General principles of therapeutic application

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Fetal precursor cell transplantation is not a ‘magic bullet’ that will cure all ills. For the best results the patients have to be selected. The selection criteria described in this text are based on the clinical experience with fetal precursor cell transplantation of the author, that was initially based on the study of the same references presented in this text, and discussions with authors of references, if possible.

Diagnostic procedures do not differ from those used by the contemporary medicine, but the evaluation of data is different. Fetal cell transplantologist must look at the patient as ‘pathophysiologist’, i.e. get a complete clinical picture of the function, and malfunction, of every organ system individually and of the whole body and comprehend the pathophysiology of all diseases a patient suffers from on a cytological level, something that no physician alive ever studied and learned in medical school. Traditional diagnoses, particularly those that serve more as ‘labels’ for administrative purposes, are of limited value in the field of fetal precursor cell transplantation.

It is not diffficult to become a master of pathophysiologic diagnosis, just go back to your medical school textbooks on pathophysiology. What is difficult is to understand all that like a ‘pathophysiological cytologist’.

Once you mastered the art of pathophysiologic diagnosis on cytological level it becomes easy to select the appropriate fetal precursor cell transplants to be used for the treatment of your patient.

The author has always practiced the pathophysiologic approach to fetal precursor cell transplantation, i.e. patient receives fetal precursor cell transplants of all those organs or tissues required by the pathophysiologic diagnosis.

The current trend in the U.S., which has not gained much ground in the rest of the world, to treat by transplantation of hematopietic stem cells, or ‘universal somatic stem cells’, all diseases known to medicine, has not proven its value. Some patients have been treated by transplantation of hematopietic stem cells, or by transplantation of umbilical cord blood stem cell transplantation, i.e. ‘mono-therapy’, while over 5 million patients have been treated by the pathophysiologic approach to fetal precursor cell transplantation, i.e. ’poly-therapy’, over the period of 70+ years. (See additional discussion of this topic in the chapter ‘Mono- vs.poly-therapy by fetal precursor cell xeno-transplantation’).

We define fetal precursor cell transplantation as a surgical procedure, individualized for each patient in terms of selection of fetal precursor cell transplants in accordance with the pathophysiologic analysis of the malfunction of all organs and tissues of the patient, details of preparation, dosage, and mode of implantation of fetal precursor cell transplants. It has been not only the German school but also Russian school that call for ‘polytherapy’. It is easier to prescribe for every single patient the transplantation of hematopoietic stem cells or of umbilical cord blood hematopietic stem cells. Transplantation of fetal precursor cells of any and all damaged organs or tissues requires a careful and detailed diagnosis and in-depth knowledge of pathophysiology, applied to a specific patient. In the hands of a specialist it is a very powerful therapeutic tool, that becomes a waste if used without a proper knowledge.

The first step is to list all abnormalities uncovered during the diagnostic process indeed. But the next step requires a preliminary logical analysis of the causative associations between various dysfunctions. The more knowledgeable and experienced is the transplantologist the more detailed and treatment oriented will be his pathophysiological analysis. Everyone is familiar with the complicated scheme of relationships between various endocrine organs and their regulatory centers. Similar relationships of one-way or mutual synergism, or of antagonism, exist between pairs of organs or groups of organs and tissues, but they become apparent only when the overall functional balance is disturbed.

Based on clinical experience the more frequent dysfunctional relationships between pairs of organs are for example those between liver and adrenal cortex, liver and adrenal medulla, thyroid and anterior lobe of pituitary, parathyroid and thyroid, etc. It has been observed that some organs are of key importance in analysis of pathophysiological relationships, i.e. thyroid, liver, adrenal cortex, sex glands. VI.BIBLIOGRAPHY [328]

Recommendations of fetal precursor cell transplants to be used for the treatment of a certain disease that you find in this text should be taken only as guidelines; they should not inhibit your clinical acumen and analytic abilities. After all our profession is driven by a success in helping our patients.

Additional points for the selection of fetal precursor cell transplants to be used for an individual patient.

1/ Any chronic disease disrupts the metabolic balance of an organism and the selection of fetal precursor cell transplants must include cell types that restore such balance.

2/ A hypofunction of any organ or tissue should be treated by fetal precursor cell transplants of the same organ or tissue, while hyperfunction of an organ or tissue requires either fetal precursor cell transplants of an antagonistic organ(s) or no cell transplants at all.

3/ For a regeneration of function of damaged organ the fetal cell transplants of the same organ alone are often not sufficient but fetal precursor cell transplants of the synergistic organs or tissues must be added. VI.BIBLIOGRAPHY [328]

The difficult part of fetal precursor cell transplantation takes place in the manufacturing laboratory, i.e. the patient does not see or experience the amount of effort and intellect that goes into the preparation of the individually and specifically for him prepared cell transplants. From the patient’s viewpoint fetal precursor cell transplantation is a very easy surgical procedure, unless it requires a preliminary minor neurosurgical, orthopaedic, or reconstructive operation.

Each fetal precursorcell transplant is implanted separately, cell transplants of different organs or tissues are never mixed in the same syringe prior to the implantation.

The usual routes of implantation, summarized in the Introduction, become more meaningful from the description of implantation sites.

Of all the possible implantation sites, the liver is by far the best, because it has been established beyond doubt that it is the most immunoprotective, i.e. it does not reject any foreign cells, for reason(s) still unknown. But, a direct intrahepatic implantation carries a definitive risk of intrahepatic haematoma.

The safer way of an intrahepatic transplantation is the intraportal one, when the cell transplants are injected into portal vein or one of its tributaries and in this way they get directly into ‘immunoprivileged’ parenchyma of liver. A minor surgical procedure to re-open the obliterated umbilical vein is the easiest approach to accomplish intraportal implantation. In two thirds of adults the umbilical vein is found not to be obliterated. The problem is that the obliterated umbilical vein can be re-opened only once. At RITAOMH attempts were made to leave an indwelling catheter in the umbilical vein of patients to allow repeated implantation of fetal cell transplants, but after a second implantation four weeks later the catheter invariably stopped functioning. All other intraportal approaches are technically more complicated, could not be repeated too many times either, and would have represented a drawback for a method of fetal precursor cell transplantation that was to become widespread (and thus had to be technically simple) by the order of the Ministry of Health of U.S.S.R. in 1984.

The implantation under the aponeurosis of the rectus abdominis muscle was developed by RITAOMH as a practical alternative. The anatomical space under the aponeurosis of the rectus abdominis muscle is not considered ‘immunoprivileged’ per se, but it is very closely connected with the portal venous system and peri-portal lymphatic channels. Thus an implantation of fetal precursor cell transplants in this space may serve the same purpose as direct intraportal implantation, and the procedure is safe, technically simple, and can be repeated as many times as necessary.

This is due to the existence of accessory portal system of Sappey, i.e. veins occurring at the site of the obliterated fetal circulation. These paraumbilical veins in the falciform and round ligaments are tributaries of the portal vein system. They unite with the epigastric and internal mammary veins as well as with the azygos vein through the diaphragmatic veins of the systemic circulation. External part of this circulation is clearly visible around the umbilicus in patients with portal hypertension as ‘caput Medusae’. The excellent drawings of F.D. Netter VI.BIBLIOGRAPHY [160] equal the descriptions in classical anatomy textbooks that follow.

“Lying in the free edge of the falciform ligament is the ligament teres, which is the obliterated remains of the left umbilical vein of the fetus, and extends from the umbilicus to the notch on the inferior border of the liver. Here it runs in the floor of the fissure for the ligamentum teres to join the left branch of the portal vein at the left extremity of the porta hepatis...While the ligamentum teres is normally avascular, there are accompanying para-umbilical veins representing a potential collateral circulation between the portal vein and systemic venous system of the anterior abdominal wall.” VI.BIBLIOGRAPHY [153]

Other classical anatomy textbooks state: “...anastomoses between portal and systemic circulations, which may offer effective collateral circulation, are as follows: ....3/ At the umbilicus, veins running on the ligamentum teres to the left portal branch, connect with the epigastric veins; enlargement of these connections may produce varicosities of veins radiating from the umbilicus, the caput Medusae.” VI.BIBLIOGRAPHY [151]

“There are three specific locations where such porta-systemic anastomoses produce grossly dilated venous varicosities: .... ....; around the umbilicus, the paraumbilical veins connect to tributaries of the epigastric veins, which drain into both superior and inferior venae cavae.” The blood can flow in both directions in the portal system which “ a consequence of the absence of valves in the portal system whereby blood can run retrogradely....” VI.BIBLIOGRAPHY [154]

The epigastric veins are draining an area where cell transplants are implanted in the process of subaponerotic implantation. “Nevertheless, under normal conditions along the length of the round ligament there is a venule, the paraumbilical vein, which originates in the abdominal wall, around the umbilicus, and runs toward the left branch of the portal vein. According to Wertheimer, it is connected with a newly formed vessel, the central umbilical vein, which is embedded completely in the round ligament....

…Accessory portal veins... are... 6/ Veins of the round ligament, originating in the abdominal wall, in the neighbohood of the umbilicus, and embedded in the round ligament. They follow the course of that ligament. Some of them terminate at the anterior border of liver, others along its longitudinal groove on the left.”VI.BIBLIOGRAPHY [152] (The round ligament and ligamentum teres is the same structure.)

Nowadays, in the era of laparoscopic surgery, an implantation into the greater omentum has become quite popular VI.BIBLIOGRAPHY [102], or into epiploic flap, VI.BIBLIOGRAPHY [175], both of which are modifications of an intraportal implantation.

“Lymph vessels from the upper and anterior surface of the liver pass into the falciform ligament to join the lower parasternal nodes.” VI.BIBLIOGRAPHY [153] “The majority of nodes and node groups are clustered around or abut a prominent blood vessel or one of its branches.” VI.BIBLIOGRAPHY [151]

“Many superficial lymphatics from the upper part of the diaphragmatic surface of the liver run through the falciform ligament, turn upward along the superior epigastric vessels, and terminate in the parasternal lymph nodes.” VI.BIBLIOGRAPHY [154] The superior epigastric vessels are running through the area where cell transplants are implanted by the the described method superior to the umbilicus in the right and left subaponeurotic space above the rectus abdominis muscle.

The actual implantation procedures are described in the chapter ‘Treatment procedure’.

The clinical effect of fetal precursor cell transplantation is delayed on average 6 – 8 weeks. Since many patients are accustomed to an immediate ‘gratification’, i.e. to feel the benefit of a medication within 10 – 20 minutes, they have to be explained that there is a ‘latency period’ between the implantation and observation of the clinical effect. The actual length of such ‘latent period’ varies from patient to patient but certain general rules have been observed:

1/ The younger is the patient, the sooner clinical effect appears.

2/ The more recent is the onset of the disease, the faster becomes apparent the therapeutic benefit of fetal precursor cell transplantation.

3/ Metabolically active organs with excellent blood supply, especially endocrine glands, respond faster to fetal precursor cell transplantation than other organs with slow metabolism.

4/ In patients with dominant sympathetic division of autonomous nervous system the clinical effect of fetal precursor cell transplantation appears faster than in those with a dominant parasympathetic division.

5/ Symptoms of disturbed autonomous nervous system regulation disappear within 4 - 6 weeks.

6/ Sclerotic changes of the old age delay the onset of the therapeutic effect, depending upon the extent and depth of tissue degeneration, and the delay of 4 to 6 months is to be expected. VI.BIBLIOGRAPHY [261]