[November 29, 1980. The foundation of AlaMMU, an interregional section of the Italian Society of Nephrology]. / Il ruolo delle Sezioni Interregionali SIN nel recupero della nefrologia ''dispersa'': storia dell'ALaMMU.

ALaMMU is a section of the Italian Society of Nephrology encompassing 5 regions of central Italy: Abruzzo, Lazio, Marche, Molise, and Umbria. It was founded in Rome in November 1980 by eight outstanding nephrologists including Drs Cagli, Pacchiarotti, Splendiani, Casciani, Brigante, Mioli, Albertazzi, and Cinotti. Its objective was to unify the scientific and social segments of local nephrology at a national level. This paper tells the story of ALaMMU with special emphasis on the organizational, social and scientific aspects. Certain local activities were employed to develop a complete set of medical knowledge according to the modern epistemology of the Nobel laureate in economics, Friedrich A. von Hayek. Since 1980, ALaMMU has promoted annual scientific meetings in all 5 regions and has formulated diagnostic and therapeutic protocols for the most important renal diseases. The lively activity led to the steady publication of the proceedings of the meetings, which gave young nephrologists a first platform for their scientific works. In addition, ALaMMU organized many courses covering a wide range of topics to contribute to the training of nephrologists locally.

[XIII Congresso Societa' Italiana di Cardiologia 1956, in Trieste and the birth of cardionephrology]. / Il Congresso della Società Italiana di Cardiologia del 1956 a Trieste e la nascita della cardionefrologia.

The Author comes recently across the proceedings volume of the forgotten XVIII Congress of the ''Società Italiana di Cardiologia'' held in Trieste on May 1956. The proceedings focus on the ''cardiopatia renale'', i.e. the heart lesion observed in Kidney disease, namely in acute glomerulonephritis. Later ''Cardiopatia renale'' changes into ''uremic cardiomyopathy'' but the terms seem uncorrect as they do not include the cardiac derangement in early stages of nephropathies. The diction ''cardiomyopaty'' in uremic seems more complete. The topic becomes very ''hot'' and the kidney- heart scientific culture grows more and more and culminates with the ''Cardionephrology'' term coined in 1991 at Assisi Meeting and then wide spread all over Europe.

[Use of diuretics in congestive heart failure: renal effects]. / Diuretici nello scompenso cardiaco e conseguenze renali.

Diuretics are an integral part of the management of symptomatic heart failure. Although they have been used for several decades, there is still some ambiguity and confusion regarding the outcome and the optimal way of using these common agents. There are no large-scale randomized controlled trials that have evaluated the effect of diuretics on mortality and long-term morbidity in diastolic and systolic dysfunction. Nonetheless, in short-term studies furosemide has demonstrated to reduce symptomatic congestive heart failure and hospitalization, and to improve exercise capacity in the setting of systolic dysfunction. In this review, the classes, sites of action and renal effect of diuretics are reviewed and the various indications, optimal doses and recommendations on effective use and disuse are discussed. Namely, this review addresses the effects of emerging diuretic agents such as eplerenone--a selective mineral corticoid receptor antagonist, nesiritide--a brain natriuretic peptide-recombinant, and conivaptan--a vasopressin antagonist, in attempt to provide an update on current knowledge, even though adequate clinic data are not available for all agents.

[Historical Archives of Italian Nephrology. The gout as a paradigmatic example of the ancient humoral theory of diseases]. / Archivi storici della Nefrologia Italiana. La gotta come paradigma e superamento dell'antica teoria umorale delle malattie.

Gout is one of the oldest known diseases. The term derives from the Latin "gutta", which means "a drop" This word expresses and describes, as no other term can, a method of interpreting the pathologies that have been with us for more than 2000 yrs. The theory of humoral disturbance goes back to the time of Hippocrates. This paper is a historical review of gout, with particular attention given to the interpretation of the origins of clinical, articular and renal involvement allowing us paradigmatically to sum up all the stages in the evolution of the etiopathogenetic and nosographic concepts of medicine through the ages.

[When the history of nephrology changed that of medicine]. / Archivi storici della nefrologia italiana: quando la storia della nefrologia cambiò quella della medicina.

Medicine owes much to nephrology. Indeed many of the practical and doctrinal acquisitions, through nephrology have derived their first intuitions, explanations and applications which have become epochal conquests of scientific progress. This article is a historical reconstruction of six of the milestones which have marked the medical and scientific human progress: Galeno, the ligature of the ureters and the birth of experimental medicine; uroscopy and the introduction of laboratory exams; the synthesis of urea in the laboratory and the beginnings of biothecnology; the kidney and the introduction of systematic parenteral antibiotic therapy; the kidney and the first artificial organs; the kidney and the start of the transplantation era.

[Historical Archives of Italian Nephrology. Goldblatt, kidney and hypertension: three steps in the history of nephrology]. / Archivi storici della Nefrologia Italiana.Goldblatt, rene e ipertensione: un trinomio epico nella storia della nefrologia.

The existence of a clear relationship between renal ischemia and hypertension has been widely documented by Harry Goldblatt and his colleagues. In their original papers they showed that gross and persistent elevation of systolic blood pressure could be produced in dogs by clamping both renal artery, or one if the other kidney had been removed. If renal arteries constriction was not too severe, a stable hypertension unaccompanied by more than mild renal impairment was produced. Subsequently, Goldblatt showed that, with severe constriction, retinal changes, arteriolar impairment and left ventricular hypertension could occur. Goldblatt has remained steadily of the opinion that essential hypertension in man is similarly due to renal ischemia occasioned either by stenosis of a main artery, or by organic changes in the smaller renal arteries down to the size of the different glomerular arteries. At first sight, it might seem like a simple matter to correctly identify the chain of events that begins with renal artery constriction and ends with persistent hypertension. Observing that a link was missing in this chain of events, Goldblatt hypothesised that the link was a humoral mechanism. Tigersted and Bergman showed that renin was the missing link. Renal ischemia as cause of hypertension in dogs opened a new chapter in the connection between kidney circulation and blood pressure elevation. This quite unexpected connection is one of the most challenging issues today and clearly demonstrates that the development of Goldblatt's ideas on renal circulation is still important and has by no means ended. Goldblatt, in his epistemologic approach to hypertension scientific challenges, realised that ideas are the building blocks of science: not flights of fancy, not notions sculpted in snow, but enduring concepts. Goldblatt's lasting ideas are more than a function of time and place: they have inherent qualities that have survived up to the present day.

[Historical Archives of Italian Nephrology. Virchow's theories on atherosclerosis and related kidney disease]. / Archivi storici della Nefrologia Italiana. Le teorie sull'aterosclerosi nella scienza nefrologica.

This article concerns the development of theories about atherosclerosis and its changing manifestations, some of which, such as renal artery disease and ischemic nephropathy, have been clearly defined only in recent times. An anatomical consequence of atherosclerosis is the stenosis of the renal artery, which opens an unexpected clinical response in blood pressure (nephrovascular hypertension) and in kidney function (ischemic renal disease). Today's historian, no less than the clinician, is called on 'to demand the consideration of basic definitions and nomenclature.' It is impossible to overrate Virchow's theory of artherosclerosis and his great contribution to the concept of artery insudation and thrombosis process. But even Virchow did not expressly stress the concept of atherosclerosis as an autonomic non-inflammatory entity; he called the condition 'chronic endoarteritis deformans.' However, his hypothesis introduced some inflammatory factors that today are the basis of novel atherosclerosis theory. Although Anitschkow introduced the theory of the influence of cholesterol on atherosclerotic development, his theory has been partially contradicted by widespread epidemiological data. Currently, a re-emerging theory on the role of inflammation and infection in atherosclerosis seems to explain many clinical facts taken in small account by other theories.

[Historical archives of Italian Nephrology. A historical review of Colucci's theories on nephropathy in pregnancy]. / Archivi storici della Nefrologia Italiana. La storia della nefropatia gravidica.

BACKGROUND: A review of segments of C. Colucci's detailed 1947 report on nephropathy in pregnancy is undertaken. In his paper, Colucci underlined the prevailing theories and concepts of nephropathy in pregnancy, questioned treatment guidelines, and used a modern epistemological approach to develop appropriate therapy. His outstanding achievement of the use of flux and reflux theories in nephropathy in pregnancy, such as the neuro-hypophysis overfunction theory, was further strengthened by the great physician Nicola Pende. CONCLUSIONS: The Author underlined new perspective regarding nephropathy in pregnancy, its etiology, and the prioritization of treatment aimed at curing function rather than struggling to understand vague and sometimes undefined hemodynamic parameters.

[Emerging risk factors and prevention of atherosclerosis in uraemia]. / Fattori patogenetici emergenti e prevenzione della cardiovasculopatia aterosclerotica nell'uremia.

A high rate of cardiovascular morbidity and mortality in uremic patients was documented early in the 1970s, and this remained unchanged according to more recent European and U.S. American registry report. In large cross-section studies of uremic patients, traditional cardiovascular risk factors such as hypertension and hypercholesterolemic have been found to have low predictive power, while emerging factors such as markers of inflammation and malnutrition, are strongly correlated with cardiovascular mortality. In addition, retained uremic solute such as b-2-microglobulin, advanced glycosylated end product (AGE), homocysteine, cysteine, sulfate may contribute to the pro-atherogenic milieu of uremia. Exhaled alkanes such as isoprene, increased during and after hemodialysis sessions, have been identified as accelerating factors of the atherosclerotic process. In patients with renal disease, even when GFR is still normal, increased sympathetic activity is demonstrable. The rising catecholamines turnover is a risk factor for cardiovascular disease for the high sensitivity of the heart and the arteries to increased sympthetic activity.

[Historical Archives of Italian Nephrology. The history of instrumentation in nephrology. Part II: microscope and haemodialyzer]. / Archivi storici della Nefrologia Italiana. La storia della strumentazione in nefrologia Parte II: microscopio e dializzatore.

Medicine in the technological era acquired many of the characteristics that concurrently marked other fields. So, by adopting procedures based on information obtained with instruments and devices, medicine developed an approach to illness that transformed it into a special form of technology. The collective effect of instrumentation deserves consideration and offers the historian opportunities for interpreting the interaction between physician and his patients in other than scientific and technological terms. The very construction of instruments and devices depends on the Author's ideas assembled with the basic theories of the time. For instance, at the end of the nineteenth century, when medical instruments became essential, the bacterial origin of diseases revolutionised their construction and application. In this context, the invention and use of the microscope became an outstanding feature of the clinical approach by disclosing the cellular universe. The microscope had become crucial in locating some major causes of physical suffering and death in man, and was considered the pre-eminent diagnostic instrument in medicine. In the nephrological field, the microscope drew the physician into a universe of physical changes that were concealed to the naked eye. The microscope made possible the verification of some of Bright's brilliant ideas, something that helped physicians classify glomerulonephritis. Many nephrologists confessed "how few things are established in this subject (nephrology) and how many more difficulties are established, we have learned by experience with the microscope". The modesty of this claim is striking. In nephrology, as in other fields, the admission of ignorance proved to be the beginning of wisdom. This wisdom, based on the admission of ignorance and assembled through the commitment and ingenuity of the pioneers of the dialysis treatment, led to the treatment of end-stage renal disease and the guarantee of success. The technique of haemodialysis has been enriched by the new lexicon, which expresses different ways and ideas on the removal of the solute.

[Historical Archives of Italian Nephrology. Diabetic nephropathy and insulin discovery: two parallel histories]. / Archivi storici della Nefrologia Italiana. Nefropatia diabetica e scoperta dell'insulina: due storie parallele.

In 1936, Kimmelstiel and Wilson described the nodular glomerulosclerosis in patients with diabetes mellitus on insulin treatment. The nodular glomerulosclerosis is referred to as diabetic nephropathy. Fifteen years earlier insulin was discovered. This discovery at the University of Toronto (Canada) in 1921-22 by Banting, Macleod, Best and Collip was one of the most dramatic events in the history of the treatment of the disease. The impact of insulin was so sensational because of the incredible effect it had on diabetic patients. Those who first watched starved, sometimes comatose, diabetics receive insulin and return to life witnessed one of the genuine miracles of modern medicine. The discovery has became the "elixir of life" for millions of human beings around the world. Insulin had not emerged out of a vacuum but was the culmination of years of work by dozens of scientists in many countries. The Canadian scientists were the first to succeed in isolating insulin. Their work, however, was accurately constructed to confirm the ideas of earlier researchers, such as Murray, Paulesco, Allen, Minkowski, Derwitt, Zuelzer. These men, in addition to Banting, Macleod, Best and Collip, knew they were making medical history but paradoxically, with their "elixir of life" they allowed some complications of diabetes to emerge. Diabetic nephropathy was one of them. The struggle of the "Toronto quartet" for credit was inspired by man's desire to have a place in history, to have a sort of immortality open to him, an aspiration that is certainly legitimate. But perhaps the Canadian group misjudged both their situation and posterity's point of view. They probably failed to consider the unintentional effect of insulin treatment: diabetic nephropathy as a consequence of adding years to a diabetic's life.

[Historical archives of Italian nephrology: The history of instrumentation in nephrology. Part I: Theoretical bases]. / Archivi storici della Nefrologia Italiana: La storia della strumentazione in nefrologia Parte I: basi teoriche.

Microscopes and artificial kidneys have greatly influenced both diagnosis and therapy of renal diseases. Nonetheless, in tracing the influence of instrumentation on nephrology, as revealed by daily activity, we have to recognise the influence of science upon medical instruments. It is for this reason that, besides strictly clinical factors, the scientific factors that contributed to the development of modern nephrology have received considerable attention. Nobody can use an artificial kidney without bearing in mind the contribution of many segments of science. Each segment has a hypothesis in its historical growth, development and decline. The notion that the advancement of science was made possible by the increasing reliance measurements and other quantitative procedure is hardly a novel one. Moreover, it is rather obvious that the experimental process and the use of instrumentation played an important role in the history of nephrology. Measurements, experiments and the use of instruments were interrelated and represented many phases of the improvements made in diagnosis and therapeutics. Naturally, in the history and epistemology of nephrology instrumentation we find conceptual mistakes and erroneous approaches to the biological reality. However, according to Popper's teachings, mistakes are good for science as they give an extra kick to its growth and development. Medical instrumentation is an assembly of scientific theories; it also controls medical theories and promotes the development of new ones. In addition, it changed our approach to the patient. In the pre-physical era, medical practice was almost entirely an intellectual process based on medical theories that the patient was not expected to understand. In the period of physical examinations the physician included the sensual dimension (oral and visual process) and made direct contact with the patient. In the instrumentation period we experience the third type of examination, in which the physician went back to the position of having less contact with the patient. This separation is reminiscent of the pre-physical diagnosis.

[Historical Archives of Italian Nephrology: The role of women in the history of Medicine and Nephrology]. / Archivi storici della Nefrologia Italiana: Il ruolo della donna nella storia della Medicina e della Nefrologia.

The aim of the present survey of the history of medicine is to provide a series of succinct assessments of the role of women in the development of nephrology. The inadequate role played by women in some areas of medicine underlines the trend that considers health history as part of external history modulating the branches of science. If "external" or social history considers women's role as marginal in many segments of society, no wonder they play a marginal role in the history of medicine. Nonetheless, when women are offered the opportunity to map out new medical paths or handle new health systems they have always been excellent. Tratula, a doctor from Salerno's medical school, is just an example. Women have been excellent in nursing and popular medicine. Florence Nightingale (1823-1910), an English woman of rare ability and humanitarian enthusiasm, was the first to understand the role of women in organising nursing. In this area she had such a striking success that her method contributed to the founding of the first school of nursing in England and in the world. On the other hand, women doctors have had many difficulties in the medical area. The first modern woman to take her degree in medicine was Elisabeth Blackwell, who graduated from the Geneva Medical School of Western New York in 1849. She managed to open a private dispensary, which within a few years developed into a great hospital and training school for women. In the nephrology area a great Australian woman entered the universal history of medicine, Priscilla Kincaid-Smith. Her outstanding contribution was to improve the diagnosis and treatment of glomerulonephritis. Her positive attitude and the novelty of a woman being on the same scientific level as men, combined to secure her unique reputation in both her own country and the world. We hope that new social trends will develop in which women with scientific ideas will be able to completely express their medical ability and the tendency to eliminate the vestiges of old traditions will be reinforced through the granting of new scientific and academic opportunities. In Italian nephrology this tendency has been accelerating.

[Historical Archives of Italian Nephrology: Scientific ideas and projects carried out by the history of medicine and nephrology]. / Archivi storici della Nefrologia Italiana: La storia della medicina e della nefrologia come pilastro metodologico e veicolo di idee e progetti.

Some recent historical celebrations of modern Italian nephrology offer the opportunity to write about the meaning of the history of medicine and nephrology. First of all, the question "what do we learn from history" is wrongly phrased. It is from trying to learn about history, from the effort required to achieve a historical and epistemological perspective, that we may learn how people as individuals or as a group solved the problems of meeting their common human needs. Medicine is itself an eminently historical endeavour. There is history in medicine as well as history of medicine. According to Paracelsus, the history of medicine is medical science and medical science is essential history in the widest sense of the word. The word "history" embraces the concepts of human nature, the world in which human nature is revealed and the thoughts guiding it through life. If the history of medicine and nephrology is observed in all aspects of their evolution, we can see how it had a beneficial role on the work of physicians by reminding them that, prior to the light of achievement, the discovery of all medical principles is preceded by errors and doubts. We report on nephrological debates, controversies and achievements and we call attention to the need to focus on the present through the involvement of medical historians in the analysis of contemporary health policy issues and clinical methodology.

[Historical Archives of Italian Nephrology: The Cerretani and charlatans: a poor page in the history of medicine and nephrology]. / Archivi storici della Nefrologia Italiana: Cerretani e ciarlatani: ovvero alcune pagine buie della storia della medicina e della nefrologia.

Cerreto is a tiny town in the Valnerine area (Umbria) famous all over the world for the phenomenon of charlatanism derived from Cerretani inhabitants. In the Middle Ages, these people started to beg for alms on hehalf of medical and religious foundations. When their occupation ended due to religious prohibition (Council of Trent) the Cerretani shifted to Charlatanism or quackery. The Charlatans exploited the absence of institutional medicine in rural areas and the credulity and superstition of many sick people. A cynical distrust of the medical profession in urban areas helped the charlatans' activity to spread. They delivered diagnostic advice and therapeutic remedies in public squares. Renal and bladder remedies were key cures from still earlier quackeries. Some historians of medicine believe that some rural or town citizens were particulalry addicted to panaceas or placebos. Charlatans from all over the world poured into the happy hunting grounds. Quackery flourished on a grand scale until education spread throughout the population and medical services were made available to the poor. Special laws to safeguard health-care, helped undermine the charlatan healing phenomenon. Popular quackery medicine neared its end in the mid twentieth century. The history of medicine never follows a linear development such as great discoveries, political reforms, growing cultural interests. By contrast, it runs parallel to local, national and world histories. The history of medicine is largely regarded as a subdivision of the history of the world. Aspects of medicine lying outside the scientific horizon are regarded as of subsidiary importance. Does the history of the Charlatan phenomenon confirm such a statement?

A link between psychosocial factors and blood pressure trend in women.

The powerful effect of psychosocial and acculturating influences on population blood pressure trends seems to be confirmed, through longitudinal observations, in the nuns in a secluded order. After initial observation had been made on culture, body form, blood pressure, diet, and other variables in 144 nuns and 138 laywomen, included as a control group, a 32-year follow-up study was undertaken. Most striking were opposite trends noted between the two groups in blood pressure trend. During the follow-up period blood pressure remained remarkably stable among the nuns. None showed a rise in diastolic blood pressure to above 90 mmHg. By contrast the control women showed the expected increase in blood pressure with age. This resulted in a gradually greater difference (Delta>30/15 mmHg) in systolic and diastolic blood pressure between the two groups, which was statistically significant. Fatal and nonfatal events were exceedingly lower in the nuns than in the control women over the follow-up period. It appears reasonable to attribute much of the difference in blood pressure to the different burden in psychosocial factor and to the preserved peaceful lifestyle of the nuns.

Onset, time course, and persistence of increased haemodialysis-induced breath isoprene emission.

Recent findings of increased isoprene emission in the exhaled breath of patients undergoing haemodialysis and experimental evidence of the potential toxic and cancerogenic effects of isoprene hydrocarbon led us to assess how long haemodialysis patients are exposed to how much isoprene after a single haemodialysis session. Patients with end-stage renal failure on regular 4-hour (from 08.00 to 12.00 h) maintenance haemodialysis three times weekly were monitored. The breath isoprene content was analyzed by gas chromatography. Intrapatient evaluations were performed by collecting samples before, during, and immediately after the haemodialysis session, during the following hours, and on the following nondialysis day. The breath isoprene content increased in all patients. Isoprene overproduction showing a biphasic pattern was first detected soon after the dialysis session ended. These data show that haemodialyzed patients seem to be consistently exposed to high endogenous isoprene concentrations. The mechanisms and implications of this endogenous isoprene overproduction need to be elucidated with regard to the mevalonic pathway and in the physiopathological setting of the uraemia-dialysis syndrome.

Plasma sulfate concentration and hyperhomocysteinemia in hemodialysis patients.

BACKGROUND: Severe hyperhomocysteinemia is common in hemodialysis patients, who also present a dramatic increase in plasma concentrations of sulfate, one of the main products of methionine and cysteine catabolism. The aim of this study was to verify the relationship between high plasma sulfate levels and cysteine or homocysteine concentrations in hemodialysis patients. METHODS: Plasma sulfate, cysteine and homocysteine concentrations and some renal efficiency parameters were determined in 18 patients with end-stage renal failure, all undergoing 4h hemodialysis three times a week. The pattern of post-dialysis rises on plasma concentrations of sulfate, cysteine and homocysteine was established. RESULTS: Plasma sulfate, cysteine and homocysteine levels were significantly higher in patients than in normal controls. Plasma sulfate concentrations positively correlated with cysteinemia (p = 0.031; r = 0.482) which, in turn correlated with homocysteinemia (p = 0.042; r = 0.460). Sulfate levels also correlated with blood creatinine (p = 0.004; r = 0.630), nitrogen (p = 0.000; r = 0.899), protein (p = 0.014; r = 0.555), and albumin (p = 0.003; r = 0.642). Post-dialysis rises in sulfate and cysteine were detected some hours before homocysteine. CONCLUSION: The results suggest that high sulfate levels, due mainly to impaired renal function, are involved in the altered metabolism of homocysteine in hemodialysis patients.

3 R study: renal outcome in renal ischemia: revascularisation or medical treatment.

Ischemic nephropathy refers to the kidney damage following stenosis or an obstructive lesion in the main kidney arteries. This disorder has been overlooked in the past and a more rational and specific use of clinical criteria, and the development of not very invasive techniques with a good diagnostic accuracy such as spiral CT angiography, NMR angiography and echo-colour-Doppler have improved our ability to identify these patients. It is therefore likely that, in the next few years, we will find ourselves treating an increasing number of patients with renovascular ischemic disorders. Transluminal angioplasty and, more recently, the use of endovascular stents, have led to a marked improvement in the treatment of stenoses and, together with vascular surgery, allow to treat almost all patients with this disorder. There is, however, a lack of prospective and controlled studies, which demonstrate the long term benefit of revascularization treatment, as compared with optimum conservative treatment in reducing cardiovascular mortality, cardiovascular events and preserving renal function. The Ischemic Nephropathy Study Group of the Italian Society of Nephrology has organized a prospective, controlled study over a period of three years, aimed at comparing the effect of revascularization versus medical therapy in 300 patients with renal artery stenosis, ranging between 50 and 90 per cent, who will be randomly assigned to the two treatments. End point will be cardiovascular mortality and morbidity and need for renal replacement therapy.

[Evidence-based medicine: reality and illusions. Extension of epistemological reflexions]. / La medicina basata sulle evidenze: realtà ed illusioni. Estensione delle riflessioni epistemologiche.

Evidence-based medicine (EBM) is a cultural and methodological approach to clinical practice helping to make decisions based on clinical expertise and an intimate knowledge of the individual patient's situations, beliefs, and priorities useful for the analysis of clinical research. As such, it can be considered the scientifically grounded art of medicine, as it appears to be an emerging paradigm of scientifically based clinical care. It de-emphasizes intuition and unsystematic clinical experience as grounds for medical decision-making and stresses the rigorous and formal analysis of evidence from clinical research. EBM converts the abstract exercise of reading and appraising the literature into the pragmatic process of using the literature to benefit individual patients, while simultaneously expanding the clinician's knowledge base. On EBM grounds, clinical, practice guidelines, pathways and algorithms or instructions can be developed with the aim of solving a problem or accomplishing a task. Nonetheless in these processes the theory of EBM shows internal and external bias. Among internal bias, economic-based interest may influence the development and diffusion of research and its results. In addition "systemic review" may be incorrectly guided, the quality filters of the literature can be inappropriately applied, the choice criteria can be only based on the positive results of evidence, but according to modern epistemology, it will be helpful for clinicians to know when their uncertainty stems from gaps between positive and negative evidence. Another bias is the difficulty to convert EBM into clinical practice recommendations. EBM set movement has shown that it is nearly impossible to make recommendations that are appropriate in every situation. Epistemological approach identifies external "bias" of EBM. It is consistent with the theory of "fact" as human construction. Every human fact can historically fade and then be restored according to new paradigms. EBM is a "fact" and its theory can be changed or removed every time by relevant new or emerging evidence approaching the development of up-to-date decision-making aids and so on, irrespective of how much previous processing of the evidence has taken place. Then EBM cannot be evaluated as the scientific "totem" of the third millennium, neither as the clinical digest of medical literature. Searching for clinical evidence, in fact, requires a great awareness of both the advantages and limitations of increasing bias. Clinicians are looking for new strategies to apply to diagnostic and therapeutic pathways and for the steps where EBM could be addressed when showing the full validity.