MICROALBUMINURIA: CARDIOVASCULAR RISK FACTOR OR SIGN OF “ARTERIOSCLEROTIC CONSTITUTION”?

Introduction।
Before illustrating the contribution of Biophysical Semeiotics to enlighten significancy and etiopathogenesis of microalbuminuria, as follows, theorical and practical interesting aspects of such renal pathology are investigated, which, without the aid of this original physical semeiotics, persists for years or decades unrecognized, untreated and, therefore, worsening.
Although the association between microalbuminuria and cardiovascular disease was initially described in individuals with diabetes, it is now well established that microalbuminuria is associated with a 1,5- to 4-fold increased risk of cardiovascular disease among individuals with and without diabetes. However, the pathophysiological mechanism linking microalbuminuria to cardiovascular disease is unknown (1, 2). It is important to stress that the association between microalbuminuria and cardiovascular disease is unlikely to reflect a direct, causal pathway, because there is no plausible mechanism that can directly link the quantitatively trivial urinary loss of albumin (15-300 mg per 24 hours) to atherothrombosis.
Authors do not agree on causal relation, due to the fact that are lacking acceptable mechanisms, which should link the trivial urinary loss of albumin (15-300 mgr/24 ore) to arteriosclerosi.
In following, I will examine the present view-point on this argument and will illustrate the original biophysical-semeiotic interpretation.

Association between Microalbuminuria and Cardiovascular Diseases: the common point of view.

Microalbuminuria is associated with several cardiovascular risk factors, notably age, male gender, hypertension, smoking, obesity, dyslipidemia (high triglyceride and low HDL-cholesterol), diabetes, hyperhomocysteinemia and, among diabetic individuals, glycemic control. According to some investigators, microalbuminuria is also associated with insulin resistance, but this is controversial.
An obvious hypothesis, therefore, is that the association of microalbuminuria with cardiovascular disease simply reflects, and can be explained by, the association of microalbuminuria with one or more of these well-known cardiovascular risk factors. However, and perhaps somewhat surprisingly, epidemiological studies show that the association between microalbuminuria and cardiovascular disease remains when such conventional cardiovascular risk factors are taken into account, even though all these risk factors have been associated with the development of microalbuminuria in prospective studies, i.e. they may play a role in its pathogenesis (www.ATHERO-ORG..com, 3 July 2002, Coen D.A. Stehouwer, MD PhD, Professor of Medicine, Department of Internal Medicine,
Institute for Cardiovascular Research, and Institute for Research in Extramural Medicine,
Vrije Universiteit Medical Center).
Finally, although there is not agreement among authors, hyperinsulinemia-insulinresistance has been correlated with microalbuminuria, as corroborate personal research (data unpublished). It seems, therefore, that a strong relation probably exists between one or more well-known cardiovascular risk factors and the loss of small amount of albumine in urine.
On the contrary, and really not surprisingly, epidemiological study demonstrate that the association between microalbuminuria and cardiovascular disease is unsolved, even when the common risk factors, cited above, show to end, over the time, in albuminuria, indicating, therefore, to play a “possible” role in its pathogenesis.
At this point, it is advisable to examine an interesting aspect of the problem, on which all authors are in agreement, summarized in a fascinating way by Coen D.A. Stehouwer (paper cited above), who suggested me the following biophysical-semeiotic considerations on the relation between microalbuminuria, inflammation, endothelial dysfunction, and atherosclerosis. I assessed such parameters “clinically” with the aid of Biophysical Semeiotics.
The most commonly held view is that microalbuminuria reflects a pathophysiological process predisposing to atherothrombosis. Atherothrombosis is a low-grade inflammatory disease of the vessel wall characterized by endothelial dysfunction and increased transendothelial passage of leukocytes. These features, therefore, could be the pathogenic factor linking microalbuminuria to cardiovascular disease.
In support of this hypothesis, increased levels of C-reactive protein (CRP), which reflect inflammatory activity, increased plasma levels of von Willebrand factor (vWf), a marker of endothelial dysfunction, and increased plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), an adhesion molecule which reflects recruitment of leukocytes into the vessel wall (1, 2), have all been associated not only with the increased risk of cardiovascular events, but also with the development of microalbuminuria.
Such associations, moreover, were independent of conventional cardiovascular risk factors. These findings indicate, on the one hand, that inflammatory activity, endothelial dysfunction and leukocyte adhesion play a role in the pathogenesis of microalbuminuria, and, on the other hand, that these processes may, perhaps, explain microalbuminuria's link with cardiovascular disease (Stehouwer CDA:, above-cited article).
In other words, above-referred data, on the one hand, show that the inflammatory activity, endothelial dysfunction and cellular adhesion play a role in the pathogenesis of albuminuria, and, on the other hand, these processes can, probably, enlighten some-how the link between microalbuminuria and cardiovascula diseases.
At the moment, without disclosing biophysical-semeiotic view-point on the significancy and real nature of urinary loss of small amount of albumin, it is opportune, however, to underscore a remarkable fact: in the really “initial”, and “primary” stages of microalbuminuria, I observed at first “clinically”, and then coroborated by laboratory data, hepato-aspecific gastric reflex, type II, which is physiologically negative (= Acute Phase Proteins absent) (See in my site, HONCode, N° 233736, http://www.semeioticabiofisica.it, Practical Applications, and Article N° 2, Appendicitis, in the Page, I hold weekly in the italian site www.katamed.it), as well as all other biophysical semeiotic signs of inflammation: Rethiculo-Endothelial System Hyperfunction Syndrome, Antibody Synthesis, a.s.o.

Etiopathogenesis of Microalbuminuria: Biophysical-Semeiotic view-point.

From a renal pathophysiological point of view, microalbuminuria must be caused by increased glomerular permeability to albumin, increased glomerular pressure, and (or) decreased tubular albumin reabsorption. The renal endothelium is intimately involved in the regulation of these processes, but how endothelial dysfunction and increased leukocyte adhesion cause microalbuminuria in molecular terms is not completely understood.
In addition, it is plausible that low-grade inflammation is causally related to the development of microalbuminuria. The main stimulators of production of acute phase reactants such as CRP are proinflammatory cytokines. Interleukin-6 may be an important mediator of mesangial cell proliferation and matrix overproduction, but also of an increase in general vascular permeability without involvement of the kidney. Thus, increased proinflammatory cytokines, as reflected by increased acute phase reactants such as CRP, may cause microalbuminuria through both renal and non renal vascular mechanisms.
As I will refer later in detail, biophysical-semeiotic data, at least in initial stages, do not agree with those of such, otherwise interesting, theories. Infact, in initial stage we can not observe neither increase of Acute Phase Proteins APP), nor body’s defence reactions (Rethiculo-Endothelial System Hyperfunction Syndrome, Antibody Synthesis, a.s.o.). In addition, there is no inflammation at glomerular level (= renal-aspecific gastric reflex, type II, i.e., caused by ungueal stimulation of kidney trigger-points, is absent).
In fact, the above-referred results should invite us to consider inflammatory activity and endothelial dysfunction as probable, and even plausible, causes of microalbuminuria, on the one hand, and atheroscleorsis, on the other hand, enlightening, by such way, the link between microalbuminuria and cardiovascular disease. However, the link between microalbuminuria and cardiovascular disease cannot be explained by increased inflammatory activity or endothelial dysfunction.
The findings reviewed above raise the possibility, and even the plausability, that inflammatory activity and endothelial dysfunction may cause microalbuminuria on the one hand and atherothrombosis on the other, and thus explain the link between microalbuminuria and cardiovascular disease. However, two recent studies (1, 2) (quite unexpectedly) show that the association between microalbuminuria and cardiovascular disease or mortality is not affected by adjustment for these determinants of microalbuminuria. Thus, inflammatory activity, endothelial dysfunction, and leukocyte adhesion apparently cannot explain the association between microalbuminuria and cardiovascular mortality, either in individuals with or without diabetes. Therefore, the problem persists unsolved: what then can explain the link between microalbuminuria and risk of cardiovascular motality?
“One possibility is that microalbuminuria reflects a prothrombotic state or another, as yet unidentified cardiovascular risk factor. Alternatively, microalbuminuria may reflect a certain susceptibility to the vascular adverse effects of a variety of cardiovascular risk factors. This concept is supported by the observation that determinants of the development of microalbuminuria, such as diabetes, hypertension, inflammatory activity, and endothelial dysfunction, do not appear to confound the microalbuminuria-cardiovascular disease link. These possibilities require further study. For the present, microalbuminuria is a clinically useful marker of increased cardiovascular disease risk, even though the pathophysiological explanation of the association remains enigmatic”, states Coen D.A. Stehouwer, author of the fascinating article, posted in the site www.ATHERO-ORG.com., often cited in the present paper, who thinks, in my opinion, in a compelling way, that microalbuminuria could be either the expression of pre-thrombotic state or of different condition, such as cardiovascular risk factor, untill now unidentified.
“Alternatively, microalbuminuria may reflect a certain susceptibility to the vascular adverse effects of a variety of cardiovascular risk factors”, the author suggests.
With this point of view is in agreement the observation, corroborated also by biophysical-semeiotic method, that determinant causes of albuminuria occurrence, such as DM, hypertension, inflammatory activity, endothelial dysfunction, are acceptable in linking microalbuminuria to cardiovascular disease. These possibilities, the author concludes, require further study.

Biophyical-Semeiotic Contribution to clarifying relation between Microalbuminuria and Cardiovascular Disease.

In order to understand, in the best and successful way, the following topic, it is unavoidable studying all articles on “Biophysical-Semeiotic Constitutions”, posted in the site http://www.semeioticabiofisica.it
In my mind, from the healthy state, white zone, slowly, really slowly, one reaches the morbid state, blach zone – DM, ATS, arterial hypertension, gouthy, dyslipidemia, malignancy, a.s.o. – going through a long, very long, intermediate stage – pre-morbid stage, pre-metabolic stage – or grew zone, which, if undiagnosed, can last years or decades, without whatever clinical syntomatology, which is the subject of present consideration, as regards arteriosclerotic coronary diseases.
The grew zone is made up of an initial stage, or Zero Stage, and by successive poli-metabolic syndrome, X syndrome or Reaven’s synrome, both classic and “variant”, we described previously (3, 4), which mostly goes before the black zone.
Due to this reason we define the grew zone as pre-morbid or pre-metaolic syndrome. (See papers also in http://www.semeioticabiofisica.it/microangiologia, in www.Staibene.it, November 2001, and in the article N° 13 of the Page, I hold in www.katamed.it).
Reaven’s syndrome, both classic and “variant”, is based on Congenital Acidosic Enzyme-Metabolic Hystangiopathy- (CAEMH-), that represents a functional mitochondrial cytopathology, inherited by mother, completely asyntomatic at the beginning, and over many years or decades, before ending up with poli-metabolic syndrome (5, 6, 7 and the sites, above referred).
In order to understand and recognize “quantitatively” the “real” arteriosclerotic risk of an individual, it could be of interest the knowledge of the nature of link exsisting between microalbuminuria and arteriosclerotic cardiovascular disease, but, in my opinion, going “beyond microalbuminuria” gives doctor more information.
Certainly, primary problem, we face with, is bed-side recognizing and defining molecular-biological events, which characterize the grew zone, including its Zero Stage, with the aid of an efficacious method, reliable and rapidly to perform on very large scale, as Biophysical Semeiotics.
We desire that such as method allows us to recognize, in a clinical and quantitative way, the Zero Stage of grew zone, and classic and “variant” Reaven’s syndrome, i.e., pre-morbid, pre-metabolic syndrome, which is the locus (space-time) of primary prevention of the most serious human diseases (8) (See above-cited sites).
First of all, we must find a key-stone (a new reading way), biophysical-semeiotic in origin, totally different from that based upon “classic” signs and symptoms of the traditional physical semeiotics, including the microalbuminuria, completely absent in pre-morbid, pre-metabolic syndrome, that permits us to make the proper bed-side diagnosis in a “quantitative” way, during the common physical examination, in whatever patient.
Let’us consider, therefore, what happen at metabolic-endocrine level in both extreme situations, at first, in white zone and, then, in black zone in order to underline existing differences, usefull to our aim, i.e., to recognize and describe the intermediate, asymptomatic stage, I named grew zone.
In fact, different metabolic-endocrine behaviour of healthy individual, and, respectively, of patient involved by classic and “variant” Reaven’s syndrome, will help us to recognize, clinically on a very large scale and during the common physical examination, people apparently “healthy”, but who absolutely need intense and accurate consideration, due to their “real” risk for cardiovascular diseases, even at the moment without microalbuminuria, that is not always present, neither in successive stages.

Arterial Abnormalities in Off-sprimg of Patients involved by Myocardial Infarction, even premature.

Among a large number of important risk factors for cardiovascular disorders is coronary artery disease in family history (9, 10).
We discusse, therefore, although briefly, the relation between relatives and parents’s CAD and offspring’s cardiovascular disorder, that we corroborated clinically by means of Biophysical Semeiotics, since it represents a perfect introduction to explaining our microcirculatory theory of arteriosclerosi,s as well as to comprehending microalbuminuria pathogenesis.
The numerous theories of arteriosclerosis pathogenesis show clearly our present insufficient knowledge of this argument, although the well-known progresses of sophysticated semeiotics, including that with images.
All authors agree, recently, about primary importance of initial endothelial damage: I will examine its underlying pathological mechanisms later on.
As knows reader, who visites the above-cited sites, over last three decades we tried to persuade the colleagues to pay accurate attention, from the “clinical” biophysical-semeiotic view-point, to the primary role played by endothelial cells in both physiology (for instance, in Microcirculatory Funcional Reserve activation) and in pathology (for instance, in the onset of cardiovascular disease).
Interestingly, the risk of ischaemia, as elechtrocardioram shows, is about 40% higher, and mortality risk due to cardiac events is 2,5% larger in individuals with “positive” family history for premature CAD than in people without such as family history (11).
Among a large variety of similar evidences, we remember that arteriosclerotic lesions were found at autoptic examinations of very young patients with family history for coronary artery disease (12). Over last decades, B-mode ultrasonography at high resolution proved to be a valid and reliable tool in order to detect the initial arteriosclerotic alterations in vessel wall (13).
Intimal and media thickening of carotid artery wall has been observed in individuals involved by risk factors for cardiovascular diseases, proving to be a remarkable marker of the presence of coronary arteriosclerosis and its complications.
Skilled reader knows perfectly that Biophysical Semeiotics allows doctor to recognize such macrovascular lesions both directly (= vessel-aspecific gastric and -caecal reflex; pathological preconditioning, a.s.o.), and indirectly by evaluating local vasa vasorum (= type II or dissociated activation) as I will demonstrate later (See in former above-cited site: Arteriosclerotic Constitution).
In a few words, in healthy, supine and psycho-physically relaxed, “intense” digital pressure, e.g., applied on brachial artery brings about “in toto” ureteral reflex (= ureter dilates) (Fig.1) of about 1 cm. in intensity (NN  0,5 cm), while, during Valsalva’s manoeuvre, ureter diameter increases at least two-fold, when compared with basal value, due to well-known reasons (acethyl-choline increases, as well as endothelial radical NO and GTP synthesis: vessel smooth muscle cells are relaxed).
On the contrary, starting from “really” initial stage of arteriosclerosis, arterial compliance appears clearly compromised. In our “clinical” research, performed and concluded a lot of years ago, we demonstrated the reduced responsiveness of brachial artery, observed at bed-side, by the use of sphygmomanometer at different pressure levels to stimulate the artery (14).
Finally, we remember that brachial artery responsiveness, blood-flow-mediated, is compromised in persons with overt arteriosclerosis as well as in symptomless individuals with coronary risk factors (16).
In healthy, finger-pulp-aspecific gastric reflex, provoked by “mean-intense” digital pressure on a finger-pulp of the subject at rest, shows a latency time (lt) of 8 sec., while, assessed a second time after exact 5 sec., starting from blood-flow recovery, and rapidly applied, lt rises to a  10 sec.
By contrast, in case of “real” arteriosclerotic risk and, obviously, of arteriosclerosis, lt persists unchanged (basal value  8 sec.) or, respectively, lowered in a clear-cut manner.
As regards the easiest performance of our method, doctor assesses the intensity of “in toto” ureteral reflex (= ureteral dilation, Fig 1) during “intense” digital pressure on brachial artery (or, of course, in whatever other artery) evaluating precisely its value in cm.
Contemporaneously, it appears also the artery-aspecific gastric reflex, which is more easy to performe by doctor not jet expert of the new semeiotics.

Fig.1

(Figure shows the correct location of the bell-piece of stethoscope and lines upon which doctor must apply digital percussion, gently and directly, in order to draw,at least in mind, cutaneous projection areas of kidney and ureter).



At this point, patient is invited to perform Valsalva’s manoeuvre (= acethyl-choline increase) lasting about 10 sec., and assesses, soon thereafter, the value of the same reflexes parameter for a second time. In healthy, the intensity of both “in toto” ureteral reflex and aspecific gastric reflex results two-fold greater or, in any case, significantly increased.
Clinical evidence shows that arteriosclerosis seriousness and the intensity reduction of “in toto” ureteral reflex and/or aspecific gastric reflex, during Valsalva’s manoeuvre, are inversely correlated.
Another easy biophysical evaluation of the same events is the comparison between basal data and those observed during boxer’s test, lasting at least 5 sec., which dilates arteries up-wards resistance vessels, and contemporaneously activates vasomotor activity of vasa vasorum, quantified by Biophysical Semeiotics, as skilled reader knows: in healthy, during such a test, the intensity of artery-“in toto” ureteral reflex results practically two-fold when compared with the basal value, and the latency time of artery- caecal reflex clearly prolonged (= histangic acidosis, temporarily reduced, as during Valsalva’s manoeuvre).
In fact, there is a clear coherence between basal -caecal and -aspecific gastric reflexes, which appear double (two-fold) after acethyl-choline secretion, induced by Valsalva’s manoeuvre and, in the second experiment, after physiological production of free-radical NO.
The same results are gathered during the test of insulin secretion acute pick and confronting the observed result with basal parameter value (See in above-cited site: Diabetes Mellitus and Glossary).
The data gathered by these dynamic methods, on the contrary, result pathologically modified in those individuals at “real” risk for arteriosclerosis, even in the first two decades of life, as we referred in former papers (17, 18, 19, 20).
These facts, we observed in a long clinical experience, corroborate, without any doubt, our microangiological theory of arteriosclerosis, since they clearly underline the earliest functional and structural lesion of arterial wall, secondary to, however, as will be said later on, Endoarteial Blocking Devices (EBD) abnormality in related microvessel, that represents, in my mind, the first of all and essential alteration, genetically inherited.
As a matter of fact, it has been demonstrated that family history of CAD points out an independent risk factor for cardiovascular diseases, showing in a clear manner “inherited” component of such as disorder (we identified as CAEMH-).
These anamnestic data have been enclose to guide-lines fo CAD prevention and is at present utilized in paediatric cardiology, beside genetic study of gene mutation, codifying lipoproteins receptors, a research surely complex and expensive, not possible to apply on very large scale.
Since, at the present, we cannot know when the first vascular (and parenchymal) abnormalities occur, an useful “clinical” method, reliable in recognizing the presence and in quantifying the seriousness of such vascular alterations, appears to be an important event.
The data of our researches parallel, and agree with, those of other authors, carried out with sophysticated methods, in the sense that they show, as markers of early arteriosclerosis, the association between reduced reactivity of brachial artery and/or carotyd intimal-media thickening, observable in young individuals with positive family history for previous myocardial infarction. Such an association is really interesting, due to the fact that abnormal vasodilatory response to acethyl-choline as well as endogenous insulin can be easy evaluated at the bed-side, as we referred in previous papers in individuals formerly involved by inherited alterations of microvessels, including particularly Arterial-Venous Anastomose (AVA), functionally speaking (19, 21, 22).
In other words, arteriosclerotic earliest abnormalities are “pre-clinical”, i.e., pre-clinical lesions; they come before decades the so-called fatty-streaks. Now-a-days, for the first time, with the aid of the original physical semeiotics, doctor is able to recognize at the bed-side these alterations, primarily functional, also by means of analogous modifications of anastomoses, including EBD, as well as of reduced arterial vasodilation – caused by a large variety of methods – always associated with intimal-media thickening or functional-structural endothelial lesions, in our opinion, taking part of primitive alteration of vasa vasorum, CAEMH--mediated.
At this points, one must remember that arteriosclerosis is notoriously a systemic disorder, which involves all circulatory tree and notably, sooner or later, is accompanied by other common diseases.
Consequently, functional and structural alterations, observed in loco, are present also in other locations in youg men, completely asymptomatic, i.e., without any clinical phenomenology. In addition, such as association between altered vascular reactivity-intimal-media thickening, observed by many authors, has been corroborated by us in a clinical way. The same we can say also as regards hypertensive patients as well as patients with suspected CAD (23, 24).
These fact, on which almost all authors agree, are referred and discussed in detail because they offer further evidence to our microcirculatory theory of arteriosclerosis: endothelial suffering, provoked by CAEMH- and worsened by numerous environmental risk factors, partly known (at least 300), due to reduced synthesis of free-radical NO, augmented secretion of vasoconstrictor factors and endothelial-dependent imbalance of haemostatic system, can predispose to monocytes and platelets adhesion, proliferation of media vascular smooth muscle cells and their migration towards intima, storage of monocytes-derived macrophages, and lipoproteins in arterial wall.
Surely, numerous other factors, as inflammation, can take part of pathogenesis of arteriosclerosis, but later, in our opinion, and always in well-defined individuals. However, the genetic factor is of primary, essential importance. It is necessary in enlightening the various moments of natural history of arteriosclerosis.
To conclude, beyond practical aspects, as early bed-side recognizing primitive functional alterations of artery wall, and successively “anatomical” modifications in symptomless individuals, unavoidable to can define arteriosclerotic constitution, former discussion about the relation, surely existing, between altered reactivity of arterial wall and initial intimal-media thickening introduces to the explanation of our “intuition” on the existence of a particular constitution, conditio sine qua non of atherogenesis, which allows to give precise answers, we lack untill now, useful to primary prevention, hopefully efficacious when applied on very large scale.

Biophysical-Semeiotic Arteriosclerotic Constitution.


Clinical evidence suggests the existence of arteriosclerotic constitution:

a) Acute Myocardial Infarction, for instance, can involve an individual “without” well-known risk factors, but “always” CAEMH---positive (as in my personal case).
Moreover, the so-called minimal changes are already present at an age, when known risk factors surely are absent;

b) not “all” dyslipidemic and/or diabetic and/or hypertensive and/or hyperomocysteinaemic patients die due to ictus, myocardial infarction or other arteriosclerotic complications;

c) not “all” hypertensive patients are going to suffer from generalized or localized (CAD) arteriosclerosis; by contrast, are described cases (15-19) of people died from arteriosclerotic complications during the first two life decades, “without” presenting well-known risk factors (18);

d) even in presence of well-known risk factors, arteriosclerosis involves defined, limited areas of arterial wall, rather than “all” wall;

Therefore, arteriosclerotic constitution does really exist, as that diabetic, osteoporotic, rheumatic, artrosic, hypertensive, glaucomatos, oncological, i.e., Oncological Terrain (See above cited site, and article N° 13 in italian site www.katamed.it, as well as two articles on Oncological Terrain in www.Staibene.it, November 2001).
In the same individual, of course, can be present contemporaneously diverse constitutions, which, in fact, originate always on the base of common inherited alteration: CAEMH--.

In following, easy clinical methods to recognize as well as to quantify the “real” arteriosclerotic risk with the aid of Biophysical Semeiotics, since two first life decade, are described. Most accurate and refined ascertaining requires necessarily a very good knowledge of original diagnostic method (19, 20, 27).

1) In healthy, “mean-intense” digital pressure, applied on whatever artery (brachial, femoral, carotid artery, a.s.o.) of a supine, psycho-physically relaxed individual, brings about aspecific gastric reflex (Fig.2) after latency time (lt) of 8-10 sec., age-dependent value.
Moreover, after artery preconditioning (doctor evaluates such a parameter value a second time, after exact 5 sec. interval) lt raises to  12 sec.

Fig.2

Figure indicates the correct location of the bell-piece of stethoscope and lines upon which doctor must apply digital percussion, directly and gently, in order to define the limit of stomach cutaneous projection area of the stomach great curve. It is sufficient to delimit a small segment of curve for assessing the reflex. Aspecific gastric reflex: in the stomach, both fundus and body dilate, while antral-pyloric region contracts.

On the contrary, in a subject at “real” arteriosclerotic risk, and obviously in arteriosclerotic patient, basal artery-aspecific gastric reflex shows a lt  8 sec., inversely related to the intensity of risk or underlying disease. In addition, really interesting from diagnosis view-point, artery preconditioning results pathological: second evaluation, performed exactly after 5 sec. from the former, shows a lt either unchanged (e.g., 8 sec.) or reduced in a clear-cut manner, when compared with basal value, in relation to the seriousness of arteriosclerotic constitution or, in case of basal value lower than normal, of underlying disease.
Identical data as those of preconditioning, one can collect at the bed-side with Valsalva’s manoeuvre, which brings about increase of acetyl-choline secretion, indicating internal and external coherence of biophysical-semeiotic theory (= loss of production and secretion of free-radical NO, due to endothelial alteration and consequently arterioles and small arterioles smooth muscle cells contractions, due to direct stimulation by acetyl-choline.
Moreover, in case of vessel wall calcium deposit (calcification involves exclusively individuals positive for “variant” Reaven’s syndrome), aspecific gastric reflex, after reaching its highest intensity, and soon thereafter lowers of a third of it.
The reader understands correctly that it is easy to evaluate the actual condition of whatever arterial vessels, for example, coronary arteries (25) and cerebral arteries (26) (See above-cited site, Practical Applications: CAD and Cerebral Tumour).

2) the subject, doctor is examining, clenches his fists: boxer’s test. In healthy, after a latency time of 10 sec. appears the aspecific gastric reflex of  1 cm. (Fig. 2), whereas in presence of either arteriosclerotic constitution or overt arteriosclerosis, lt results, once again,  10 sec. and reflex intensity is > 1 cm.
If doctor performs such as evaluation, applying boxer’s test, after exact 5 sec. from the first one (preconditioning), the data observed are the same of those formerly illustrated at point 1).

In conclusion, these two easy methods, applied also in “dynamic” way, are reliable and sufficient to allow recognizing arteriosclerotic constitution, that can be quantified with the aid of parameter values, observed during basal and dynamic evaluation.
Without facing physiopathological discussion of biophysical-semeiotic signs, certainly interesting, but not pertinent to the aims of present article, the illustrated physical examination allows doctor to collect useful information on function as well as structure of adventitial microcirculatory bed, steadly correlated with nutritional condition of local artery wall, i.e., with local Microcirculatory Functional Reserve.
It is easy to understand that the very good knowledge of this new physical semeiotics permits doctor to gather a large variety of clinical microangiological signs, really abundant of information.

Among these interesting signs, I am going to illustrate only some, which allow a refined evaluation of anatomy and function of microcircle, including the adventitial microvessels – vasa vasorum – both at rest and during activation:


1) in healthy, “mean-intense” (but not highest) digital pressure, applied upon a finger-pulp of a supine and psycho-physically relaxed individual, causes upper ureteral reflex (= dilation of upper third of ureter), which gives information on type II, group B AVA, according to Bucciante. At this point, if digital pressure becomes highest, reflex disappears, underscoring the normal structur-function (elasticity) of the same anastomoses, which physiologically control microcirculatory blood-flow.

2) under identical circumstances, the behaviour of mean ureteral reflex (= mean third of ureter dilation) appears the same: it gives information on the real situations of local Endoarteriolar Blocking Devices (EBD) (Fig.3)


Fig. 3

Arrow indicates a particular endoarteriolar formation, like elephant trunk (EBD), whose contraction increases the flow-motion towards, and along, capillaries and post-capillaries venules. On the contrary, the relaxation of EBD smooth muscle cells decreases the blood-flow towards nutritional capillaries. (For kind permission of Prof. S.B.Curri, whose as much excellent as large literature in the field of microcircle and microcirculation originated my enthusiasm about the study of this fascinating and almost ignored branch of Medicine)

3) “mean-intense” digital pressure, applied as illustrated above, provokes upper ureteral reflex (See example 1), which shows the opening of type II, group B AVA. However, if the individual arises his (her) arm in vertical position, the reflex rapidly disappears: closure of AVA, aimed to supply a larger amount of blood flow, and, consequently, to control histangic pH also during such posture test;

4) under identical condition, described above at point 3), if the subject lowers vertically his (her) arm, the intensity of upper third ureteral reflex increases rapidly: type II, group B AVA augment their diameter, and, therefore, their haemoderivative function increases, aiming to maintain a physiological microcirculatory blood-flow in normal ranges, under different positions. Such as physiological microcirculatory adaptations clearly suggest the normal functioning of venular-arteriolar reflex (VAR):

5) in healthy, “mean-intense” digital pressure on a finger-pulp brings about aspecific gastric reflex after a latency time of about 10 sec. (lt value is obviously age-dependent). This value persists unchanged, under physiological condition, when the arm is located in every of three posture positions, due to functional microvessel adaptations, explained above.
All these dynamic tests result altered, obviously of a different degree, in case of arteriosclerosis, starting from the earliest stage, i.e., arteriosclerotic constitution.

BIOPHYSICAL-SEMEIOTICS OF MICROALBUMINURIA.

In table 1, is summarized the diagnostic biophysical-semeiotic iter, usefull and reliable in bed-side recognizing presence and nature of nephrone disease, even clinically silent and localized.
Really, Biophysical Semeiotics does not allow doctor to make “clinical” diagnosis of microalbuminuria, but surely permits to exclude it (100%) or to suspect it, in rational way, conditio sine qua non of ascertaining the real nature of an aspecific damage of nephrone, even limited in some areas of kidney.
In fact, facing the problems of kidney showing normal size, i.e., when are absent biophysical-semeiotic signs of inflammation, parameter values of kidney-aspecific gastric and –caecal reflexes are still in “extreme” limits of normality or clearly pathological, preferably when assessed in selective way, by stimulating, at first, renal trigger-points of upper third, then those of mean third, and finally those of lower third.
Nephrone suffering, even circumscribed, is outlined by renal preconditioning, whose results – lt of kidney-aspecific gastric reflex unchanged or pathological, i.e., reduced in second evaluation – is aspecific expression of nephropathy.
Of essential importance proved to be the “selective” evaluation of renal vasomotion, which shows the characteristic type II, dyssociated microcirculatory activation or, in initial and slight forms, type III, dyssociated microcirculatory activation: the fluctuations of upper third of ureter (vasomotility: arterioles and small arterioles, according to Hammersen) are increased with AL + PL of 7-8 sec. (NN = 6 sec.), while the oscillations of lower third of ureter (vasomotion: nutritional capillaries and post-capillary venules) are normal with AL + PL of 6 sec., but large “in toto” ureteral reflex: > 1 cm.(= interstitium).

In conclusion, from biophysical-semeiotic data, it is likely that the base of microalbuminuria is an inherited microvascular-microcirculatory alteration of nephrone, even circumscribed, primarily functional, acidosic, that cause function abnormality of the vascular smooth muscle cells and, then, of Endoarterial Blocking Devices (EBD), involved selectively, although systematically (including vasa vasorum), by a particular mitochondrial cytopathology, CAEMH-, influencing in negative manner both microvessel dynamics and haemoreology (hyperviscosity) under sympathetic hypertonus conditions, ischaemia, and hormonal impairement (IIR), as we observe frequently in pre-morbid or pre-metabolic syndrome, as wel as in subsequent Reaven’s syndrome, classic and “variant” (3, 4).
Therefore, from the above-referred data, gathered by the aid of Biophysical Semeiotics, microalbuminuria, if present, does not represent a “causal factor” of CAD, and , in general, of ATS, but an early microvascular functional CAEMH--induced abnormality of the nephrones, whose patho-physiological mechanisms are the same of ATS, according to our microcirculatory theory of arteriosclerosis, which allows doctor to foresee only the future onset of CAD.
In performing efficacious prevention of arteriosclerosis, applied on very large scale, I suggest to go “beyond microalbuminuria”, that is present “exclusively” in case of selective microvessel suffering of the nephrone, caused by the mitochondrial cytopathology, we termed Congenital Aciodosic Enzyme-Metabolic Histangiopathy, conditio sine qua of the most serious human diseases (5, 6, 6, 7).

BIOPHYSICAL- SEMEIOTIC DIAGNOSTIC ITER OF GLOMERULAR-TUBULAR SUFFERING

KIDNEY AUSCULTATORY PERCUSSION

TEST OF SIMULATED URINATION

INFLAMMATORY SIGNS (RESHS “COMPLETE”, ACUTE PHASE PROTEINS, A.S.O.)

CIRCULATORY IMMUNOCOMPLEXES SYNDROME

AUTOIMMUNE LOCAL SYNDROME

TYPE I AND II KIDNEY-ASPECIFIC GASTRIC REFLEX

KIDNEY-CAECAL REFLEX

RENAL PRECONDITIONING

ERITHROPOIETINE TEST

VASOMOTILITY AND VASOMOTION OF KIDNEY



Tab. 1

Sergio Stagnaro MD
Via Erasmo Piaggio 23/8
16039 Riva Trigoso (Genoa) Europe
Founder of Quantum Biophysical Semeiotics
Who's Who in the World (and America)
since 1996 to 2009
Ph 0039-0185-42315
Cell. 3338631439
www.semeioticabiofisica.it
dottsergio@semeioticabiofisica.it




Bibliografia.

1. Jager A, van Hinsbergh VW, Kostense PJ, Emeis JJ, Nijpels G, Dekker JM, Heine RJ, Bouter LM, Stehouwer CD. C-reactive protein and soluble vascular cell adhesion molecule-1 are associated with elevated urinary albumin excretion but do not explain its link with cardiovascular risk. Arterioscler Thromb Vasc Biol 2002;22:593-98.
2. Stehouwer CD, Gall MA, Twisk JW, Knudsen E, Emeis JJ, Parving HH. Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: Progressive, interrelated, and independently associated with risk of death. Diabetes 2002;51:1157-65.
3. Stagnaro S.-Neri M., Stagnaro S., Sindrome di Reaven, classica e variante, in evoluzione diabetica. Il ruolo della Carnitina nella prevenzione del diabete mellito. Il Cuore. 6, 617, 1993 (Pub-Med indexed for Medline).
4. Stagnaro-Neri M., Stagnaro S., La “Costituzione Colelitiasica”: ICAEM-, Sindrome di Reaven variante e Ipotonia-Ipocinesia delle vie biliari. Atti. XII Settim. It. Dietol. ed Epatol. 20, 239, 1993.
5. Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. X Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. Atti, 61. 6-7 Novembre, 1981, Siena.
6. Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica condizione necessaria non sufficiente della oncogenesi. XI Congr. Naz. Soc. It. di Microangiologia e Microcircolaz. Abstracts, pg 38, 28 Settembre-1 Ottobre, 1983, Bellagio.
7.Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. Una Patologia Mitocondriale Ignorata. Gazz Med. It. – Arch. Sci. Med. 144, 423,1985 (Infotrieve).
8) Stagnaro S., West PJ., Hu FB., Manson JE., Willett WC. Diet and Risk of Type 2 Diabetes. N Engl J Med. 2002 Jan 24;346(4):297-298. [MEDLINE].
9) Phillips R.L., Lilienfeld A.M., Kagan A. Frequency of coronary heart disease and cerebrovascular accidents in parents and sons of coronary heart disease index cases and controls. Am. J. Epidemiol. 100, 87-100, 1974.
10) Friedlander Y., Siscovic D.S., Weinmann S. et al Phillips R.L., Lilienfeld A.M., Kagan A. Family history as a risk factor for primary cardiac arrest. Circulation. 97, 155-60, 1998.
11) De Bacquer D., De Backer G., Kornitzer M., Blacburn H.Parental history of premature coronary heart disease mortality and signs of ischemia on the resting electrocardiogram. J.Am.Coll.Cardiol. 33, 1491-8, 1999.
12) Kaprio J., Norio R., Pesonen E, Sarna S. Intimal thickening of the coronary arteries in infants in relation to family history of coronary artery disease.Circulation. 87, 1960-8,1993.
13) Gaeta G., De Michele M., Cuomo S., et al. Arterial abnormalities in the offspring of patients with premature myocardial infarction. N.Engl.J.Med. 343,840-45,2000.
14) Celermajer D.S., Sorensen K.E., Gooch V.M., et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of artheriosclerosis. Lancet. 340, 1111-8,1992.
15) Stagnaro-Neri M., Stagnaro S., Il diagramma venoso nelle arteriopatie obliteranti periferiche. Atti Congr. Naz. Soc. It. Flebologia Clinica e Sperimentale. Firenze 10-12 Dicembre 1990. A cura di G. Nuzzaci, pg. 169, Monduzzi Ed. Bologna.
16 Neunteufl T., Katzenschlager R., Hassan A., et al. Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis. 129, 111-8, 1997.
17) Stagnaro S., Valutazione percusso-ascoltatoria della microcircolazione cerebrale globale e regionale. Atti, XII Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. 13-15 Ottobre, Salerno, e Acta Medit. 145, 163, 1986.
18) Stagnaro-Neri M., Stagnaro S., Aneurisma Aortico Addominale: una Diagnosi clinica con la Semeiotica Biofisica. Acta Cardiol. Medit. 14, 17, 1986.
19) Stagnaro-Neri M., Stagnaro S., Auscultatory Percussion Evaluation of Arterio-venous Anastomoses Dysfunction in early Arteriosclerosis. Acta Med. Medit. 5, 141, 1989.
20) Stagnaro-Neri M., Stagnaro S., Modificazioni della viscosità ematica totale e della riserva funzionale microcircolatoria in individui a rischio di arteriosclerosi valutate con la percussione ascoltata durante lavoro muscolare isometrico. Acta Med. Medit. 6, 131-136, 1990
21) Stagnaro S., Stagnaro-Neri M., Valutazione percusso-ascoltatoria degli attacchi ischemici transitori e della insufficienza cerebrovascolare cronica in pazienti trattati con mesoglicano. Atti, IX Congr. Naz. It. Patologia Vascolare. Copanello, 6-9 Gennaio 1987. A cura di R. Del Guercio, G. Leonardo e G. Zanini. Pg. 765, Monduzzi Ed. Bologna, 1987.
22) Stagnaro-Neri M., Stagnaro S., Microangiologia clinica della ipertrofia prostatica benigna. Ruolo patogenetico delle modificazioni del sistema microlovascolotessutale valutate con la Semeiotica Biofisica. Acta Cardiol. Medit. 14, 21, 1986.
23) Ghiadoni L., Taddei S., Virdis A, et al. Endothelial function and common carotid artery thickening in patients with essential hypertension. Hypertension. 32, 25-32, 1998.
24) Enderle M.D., Scroeder S., Ossen R., et al. Comparison of peripheral endothelial dysfunction and intimal media tickness in patients whit suspected coronary artery disease. Heart. 80, 349-54, 1998.
25) Stagnaro-Neri M., Stagnaro S., Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 13, 109, 1997.
26) Stagnaro S. Depression, Anxiety and Psychosis. B C Medical Journal, Volume 43, Number 6, page 321, July-August, 2001.
27) Stagnaro-Neri M., Stagnaro S. Indagine clinica percusso-ascoltatoria delle unità microvascolotessutali della plica ungueale. Acta Med. Medit. 4, 91 ,1988.
28) Stagnaro Sergio. New bedside way in Reducing mortality in diabetic men and women. Ann. Int. Med.2007. http://www.annals.org/cgi/eletters/0000605-200708070-00167v1
29) Stagnaro-Neri M., Stagnaro S. Introduzione alla Semeiotica Biofisica. Il Terreno Oncologico. Ed. Travel Factory, Roma, 2004. http://www.travelfactory.it/
30) Stagnaro Sergio. Newborn-pathological Endoarteriolar Blocking Devices in Diabetic and Dislipidaemic Constitution and Diabetes Primary Prevention. The Lancet. March 06 2007. http://www.thelancet.com/journals/lancet/article/PIIS0140673607603316/comments?totalcomments=1, and especially www.fce.it, http://www.fceonline.it/docs/stagnaro.pdf
31) Stagnaro Sergio. Biophysical-Semeiotic Bed-Side Detecting CAD, even silent, and Coronary Calcification. 4to Congreso International de Cardiologia por Internet, 2005, http://www.fac.org.ar/ccvc/marcoesp/marcos.php.
32) Stagnaro Sergio. Role of Coronary Endoarterial Blocking Devices in Myocardial Preconditioning - c007i. Lecture, V Virtual International Congress of Cardiology. http://www.fac.org.ar/qcvc/llave/c007i/stagnaros.php
33) Stagnaro Sergio. Bedside Evaluation of CAD biophysical-semeiotic inherited real risk under NIR-LED treatment. EMLA Congress, Laser Helsinki August 23-24, 2008. "Photodiagnosis and photodynamic therapy", Elsevier, Vol. 5 suppl 1 august 2008 issn, Page S17.

PRE-METABOLIC SYNDROME, CLASSIC AND VARIANT, PRECEEDES FOR DECADES THE METABOLIC SYNDROME.

Introduction.

First of all, before studying an argument playing a primary role in the Clinical Microangiology, such as microcirculatory activation in the post-absorptive state, under physiological as well as pathological conditions, unavoidable in bedside diagnosing Pre-Metabolic Syndrome, it is necessary that reader has steady knowledge of the topics illustrated in earlier articles on Microcirculatory Physiology (1-11) (See my website www.semeioticabiofisica.it and www.semeioticabiofisica.it/microangiologia, especially URL

(http://www.semeioticabiofisica.it/microangiologia/Documenti/Eng/Pre-metabolic%20syndrome%).

Doctor must be skilled at auscultatory percussion of both kidney and ureter, which allows to outline properly skin projection area of urinary tract and evaluate three ureteral reflexes, i.e., upper, middle, and lower, caused by “light” stimulation of trigger-points of the diverse examined biological systems (Fig 1). In fact, upper, middle, and lower ureteral reflexes give information on both functional and structural conditions of small arteries and arterioles, according to Hammersen (= upper ureteral reflex), Endoarterial Blocking Devises (EBD) (= middle reflex), as well as capillaries and post-capillary venules (= lower reflex) (1-4).

At the begin of third millennium, the researchers on type 2 Diabetes Mellitus initiate fortunately to find new ways in the prevention, diagnosis, therapeutic monitoring, in a direction, I have indicated more than 20 years ago (1-3).

My old Rapid Response to BMJ proved to be really warning: Sergio Stagnaro. “Pre-Metabolic Syndrome. Locus of Type 2 Diabetes Primary Prevention”. 1 August 2003, (http://bmj.com/cgi/eletters/327/7409/266#35204.

Nowadays physician’s opinion has clearly changed on the fasting glycemia (FPD), considering the post-prandium glycemia (PPG) more predicative of so-called “complications”, since it is somehow related to the endocrine-metabolic situation of post-absorptive state, which we can fortunately evaluate from biophysical-semeiotic view-point, as follows.

Over the last two decades, I have suggested to distinguish, in a clear-cut way, Glycemology from Diabetology; the later includes, unfortunately, less physicians among its followers than the first (1).

Indeed, the value of PPG is a reliable barometer of diabetic condition, physiologically based, because its abnormalities are predicative of the disease, and, thus, represents an useful data for the prevention as well as for glycosilated hemoglobins intensity, to which is related. Moreover, there is an increasing number of authors, who consider PPG abnormalities related to, and predicative of, future micro- and macro-scopic diabetic complications.

As it is easy to understand, scholars agree generally nowadays with the direction clinically provided with the aid of Quantum-Biophysical Semeiotics (1, 2, 3), and, in our mind, this event represents an epoch-making time in the war against diabetes mellitus, as I wrote earlier (bmj.com, 10 June 2001, in the Rapid Response: “Bed-side primary prevention is the major step in the war against diabetes mellitus”).

In fact, apart from the therapy, based on the utilization of a-glucosidase-inhibitors and fast insulines, such a thinking change, originated from physio-pathological, epidemiological, endocrine-metabolic findings, correlates with microcirculatory phenomena, which cause diabetes mellitus onset, on the base of diabetic constitution-dependent inhereted real risk, i.e. genetically directed, such as diabetic as well as dyslipidemic constitutions (See my website, www.semeioticabiofisica.it, “Biophysical-Semeiotic Constitutions: URL www.semeioticabiofisica.it/constitutions.htm) we have some years ago indentified clearly, and described as Congenital Acidosic Enzyme-Metabolic Histoangiopathy, at the URL: www.semeioticabiofisica.it/Documenti/Eng/istangiopatia cong.acidos.enzimo, initially evolved to pre-metabolic syndrome, and, then, to metabolic syndrome, both classic and “variant”, slowly worsening to diabetes (1, 2, 3).

Physiological and pathological microcirculatory activation in the post-absorptive state.

If doctors do not know the original physical semeiotics, and consequently the large variety of essential results of the research, performed in the diabetology by the aid of this precious clinical tool, they must pay a particular attention to PPG, surely of greater significance than that of FPG, as regards the primary prevention of diabetes mellitus, since it represents for such authors the early alteration, predicative of the future disease and its complications.

At this point, we briefly remember (this argument, certainly interesting, is beyond article’s aims) that PPG increases oxidative processes as well as activates PKC, bringing about vascular spasms and histangic lesion, as we have demonstrated by the original semeiotics, at which we will come back later on (4).

However, in our opinion, such as change of thinking among physicians must be considered of great value, even as the beginning of a long way, which over time, hopefully short, will reach a point, where micorcirculatory abnormalities, in particular the microcirculatory activation, playing a primary role, will be considered expression of alterations predicative of diabetes mellitus, and, thus, characteristic signs of the primary prevention locus.

Indeed, the phenomenon of type I, associated, type II, dissociated, and type III incomplete or “variant” form of the type II, microcirculatory activation plays a pivotal role in physiology and, respectively, in the pathogenesis of most common and dangerous human diseases, including diabetes mellitus, which originate on the base of CAEMH (1-4).

From the above remarks it follows that the early bed-side recognising microcirculatory abnormalities, as well as their “quantification” with the aid of Quantum-Biophysical Semeiotics represents, in our mind, a milestone in natural history of this syndrome, i.e., pre-metabolic syndrome, of physical semeiotics in general, and particularly of primary prevention.

On this subject, we must briefly remember, especially as regards the macroangiopaties, that the estimation of both microcirculatory function and structure, including the adventitial one, plays a primary role in bed-side diagnosing these common and serious diseases, starting from initial, subclinical stage. In fact, clinical and experimental evidence suggests that partial occlusion of a muscular artery – vasa publica, according to Ratschow – provokes quickly the compensatory, associated, type I, microcirculatory activation, in both local adventitial vasa privata and in distal related tissues.

Doctor must bear in mind that the microcirculatory bed represents the “peripheral heart”, which increases its autochthonus, sphygmic activity, when local blood supply decreases, even in a light manner, due to haematologic (anemia) as well as vascular causes, or cardiac insufficiency, which act up-wards. If these disorders, of course, are not promptly eliminated, such an activation of vasomotility and vasomotion slowly ends in the dangerous micorcirculatory insufficiency and, ultimately, of failure of local microcirculatory bed, characterized by the spatial inhomogeneity, accurately illustrated in some papers of my above cited site www.semeioticabiofisica.it/microangiologia.

Adventitial microcirculatory biophysical-semeiotic evaluation, in case of aortic aneurism, gives us an example of the preventive-diagnostic value of evaluating local microcirculatory situation (See URL: Practical Application, Abdominal Aortic Aneurism,

www.semeioticabiofisica.it/Documenti/Eng/Aneurism A Aorti_eng.doc). The anatomical lesion of aortic wall, really, can be evaluated at the bed-side by assessing adventitial microcirculatory activity of aneurism.

Pathophysiology of the “peripheral heart” Failure.

One can easily understand that microcirculatory activation aims to maintain physiological blood-flow in the nutritional capillaries and post-capillary venules, and, thus, to supply related parenchyma with sufficient material-energy-information.

As regards diagnosis as well as prevention, it is plain the usefulness of knowing the course of these adaptable microcirculatory events, never observed till now at the-bed side, i.e. clinically, by data collected with a simple stethoscope during physical examination.

As clinical and experimental evidence demonstrates, e.g., in case of partial, incomplete jatrogenetic occlusion of ileo-phemoral artery, in healthy, cutaneous, sub-cutaneous, muscular microcirculation downwards, at least in the first minutes, is activated, according to type I, associated. Clearly, such event can be observed also in case of non complete obstruction of wathever other vessel, for instance, the carotid, which brings about in related distal tissues the greatest increase of cerebral “vasomotion” (“vasomotion” indicates both vasomotility and vasomotion) (5, 6, 7, 8) (Fig 1, 2, 3).

Once again, the final result of Microcirculatory Functional Reserve (MFR) is maintaining tissue energy in normal range, which unfortunately is often only transitory, since till now doctor was not able to recognize “clinically” this dangerous situation of “unstable compensation” of the peripheral heart and, thus, of blood-flow, flow- and flux-motion, maintained in physiological ranges, although at lower levels, in related tissue components.

In other words, at the bed-side, till now, doctor is not capable to recognize the minimal, initial, rapid reactions of “distal” microcirculatory activation, secondary to macroangiopathy in its early and asymptomatic stage. MFR activation can last “silent” even years before clinical phenomenology occurs, obviously related to “peripheral heart decompensation”.

From the above remarks it follows that, in an individual psychophysically relaxed and in supine position, i.e. in a state of complete rest, recognizing type I, associated, microcirculatory activation by “light” digital pressure, e.g., on the skin of a limb or on a finger-pulp, allows doctor to assess three ureteral reflexes and, then, diagnosing without doubt the presence of macrovascular disorder up-wards, even initial and/or in early, symptomless stage, which can be diagnosed by numerous biophysical-signs, characteristic of the angiopathy (See above-cited sites).

“At rest”, the presence of type I, associated, peripheral microcirculatory activation in an apparently healthy individual indicates a “silent” macroangiopathy up-wards, i.e., in related vasa publica, according to Ratschow, that doctor must assess accurately and promptly treat.

By contrast, if the patient presents with clinical signs, characteristis of pripheral vascular disorders, such as intermittens claudicatio, the micocirculatory activation (“peripheral heart” activated) modifies over time and becomes of type II, dissociated, and, ultimately, ends in the dangerous situation of pathological functional microcirculatory “rest”, due to microvessel sphygmicity failure: vasomotion shows AL + PL £ 5 sec. ( NN = 6 sec. at rest), I = 0,5 cm. ( NN = 0,5 – 1,5 cm.), periods fixed at 10 sec. ( NN = 9 – 12 sec.) (Fig.s At URL (http://www.semeioticabiofisica.it/microangiologia/Documenti/Eng/Pre-metabolic%20syndrome%).

From the clinical-microangiological point of view, such as situation characterizes “peripheral heart” failure. The above-described pathological condition can be localized in a very small area of a limb – finger, calf, a.s.o.), where patient feels the “ischaemic” pain.

In conclusion, bed-side evaluation of microcirculatory activation (activation of MFR) represents a noteworthy progress in the field of physical semeiotics or, more precisely speaking, in Biophysical-Semeiotic Clinical Microangiology, playing a primary role, from now on, in the diagnosis, prevention, prognosis, therapeutic monitoring and research of all biological systems.

Bed-side recognizing microcirculatory activation, localized in various, well-defined biological systems, easy and rapid to perform, in a long experience proved to be reliable and useful in both phsiological and pathological conditions, offering original ways of clinical research.

Post-Prandial and Post-Absorptive State Activation, in physiological and pathological conditions: Pre-Metabolic Syndrome.

The microcirculatory behaviour in post-absorptive state, i.e., at least 3-4 hours after meals (this time, however, can be lower, because it is in relation to the food amount, the subject has eaten, his digestion as well as absorption capacity, insulin-secretion and insulin-receptors sensitivity), in the liver, scheletric muscle, adipose tissue, both central and peripheral, brain, pancreas, is essential in order to assess the particular metabolic-endocrine situation, as well as the complete and deep understanding the pre-metabolic syndrome, scientifically defined.

The assessment of the microcirculatory activation of pancreas, liver, striated muscle, adipose tissue, both central and peripheral, under physiological as well as pathological conditions, allowed to define precisely the pre-metabolic syndrome , i.e. the grey zone.

In fact, it is not possible to realize the essence of this particular condition of biological systems, real locus (site) of the primary prevention of most common and serious human disorders, without the steady biophysical semeiotic knowledge of both absorptive state and post-absorptive state, more or less abnormally modified, when the slow transition initiates from CAEMH to pre-metabolic syndrome, frstly, to metabolic syndrome subsequently, or Reaven’s syndrome, both classic and “variant”, and ultimately to the diseases.

With reference to the “variant” form of metabolic syndrome, we previously described (2), it is interesting to note that under such as condition only epatic microcirculation behaviour appears physiological, as regards insulin action, since local insulin-receptors are normally functioning, helping, thus, to defining and recognizing it by a refined way (10, 11). In a few words, hepatic and pancreatic microcirculation is identical, in the sense that the former parallels the later (Fig.1 and 2).

To recognize at the bed-side the presence of these bridge-events in a “quantitative” manner, which link the “whithe zone”, physiological, to the “black zone”, pathological, representing, thus, the “grey zone”, or pre-morbid stage, or better speaking pre-metabolic syndrome, that can last for years or decades, it is unavoidable that doctor has a steady knowledge of this original clinical method, which allows him to estimate “quantitatively” the microcirculatory condition, both functional and structural, in the different tissues, beginning generally from thre-four hours after meals. Fortunately, the preconditioning of diverse biological systems, mentioned above, facilitates enormously the diagnose of pre-metabolic state (See later on).

In fact, as the reader undestands easily, clinical evaluation of metabolic situation thre-four hours after meals, i.e. in the post-absorptive state, is adaptable also in evaluating metabolic condition, regarding glucose, lipids and proteins, soon thereafter the meals (absorptive state): for example, interesting data are collected by the evaluation of pancreatic, hepatic, muscular, abdominal sub-cutaneous adipose tissue (very different is the metabolism of “distal” adipose tissue, e.g. thigh,whose insulin-receptors are always physiologically functioning) microcirculation under both rest condition and after giving two coffee-spoons of sugar dissolved in water. After two minutes, or less, appears gastric hypermia, due to digestive phenomena, increased peristaltic gastric wave velocity (= period 12 sec. versus 18 sec.), and glucose absorption: gastric “vasomotion” results clearly increased according to type I. Soon thereafter, doctor observe the activation of pancreatic microcirculation, and, then, successively, the hepatic, muscular and adipose tissue microcirculatory activation.

At empty stomach, swallowing 2-3 coffee-spoons of sugar dissolved in water, allows doctor to estimate functional gastric digestive activity, and, successively the functional metabolic capacity of pancreas, liver, skeletal muscle, adipose tissue, both central and peripheral, and heart.

As far as pancreatic microcirculatory activation after giving two coffee-spoons of sugar dissolved in water is concerned, we must remember that this test proved to be of diagnostic value in diabetology greater than that of the OGTT, which is surely more expensive and complex.

In healthy, there is enlargement solely of the pancreatic interstitium (= “in toto” ureteral reflex ³ 1 cm.), indicating pulsated ormonal secretion, actually, as demonstrates also the deterministic-chaotic behaviour of interstitiomotility

In contrast, during the test (as well as in the absorptive state), in all biological systems, referred above, doctor observes the phenomenon of absorption, characterized by “in toto” ureteral reflex of smallest degree: < 1 cm. We underscore that these data, reader must know perfectly, play a paramount role in recognizing such as metabolic condition, i.e. pre-metabolic syndrome. In fact, there is a strict relation between “in toto” ureteral reflex intensity, on the one hand, and both absorption or tissue secretion-output, on the other hand.

The “in-toto” ureteral reflex intensity < 1 cm. during “light-moderate” stimulation of trigger-points of a biological system indicates a condition of tissue absorption of material-energy-informaton, while the intensity ³ 1 cm. is expression of actual secretion, or output of metabolites or hormons.

Moreover, it is easy to understand that pancreas interstititum is steadily large (“in toto” ureteral reflex ³ 1 cm.), although according to a deterministic-chaotic behaviour, related to insulin secretion pulsatility, as shows clearly the pancreatic diagram as well as pancreatic microvascular fluctuations.

Such as biophysical-semeiotic knowledge allows doctor, for the first time, to recognize if the individual, he examines, is fasting or not: the examination gives a lot of information, but, at times, it is missleading due to erroneous estimate in the transition from absorptive to post-absorptive state, which really lasts only for a few minutes.

This doubt can be easily resolved by dynamic tests, which stimulate (as VI dermatomere-pancreatic reflex during “middle-intense” stimulation) or restrain (“intense” stimulation of pancreatic trigger-points, apnea test, boxer’s test, Restano’s manoeuvre) insulin secretion: in former case, in fact, hepatic interstitium immediately appears smaller, i.e. < 1 cm., while it increases clearly during stress tests, that notoriously cause reduction of the insular hormone secretion.

In addition, interestingly appears the perfect agreement of AL + PL duration of both vasomotility and vasomotion in all aforementioned biological systems.

By contrast, in hyperinsulinemia-insulinresistance, where lacking is the increase of kidney volume during insulin acute pick secretion (evaluation test of insulin secretion, of greatest value) as well as suprarenal glands show a diagramm of disactivated microcirculation (See: test of hyperinsulinemia-insulinresistance by renal and suprarenal gland diagrams: Glossary), AL + PL in “peripheral biological systems is 7 sec., while the pancreatic AL + PL is > 7 sec., in direct relation to glicidic dysmetabolism (Fig. 1 and 2).

In absorptive state, the dissociation of AL + PL of vasomotility values between pancreas and peripheral tissue, e.g., pancreatic AL + PL > 7,5 sec., while the value in other biological systems is 7 sec., indicates glicidic dysmetabolism as well as hyperinsulinemia-insulinresistance.

It is important for doctor to know that the unique exception, under above-mentioned condition, is the “normal” microcirculatory activation of “peripheral” adipose tissue (for example, thigh adipose tissue), whose insulin receptors are normally sensitive to hormone in “all” cases.

As a matter of fact, during the absorptive state AL + PL of vasomotility duration is identical to that of the pancreas, while obviously in the post-absorptive state results the shortest of all, because the sensitivity of these insulin receptors in a moment of hyperinsulinemia capable to restrain the hepatic glucose output and FFA output from adipose tissue: pancreatic AL + PL 8 sec., hepatic (in classic Reaven’s syndrome, but not in the “variant” form) and “central” adipose tissue parameter value 7 sec., while in “peripheral” adipose tissue only 6 sec.

In the “variant” Reaven’s syndrome, under the same condition, hepatic “vasomotion” AL + PL lowers to only 6 sec., due to physiological response of the local insulin receptors, that characterizes such as particular form, conditio sine qua non of lithyasis as well as tissue calcium deposit, including vasal wall.

A long well established experience allows us to state that, at the moment, biophysical-semeiotics clinical evaluation of the absorptive state and post-absorptive state microcirculation represents the uppermost attained goal, as well as the most fruitful area of research in Clinical Microangiology.

Bed-side diagnosing pre-metabolic syndrome by means of biophysical-semeiotic preconditioning.

Biophysical-semeiotic preconditioning of pancreas, lever, skeletric muscle, adipose tissue, both central and peripheral, allows doctor to recognize the pre-metabolic syndrome easily and rapidly; it is performed in two different ways, micro- and macroscopic (fully illustrated in the site www.semeioticabiofisica.it/microangiologia, at the URL:

www.semeioticabiofisica.it/microangiologia/Documenti/Eng/A PRECONDIZIONAMENTO%:

1) macroscopic way: direct and quantitative evaluation of non-linear dynamic behaviour of a biological system (e.g., pancreas), by drawing the relative diagram, and /or, more practical in every day practice, by caecal and/or gastric aspecific reflex latency time (lt);

2) microscopic way: quantitative evaluation of local microcirculatory activation type and intensity.

As an example of the former way, i.e., “macroscopic”, of assessing the preconditioning we consider that cardiac, earlier illustrated (2): “mean-intense” digital pressure with the aid of bell-piece of stethoscope, placed on left heart ventricle projection area, in healthy, provokes ventricular dilation, lasting for 7 sec. Continuing such as stimulation – or if it is again applied after an interval of exact 5 sec. for one or two times – this periods lowers to 6 sec. and ultimately to 5 sec. (BioMedCentral, Biophysical Semeiotics is really useful in order to bed-side recognizing heart ischaemic disease, even before its onset, i.e., real risk of coronary artery disease.

http://www.biomedcentral.com/1471-2261/3/12/comments/comments).

By contrast, in case of ischaemic heart disease, for example, initial, first duration is ³ 7 sec., in relation to the seriousness of coronary disorder, and persists unchanged during successive evaluations. Identical results are gathered in case of valvular, hypertensive and amiloydosis cardiopathy.

Contemporaneously, in healthy, lt of the cardio-caecal and –gastric aspecific reflexes rises from 8 sec. to 10 sec. (age-dependent), while it is unchanged (about 8 sec.) in the initial or not severe disease – intermediate preconditioning, type II - , whereas it worsens in the advanced disease – pathological precoditioning, type III – nth expression of internal and external coherence of the biophysical-semeiotic theory.

In the later way, “microscopic”, i.e., in assessing tissue-microvascular unit activation, basal vasomotility as well as vasomotion show the typical physiological deterministic-chaotic behaviour.

At the end of the third stimulation, caused by pressure of the bell-piece of stethoscope, as above referred, we observe microcirculatory activation, type I, associated: AL + PL of the fluctuations of III upper (vasomotility) and of third lower (vasomotion) ureter persist for 7-8 sec. (NN = 6 sec.); it is necessary to estimate togheter, as an identical parameter, AL + PL, wich indicate the velocity, intensity and duration of arterioles and, respectively capillaries and post-capillaries venules opening, according to a synergistic model.

In fact, the transition from the rest state to the activation occurs by degrees: firstly PL increases (3 sec.® 5 ® 6 sec. ® 7 sec. ® 8 sec.), whereas intensity and height of oscillation wave remain the same. Subsequently, all fluctuations become highest spikes (HS), aiming to supply gradually a greater flow-motion (Fig. at URL

(http://www.semeioticabiofisica.it/microangiologia/Documenti/Eng/Pre-metabolic%20syndrome%).

With reference to this topic, it is necessary to remember the important function, played by EBD in this original clinical investigation, where their opening becomes more and more intense and prolonged during physiologic preconditioning occurrence, while “closure” duration progressively shortens. On the contrary, in pathology it is always observable ab initio, an alteration, firstly functional, and, then, structural, of the endoarteriolar blocking devices so that estimating EBD, from both functional and structural view-point, gives the same information as the preconditioning, expression of strict logic connection of theory, we support.

To summarize, in healthy the preconditioning brings about, as natural consequence, an optimal tissue supply of material-information-energy, by increasing local flow-motion as well as flux-motion.

At this point, we come back to the former example: in the initial phase of coronary heart disease, what evolves very slowly toward successive phases, “basal” biophysical-semeiotic data can “apparently” result normal. However, under careful observation, the duration of cardio-gastric aspecific reflex results prolonged: > 4 sec. (NN £ 4 sec.), indicating a local microcirculatory disorder.

Really, in these conditions, EBD function is clearly compromised, but for some time the increased vasomotility counterbalances efficaciously the impaired supply of normal blood amount to parenchyma: also the vasomotion, at rest, shows parameter values oscillating in physiological ranges, due to the augmented arteriolar sphygmicity; such a condition can be “technically” defined peripheral heart compensation.

Noteworthy, from the diagnostic point of view, are also the cardio-caecal and -gastric aspecific reflexes, when accurately assessed: after a lt still normal (8 sec.), doctor observes a reflexes duration, before the successive one initiates, of 4,5 sec. (NN £ 4 sec.), and a differential lt (= duration of reflex disappearing before the beginning of the following) of only 3 sec. (NN > 3 <>

Clinical recognizing of these “slight” abnormalities, really useful in diagnosing initial and/or symptomless disorders, altough not difficult to perform, requests a good knowledge, a steady experience and a precise performance of the new semeiotics.

In these cases, preconditioning allows in simple and reliable manner to recognize the pathological modifications, mentioned above, which indicate the altered physiological adaptability, even initial or slight, of the biologial system to changed conditons as well as to increased tissue demands (Tab.1).

Physiological, type I Preconditioning ® Tissue-microvascular unit activation ® MFR normal ® outcome +

(Physiological DEB Function) type I, associated

Intermediate, type II Preconditioning ® Tissue-microvascular unit activation ® MFR compromised ® outcome ±

(EBD function slightly modified: closure) type II

Patological, tipo III Precondizioning ® Tissue-microvascular unit activation ® MFR absent ® outcome -

(EBD function pathological) type II, dissociated

Tab. 1

From the above remarks it appears plain that the various parameters of caecal, gastric aspecific and choledocic reflex, type of activation and, then, EBD function, related to a defined biological system, parallel the data of preconditioning.

Another example to clarify the abstract value of the concept: in healthy, pancreatic-gastric aspecific and –caecal reflex is characterized by lt of about 12-13 sec., D of £ 4 sec. and differential lt or fractal dimension > 3 <> (NN = 3,81). Contemporaneously “basal” pancreatic “vasomotion” shows the typical deterministic-chaotic behaviour, known to reader by now, in which AL + PL lasts 6-7 sec. physiologically, fluctuations intensity varies from 0,5 to 1,5 cm. (conventional value), the period fluctuates between 9 sec. to 12 sec., average value 10,5, fractal number (8).

Soon therafter pancreatic preconditioning (“mean-intense” cutaneous pinching of VI thoracic dermatomere for 15 sec., repeated three times with 5 sec. interval exactly), in healthy, caecal-, gastric aspecific-, and choledocic-reflexes show lt of 14 sec. (NN basal value = 12 sec.), duration £ 3,5 sec., and differential lt > 3,81 £ 4. Simultaneously, occurs pancreatic microcirculatory activation, according to type I, associated, with AP + PL of 7-8 sec., intensity of the ureteral fluctuations, both upper and lower, greatest (1,5 cm.), as we observe in HS, EBD physiologically activated:middle ureteral reflex intensity, brought about by “mean” stimulation of related trigger-points of 1,5-2 cm., reflex duration 22-24 sec. (basal 20 sec.), and duration of its disappearance 4 sec. (basal 6 sec.).

By contrast, in impaired glucose tollerance (IGT), above-referred parameters, at least in its initial phase (= pre-metabolic syndrome) and in slight cases, do not modify, but worsen statistically exclusively in advanced stages, in relation to disease seriousness: lt decreases to £ 11 sec., while the duration rises to ³ 4 sec., and differential latency time results smaller than that initial, border-line (= 2,5-3 sec.): <> Under this condition, microcirculatory activation is of type II, dissociated, indicating the actual situation of pre-morbid state in an individual completely symptomless, even for decades.

Interestingly, the preconditioning can be easily applied in estimating both function and structure of all biological systems, which at this moment, at rest, can reveal apparently normal conditions, but, in reality, show clear-cut abnormalities of numerous parameters values of the biophysical-semeiotic signs (Tab. 2).

HEALTH	Tl 12 - 14 sec.	Duration <> sec	Differetial lt >3£4	mvtU. activation type I associated
IGT in slow diabetic evolution	Tl normal or £ 11 sec.	Duration ³ 4 sec.	Tl differenziale £ 3 - 2,5	mvtU. activation typeII dissociated

Tab. 2

Parameters of pancreatic-gastric apecific and –caecal reflex after the preconditioning in healthy and in a individual with impaired glucose tollerance in slow diabetic evolution.

(explanation in the text).

Gradual worsening of the parameters values of reflexes, observed bed-side with the preconditioning, related to the actual functional and structural conditions of the investigated biological systems, can be “geometrically” represented, in a refined way, by the temporal changes of the “strange attractor”, apparently such at rest, which, after proper tissue stimulations, firstly becomes a “close-loop attractor”, and, ultimately, a “fixed-point attractor”: from the biological view-point, the life is the trajectory of the strange attractor of biological systems”.

Tissue microcirculation in the post-absorptive state in various diabetic stages.

In the interest of reader, to facilitate the understanding of following argument, we refer briefly some fundamental knowledges of the original semeiotics, remembering elementary concepts of glycidic metabolism after three-four hours, at least, after meals, in healthy, in case of IGT, and finally in diabetes mellitus, showing that, at every moment of the day, doctor is able to evaluate insulin-secretion, as well as insulin-resistance at the bed-side by means of Biophysical Semeiotics (1, 2, 9, 10, 11). In this connection, both acute pick of insulin-secretion test (See later on) and post-prandial glycemia (PPG) are really fundamental.

In fact, doctor is able to recognize “clinically” initial abnormalities of glycidic metabolism, since insulinemic pick results always reduced, even in different degree (assessed as latency time, duration and intensity of pancreatic-aspecific gastric reflex, for instance (NN = lt 12-13 sec., D 3 < productid="1,5 cm" st="on">1,5 cm.), and prescribe early, in selective and rational way, the best therapy, including diet, etymologically speaking, carrying out efficaciously diabetes mellitus primary prevention on a very large scale.

If doctor evaluates over and over again, at least three times, with unavoidable intervall of 5 sec. – biophysical semeiotic preconditioning – the acute pick of insulin secretion, he observes the described diabetic pathological condition, even initial and/or slight, characterized by various degrees of basal parameters values: at basal line, in diabetes mellitus the VI thoracic dermatomere-gastric aspecific reflex lt (i.e. acute pick of insulin secretion) is <> (NN = 12-13 sec.), D > 4 sec (NN > 3 <>differential lt before the occurring of successive reflex <>(= > 3 <>

In reality, it appears very interesting that these values are statistically modified, in the pathological sense, in case of both IGT and its different stages during diabetic evolution, particularly after biophysical semeiotic preconditioning: lt appears reduced over time, lowering from 12-13 sec. or > 13 sec. in case of insulin hypersecretion, to 10 sec. or £ 9 sec., inversely related to the seriousness of hormone secretion impairement.

In contrast, in healthy, pancreatic islets preconditioning brings about a clear-cut amelioration of all pancreatic-gastric aspecific reflex parameters, by significant way. Contemporaneously, both pancreatic and peripheral microcirculatory bed is activated, according to type I, associated, where vasomotility as well as vasomotion clearly increased in the pancreas: AL + PL rises from 6 sec. to 8 sec., I becomes maximal, i.e. 1,5 cm. (HS) and DEB result activated (closure duration <> 20 sec.) (Fig. 1, 2, 3).

As regards the peripheral tissues, the values depend on the presence or absence of classic or “variant” metabolic syndrome, as referred above.

On the contrary, in case of IGT, the values of ureteral reflex parameters are the same of those typical of dissociated microcirculatory activation, where only the vasomotility appears increased, while the vasomotion is lowered, and, as usually, is observable DEB dysfunction, more or less intense (Fig. 2).

It follows that doctor observes histangic disorder, acidosic in origin, indicating the real pathogenetic role played by microcirculatory activation, type II, dissociated, in whom, in our mind, the abnormal activity of Endoarterial Blockomg Devises (DEB), ubiquitarious in contrast to AVA, type II, group A and B, as well as AVA, type I, according to Bucciante) plays a primary role in the onset of most common and dangerous human diseases, degenerative, connective and neoplastic in nature.

Histangic different response to endogenous insulin, in physiology, in Pre-Metabolic Syndrome and in pathology.

Biophysical-semeiotic evaluation of pre-metabolic syndrome, characterized by the absence of disease due to compensation, even unstable, as regards receptorial hyporesponsiveness, is based chiefly on clinical and quantitative evaluation of insulin-resistance (11) in insulin-dependent tissues, as liver, striated muscle, “abdominal” adipose tissue, bresat and thorax, whose metabolic behaviour is clearly more “vulnerable” than the peripheral adipose tissue.

Physiologically, endogenous insulin, secreted by means of the stimulation of VI thoracic dermatomere due to digital pressure or prolonged pinching of the related skin, activates various microcirculatory systems also of these biological systems.

By contrast, interestingly, since the first stage of slow and progressive evolution of CAEMH to metabolic syndrome, classic or “variant”, i.e., in the above-illustrated condition termed pre-morbid or pre-metabolic state, insulin brings about type II microcirculatory activation, dissociated, and consequently tissue acidosis, subsequent to the reduction of insulin-receptor activity (responsiveness) toward its hormone, as well as nor-epinephrine (nor-adrenalin) as well as epinephrine (adrenalin), and, thus, compensatory increase of insulin, epinephrine and nor-epinephrine (= enhancement of suprarenal glands macro-fluctuations as well as microcirculatory oscillations), causing the well-known abnormal consequences.

At the begin of this paper we have remembered that, in healthy, the insulin activates the microcircle, while under pathological conditions, such as hyperinsulinemia-insulinresistance, evolving slowly towards diabetes mellitus, provokes increase of free radicals and Protein-Kinase-C (PKC), which, in turn, causes macro-and micro-vascular spasms (Millennium of Diabetes Treatment, Medscape 2000), as we previously demonstrated clinically (2, 9,11). It follows that the microcirculatory bed is activated, according to activation type II, dissociated.

To recognize and “quantify” clinically the interesting and dangerous hyperinsulinemia-insulinresistance, clinically silent, by the easiest way doctor performs the basal evaluation of lt of finger-pulp-gastric aspecific or caecal reflex. After acute pick of insulin secretion (=cutaneous pinching, lasting about 15 sec., inwards to the crossing point of hemiclavicular line and homolateral costal arch: VI thoracic dermatomere), doctor assesses for the second time lt of the same reflexes, which physiologically rises from 7-8 sec. to 9-10 sec., while in the later, pathological condition, i.e, in pre-metabolic stage, characterized by hyperinsulinemia-insulinresistance, the lt first appears unchanged and, then, becomes shorter, in inverse relation to the seriousness of dysmetabolic condition.

In this condition, hyperinsulinemia causes the microcircultory activation, type II, dissociated, and, then, the “centralization” of flow-motion.

Doctor observes characteristic behaviours of insulin receptors at renal level, which account for the reason of the renal test of hyperinsulinemia-insulinresistance, mentioned above (See Glossary in the site Semeiotica Biofisica): receptorial down-regulation, consequence of the increased hormonal blood level, hinders the physiological response of kidneys to acute pick of insulin secretion, characterized by microcirculatory activation, type I, associated, wich explains the insulin-dependent modifications of kidney diagramm: in healthy, after a lt of 3 sec., the kidney enhances intensely its size (congestion) for 10 sec., while in the diabetic lt rises to only 6 sec. with slight and short increase of its diameters and prevailing renal decongestion.

In the pre-metabolic syndrome and in the steady IGT, one speaks of insulin-resistance if AL + PL value of both pancreatic vasomotility and vasomotion in the post-prandial state is higher than that osserved in the liver (with the exception of “variant” metabolic syndrome), striated muscle and abdominal adipose tissue.

In other words, under such as situation, peripheral metabolic activity needs a more amount of insulin to counterbalance insulinreceptors abnormal sensitivity, and thus to maintain in physiological ranges the glico-lipidic metabolism, by the aid of hyperinsulinemia (2, 9). In this condition, the renal test of hyperinsulinemia results negative, i.e., pathological, as described above.

However, when endocrine pancreas goes on slowly toward functional insufficiency, even with different intensity, in the post-absorptive state the duration of AL + PL is greater in peripheral tissues (liver, “central” adipose tissue, striated muscle) than in the pancreas. From the metabolic-biochemical view-point, these events are explained by the fact that the insulin dos not reach sufficient blood level to “check” glucose secretion by the liver as well as FFA by abdominal-thorax adipose tissue away from the meals. Notoriously, physiological amount of hormone controls, on the one hand, glucagone activity (hepatic glucogenolysis and no-glucogenogenesis) and, on the other hand, lipolysis (free fatty acids secreted in the blood).

The curbing insulin action influences, of course, microvascular system function in diverse tissues, where vasomotility and vasomotion show the same intensity.

In fact, as I demonstrated clinically, there is a strict functional relation between parenchyma and relative microcircle (Introduzione alla Semeiotica Biofisica), which allows bed-side anatomo-functional evaluation of a precise parenchyma by assessing the relative microcircle, representing, thus, the climax of Clinical Microangiology.

At this point, as regards what is illustrated above, it is of great interest the fact that, if the parenchyma is activated in the sense of absorption and/or synthesis (for example, the liver synthesizes glucogen, as we observe in post-prandial state), intertitium appears “minimal” (= “in toto” ureteral reflex, brought about in the first 6 sec., after “light” stimulation, is really small: < 1 cm. (NN = 0,5 cm.), while in case of microcirculatory activation indicstes the presence of secretion (FFA or glucose output in blood stream) the interstitium is clearly “large” : > 1 cm. (12, 13, 14, 15).

In contrast, when glycidic metabolism is altered, even in initial and/or silent stage, rceptor insulin sensitivity results reduced and consequently we observe hyperinsulinemia in order to counterbalance such hormone insufficiency, increase of hepatic glucoeogenesis as well as glicogenolysis, initially properly controlled ba periheral absorption (adipose tissue and muscles, including the myocardium), achieving, thus, a new steady state plamatic glycidic concentration (1, 2, 9, 11, 12).

In this metabolic situation, which can last for years or decades, the microcirculation in the diverse tissues is necessarily activated, i.e., the vasomotility and vasomotion are showing progressively basal conditions and, then, a large variety of microcirculatory situations, different from both quantitative and qualitative point of view, whose investigation open new and fascinating ways in medicine and particularly in primary prevention.

Pre-Metabolic Syndrome: microcirculatory activaton in initial phases of principal diseases. Two pressures test.

In following, we refer the data of our research, initiated in October 1998 in patients with pre-metabolic syndrome, to study the microcircle in the initial phases of principal human diseases. These results appear to be, from now on, really interesting altough referred exclusively to some diseases, though very frequent to observed in day-to-day practice: diabetes mellitus, arteriosclerosis, dyslipidemia, ischaemic heart disease, arterial hypertension, kidney and gall-bladder-stones, and malignancies.

From at least 20 years, we claim unheeded that CAEMH-a represents the conditio sine qua non of most common, serious, human pathologies (1-6, 18-20). The unavoidable way from this functional mitochondrial cytopathology to various diseases has been clinically recognized and indentified by us as poli-metabolic alteration, metabolic X syndrome, we termed untill now as Reaven’s Syndrome, of whose we described the so-called “variant” form (2, 9), which preceeds and then can be associated with kidney and gall-bladder-stones, as well as the calcium deposit in all tissues, incuding arterial walls, and consequently we consider it the conditio sine qua non of lythiasic disorders.

The microangiological data, observed in the post-absorptive state, corroborate our former statements, enlightening the complexity of physio-pathological mechanisms at the base of malignancies (See in the above-cited site: Oncological Terrain) as well as metabolic and infectious diseases, unfortunately nowadays not complicately utilized on large scale.

In addition, this biophysical-semeiotic microangiological study allows to gather at the bed-side essential information, which provides the possibility of the interpretation of the real nature of the passage from health stage – white zone – to that of disease – black zone – explaining, although incompletely, clinical significance and suggesting, thus, nosological definition of the term pre-metabolic state, premetabolic syndrome, Grey Zone, place of the “primary” prevention, rationally and individually realized.

White Zone ® Pre-Metabolic Syndrome or Grey Zone ® Black Zone

The activation of tissue-microvascular system is not a monotonous event, always identical. The transit from basal state, or at rest, to that of “active hyperemia” is dependent from the primitive parenchyma activation.

After the end of post-prandial stage, i.e. about 3 hours after the meal, in healthy, insulin secretion modulates the glucagonic activity, hepatic glycogenolysis and lipolysis. Consequently, physiologically, in the post-absorption state, we observe in the pancreas, striated muscle, adipose tissue, both “central” and “peripheral”, and in the liver a functional situation, characterized by a “vasomotion” showing periods and intensity with deterministic-chaotic behaviour and normally functioning AVA.

The physiological steady-state of glycemia indicates that glycemic concentration are normal on an empty stomach, since there is perfect relation between vasomotility as well as vasomotion in all tissues: AL + PL = 7 sec.; I = 1 - 1,5 cm.; fD = 3, and AVA, including EBD, normally functioning (Fig. 1, 2, 3).

It is plain that it exsists “always” microcirculatory activation in the tissues, although time-dependent of different intensity: biological systems are systems open to exchange of material-energy-information.

It follows that the caecal reflex (= caecal dilation, caused by mean digital pressure on whatever biological system) latency time appears physiological in all tissues, mentioned above (pancreas = 12 sec.; liver = 10 sec.; adipose tissue = 10 sec.; striated muscle = 10 sec. and, ultimately, brain and heart = 6 and respectovely 8 sec., age-dependent, of course).

The two pressure test gives rapidly interesting information as regards parameters values of tissue oxygenation. In fact, they allow to recognize promptly the physiological “vasomotion”: soon therafter caecal reflex appears, doctor increases manual, digital pressure (even the pressure caused by the bell-piece of stethoscope), in relation to the type of stimulation, enhancing, thus, the intensity of related trigger-points stimulation.

In our case, i.e., stimulation with a lasting “light-moderate” pinching, doctor increases its intensity, obviously. Temporaneously, the reflex rapidly disappears for th duration, in healthy, of > 3 sec.<>

The referred results, i.e. the information given by the two pressure test, is related to the activation intensity of local microcirculatory system (FMR, functional microcirculatory reserve), causing a greater O₂ and metabolites supply to tissues, resulting in clear amelioration of of tissue pH, and, thus, caecal reflex disappearing, wich indicates, therefore, histangic acidosis.

In contrast, when the microcircle is already activated, as during the gland secretion, and basal lt is physiological (= normal tissue oxygenation), the two pressure test results abnormal, showing value lowered to <>

Microcirculatory activation in glucose metabolism impairment.

At this point, to understand properly the essence of pre-metabolic syndromewe, we must consider the vasomotility and vasomotion in early stages of IGT during the absorptive state and, then, in post-absorptive state. Of course, these are different events related to residual insulin secretory activity of Langheran’s islets cells, variable from individual to individual, as well as in the same subject, over time. We must remember the normal function of insulin receptors of lever, characteristically present in the “variant” form of metabolic syndrome (2, 21).

In the IGT, in initial stage, insulin secretion in general appears substantially “increased”, likely due to reduced insulin receptor sensitivity, including the same receptors of Langheran’s b-pancreatic cells (the question about the relation between insulin-resistance and hyperinsulinemia untill now are not clarified, although doctors speak about compensatory hyperinsulinemia)

At the beginning of the process, both hepatic glycogenolysis and neoglycogenesis are normal, successively glycogenolysis enhances, analogously to the lipolysis in adipose tissue, depending from receptor sensitivity, as well as responsivity as far as insulin is concerned.

It follows that the microcirculatory activation in the liver, brain, adipocytes and in striated muscle shows always a pathologial behaviour, although different from case to case, as referred above in case of pre-metabolic syndrome.

From biophysical-semeiotic view-point, glucose dysmetabolism is characterized by the “dissociation” between pancreatic microcirculatory activation, assessed as AL + PL duration, and that peripheral. In brief, in presence of reduced receptor sensitivity, obviously, in the absorptive state, i.e., untill 3-4 hours after meals, the opening duration of microvessels is more intense at level of pancreatic cells (AL + PL = 8 sec.) rather than in the striated muscle, liver (in the absence of “variant” form” metabolic syndrome) or adipose tissue of thorax and abdomen, where AL + PL persits for 7,5 sec., exclusively in the vasomotility (Fig. 1).

It is now well known that, under this condition, in thight adipose tissue there is a microcirculatory activation similar to the Langheran’s pancreatic islets (AL + PL = 8 sec.), because local insulin receptors are physiologically functioning.

On the contrary, during the post-absorptive state, due to the reduced “curbing” insulin action – hyperinsulinemia-insulinresistance – we observe microcirculatory events completely opposite: pancreatic AL + PL really intense, showing value of 7-8 sec., while in the liver AL + PL is 8-9 sec. (apart from “variant” type of metabolic syndrome, where the value is 7-8 sec. as that pancreatic), as well as in thoracic and abdominal adipose tissue.

Once again, at level of thigh adipose tissue, the microcirculation appears similar to that in pancreas: AL + PL = 7-8 sec. Interestingly, in striated muscle microcirculatory activation is usually reduced (AL + PL = 6-7) in comparison with the pancreatic one, since muscular tissue is always in greater or less absorption state, actually in presence of reduced insulin receptor sensitivity.

Therefore, in the initial stages of IGT, local microcirculatory activation is capable to maintain, “at rest”, an apparently normal supply of material-energy-information to parenchymas, whereas in advanced IGT, when “peripheral” microcirculatory pattern, related to “vasomotion” in post-absorptive state, it results as follows: AL + PL = 8-9 sec., I = 1,5 (HS), caecal reflex lt normal, D > 4 sec. £ 5 sec.

In contrast, under the same condition, we observe pancreatic microcirculatory activation dissociated, type II, with AL + PL (Fig. 2), exclusively at the level of vasomotility, clearly increased (8 sec.), showing differential lt of the pancreatic-caecal reflex <>test of two pressures results pathological (increasing pinching intensity at level of VI thoracic dermatomere causes the disappearance of caecal and/or gastric aspecific reflex for solely 1 sec.).

In realty, interestingly, the accurate biophysical-semeiotic evaluation in IGT allows doctor to ascertain that the lt of pancreatic-gastric aspecific and/or caecal reflex is normal (12 sec.), but reflexes duration is greater (³ 4 sec.) and differenzial lt (= duration of reflex disappearance) shorter (fD £ 3 sec.), indicating clearly the conditon of unstable metabolic equilibrium, which can be recognized by the precious tool of preconditioning.

It is impossible to request further performances to a similar microcircle, which is functioning, at rest, even in initial phase, at maximal level of its activity, and successively goes on toward a slow and progressive failure, as the test of two pressures clearly demonstrates.

Hyperinsulinemia-insulinresistance as independent risk factor of the most severe human diseases.

The following clinical and expermental evidence, formerly illustrated, demonstrates clearly the primary role of hyperinsulinemia-insulinresistance, in the pathogenesis of a large number of human diseases, as we claim from the clinical view-point: after assessing basal parameters of finger-pulp – caecal reflex, as well as local vasomotility and vasomotion, doctor provokes, by mean (not to much intense) pinching of VI thoracic dermatomere, the acute pick of insulin secretion (2, 9, 11). Soon thereafter, doctor estimates the reflex parameters for the second time: in healthy, physiological microcirculatory activation ameliorates tissue O₂, likely to what occurs during the two pressures test, while in the IGT the favourable influences become more and more smaller and finally disappear, in inverse relation to the impairement degree of glucose metabolism or, more exactly speaking, in relation to the reduced sensitivity of insulin receptors as well as to “vasocontraction”, present in this pathologic situation.

The vascular response to the acute pick of insulin secretion in healthy is clearly different from that we observe in hyperinsulinemia-insulinresistance: in the former, in fact, there is microcirculatory activation, whilst in the later, there is progressive disactivation and subsequent histangic lesion.

Finally, when metabolic syndrome, both classic and “variant”, is leading to DM, “endogenous” insulin worsens transitory all reflex parameters during the test of acute pick of insulin secretion.

From Clinical Microangiology view-point, noteworthy in the pre-metabolic stage are functional and structural AVA abnormalities, in particular those of EBD, as well as the progressive, variable in intensity, dissociation between vasomotility and vasomotion (1, 2, 9, 11, 21), which allows to realize a subdivision of microcirculatory activation, useful for bed-side diagnosing as well as therapeutic monitoring.

As a matter of fact, two are the chief types of microcirculatory activation (it exists also the microcirculatory activation type III, incomplete, as the reader knows well: Type I, associated, global or circumscribed, in whom both the vasomotility and the vasomotion show increase of their fluctuations and AL + PL duration of 7-8 sec., while AVA are predominantly “closed” (Fig.2); Type II, dissociated, global or confined, when only the vasomotility is increased, whilst the vasomotion, initially is normal (AL + PL of 6 sec.), but progressively becomes reduced, characterized by short (<>plateau line and from a period fixed at 10 sec. The AVA are mainly “open” in hyperstomy stage (we remember that the adjactive “open” indicates the intense blood-shunt along arterious-venous anastomoses) (Fig. 3). Between these two “extreme” types, we may observe a large variety of intermediate forms.

In the type I, global, physiological microcirculatory activation (involving all tissues, mentioned above: the so-called active hyperemia) and in the type II, global, pathological, really we encounter a large variety of microcirculatory patterns during the post-absorptive state, whose evolution will lead over time to different disorders, if doctor does not suggest the correct and prompt therapy.

For example, in cancer the microcirculatory bed shows type II, dissociated, pathological activation, characterized by intense vasomotility with AL + PL of 8 sec. as well as maximal oscillations (1,5 cm.= HS), but the vasomotion shows AL + PL of only 5 sec., whose intensity is minimal and fixed at 0,5 cm., and AVA in hyperstomy phase. Such as behaviour is extrem from the pathological point of view, preceded and accompanied by an intense oncological terrain.

From the above remarks it is plain that we face interesting microcirculatory problems, really original, and that we are moving in a field of research, interesting and fascinating, due to its implications.

The doctor, who rightly shares our enthusiasmus, will necessarily share also the need, we are feeling strong, to reach all possible goals, conducting our research on a ground “to which not even the angels would dare to put their foot”.

When these targets will be attained, it will start and hopefully perform successfully the “primary” prevention of the most common and serious human diseases, invalidating or deadly, conducted in a personal, prompt manner, in rationally selected individuals, on a very large scale, by means of Biophysical Semeiotics.

In NIDDM (but even in IDDM) pancreatic microcirculatory activation is, of course, of type II or dissociated. In fact, in type 2 diabetes mellitus the stady-state is laying at a glicemic level higher than that physiological, but the hepatic glucose secretion as well as its perpheral utilization (due to the mass-effect of glucose) are the same. Performing the acute pick of insulin secretion does not normalize micorcirculation in these disease, at the most reduces its activation.

Really, we can observe cases of IDDM in which extra-pancreatic microcircle, or a part of it, result normally functioning. In other words, the pathological microcirculatory activation in diabetes mellitus doen not involve all tissue-microvascular units of the patient, since CAEMH-a, due to its definition, varys from subject to subject, from tissue to tissue and, finally, from part to part of the same tissue.

In ischemic heart disease doctor observe microcirculatory activation, type II and coronary EBD disactivation, and sometime in adipose tissue, as in dyslipidemia, even if it was present solely over the past years. In ATS one recognizes the pathological adventitial microcirculatory activity of the involved arteries. In these conditions, obviously, the AVA are hyperfunctioning (blood-shunting in microcirculatory bed) and subsequent tissue hypoxia. The acute pick of insulin secretion reduces the microcirculatory activation: AL + PL decreases from 8 sec. to about 6 sec., with clearly pathological consequences.

Interestingly, one observes a microcirculatory pattern typical of the dysplipidemia, actually present or not, in which firstly there is microcirculatory activation of type II “partial” (striated muscle and adipose tissue), to which follows the type II also in the liver and myocardium, when insulin-resistance and hyperinsulinemia pathologically activate the microcircle, so that over time microvascular activation pattern changes slowly.

At the moment, the biophysical-semeiotic research in pre-morbid stage is a long way within the bounds of it possibilities. However, we are allowed to state that the metabolic syndrome, classic or “variant” (2), represents the link from CAEMH-a to DM, arterial hypertension, dyslipidemia, gout, ATS, cancer, a.s.o.

Between CAEMH and metabolic syndrome, classic and “variant”, there is the territory, until now “unexplored”, i.e. Pre-Metabolic Stage, locus of the primary prevention of most common and severe human diseases.

Likely, as monstrates the tissue-microvascular unit activation during the postabsorptive state, hyperinsulinelia-insulinresistance, as an effect re-acting on its cause, worsens the histangic acidosis: e.g., the adventitial microcircle or vasa vasorum, is not capable to eliminate the catabolite from the arterial wall, which consequently appears damaged by the excess response – responsivity – to arteriosclerotic risk factors, according to our “Microcirculatory Arteriosclerotic Theory”, at the base of CAD (23, 24).

Clinical and experimental evidence shows that it is more dangerous for the tissues the abnormal elimination of the local catabolites, than analogous reduction of blood-supply to the same tissue: in healthy, digital “intense” pressure of the thumb finger-pulp against that of forfinger, brings about caecal reflex (= tissue acidosis) after latency time of 8 sec. (age-dependent, of course). After the beginn of digital pressure on brachial artery, obstructing it “partially” so that “radial pulsations” result clearly less intense than before, for 5 sec., lt of caecal reflex decreases to 6 sec. By contrast, a “light” pressure for 5 sec. upon inner surface of the same arm, able to ostruct exclusively brachial vein and local superficial lymphatics, causes caecal reflex after only 4 sec., as a consequence of interstitial stasis, compromised elimination of catabolites anf hydrogenions, and, then, the greater tissue lesion.

In conclusion, we have always to remember that during the slow evolution of pre-metabolic syndrome toward hyperinsulinemia-insulinresistance, IGT, type II DM, and/or Arterial Hypertension, Dyslipidemia (metabolic syndrome, both classic and “variant”) the microcirculatory activation, type I, becomes of type II, showing really a large variety of patterns, which shows a progressive dissociation, until “vasomotion” appears characterized by AL + PL of 5 sec. and I of 0,5 cm., while AVA dysfunction results more and more intense, characterized by permanent hyperstomy. Bed-side recognizing microcirculatory activation “even” at rest, and classifying it correctly by a clinical method, open new and promising outlooks on the primary prevention.

Bibliografia

1) Stagnaro S., Stagnaro-Neri M. Valutazione percusso-ascoltatoria del Diabete Mellito. Aspetti teorici e pratici. Epat. 32, 131, 1986.

2) Stagnaro S.-Neri M., Stagnaro S., Sindrome di Reaven, classica e variante, in evoluzione diabetica. Il ruolo della Carnitina nella prevenzione del diabete mellito. Il Cuore. 6, 617, 1993. [Medline]

3) Stagnaro S. Diet and Risk of Type 2 Diabetes. N Engl J Med. 2002 Jan 24;346(4):297-298. [Medline]

4) Stagnaro Sergio. Newborn-pathological Endoarteriolar Blocking Devices in Diabetic and Dislipidaemic Constitution and Diabetes Primary Prevention. The Lancet. March 06 2007. http://www.thelancet.com/journals/lancet/article/PIIS0140673607603316/comments?totalcomments=1, and especially www.fce.it, http://www.fceonline.it/docs/stagnaro.pdf

5) Stagnaro S., Valutazione percusso-ascoltatoria della microcircolazione cerebrale globale e regionale. Atti, XII Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. 13-15 Ottobre, Salerno, e Acta Medit. 145, 163, 1986.

6) Stagnaro-Neri M., Stagnaro S., Auscultatory Percussion Evaluation of Arterio-venous Anastomoses Dysfunction in early Arteriosclerosis. Acta Med. Medit. 5, 141, 1989.

7) Stagnaro-Neri M., Stagnaro S., Modificazioni della viscosità ematica totale e della riserva funzionale microcircolatoria in individui a rischio di arteriosclerosi valutate con la percussione ascoltata durante lavoro muscolare isometrico. Acta Med. Medit. 6, 131-136, 1990.

8) Stagnaro-Neri M., Stagnaro S., Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 13, 109, 1997.

9) Stagnaro S., Stagnaro-Neri M., Valutazione percusso-ascoltatoria del sistema degli oppioidi endogeni nei pazienti cefalalgici. Contributo alla definizione della costituzione emicranica. Epat. 33, 35, 1987.

10) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: valutazione clinica del picco precoce della secrezione insulinica di base e dopo stimolazione tiroidea, surrenalica, con glucagone endogeno e dopo attivazione del sistema renina-angiotesina circolante e tessutale – Acta Med. Medit. 13, 99, 1997

11) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: la manovra di Ferrero-Marigo nella diagnosi clinica della iperinsulinemia-insulino resistenza. Acta Med. Medit. 13, 125, 1997.

12) Signorelli S. Regional Pathology of the smole vessels and diabetic microangiopathy. Acta Diabetol. Latina, pag.367-370, Vol. XXII, 104,1985.

13) Gaehtgens P. Relevance of the Microcirculation for Ischemic Disease. In: Microcirculation and Ischaemic Vascular Disease. Advances in Diagnosis and Therapy. Proceedings of Congress. Munich, 1980,pag. 3-7.Edited by Messmer, Abbott,USA.

14) Hassmann F. Patterns and Structure of the Microcirculatory Bed. In: Microcirculation and Ischaemic Vascular Disease. Advances in Diagnosis and Therapy. Proceedings of Congress. Munich, 1980pag. 3-7.Edited by Messmer, Abbott,USA.

15) Schmidt-Schonbein H. Physiology and Pathophysiology of the Microcirculation and Consequences of its treatment by Drugs. In: Microcirculation and Ischaemic Vascular Disease. Advances in Diagnosis and Therapy. Proceedings of Congress. Munich, 1980, pag. 12-16. Edited by Messmer, Abbott,USA.

16) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica condizione necessaria non sufficiente della oncogenesi. XI Congr. Naz. Soc. It. di Microangiologia e Microcircolaz. Abstracts, pg 38, 28 Settembre-1 Ottobre, Bellagio, 1983.

17) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. X Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. Atti, 61. 6-7 Novembre, Siena, 1981.

18) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. X Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. Atti, 61. 6-7 Novembre, Siena 1981

19) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. Una Patologia Mitocondriale Ignorata. Gazz Med. It. – Arch. Sci. Med. 144, 423,1993. (Infotrieve)

20) Dinnoen S., Gerich J., Rizzo R.: Carbohydrate Metabolism in non insulin-dipendent Diabetes Mellitus. N.Engl.J.Med. 327,707-708,1992.

21) Stagnaro-Neri M., Stagnaro S., La “Costituzione Colelitiasica”: ICAEM-a, Sindrome di Reaven variante e Ipotonia-Ipocinesia delle vie biliari. Atti. XII Settim. It. Dietol. ed Epatol. 20, 239, 1993.

22) Stagnaro-Neri M., Stagnaro S., Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 1997, 13, 109.

23) Stagnaro Sergio. Role of Coronary Endoarterial Blocking Devices in Myocardial Preconditioning - c007i. Lecture, V Virtual International Congress of Cardiology, 2007. http://www.fac.org.ar/qcvc/llave/c007i/stagnaros.php

24) Stagnaro Sergio. Bedside Evaluation of CAD biophysical-semeiotic inherited real risk under NIR-LED treatment. EMLA Congress, Laser Helsinki August 23-24, 2008. "Photodiagnosis and photodynamic therapy", Elsevier, Vol. 5 suppl 1 august 2008 issn, Page S17.

* Sergio Stagnaro MD

Via Erasmo Piaggio 23/8

16039 Riva Trigoso (Genoa) Europe

Founder of Quantum Biophysical Semeiotics

Who's Who in the World (and America)

since 1996 to 2009

Ph 0039-0185-42315

Cell. 3338631439

www.semeioticabiofisica.it

dottsergio@semeioticabiofisica.it