunctionTypically Expressed onComments CD133 Early hematopoietic stem cells (HSC), neuronal stem cells, glial stem cells Progenitor marker CD243 Multi drug resistance R (MDR-1) Liver cells, gastrointestinal tract endothelial, brain, adrenal gland Early pluripotent stem cells Ki-67ProliferationProliferating G1 and S phase Alkaline phospha- tase Granulocytes, osteoblasts, mesenchymal stem cells, embryonal stem cells Source: Data on file

17 Stem cells - Stage Source: Data on file

18 Stem cells - Stage Source: Data on file

19 Stem cells - Stage Source: Data on file

20 Stem cells - Stage Source: Data on file

21 Stem cells - Undifferentiated Source: Data on file

22 Stem cells - Therapy Source: Data on file

23 Stem cells - Isolates Abb No 12 Fresh Sample Culture 7d without growth factors Culture 7d with growth factors with /without serum Source: Data on file

24 Stem cells - Isolates Culture 7d Minus/Plus Essential Growth Factors Source: Data on file

25 Patient Case History Patient: male, dob: 1957-06-30 Diagnosis: Secondary Immune Deficiency Syndrome (since birth) (IgM deficiency), (FS Syndrome)  Recurrent zoster infections, (genital, abdominal, face)  Exacerbating since 1999 (3-4 attacks per year)  Increasingly impaired concentration (since 2000)  Increasing fatigue (since 2000)  12/1999: (PNP) Peripheral Polyneuropathy of legs  Arthrosis of left shoulder joint Source: Data on file

26 Patient Case History/Diagnostics Lab results Jan. 2000 EBV-IgG: 112 HSV-IgG: 1:82000 IgM: 29 mg/dl Nov. 2000 EBV-IgG: 80 HSV-IgG: 1:20000 IgM: 35 mg/dl Oct. 2001 EBV: 116 HSV: 1:24000 VIgM: 19 mg/dl CMV-IgG: 1:590 (for the first time positive) Dec. 2002 EBV-IgG: 134 HSV: 1:56000 IgM: 26 mg/dl CMV: 1:230 (normal) May 2006: EBV-IgG: 166 HSV-1gG: 1:32000 CMV: neg. IgM: 21 mg/dl Source: Data on file

27 Patient Case History/Therapy Since 1999: Administration of immune globulin Immune therapy with ▪ Thymus extract ▪ Photopheresis Regenerative therapy with growth factors for ▪ Brain ▪ Nerves ▪ Bones Administation of umbilical cord stem cells 2004 Result: 1) Improved lab results 2) Improved concentration and stamina 3) Fewer infections and zoster attacks Source: Data on file

28 Patient Case History/Results Brain PET: Comparison 07/04 vs 10/05 Reduction of glucose consumption in % related to the max. activity of the cerebral cortex (=100%) RegionRight % of max. activity Left % of max. activity G. orbitales7570 G. front. sup.75 G. cinguli80 G. praecentr.70 G. postcentr.75 Lob. parietalis inf.80 Lob. parietalis. sup.75 G. temp. inf.7075 G. temp. med.8075 G. temp. sup.80 G. occipito-temp. lat.7075 Cerebellum7075 Thalamusmoderate reduction in comparing sides Nucl. lentif.minor reduction in comparing sides Source: Data on file (Report Dr. Hörr, 31.10.2005)

29 Patient Case History/Summary ▪ In comparison with a normal collective (n21) the glucose absorption is reduced by a moderately diffuse rate. A region in the white substance left front is also accentuated. ▪ The maximum glucose absorption of the cortex is reduced with its almost 20 umol/100 g and lies moderately below the standard range of 30 (+/- 5) umol/min/100 g brain tissue as as determined at the Clinic. ▪ Accentuated by nature are the changes described in the chart, in particular in the cerebellum, the ventral polar segments of the temporal lobe, occipitotemporal and high parietal. ▪ In comparison with the previous examination of 19.07.2004 a drastic improvement of the general metabolism to almost twice the glucose consumption is revealed. ▪ The inhomogeneities in particular in the cerebellar and occipitotemporal segment appear to be by far lower than in the previous examination. Source: Data on file

30 T.W.m. 2004 13umol

31 T.W.m. 2005 20umol

32 CFS current diagnosis and therapies Compendium Prof. Dr. Bieger Germany presented by Dr. Ursula Jacob

33 Neuroendokrine Störungen-Tabelle.Bild-2005 CFS Over 80% post-infective Ca. 20% idiopathic Neurodysregulation Fatigue Fibromyalgia Depression Insomnia Cognition IBS Fatigue Subf. temperature Rec. Herpes T-cell defect NOx Inflammation Immune defect

34 Pattern of change in individual symptom factors in participants with (orange) and without (white) post- infective fatigue syndrome. I Hickie et al: BMJ. 2006 333(7568): 575- Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study CFS.Fatigue.Postinfectious-BMJ.08.06

35 Report Male, 23 J. D830-0808, 11.11.05 Diagnosis: Chronic Fatigue EBV-Reactivation B06 x 2 atypEBV-Serologie.Hämochromatose.11.05 

36 Positive staining of B lymphocytes with monoclonal antibodies against EBV antigens EA (A), BZLF1 (B), and VCA (C) by immunostaining with the APAAP technique (original magnification × 1,000). Lytic Replication of Epstein-Barr Virus in the Peripheral Blood: Analysis of Viral Gene Expression in B Lymphocytes During Infectious Mononucleosis and in the Normal Carrier State NS Prang et al: Blood, 89: 1997: pp. 1665-1677 EBV.Infektion.aktiv.Antigennachweis-Prang.1997

37 NK-cell Activity-CFS-Patients.ppt NK-Cell Activity in Different Patient Groups Quelle: IMMUNOSCIENCE LABORATORY INC. NK-CELL ACTIVITY (LYTIC UNITS) 80 70 60 50 40 30 20 10 0 SOLDIERS CONTROL CIVILIAN CONTROL CFS PATIENTS TOXIC CHEMICAL EXPOSURE ALCOHOL INTOXICATION CANCER PATIENTS 78±21 units 41±19 units 13±6 units 10±8 units 8±9 units 6±5 units

38 Neuroendokrine Störungen-Tabelle.Bild-2005 Neuro- endocrine Immun- Dysfunction MCS Restless legs PTSD Parkinson FMS Fibromyalgia Irritable Colon Depression ADS/ ADHS Adiposity Insomnia Burn-Out CFS PMS Menopause Migraine

39 Fibromyalgie.Bildserie.2005 Chronic Fatigue Syndrome, Fibromyalgia, and Multiple Chemical Sensitivities in a Community-Based Sample of Persons With Chronic Fatigue Syndrome-Like Symptoms Psychosomatic Medicine 62:655-663 (2000) Frequency and Percentage of Coexisting Diagnoses for Each Fatigue Status Group. ( ) estimates of previous literature reports. ICF = idiopathic chronic fatigue not meeting full CDS criteria. CF explained = patients with fatigue due to psychiatric or other medical condition. CFSICFCF explained no Fatigue MCS 40,6 %46,7 %43,817 % FM 15,6 % (20 – 70%) 4,4 %6,7 %0 % MCS + FM 3,1 %6,7 %5,6 %O %

40 Occurence of complications in (%) by CFS or in combination CFS with FMS and MCS (Ciccione, 2003)

41 Comparison of the prevalence of abnormal LBT in controls and subjects with IBS and fibromyalgia A link between irritable bowel syndrome and fibromyalgia may be related to findings on lactulose breath testing Annals of the Rheumatic Diseases 2004;63:450-452 Conclusions: An abnormal lactulose breath test is more common in fibromyalgia than IBS. In contrast with IBS, the degree of abnormality on breath test is greater in subjects with fibromyalgia and correlates with somatic pain. Fibromyalgie.Bildserie.2005

42 Stressor - Exposition hypothalamic activation blocked Neuroregulation Modulation caused by : environmental factors / harmful substances, over-training, infections EBV/HHV6-Reactivation ACTH, Substance P HGHC DopamineNoradrenaline GABA Glutamate fatigue, depression pain, cognition appetite, craving sleep, motivation aggression, fear chemical intolerance Inflammation Cytokine activation Virus reactivation, Infection T-cell activation, INK-cell defect Serotonin Modulation caused by: earlier traumatic events neuroplasticity, genetic factors, allergy, inflammation Cortisol Stress.CFS.Stressorexposition.Schema efferent Hyposensitivity CRH

43 CONSUMERS CONCERN ABOUT STRESS & ANXIETY GREAT BRITAIN44 %GERMANY41 % FRANCE42 %USA48 % JAPAN62% Source: Leatherhead Food RA, Health Focus 10-15% OF THE POPULATION SUFFER FROM ANXIETY ILLNESS STRESS AT WORK : A VERY COMMON PROBLEM - a very high cost in terms of workers’ health - absenteeism & lower performance Cost of work-related stress/year: $200 billion worldwide Source: International Labour Office -> European Union : € 20 billion - 40 million workers affected -> United Kingdom : 40 million workdays lost annually -> United States : $ 60 billion - 550 million workdays lost annually Source: Guidance on work-related stress/European Commission/Spice of live or kiss of death Stress-related disorders affect nearly 400 million people worldwide Source: WHO-2000 Worldwide Stress Stress in Deutschland.International-2004

44 ScienceDaily. Retrieved February 19, 2008, Night-time noise from aircraft or traffic can increase a person's blood pressure even if it does not wake them, according to a new study published in the European Heart Journal. Scientists from Imperial College London and other European institutions monitored 140 sleeping volunteers in their homes near London Heathrow and three other major European airports Aircraft noise events caused an average increase in systolic blood pressure of 6.2 mmHg and an average increase in diastolic blood pressure of 7.4 mmHg. Similar increases in blood pressure were seen also for other noise sources such as road traffic Stress.Fluglärm.Blutdruck.Schlaf-SD.02.08 Aircraft Noise Raises Blood Pressure Even While People Are Sleeping, Says Study

45 Wilbert-Lampen U et al. N Engl J Med 2008;358:475-483 The FIFA World Cup 2006 in Germany started on June 9, 2006, and ended on July 9, 2006. The 2006 World Cup matches with German participation are indicated by numbers 1 through 7: match 1, Germany versus Costa Rica; match 2, Germany versus Poland; match 3, Germany versus Ecuador; match 4, Germany versus Sweden; match 5, Germany versus Argentina; match 6, Germany versus Italy; and match 7, Germany versus Portugal (for third-place standing). Match 8 was the final match, Italy versus France Cardiovascular Events during World Cup Soccer Daily Cardiovascular Events in the Study Population from May 1 to July 31 in 2003, 2005, and 2006. Stress.FußballWM.KHK.Herzinfarkte-NEJM.01.08

46 NEURO-REGULATION I Stress hormone axis HPT – AP – ADR Catecholamine – Serotonin – ANS-axis

47 Major components of the central and peripheral stress system Stress Resonse System-Scheme.ppt GP Chrousos J Allergy Clin Immunol 2000, 106:S275-91 Locus ceruleus Noradrenergic system Noradrenaline Arcuate nucleaus Paraventricular nucleus Sympathetic ganglion Dorsal root ganglion CRH AVP POMC Peptides Cortisol ACTH Adrenaline Noradrenaline Pituitary Noradrenaline Neuropeptides Stress system Cholinergic* Serotonergic* GABA/BZD - POMC peptides - The hypothalamic CRH and central noradrenergic neurons mutually innervate and activate each other, although they exert presynaptic autoinhibition through collateral fibers. AVP from the paraventricular nucleus synergizes with CRH on stimulating ACTH secretion. The cholinergic and serotonergic neurotransmitter systems stimulate both components of the central stress system, although the gamma aminobutyric acid / benzo-diazepine (GABA/BZD) and arcuate nucleus proopiomelanocortin (POMC) peptide system inhibit it. The latter is directly activated by the stress system and is important in the enhancement of the analgesia that takes place during stress.

48 SALIVA CORTISOL IN RELATION TO HIGH AND LOW STRESS.ppt Stress Saliva Cortisol.ppt P Björntorp, R Rosmond: Obesity and Cortisol : Nutrition 16: 924-936, 2000 MorningLunchBedtime 15 10 5 0 Salivary Cortisol (ng/ml) Normal Low Stress High Stress Burn-Out Inverted pattern Stress.Burnout-Cortisol.Saliva-Kurven

49 B07 NeuroStress.endDepression.Hypercortisolismus.Therapierefraktär Result: 803-0730 Female 60 J., 31.01.07 Diagnosis Endogenous depression Refractory to therapy– numerous antidepressants without success – significant weight gain, fear, hot flashes, fatigue, elevated blood pressure Hypercortisolism !

50 2650226.pptB08 Burnut.NNR-Schwäche.Frgl. HVL-InsuffizienzResult: 265-0226, 01.02.2008 Female 47 J.DiagnosisBurnOut Hyperthyroidism, maybe anterior pituitary deficiency Diagnostic NeuroStress Profile ADR-Steroid extremely low (ACTH low); NT normal Total Burn-Out !   

51 ACTH, plasma cortisol and salivary cortisol responses in CFS patients over time ACTH, plasma cortisol and salivary cortisol responses over time and integrated endocrine responses (inserted bar graphs) of CFS patients ( or black) and healthy controls ( or gray) in the TSST J Gaab et al: Psychoneuroendocrinology (2005) 30:188-198 Cortisol Saliva Cortisol Plasma ACTH CFS.Stresshormonachse.Inflammation-2005 Saliva Cortisol

52 120 100 80 60 40 20 0 CFS with psych. comorbidity Controls Cortisol (nmol / 24h urine) CFS.Cortisol.24hUrin-01.07 24h urinary cortisol in CFS with and without mental alteration (depression) CFS

53 Stress Chronic Stress Burn-Out Hypocortisolism Depression Hypercortisolism NeuroStress Stress.akut.chron.Schema-04.06 Rapid activation of the HPT-AP-ADR-axis, Cortisol-Noradrenaline/Serotonin increase Chronic hyperactivity of the HPT-AP-ADR- axis, elevated Sympathic tone, genetic disposition Acute Stress CRH-period stimulation CRH-insensitivity Fatigue Hypocortisolism 5HT-Deficit

54 NEURO-REGULATION II HPT – AP – ADR Stress hormone axis CNS-ANS-axis Catecholamine – Serotonin GABA - Glutamate

55 Neurotransmitter Neurotransmitters are the chemicals within the vesicles that synaptically separated neurons utilize for chemical communication

56 The impact of neurotransmittersGABA GLUTAMAT Noradrenaline Serotonin Dopamine anxiety crankiness cognitive function disposition appetite sex aggression motivation happiness power Ergotropic sympathetic guided potency Trophotropic drive Neurotransmitter-Wirkprofile x 2 –04.06

57 CMI Chronic Multisystem Illnesses Serotonin is reduced in about 45 % of FMS-patients Increased dopamine sensitivity Substance P, neuro-peptides highFMSFibromyalgia CFS Chronic Fatigue Syndrome MCS Multiple Chemical Sensitivity Serotonin is low in > 80 % of CFS-patients Hypocortisolism DHEA/S low Serotonin is low in > 70 % of MCS-patients Latent hypocortisolism Substance P elevation/neuroinflammation ?

58 Possible causes of neurotransmitter troubles stress unbalanced diet ambient toxins genetic factors illness (Inflammation)

59 Serotonin.Tryptophan.Lebensmittel.Bildserie.04.08 Some tryptophan-rich foods as example for 100 Gram: Lactalbumin 6900 mg Whey protein 2100 mgEgg 1800 mg Nuts 1000-1800 mg Pears1400 mg Potatoes 1400 mg Cheese 1400 mg Onions 1400 mg bananas, curd, cheese, salmon, turkey, duck, avocado, potatoes Tryptophan

60 Tryptophan Metabolism Tryptophan Kynurenine Quinolinic acid Picolinic acid Serotonin TDO IDO Immune cell Nerve cell Endothelial cell IFN  (IL-12), TNF  /PGE 2, Liver, kidneys astrocytes 5% Neurotoxicity iNOS, NMDA/Glutamate-Agonists Melatonin Bupropion (Zyban, Wellbutrin) SSRI‘s Antioxidants Coxib (iCOX2) Boswellia Kynurenic acid iNOS, NMDA/AchR-Antagonist Neuroprotection Tryptophan Stress/Cortisol Prolactin 95% SSRI‘s Antioxidants Coxib (iCOX2)

61 DOPA - Decarboxylase Tetrahydrobiopterin Folic acid Tryptophan 5-HTP 5-Hydroxytryptophan Vit B6 Serotonin Tph 2 Tryptophan- Hydroxylase 5HTTP 5HT-Transporter MAO Monoaminoxidase 5HTA1,2 5HT-Receptor Genetic!

62 AccuracyGeneSNP 76,3 % Tph2, NR3C1 1, NRC1, NR3C1 2 CRH2 rs1386486, rs1866388, rs6169, rs6188, rs2284217 75,2 %Tph2, NRC1, NR3C1 2, CRH2 rs1386486, rs6169, rs6188, rs2284217 „ Tph2, COMT, NRC1, NR3C1 2 CRH2 rs1386486, rs4633, rs6169, rs6188, rs2284217 „ Tph2, Tph2 2, NR3C1 1, NRC1 CRH2 rs1386486, rs4760750, rs6169, rs6188, rs2284217 CFS. Candidate genes-neurohormoal axis.2006 BN Goertzel et al. Pharmacogenomics (2006) 7: 475-83 Combinations of SNPs in neuroendocrine effector and receptor genes predict CFS The top three genes containing SNPs accounting for the highest accumulated importance were Tph2 (neuronal tryptophan hydroxylase), COMT (catechol-O-methyltransferase, and NR3C1 (nuclear receptor subfamily 3, group C, member 1 glucocorticoid receptor.

63 Serotonin - Biosynthese.ppt Folic acid Tryptophan 5-HTP 5-Hydroxytryptophan Vit B6 Tryptophan- Hydroxylase Serotonin 5-HAT/5-Hydroxytryptamine Melatonin Kynurenine N-Acetylserotonin IDO Indolamine-2,3-Dioxigenase  -Interferon 5-HIES 5-Hydroxyindol- acetic acid Up to 95% 1-10% Nicotinic acid Vit B3 NAD/NADH > 90% Protein synthesis 5-90% *very low levels of B-6 required so when B-6 is low this step goes first resulting in increased amounts of xanthurenic acid Inflammation !


65 Cytokine characteristics in CMI Zytokincharakteristika bei CMI MCSCFS FM TNF-α (-) + IL-1 (-) + ++ IL-6 + + IL-8 ++ ++ IL-2 (+) IFN-gamma +++ -/+ IL-10 +(+) - - Patarca R: Cytokines and Chronic Fatigue Syndrome. Ann N.Y Acad Sci 2002: 185-200 Wallace DJ et al: Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study. Rheumatology 40: 743-749, 2001 Mayer WR, Bartram F, Bieger WP: MCS- Eine chronische Entzündung? Z Umweltmedizin 10: 88 – 96, 2002 CMI = Chronic Multisystem Illness

66 anorexia increased appetite nausea agitation fatigue/exhaustion emotion insomnia added sleep pain analgesia headache, migraine no pain subfebrile temperature no fevermetabolic activation (catecholamine, CRF), normalising (glucocorticoid inhibition) inflammatory reaction relaxed acute phase reaction IL-1, IFN-gamma, TNF-alpha, PGE2 Sickness-Stressreaktion.ppt Abnormal stress Normal reaction stress reaction

67 Oxidants, harmful substances Cytokines IL1, IL6, TNFa ROS NF  B IBIB UV-light rays Gene-activating Viruses and germs Acute Stress Noradrenaline NFATAP-1 5-LOX Inflammation Cytokines IL1  IL8, TNF  IL6 Arachidonic Acid Phospholipase A2 ROS COX2 COX1 iNOS ONOO Chronic Stress Adrenaline

68 Nitric Oxide Synthesis Arginine + O 2 NO + Citrulline  NO 2  + NO 3  NOS eNOS nNOS mtNOS iNOS Arginine succinate

69 Der mitochondriale Energiestoffwechsel besteht aus Pyruvatoxidation (PDHC), ß-Oxidation der Fettsäuren, Zitratzyklus und vor allem der oxidativen Phosphorylierung. Gebildete Redoxäquivalente (NADH, FADH2) werden in der Atmungskette mit molekularem Sauerstoff (O2) zu Wasser umgesetzt. Dabei freigesetzte Energie wird vom Komplex V zur Synthese des universellen Energieträgers Adenosintriphosphat (ATP) verwendet. So werden in den Mitochondrien über 90% des Energiebedarfs des Körpers bereit gestellt. Mitochondria are the fountain of energy for the body Mirochondrien.Enerhgiestoffwechsel.2005

70 BE Neurostress.KKT.Atlas. BHS.S100.NoTyrosin.2005 Result Female, 57 J. VS D830 0668 25.7.2005 2-2 Treatment: Fresh cell extracts (adrenal), Micronutrients including: OPC, carnitine, alpha-lipoic acid, curcumin, omega-3    Diagnosis: Whiplash injury Fatigue EBV-reactivation, Anxiety disorder

71 BE Neurostress.KKT.Atlas. BHS.S100.NoTyrosin.2005 Page 2 Treatments: Fresh cell extract (adrenal/thymus) Micronutrients including: OPC, carnitine, alpha-lipoic acid, curcumin, omega-3    S-100 18,6 NSE 33

72 FATIGUE – DIAGNOSTIC I. NeuroStress Cortisol 8, 12, 20 hrs ; DHEAS 8, 20 hrs Catecholamine (Adrenaline, Noradrenaline, Dopamine), Serotonin,GABA, Glutamat e Glycine, Taurine, Glutamine, TSH, ACTH, Prolactin II. Inflammation CRPs, NF-kB, MPO Cytokine ( IL-6, IL-1ß; TNF-alpha, sIL2R, IFN-gamma) ITT® Immuntoleranztest (IL 2, IL 10, INF- ,TNF-  ) III. Neuro-inflammation S-100, NSE, alpha-Crystalline Nitrotyrosine, Citrulline III. Micronutrient Glutathione cellulär, CoQ10, Homocysteine ( B12, Folate ), Vitamin B6 Zinc, Selenium, Ferritin, Magnesium, Vitamin D CMI.CFS.FMS-Diagnsotik.Therapie.Schema-06.08

73 CFS – diagnostic ladder Grade I Cortisol 8, 12, 20 hrs ; DHEAS 8, 20 hrs Catecholamine (Adrenaline, Noradrenaline, Dopamine) Serotonin,GABA, Glutamate Grade II ITT ©, EBV (RNA/DNA), Borrelia-Ab NF-kB, Cytokine: CRPs, TNF ,IFN  GSH, Hocy, Vit B6, Q10, Vit D, TSH, Ferritin Grade IV Nitrotyrosine, S-100, Zn (E), Se (E), Mg (E) ACTH, Prolactin, Testosterone Immune status Grade III HHV6 (DNA), CMV-Ab,NK-Check ANA, IgG, IgA, IgM, IgE CMI.CFS.FMS-Diagnsotik.Therapie.Schema-06.08

74 Pivotal neurotransmitter concept Inhibition AS-Therapie.Inhib.Excit-Konzept-04.06 (GABA, Serotonin, Glycine, Theanine) Rearrangement of the balance between Excitation (Adrenaline, Noradrenaline, Glutamate, Histamine)

75 Amino acid - Support Amino acids/Neurotransmitters Tyrosine (N-Acetyl-Tyrosine, Phenylalanine) 5-HTP (Tryptophan), Glycine, Glutamine, Mucuna (DOPA) Modulators Taurine, Theanine, NAC, EGCG, Rhodiola Cofactors Vit C, Vit B6, Folic acid, Vit B12, Selenium, Calcium, Magnesium, SAMe, Cysteine, Tocotrienol

76 5-HTP Immediate Serotonin-precursor No regulatory feedback-inhibition (Tph 2) Well absorbed in the intestinal tract Free passage through the blood brain barrier Dose-constrained serotonin elevation Boosts stress hormone axis (Cortisol) No immunsuppression (Trp  Kynurenin building) No neurotoxicity (Trp  Chinolinic acid) Dosage: 50-800 mg / day NeuroStress.AS-Therapie.Wirkstoffe x 35-09.06

77 GABA (Gamma Aminobutyric acid) GABA-Rezeptor.Regulation.Schemata-2007 Taurine GABA-receptor modulation ++ Neuroprotective, blocks Glutamate toxicity Glutamine GABA-synthesis 5-HT(P) stimulation of GABA-activity 5-HT is necessary for GABA function Theanine increase GABA effect promote GABA synthesis Rhodiola Excitatory in low doses, inhibitory in high doses Progesterone increase GABA-effect ++ Neuroprotective (allo- Pregnanolone) Barbiturate promoteGABA-effect Melatonin increase GABA-binding Benzodiazepine Locked on GABA-Receptor, high affinity

78 FATIGUE -THERAPY Level I Indiv. micronutrients 5-HTP 100 mg Taurine 150 mg Theanine 50 mg NAC 110 mg plus: Vit B6, B12, Vit C, Folic acid, Mg, Zn, Se Level II Indiv. micronutrients 5-HTP 200 mg Tyrosine1200 mg NAC 200 mg Theanine 136 mg plus: Vit B6, Vit C, Folic acid, Calcium Or Indiv. micronutrients 5-HTP 50 mg Tyrosine 50 mg Glutamine 350 mg Taurine 250 mg Theanine 75 mg plus: Vit B6, Vit C, Folic acid, Tocopherol, Mg CMI.CFS.FMS-Diagnsotik.Therapie.Schema-06.08

79 Melatonin is produced in darkness from Serotonin via N- Acetylserotonin in the pineal glad Neuronal Antioxidant – in reduced and in oxidised form Potentiates GABA-Receptor building Operates as sedative Operates to promote sleep Antagonist of Glutamate and Chinolinic acid (Trp-KYN- Metabolite) Operates as an anticonvulsant Melatonin Neuroprotection


81 Patient: C.J. (04/13/44) m. Diagnosis: CFS following drug abuse over 20 years, Osteopenia, Lack of concentration Therapy: Fresh cell extracts ( thymus, cerebrum, gut ) Detox

82 Patient: C,J (04/13/44) m. 26.03.200827.10.2008

83 Patient: M.J. (12/11/62) f. Diagnosis: Coma for 4 months following accident Meningitis, Adrenal dysfunction Therapy: Fresh cell extracts (brain, adrenal, gut, cartilage) Hormone balance

84 Patient: M,J (11.12.62) 05.11.200820.11.2007

85 Patient: M,J (11.12.62) 05.11.200822.09.2009

86 Patient: H.G. (01/08/64) m. Diagnosis: Hemochromatosis Heavy metal intoxication Diabetes - Type II Therapy: Fresh cell extracts (adrenal, pancreas, liver, thymus) Detox

87 Patient: H.G. (08/01/64) m. 19.09.2008

88 Patient: H.G. (08/01/64) m. 10.12.2009

89 Patient: H.G. (08/01/64) m. 17.03.2010

90 Patient: H.G. (08/01/64) m. 04.05.201017.03.2010

91 Patient: F-K.G. (09/03/39) f. Diagnosis: Multiple Sclerosis, Irritable bowel syndrome CFS Therapy: Fresh cell extracts (nerve, brain, gut, adrenal, thymus) Physiotherapy

92 Patient: F-K.G (09/03/39) f. 15.11.2007

93 Patient: F-K.G (09/03/39) f. 15.11.2007 09.01.2008

94 Patient: F-K.G (09/03/39) f. 09.01.200831.01.2008

95 Patient: F-K.G (09/03/39) f. 31.01.200831.07.2008

96 Patient: F-K.G (09/03/39) f. 09.01.200931.07.2008

97 Patient: G.U. (08/19/54) f. Diagnosis: Heavy metal intoxication CFS Hormonal imbalance Therapy: Fresh cell extracts (ovary, adrenal, thymus) Detox

98 Patient: G.U. (08/19/54) f. 17.12.2007 05.06.2008

99 Patient: G.U. (08/19/54) f. 01.12.2008 05.06.2008

100 Patient: G.U. (08/19/54) f. 01.12.200815.12.2009

101 I hope you didn’t fall asleep… Thank you very much for your kind attention!

102 Freitag, 27. März 2015 privat clinic Dr. Ursula Jacob Silberwaldstraße 34 72280 Dornstetten-Hallwangen Tel.: +49 (0) 7443 – 964 24 – Fax: +49 (0) 7443 – 964 24 – 99

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