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Sunday, April 26, 2009



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 (, 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,, Practical Applications, and Article N° 2, Appendicitis, in the Page, I hold weekly in the italian site, 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, 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

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, in, November 2001, and in the article N° 13 of the Page, I hold in

Reaven’s syndrome, both classic and “variant”, is based on Congenital Acidosic Enzyme-Metabolic Hystangiopathy-a (CAEMH-a), 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 ³ 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.


(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-a).

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-a-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-a 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--a-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, as well as two articles on Oncological Terrain in, 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--a.

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 ³ 12 sec.


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.


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-a, 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-a-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).












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


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-a, 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.

29) Stagnaro-Neri M., Stagnaro S. Introduzione alla Semeiotica Biofisica. Il Terreno Oncologico. Ed. Travel Factory, Roma, 2004.

30) Stagnaro Sergio. Newborn-pathological Endoarteriolar Blocking Devices in Diabetic and Dislipidaemic Constitution and Diabetes Primary Prevention. The Lancet. March 06 2007., and especially,

31) Stagnaro Sergio. Biophysical-Semeiotic Bed-Side Detecting CAD, even silent, and Coronary Calcification. 4to Congreso International de Cardiologia por Internet, 2005,

32) Stagnaro Sergio. Role of Coronary Endoarterial Blocking Devices in Myocardial Preconditioning - c007i. Lecture, V Virtual International Congress of Cardiology.

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.

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