[The paradigm shift for peptic ulcer disease]. / Magsårssjukdomens paradigmskiften ­ från högspecialiserad vårdorganisation till egenvård.

Knowledge development and paradigm shift for peptic ulcer disease is described over a fifty-year period using four levels of knowledge that place demands on the healthcare organization. When medical knowledge reached a healing level, continuity became subordinate. However, accessibility to treatment became more important. An important task for future healthcare will be to define and create broader knowledge structures. Efficiency losses can occur when control instruments apply to medical problems at low levels of knowledge which are not mature for this.

Rise and fall of peptic ulceration: A disease of civilization?

Humans and Helicobacter pylori have evolved and adapted over tens of thousands of years. Yet peptic ulcer disease appeared to be rare prior to the 19th century. The prevalence of peptic ulcer disease increased between 1850 and 1900 and culminated in a cohort at high risk that was born at the end of the 19th century. This coincided with the provision of safe water and improvements in sanitation and personal hygiene. One hypothesis for the emergence of peptic ulcer disease focuses on the rate of development of atrophic gastritis induced by H. pylori. The hypothesis developed in this article focuses on delay in the age of acquisition of H. pylori to a time when immune and inflammatory responses to the infection were more mature. Whereas the acquisition of H. pylori in infancy usually resulted in mild pangastritis, hypochlorhydria, and a low risk for peptic ulcer disease, delayed acquisition could cause either more severe pangastritis (predisposing to gastric ulceration) or gastritis largely restricted to the antrum of the stomach (predisposing to duodenal ulceration). The decline in the prevalence of peptic ulcer disease over the past 100 years parallels the decline in the prevalence of H. pylori. The epidemic of ulcer disease in the first half of the 20th century seems likely to be an adverse effect of important public health measures undertaken in the latter half of the 19th century.

"Stress" is 80 Years Old: From Hans Selye Original Paper in 1936 to Recent Advances in GI Ulceration.

The first scientific publication on 'general adaption syndrome', or as we know today 'biologic stress' has been published in Nature in 1936 by the 29-year old Hans Selye. His results in that short publication that contained no references or illustrations, were based on experiments in rats that were exposed to severe insults/ stressors, but his idea about a 'nonspecific bodily response' originated from his observations of sick patients whom he had seen as a medical student and young clinician. Autopsy of stressed rats revealed three major, grossly visible changes: hyperemia and enlargement of the adrenals, atrophy of the thymus and lymph nodes as well as hemorrhagic gastric erosions/ulcers (the "stress triad"). Based on this and additional observations, he concluded that the key master organ in stress reactions is the adrenal cortex (although he also accepted the limited and short lasting effect of catecholamines released from the adrenal medulla) which stimulated by an increased secretion of ACTH, secreted by the anterior pituitary gland. He thus identified the first molecular mediators of the stress reaction, i.e., steroids released from the adrenal cortex that we call today glucocorticoids, based on his classification and naming of steroids. At the end of a very productive life in experimental medicine, Selye recognized that under both unpleasant and demanding stressors as well as positive, rewarding stimuli adrenal cortex releases the same glucocorticoids and only certain brain structures may distinguish the stimuli under distress and eustress - terms he introduced in 1974, that also contained his last definition of stress: the nonspecific response of the body on any demand on it. After brief description of the history of stress research, the rest of this review is focused on one element of stress triad, i.e., gastroduodenal ulceration, especially its pathogenesis, prevention and treatment. Following a short description of acute gastroprotection, discovered by one of Selye's students, we discuss new molecular mediators of gastroduodenal ulceration like dopamine and new drugs that either only heal (very potently, on molar basis) or prevent and heal ulcers like sucralfate derivatives and the relatively new peptide BPC-157. We conclude that despite the extensive and multidisciplinary research on stress during the last 80 years, a lot of basic and clinical research is needed to better understand the manifestations, central and peripheral molecular regulators of stress response, especially the modes of prevention/management of distress or its transformation into eustress and the treatment of stress-related diseases.

The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puscas (1932-2015).

Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) started to be used in the treatment of peptic ulcers in the 1970s, and for more than two decades, a group led by Ioan Puscas used them for this purpose, assuming that by inhibiting the gastric mucosa CA isoforms, hydrochloric acid secretion is decreased. Although acetazolamide and other sulfonamide CAIs are indeed effective in healing ulcers, the inhibition of CA isoforms in other organs than the stomach led to a number of serious side effects which made this treatment obsolete when the histamine H2 receptor antagonists and the proton pump inhibitors became available. Decades later, in 2002, it has been discovered that Helicobacter pylori, the bacterial pathogen responsible for gastric ulcers and cancers, encodes for two CAs, one belonging to the α-class and the other one to the ß-class of these enzymes. These enzymes are crucial for the life cycle of the bacterium and its acclimation within the highly acidic environment of the stomach. Inhibition of the two bacterial CAs with sulfonamides such as acetazolamide, a low-nanomolar H. pylori CAI, is lethal for the pathogen, which explains why these compounds were clinically efficient as anti-ulcer drugs. Thus, the approach promoted by Ioan Puscas for treating this disease was a good one although the rationale behind it was wrong. In this review, we present a historical overview of the sulfonamide CAIs as anti-ulcer agents, in memoriam of the scientist who was in the first line of this research trend.

[Naming and classification of steroids and human stress ulcers. Articles of historic significance published by Hans Selye 70 years ago]. / A szteroidok elnevezése, felosztása és az emberi stresszfekélyek. Selye János 70 éve megjelent történelmi jelentoségu cikkei.

The name of Hans Selye is mostly known worldwide as the discoverer of stress reaction. Yet, he made numerous other seminal and clinically relevant discoveries. Namely, since he had a focused research on steroid hormones originating from the adrenal cortex that play a crucial role in stress response, he was the first who introduced about 70 years ago the first classification of steroids that is still valid nowadays. This is based on three objective facts: (a) the names of steroid groups are identical with their organ of origin (e.g., corticoids from the adrenal cortex, testoids/androgens from the testis); (b) chemical structures of the steroids are identical within a group (e.g., all corticoids have pregnane nucleus with 21 carbon atoms); and (c) the biological effects are homogenous within a group (e.g., all glucocorticoids exert catabolic effect, while androgens are anabolic). It should be emphasized that Selye also discovered in animal models the pro-inflammmatory effect of mineralocorticoids and the anti-inflammatory properties of glucocorticoids, about 8-10 years before Nobel Prize was awarded to a physician for the first clinical use of adrenocorticotrop hormone and cortisone. Last, but not least, Selye was the first who recognized about 70 years ago the occurence of stress ulcers in humans, based on clinical reports on the huge increase in the number of perforated gastric anti-duodenal ulcers during bombings of London in World War II. The subsequent ulcer research by Selye`s former students and their contemporaries resulted in the recognition of anti-duodenal ulcer effect of dopamine, and the central gastroprotective actions of thyreotrop releasing hormone and endogenous opioids. Thus, Hans Selye made much more contributions to medical science and clinical practice than 'just' the discoverer of biologic stress response.

[Peptic ulcer disease and helicobacter pylori: How we know what we know]. / Peptische Ulzera und Helicobacter pylori: Wie wir wissen, was wir wissen.

The bacterium Helicobacter pylori is one of the main causes of peptic ulcers. But how was this causal relationship demonstrated? A historical and philosophical analysis of a series of studies conducted during the 1980s can elucidate the question. In the beginning, a mere correlation between the newly discovered bacterium and peptic ulcers was found in gastric biopsies. It remained an open question whether the bacterium caused the disease, or whether it constituted merely an opportunistic infection. Yet determining the direction of causality was difficult in the absence of an animal model: Even though gastritis was observed in a courageous self-experiment involving a swallowed bacterial culture, tf!e significance of the individual case was small. The failings of the self-experiment could only be rectified by a randomised, placebo-controlled trial which met the requirements of Koch's third postulate. Moreover, it was necessary to gain an initial understanding of the mechanism by which the causal relationship between H. pylori and peptic ulcers is mediated: How, forexample, does the bacterium survive in the acid environment of the stomach? The study of the case from the perspective of the history and philosophy of science illustrates how medical knowledge is established incrementally.

Heuristic reevaluation of the bacterial hypothesis of peptic ulcer disease in the 1950s.

Throughout the first half of the twentieth century the research on peptic ulcer disease (PUD) focused on two rivaling hypothesis: the "acidity" and the "bacterial" one. According to the received view, the latter was dismissed during the 1950s only to be revived with Warren's and Marshall's discovery of Helicobacter pylori in the 1980s. In this paper we investigate why the bacterial hypothesis was largely abandoned in the 1950s, and whether there were good epistemic reasons for its dismissal. Of special interest for our research question is Palmer's 1954 large-scale study, which challenged the bacterial hypothesis with serious counter-evidence, and which by many scholars is considered as the shifting point in the research on PUD. However, we show that: (1) The perceived refutatory impact of Palmer's study was disproportionate to its methodological rigor. This undermines its perceived status as a crucial experiment against the bacterial hypothesis. (2) In view of this and other considerations we argue that the bacterial hypothesis was worthy of pursuit in the 1950s.

HANS SELYE 70 YEARS LATER: STEROIDS, STRESS ULCERS & H. PYLORI.

Although Hans Selye is mostly known for his discovery & development of the stress concept, he also introduced the first physiologically sound, structure-activity classification of steroids that was also based on the chemical structure of steroids in 1943. He not only introduced the names of glucocorticoids & mineralocorticoids but discovered the anti- & pro-inflammatory properties, respectively, of these steroids in animal models. Furthermore, he not only described the first stress-induced gastric ulcers in rats (1936) & characterized the first human 'stress ulcers' during the air-raids in London during World War 11 (1943). Thus, Selye was a much more productive & creative scientist than it is generally considered.

HANS SELYE AND THE STRESS RESPONSE: FROM "THE FIRST MEDIATOR" TO THE IDENTIFICATION OF THE HYPOTHALAMIC CORTICOTROPIN-RELEASING FACTOR.

Selye pioneered the stress concept that is ingrained in the vocabulary of daily life. This was originally build on experimental observations that divers noxious agents can trigger a similar triad of endocrine (adrenal enlargement), immune (involution of thymus) and gut (gastric erosion formation) responses as reported in a letter to Nature in 1936. Subsequently, he articulated the underlying mechanisms and hypothesized the existence of a "first mediator" in the hypothalamus able to orchestrate this bodily changes. However he took two generations to identify this mediator. The Nobel Laureate, Roger Guillemin, a former Selye's PhD student, demonstrated in 1955 the existence of a hypothalamic factor that elicited adrenocorticotropic hormone release from the rat pituitary and named it corticotropin releasing factor (CRF). In 1981, Wylie Vale, a former Guillemin's Ph Student, characterized CRF as 41 amino acid and cloned the CRF1 and CRF2 receptors. This paves the way to experimental studies establishing that the activation of the CRF signaling pathways in the brain plays a key role in mediating the stress-related endocrine, behavioral, autonomic and visceral responses. The unraveling of the biochemical coding of stress is rooted in Selye legacy continues to have increasing impact on the scientific community.