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
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
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).
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.
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 =
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
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: <
The “in-toto” ureteral reflex intensity <
Moreover, it is easy to understand that pancreas interstititum is steadily large (“in toto” ureteral reflex ³
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. <
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.
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:
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.
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
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
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
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 (
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).
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.
£ 3 - 2,5
mvtU. activation typeII dissociated
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”.
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.
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: <
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
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
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 -
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.
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 (
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
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]
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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.
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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.
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
* Sergio Stagnaro MD
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