The impact of chronic reduced microcirculation on tissue function and on neoplastic promotion.

I hypothesize that chronic reduced microcirculation, even limited to micro areas of tissue, may lead to respiratory deficiencies, to a proliferation of simplified cells as a result of a lack of energy, and to defects in immune control. In these situations, reduce resistance and specific hypofunction might occur in organs (should the entire organ be involved) and cell alterations might come about, as several authors have described experiments in conditions of hypoanoxia. The mutated cells, possibly in these areas as well, could more easily emerge as neoplasia because they are removed from immune control and surrounded by a terrain of reduced resistance. Infant leukaemias would be easier to control than adult forms because it is harder for antineoplastics to reach the latter's site of origin.

[Importance of microcirculation in the pathogenesis of various disease conditions, especially hyperplasia and neoplasms]. / Importanza del microcircolo nella patogenesi di vari eventi morbosi in particolare delle iperplasie e neoplasie.

The possibility is considered that a contraction or an increase in the tone of the smooth muscular fibrocells of the vessels may direct the blood flow prevalently thorough preferential channels, with elusion of much of the capillary circulation. This event may lead to a slowdown or change in the function of organs and systems. The persistence of preferential route circulation leads to respiratory and metabolic trouble in the cells of tissues and basic and fibrillar substance of connectives. The main consequences of such a condition are thought to be a reduction in cationic pump activity, a reduction in synthesis of highly energetic products and a numerical increase in the synthesis of structurally simpler proteins. The possibility that a microcirculatory disturbance, triggering tissue hypoxia and permitting the presence of substrates, may be considered as the promoter of neoplastic proliferation, is suggested. Finally, the principles by which von Ardenne instituted prophylaxis of neoplasia and the diffusion of metastasis are enhanced.

[Microcirculatory changes in infancy and old age]. / Modificazioni microcircolatorie nel bambino e nel vecchio.

An account of the microcirculatory unit according to Zweifach is followed by an explanation of the marked differences in capillary and tissue perfusion in children and aged. Prolonged hypertonia of the metarteriolar smooth muscle cells of the precapillary sphincters depresses capillary perfusion, even though the preferential circulation remains, resulting in marked changes in cellular metabolism in the tissues. If the capillary circulation is excluded for a sufficiently long period, less oxygen and substrates will be transported to the tissues concerned, intravasal red cell clumping will exacerbate hypoxia, and drainage of metabolic residues will be reduced. Microcirculatory vasoconstriction may be the result of heat, touch, noise, hormonal factors, medicaments, toxic, nervous, psychic factors, etc. Whit time, continuous damage to the microcirculation leads to involution of the microcirculation in favour of the preferential circulation, creation of an increasingly large number of arteriovenous short-circuits, and hyperstomia of arteriovenous anastomoses. Depressed capillary circulation leads to a reduced flow of liquids through the vessel walls owing to a diminished diffusion surface with consequent progressive lessening of tissue metabolic activity. Involution of the microcirculation is thus one of the main steps in the ageing process. A cell's metabolic pattern is dependent on the environment in which it lives, as well as its stock of enzymes and differentiation stage. This environment is greatly changed by alterations of the microcirculation. The gradual depression of the microcirculation during ageing, coupled with the consequent diminution of perfusion of tissues and interstitial liquids are thus of significance in ageing itself, in the slowing down of tissue change, and increased entropy to the energy levelling coincident with death.

[A pathogenetic hypothesis based on the use of chlorpromazine of organic disorders probably due to microcirculatory changes]. / Ipotesi patogenetica, in base all'uso della cloropromazina, concernente alcune sofferenze d'organo probabilmente legate a modificazioni microcircolatorie.

In the introduction it is noted that, in the physiopathology, specific pathogenetic elements are missing concerning irritative stimulation, turbid fat pathosis, digital hippocratism of chronic affections (for example, pulmonary affections), the most frequent onset of telarche and of the swelling of the areola of the breast on the left hemithorax in the premenstrual syndrome, fibrosis, cyrrosis, certain types of insipid diabetes, etc. In the opinion of the author, the use of chloropromazine, in doses that have proved to be harmless, has contributed to the clearing up of some questions concerning a few pathologies of internal organs: the liver, the spleen, the brain-and enable us to pose some hypotheses about the swelling of the liver, the origin of scleroses and cirrhoses and some splenic and encephalic swellings. The author suggests that the fundamental reason is to be sought in changes in the microcirculation which are linked to insufficient capillary and sinusoidal circulation. Two cases of insipid diabetes are mentioned which were treated with chloropromazine and for which an improvement in the trophism of the diencephalic cells was hypothesized, due to an improvement in the local circulation. A similar physiopathological microcirculatory behaviour is attributed to digital hippocratism, the P. Marie and Bamberger syndrome (similar to those determined by cyanotic congenital cardiopathies), both due to chronic suppurative processes, and the slightly more frequent onset of telarche on the left hemithorax. It is expected that other pathologies may be explained by a similar physiopathological mechanism, malignant tumor inclusive.

[Edema in acute diffuse glomerulonephritis, rheumatic peliosis and epidemic parotitis]. / L'edema nella glomerulonefrite acuta diffusa, nella peliosi reumatica e nella parotite epidemica.

The Authors present a substantial series of infant APING in which the venous blood gas analysis shows poor use of oxygen, due to a probably reduced cellular combustion associated with low pCO2, high pH, which are characteristic of arterial blood travelling through anastomotic paths and preferential channels at the microcirculation level. They emphasize the contemporaneous increase in volemia, even with oedema present, and the poor permeation of the capillary wall found with the Landis test, contrary to what happens in glomerulonephrosis with minimal changes which features increased systematic capillary permeation with hypovolemia. The look of the oedema, together with the hypervolemia, led to the suspicion that the nephritic oedema was a sign of mainly intracellular oedema. In the opinion of the Authors these nephritic forms would seem to show systemic cellular respiratory suffering sensitive to the action of chlorpromazine, which has also dealt swiftly and cleanly with the oligoanuresis. The Authors consider 52 cases of Schöenlein-Henoch vasculitis which showed very rapid detumescence of periarticular swelling and those on the back of the hands and feet, as well as the disappearance of skin petechias and melena following treatment with chlorpromazine. They also mention two cases of Kawasaki's disease which seemed to react favorably to the combination of the action of chlorprmazine with acetylsalicylic acid. The effects obtained with chlorpromazine in 27 cases of epidemic parotitis with periscialoadenitis elastic tumescence are reported, with the focus on the reduction of the perisalivary tumescence. It is important to point out the very rapid disappearance of epigastrial pain, probably pancreatic in origin.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pathogenesis of neoplasms]. / Riflessioni sulla patogenesi delle neoplasie.

The Authors discuss the aspect and the function of the Microcirculatory Unit and the chronic reduction of circulation in true capillaries and therefore of tissue perfusion increasingly evident with the advancement of age, the structural simplification of proteins, the instability of the cells' genome and the increasing remoteness of the immunity system's control. In view of these considerations, they propose the possibility that the onset of tumours may be due to the accentuation of mutageneous substances and the reduction of tissue perfusion with age. When perfusion is maintained of periodically resumed, hypoxy only determines hyperplasia but not cell degeneration or mutations.

[Compromised tissue perfusion for defective microcirculation in children]. / Difetto di perfusione tessutale da carenza microcircolatoria nel bambino.

After a brief review of the anatomic and physiological features of the microcirculatory system, the Authors describe a new interpretation of skin edema in acute diffuse infantile glomerulonephritis, in Henoch-Schönlein's purpura, in epidemic parotitis and in Kawasaki's disease. They attribute the cellular swelling typical of elastic oedema of these diseases to respiratory deficiency due to reduced tissue perfusion following insufficient circulation in real capillaries. The ensuring drop in energy is rapidly resolved by use of very small doses of a calcium antagonist, chloropromazine, which also affects hemorheology. The Authors refer to works which regard the microcirculatory hypothesis in encephalic pathology (similar to that arising in subjects who live at high altitudes where oxygen is scarce), in cranial trauma and in psychic depression. The Authors describe the surprising find, following a fortuitous observation, that in certain forms of hepato-splenomegaly--among which a case of splenomegaly with hepato-megaly and initial cirrhosis--three hours after the administration of doses of chloropromazine ranging from 0.5 to 1.0 mg/kg, the liver and spleen considerably reduced in volume, followed by the patients' ensuing excellent general conditions and functionality of their organs. The article then references many other Authors who in the course of time have acknowledged the fact that hypoxia stimulates proliferation, even of osteoblasts. Mention is made of the fact that many medications and therapeutic measures may cause vasoconstriction at microcirculatory system level, similarly to several antineoplastic drugs, X-rays, hyperbaric oxygen treatment, as well as traumas, low environmental temperatures and surgical operations. For this reason, in order to contrast vasoconstriction in many pathological conditions and in certain therapies, the Authors suggest the addition of the use of calcium antagonists to usual therapy. This conclusion is reached in consideration of the fundamental fact that the energy deficiency arising in the hypoperfused tissue areas allow an accumulation of amino acids, mainly deriving from protein disgregation, used with a low consumption of energy to synthesize a great number of simplified proteins. Final reference is made to the concept expressed on hypoxia and simplified structural proliferation in an article published in "Medical Hypotheses" of 1995 referring to neoplastic promotion.

[Clinical course and therapy in 94 cases of rheumatic peliosis hospitalized at the Trento Pediatric Center from 1967 to 1986]. / Evoluzione clinica e terapia di 94 casi di peliosi reumatica ricoverati al Centro Infantile di Trento dal 1967 al 1986.

Therapy and clinical evolution are described in 94 cases of rheumatic peliosis accepted in about twenty years in the second division of the pediatric department. In 52 cases (55 per cent) at the first stage of the disease chlorpromazinic treatment only was performed and gradually replaced by prednisonich therapy; in other 36 lighter cases, (37 per cent) the treatment was prednisonic only. Other six cases were not treated at all. It is pointed out the chlorpromazine capacity to make every clinical sign vanish in a few days only allowing to practise prednisonic treatment and therefore obstaining remarkable reduction of the child's pain. It is also remarked the harmloness of the treatment performed which is therefore recommended in the therapy of Schoenlein Henoch disease.

Importance of microcirculatory alterations in the initial hypertensive, oligoanuric phase of acute post-infective glomerulonephritis in infancy.

By applying the blood gas analysis to the venous blood of 17 children affected by DPGN, the authors have observed an increase of the PvO2 and a reduction of the PvCO2 in the oligoanuric and hypertensive phase, which is attributed to a minor utilization of O2. The authors relate a probable cellular respiratory defect with the initial skin tumefaction in these cases. This respiratory dysfunction would be due to intravascular red cell aggregation, to the reduction of perfusion of the exchange vessels and to the passage of the blood through preferential circuits.