Treatment Of Scurvy Research Articles

All that glitters is not gold: Why randomized controlled trials are bronze standard (at best) in determining best practices for the treatment of posttraumatic stress disorder

The randomized controlled trial (RCT) is considered the gold standard for evaluating the effectiveness of interventions or treatments across fields of physical and psychological medicine. While the RCT is well-placed for issues best addressed with a medical model approach—its origin story, the study and treatment of scurvy, an ideal exemplar—its stature and use must be challenged in cases of experiential phenomena, such as posttraumatic stress disorder (PTSD), where there is no one answer, treatment, or approach that suits all persons. Uncontested, its evidentiary superiority threatens to have deleterious effects on determining best practices for the treatment of PTSD.

Clinical Diagnosis and Treatment of Scurvy in a Young Adult With Poor Dietary Habits: A Case Report and Literature Review

Scurvy, once prevalent among sailors, is now rare due to improved access to fresh fruits and vegetables yet persists in individuals with poor dietary habits. We report a case of a 35‐year‐old male presenting with month‐long, nonpainful, nonitchy lower extremity lesions. A dermatological examination revealed follicular hyperkeratosis, perifollicular bleeding, corkscrew hairs, bleeding gums, and hemorrhagic purpura. Despite unavailable plasma vitamin C testing, scurvy was diagnosed based on clinical features and dietary history. Treatment with vitamin C resulted in significant improvement within 10 days. Inadequate intake of fruits and vegetables causes vitamin C deficiency, impairing collagen synthesis and leading to typical scurvy symptoms. This case underscores the importance of considering scurvy in patients with compatible symptoms, focusing on clinical diagnosis and treatment response when testing is unavailable. Management includes vitamin C supplementation and dietary changes, emphasizing healthcare providers’ role in promoting sufficient fruit and vegetable consumptions to prevent nutritional deficiencies.

Clinical therapeutic trials.

The term clinical trial implies an investigation of a therapeutic intervention in the pursuit of evidence of benefit, short or sustained, and observations on the possibility of toxicity related to the therapeutic intervention. It is possible that the first clinical trial took place in the court of the Babylonian King Nebuchadnezzar circa 600 BC, as recorded in Chapter 1 of the Book of Daniel, verse 3-20. However, it is in the last 500years that there has been good written documentation at attempts to interpret therapeutic benefit from the use of treatments. Lind's demonstration on the usefulness of oranges and lemons in the treatment of scurvy in 1747, and the unethical experiment by Edward Jenner (1749-1823) on the inoculation in 1796, of an 8-year-old boy, with cow pox obtained from a milk maid, followed by an attempt to give the young boy smallpox by direct inoculation 18days later, are striking examples of clinical trials. Human ethics, strict clinical observations, statistics, the governed scientific purity of therapeutic agents, and safety testing of therapeutics, devices, and physical interventions, have created the basis for the modern clinical trial.

The interplay between vitamin C and thyroid.

Vitamin C (ascorbic acid) is a water-soluble vitamin, that plays a key role in the prevention and treatment of scurvy. As vitamin C is an antioxidant and thyroid function may be affected and may affect vitamin C levels, for the first time, we aimed to provide a detailed review of all human studies evaluating the different roles of vitamin C in the thyroid gland. Thyroid cancers, goitre, Graves' disease and other causes of hyperthyroidism and hypothyroidism were the conditions discussed in this study. Furthermore, vitamin C addition to other medications such as levothyroxine was also reviewed. In this study, we reviewed the relevant literature regarding the association between vitamin C and thyroid diseases using original studies from PubMed, Scopus, Embase, and Web of Science. In this review, we found anti-cancer effects for intravenous (IV) administration of vitamin C in addition to the beneficial effects of using it in combination with radiotherapy and chemotherapy. As autoimmune diseases affect some antioxidant markers, some studies reported a significant difference in blood vitamin C levels in patients with autoimmune thyroid diseases such as Graves' disease. Despite many studies evaluating the effects of IV administration of vitamin C in mentioned diseases, there is a lack of evidence for oral consumption of vitamin C. To conclude, there is a lack of evidence, especially clinical trials, for the therapeutic effects of vitamin C on thyroid diseases; however, promising results were reported in some studies in the literature.

The oral manifestations of scurvy in the 21st century

Scurvy is a vitamin deficiency historically associated with pirates and sailors that affects collagen synthesis, leading to hemorrhage, skin, and oral lesions. In the 18th century, the lack of consumption of foods rich in vitamin C was found to cause such a severe condition, whose early diagnosis increases the likelihood of a better prognosis. A 58-year-old female patient complained of fatigue, body pain, and gingival bleeding for nearly 24 months. In 2001, she was diagnosed with lupus, now in remission, and osteoporosis more recently. On clinical examination, gingivitis with spontaneous bleeding was observed, despite the patient’s good hygiene, as well as some petechiae over the body. Due to the hypothesis of a possible autoimmune dermatological disease, the patient was referred to a dermatologist, who requested a series of tests, including vitamin C dosage. The results showed a concentration below 0.25mg / dL (IR, 4 to 2.0 mg / dL), and thus the diagnosis of scurvy was established. The patient was administered vitamin C replacement and in about 3 months, the symptoms started to improve. In some cases, such as this, hospitalization is required for intravenous replacement due to bleeding risks. This case report highlights the importance of the dentist in the early diagnosis and treatment of scurvy. This condition causes oral lesions that are often confused with other more common conditions, such as gingivitis or autoimmune dermatological response. Therefore, we recommend a comprehensive physical examination and anamnesis, including dietary history.

PHYTOCHEMICAL, PHARMACOLOGICAL SCREENING AND IMPORTANCE OF MARSDENIA TENACISSIMA: A REVIEW

In conventional methods of medication, Marsdenia tenacissima (family: Apocynaceae) is used in the treatment of scurvy, urinary diseases, arthritis, heart disease, skin disease, pruritus, vomiting and intermittent fever. Estimation of biological activities confirmed that M. tenacissima plant shows antipyretic, antioxidant, anticancer and anti-HIV activities. This assessment presents the phytochemical constituents, traditional importance and pharmacological activities accounted for the plant in recent literature and it will be supportive to explore incisive information about M. tenacissima for the researchers.

Reports on Greenlandic and Faroese medicine from an eighteenth-century medical book

ABSTRACT The authors analyse descriptions of Greenlandic and Faroese medicine found in an Italian medical publication from the 18th century entitled, Europae Medicina a Sapientibus Illustrata […], which was printed in Brescia, in Northern Italy, in 1747. The author of these descriptions, Francesco Roncalli Parolino (1692–1769), was a renowned European physician. Roncalli Parolino focused his study on the treatment of scurvy and he promoted the inclusion of the Greenlandic and Faroese therapy into the broader European context. He was influenced to do this due to the already integrated European perspective of medicine which his book follows. Like now, medicine in 18th-century Europe was multicentric and characterised by rich intellectual activity, which contributed to the enhancement of clinical practice during this period. At the time, Greenland and Faroe Islands were also integrated into this European context because they contributed for medical-scientific development that would lay the foundations for modern medicine. Francesco Roncalli Parolino obtained just recognition for these regions through the advancement and defence of their valuable medical contributions.

Scurvy in children: Down but not out

Background: Scurvy, a common disease of the past, has become rare in the modern era. Because of lack of awareness regarding its clinical and radiological manifestations, diagnosis of scurvy is often missed or delayed resulting in unnecessary and potentially harmful diagnostic and therapeutic interventions. Dermatological manifestations are a very important component of the clinical picture and can suggest the diagnosis to the unsuspecting physicians. The objectives were to describe the clinical presentation of scurvy in children in the modern era and to highlight its dermatological manifestations. Methods: This was a retrospective chart review of children diagnosed with scurvy over a period of 10 years at a tertiary care hospital. Results: Eleven children, 6 girls and 5 boys, aged from 21 months to 16 years with scurvy were identified. All the children had an underlying disorder that predisposed them to scurvy, with cerebral palsy in 10 and autism spectrum disorder with celiac disease in one child. All had presented with musculoskeletal complaints of irritability, limb pain, painful restriction of movements, and in some cases, swelling of the affected limb. Dermatological signs consisting of various combinations of perifollicular hyperkeratosis and hemorrhages, petechiae, ecchymosis, corkscrew hair, and bleeding gums were present in 10 children. Characteristic radiographic changes were seen in all the 8 children who underwent this examination. All children responded dramatically to treatment with oral Vitamin C. Conclusions: Awareness of clinical and radiographic signs of scurvy allows early diagnosis and treatment of scurvy. Dermatological manifestations are the most noticeable and helpful clues to the diagnosis of scurvy.

Ethnopharmacological, phytochemistry and other potential applications of Dodonaea genus: A comprehensive review

Abstract Dodonaea (family Sapindaceae) - a genus of flowering plant (above 70 species recorded) and used for various activities. Dodonaea viscosa, D. angustifolia, D. spatulate, D. polyandra and D. ceratocarpa are well-known species of this genus. In spite of the possible health support, different plant species from this genus are not extensively noticed in the modern medicine system. Dodonaea genus has been traditionally used in the treatment of scurvy, inflammation, kidney pain, sore throat, intestinal parasite, herpes, wounds burn, rheumatism, cough, backache, toothache, skin burn, skin infection, tumor and wound healing. Plant leaves, stem and fruits are occasionally used in the formulation of traditional medicine. In terms of phytoconstituents, flavonoids, flavones and their derivatives, terpenoids and saponins are major isolated compounds. They have shown antimicrobial, antioxidant, anti-inflammatory, antidiabetic, hepatoprotective and anti-plasmodial activities. Plants of Dodonaea genus show insecticide, weedicide, pesticide activity and exhibit allelopathic effect. Further, some isolated bacteria from roots of D. viscosa have been used in other plants as a plant growth-promoting rhizobacteria. Additionally, leaf extract has also been used in nanoparticle synthesis. These particles have shown a significant antioxidant activity; and antibacterial activity towards both gram positive and gram negative bacteria. Overall, this review paper aims to describe the different aspects of Dodonaea genus such as botanical description, ethnomedicinal uses, phytochemistry, pharmacological and agricultural applications of Dodonaea genus. Besides, some other miscellaneous studies and applications have been also reviewed.

The life and legacy of Doctor James Lind

James Lind has been described as the founding father of Naval Medicine. He is most remembered for conducting the first controlled clinical trial of different treatments for scurvy, and the summary of his findings, in his ‘ Treatise of the Scurvy ’ has subsequently made him a household name (in

The Evolution of Federal Regulation of Human Drugs in the United States: An Historical Essay.

Drug development prior to 1800 was based almost completely on observational trial and error. The earliest known exception was a controlled drug trial conducted by James Lind in 1747 on an English ship to show the effectiveness of citrus fruit in the treatment of scurvy. Clinical tests, but not concurrent comparative trials, were conducted by Charles Maitland in 1722 in London to show the effectiveness of variolation in preventing smallpox, and a controlled drug trial was conducted by Edward Jenner in London in 1796 to show the effectiveness of material taken from cowpox sores of young milkmaids (later called smallpox vaccine) in preventing smallpox. In 1775, William Withering learned from an elderly woman herbalist in Shropshire, England about her use of the Foxglove plant (whose active ingredient Withering later determined to be digitalis) in treating heart disease, and in 1785 published the results of his treatment of 158 patients with the drug, but he did not conduct a controlled study.

Phytochemical Screening, Phenolic Content and Antioxidant Activity of Citrus aurantifolia L. Leaves Grown in Two Regions of Oman

Lime or Citrus aurantifolia L., is a small citrus fruit that belongs to the family Rutaceae. The fruit and leaves of C. aurantifolia have been used traditionally for weight loss, skin care, relief from constipation and treatment of scurvy, etc. The purpose of this study was to determine the flavonoid, total phenolic content and investigation of anti-oxidant potential of Citrus aurantifolia leaves grown in Oman. Lime leaves were collected from Batinah (Nakhal) and Ad-dakhiliya (Nizwa) region of Oman. The leaves were dried, powdered and extracted with ethanol using a hot extraction method. Standard chemical tests were used to check the presence of secondary plant metabolites in the lime leaves extract. Quantitative analysis of the phenolics and flavonoids were done by colorimeteric methods. The antioxidant activity was assessed by DPPH and phosphomolybdenum in vitro assay methods respectively. Chemical analysis of the lime leaves extract showed the presence of major secondary plant metabolites. The obtained results revealed variation in the content of flavonoid (41.38-64.2 μg of QE/mg of dry extract) and phenolic compounds (96.55-322.57 μg of GAE/mg of dry extract). Both the lime leaves extracts from Nakhal and Nizwa showed concentration dependent moderate anti-oxidant activity (11.79-56.89 and 10.11-51.91%). Lime leaves from Batinah region also exhibited better total antioxidant capacity calculated with reference to the standard gallic acid. The aerial part of C. aurantifolia seems to be a rich source of flavonoids. Further studies are recommended to isolate and quantify the pure phytoconstituents from lime leaves grown in the Batinah (Nakhal) region which might serve as natural antioxidants in food and drug industry.

Scurvy in the Context of End-Stage Liver Disease

The authors present a case of scurvy in a 38-year-old woman with a history of alcohol abuse and end-stage liver disease. Their case demonstrates that nutritional deficiencies are a concern in patients affected with alcoholic liver disease. The history, symptoms, and treatment of scurvy are also discussed.

Scurvy aboard Ferdinand Magellan's voyage of circumnavigation.

One of the greatest feats of explorationwas FerdinandMagellan’s voyage of circumnavigation (1519-1522). The story of this Spanish expedition was chronicled by Antonio Pigafetta, who traveled with Magellan and kept a diary. Pigafetta’smostharrowingaccountconcerns their crossingof thePacific Ocean, duringwhichMagellan’s crew endured a deadly encounter withscurvy.Scurvy isadiseasecausedbyvitaminCdeficiencythatwould plague sailors for thenext3 centuries. This nightmarebeganonNovember 28, 1520, afterMagellan (1480-1521) andhis crewsuccessfully completed their crossingof the treacherous Straits ofMagellan andentered thePacificOcean. This accomplishment fulfilledMagellan’s dream, first envisioned 500 years ago, of finding a westward maritime route from Europe that would lead to the Spice Islands of Indonesia. Concerning thePacific crossing,Pigafettawrites: “Wehadbeenthree monthsandtwentydayswithout takingrefreshmentofanykind.”Magellan’s crewhadexhausted their food stores andwere forced to subsist on rottenbiscuitsandyellow,putrefiedwater. Indesperationthemenateanything: cowhides, sawdust, and even rats. Amidst starvation conditions, manyofMagellan’smenbecameill,asPigafettagraphicallydescribes: “But aboveall othercalamities thiswas theworst: in somementhegumsgrew over the teeth, both lowers anduppers, so that they couldnot eat in any way and thus they died of this sickness. Nineteenmendied....” Pigafetta’s most striking clinical observation was gingival hypertrophy, a featureof scurvy inwhichdefectivecollagensynthesis leads to the lossof support forbloodvesselwalls. Thegums, thereforebecomered, swollen, friable, andhemorrhagic. Thegingival abnormalities occur only in the presence of teeth. Other dermatologic features of scurvy include follicular hyperkeratosis associated with corkscrew hairs, perifollicular hemorrhage, petechiae, ecchymosis, and poor wound healing. On March 6, 1521, Magellan’s expedition reached Guam and procured fresh foods thatenabled thecrewto recover fromtheir illness.Unfortunately,Magellanwas laterkilled inabattle in thePhilippines.OnSeptember8, 1522, the lastshipofMagellan’soriginal fleetof5vesselsdocked inSpain, completing thevoyagearoundtheworld.Onboardwere 18survivorsof theexpedition’soriginal 266men.Mosthadperished in thePacific travels. With the adoption of James Lind’s 1753 landmark dietary recommendations for the prevention and treatment of scurvy, epidemics of thediseaseon thehigh seas subsided. Scurvy, however, can still be clinically seen in populations at risk for malnutrition, such as elderly individuals, indigentpersons,andalcoholics.Thevitaminpropertiesofascorbic acid (vitamin C) were codiscovered by Albert Szent-Gyorgyi and Charles Glen King between 1928 and 1932. Szent-Gyorgyi was later awarded the 1937 Nobel Prize in Physiology or Medicine. Magellan’s voyage of circumnavigationwas amonumental achievementand testofhumanendurance. It also illustratedour frailty andhow fatal it could be for anyone to lack even a single vitamin. Today, mankind looks toward theheavens for further spaceexploration.At thesame timewe realize that our lives are so inextricably boundwith theEarth, a planet whose surface was first circumnavigated nearly 500 years ago.

A bibliographic review on the family Araceae with foccus on the generaPistia, Philodendron and Montrichardia: botanical, phytochemical and biological activity aspects

The present paper reports a broad literature review on the Araceae family, focusing the genera with popular allegation of medicinal use. The review was carried through different databases, specialized periodicals and books. The Araceae family comprises ornamental, toxic and medicinal plants. Species with allegations of popular use against serpent bites and scurvy, as well as vermifuge, laxative, and hemostatic, among other uses, are described. The Pistia genus includes P. stratiotes, popularly known as santa-luzia with, repolho-d’agua, alface-d’agua and golfo, with popular allegations of activity as diuretic, antipyretics, stranguria, hematuria, diabetes, hemoptysis, hydropsy, arthritis, liver affections, and treatment of scurvy. However, these popular allegations lack of validation studies. Phytochemically, steroids have been isolated from this species. Certainty the mostly studied genus of this family in terms of biological activities is Montrichardia that has been evaluated for antiplasmodial, antibacterial, antifungal, and antinociceptive activities. Another genus of this family with allegation of popular use is Philodendron, with the following allegations: treatment of serpent bites and pain killer, laxative, hemostatic and vermifuges. Phytochemical studies led to the isolation of sitosteol and other substances. Biological studies confirmed activities against Trypanosoma cruzi and Trichomonas vaginalis, but the mechanisms involved in toxicity are still not completely elucidated. In summary, this family includes different species with therapeutical potential that deserve validation studies.

Captain James Cook in Atlantic Canada: The Adventurer & Map Maker's Formative Years (review)

Reviewed by: Captain James Cook in Atlantic Canada: The Adventurer & Map Maker's Formative Years Jeffers Lennox Captain James Cook in Atlantic Canada: The Adventurer & Map Maker's Formative Years. Jerry Lockett . Halifax: Formac Publishing, 2010. Pp. 198, $29.95 When Captain James Cook's mutilated remains were discovered at Kealakekua Bay in February 1779, they were identified as his because of a scar on his right hand. Fifteen years earlier, while surveying in Newfoundland, a powder horn had exploded and nearly severed Cook's thumb. As Jerry Lockett argues in this insightful study of Cook's formative years, the famous explorer who met an early demise in the Pacific cut his teeth - and valuable extremities - in Atlantic Canada. There are dozens of biographies examining the life and times of Captain James Cook. Lockett's study is a valuable contribution because he takes as his focus not the 'captain,' but rather the 'master.' Instead of recounting Cook's famous exploits, Lockett addresses a curious gap in much of the literature: how did the time Cook spent in Atlantic Canada, the skills he learned there, and the people he met influence his development as surveyor, navigator, and future explorer? Answering these questions involves engaging with naval, geographic, and medical histories, each of which speaks to a different element of Cook's experience, including his ability to manage a ship and its crew, his study of chart-making and surveying, and his fascination with preventing scurvy and assessing available anti-scorbutics. Lockett's narrative weaves through the various phases of Cook's early years: his experience on merchant ships and his decision to transfer to the navy (likely because of better working conditions and [End Page 551] more advancement opportunities); his impressive work as a master serving under Captains Hugh Palliser, George Simcoe, and others; his encounter with Samuel Holland on the beaches of Louisbourg after the fortress fell in 1758, which inspired Cook to take up surveying and hydrography; and, finally, how Cook used his newly acquired skills to impress his superiors and move up the naval ranks. Lockett describes the good fortune Cook had to serve under men such as Palliser and Simcoe, while also stressing that Cook was hard working and self-motivated, two traits that brought him to the attention of his captains. The young Cook was eager to learn from others and benefited greatly from Holland's instruction in surveying, but he also taught himself astronomy and arithmetic better to perform his duties as master and increase his chances for personal advancement. His charts of the St Lawrence (with Holland) and especially Newfoundland were remarkable achievements that served the British navy well. By investigating Cook's time in Atlantic Canada, Lockett inadvertently illustrates why other historians have overlooked this period in Cook's development. The extant records, including Cook's logbooks, which 'were so lacking in matters of human interest' (99), provide only glimpses of personality or lived experience. The twenty-one months Cook spent in Halifax - during a time when the growing settlement was awash in rum, peopled primarily with soldiers and seamen, and surrounded by powerful Mi'kmaw forces - 'is the period of his life about which we know the least' (105). To compensate for these blind spots, Lockett traces the development of related historical topics. The causes and treatment of scurvy, a pestilence that Cook went to great lengths to prevent, receive several pages of investigation; the search for longitude at sea, including the development of John Harrison's marine chronometer and other technological advancements, is similarly subjected to lively examination; and the maintenance of ships at sea and on land is fully described. At times the historical context almost overwhelms the subject, which suggests just how difficult a task is assessing Cook's time in Nova Scotia, Quebec, and Newfoundland. Similarly frustrating is the lack of adequate references for what sources do exist. Lockett is writing a popular work, which means historians hoping to follow his leads and assess his use of evidence will be ultimately disappointed. Though the book draws on archival research from London and Halifax and features several illustrative maps and images, the inability to evaluate sources and build on...

Scurvy: Past, present and future

This study outlines the major landmarks in the research on scurvy and its relationship to vitamin C. A thorough search including original manuscripts, books and contemporary reviews published in PubMed was conducted using as keywords “scurvy”, “vitamin C”, and “history of medicine”. Observations on scurvy first appear in Egyptian medical scrolls 3500 years ago, and continue through to the discovery of vitamin C and the modern research on the physiological role of ascorbic acid. The observations of great navigators during the 15th and 16th centuries, when scurvy plagued ships' crews, played an important role in clarifying scurvy's etiology. Among the personalities in the history of the disease, James Lind and Albert Szent-Györgyi are most noteworthy, the first for conducting the first clinical trial on the treatment of scurvy with lemon and orange juices, and the second for discovering and identifying vitamin C.

Scurvy: Forgotten But Definitely Not Gone

Scurvy, a disease of vitamin C deficiency, is purportedly rare in the United States yet frequently may be misdiagnosed. Presenting symptoms include bone pain, limping, rashes, or spongy bleeding gingiva. These symptoms mimic many other disorders, which often results in numerous unnecessary, invasive, and expensive procedural investigations. The strongest indication of a scurvy diagnosis is the dramatic response to the administration of vitamin C. This case report demonstrates the complexities involved in determining the cause of one child's symptoms. A thorough nutritional history and a shrewd clinician are essential to the early diagnosis and treatment of scurvy.

Kontrollierte klinische Studien vor Archie Cochrane

The James Lind Library is an excellent source for documents on the history of the controlled clinical trial. It was named after the 18th century naval surgeon James Lind who performed a multi-arm controlled clinical trial on the treatment of scurvy. Iain Chalmers is a co-founder of the James Lind Library. In his presentation at the 10th anniversary of the GCC, he told us about a number of exemplary studies with special consideration of the evolution of methods to avoid allocation bias. He particularly stressed that over the centuries many individuals from many different countries have contributed to the standard of the randomised controlled trials of our days.

L’essai clinique contrôlé randomisé

It is generally agreed that the first comparative clinical trial in history was done by James Lind in 1747, in the treatment of scurvy. The general bases of modern experimental medicine were published by Claude Bernard in 1865. However, it is the development of new drugs and the evolution of methodological concepts that led to the first randomized controlled clinical trial, in 1948, which showed that the effects of streptomycin on pulmonary tuberculosis were significantly different from those of a placebo. Today, "evidence-based" medicine aims to rationalize the medical decision-making process by taking into account, first and foremost, the results of controlled randomized clinical trials, which provide the highest level of evidence. In the second half of the 20th century it became clear that different kinds of clinical trials might not provide the same level of evidence. Practitioners' intimate convictions must be challenged by the results of controlled clinical trials. Take the CAST trial for example, which, in 1989, tested antiarrhythmic drugs versus placebo in patients with myocardial infarction. It was well known that ventricular arrhythmias were a factor of poor prognosis in coronary heart disease, and it was therefore considered self-evident that drug suppression of these ventricular arrhythmias would reduce the mortality rate. In the event, the CAST trial showed the exact opposite, with an almost 3-fold increase in total mortality among patients with coronary heart disease who were treated with antiarrhythmic drugs. These results had a profound impact on the use of antiarrythmic drugs, which became contraindicated after myocardial infarction. A clinical trial has to fulfill certain methodological standards to be accepted as evidence-based medicine. First, a working hypothesis has to be formulated, and then the primary outcome measure must be chosen before beginning the study. An appropriate major endpoint for efficacy must be selected, in keeping with the primary outcome. One may choose either a single endpoint (for instance all-cause mortality; or a composite criterion taking into account various manifestations of the same health disorder (for instance cardiovascular mortality plus non lethal myocardial infarction plus non lethal ischemic stroke). The trial must be controlled, i.e. must compare the intervention with a standard or dummy treatment. A randomization process is used to ensure that the groups are comparable. The patients must be monitored and the results analyzed in double-blind manner The required number of patients is calculated based on the working hypothesis ("superiority" trial or "equivalence" trial), as well as the spontaneous variability of the main endpoint, and the alpha and beta statistical risks. The experimental design (cross-over or parallel groups) is chosen according to the primary outcome measure and the disease characteristics. Finally, the results must be analyzed in an intention-to-treat manner, taking into account all the patients who were initially randomized. The results of these methodologically sound trials form the basis for official therapeutic guidelines, which help physicians to choose the best treatments for their patients. However, extrapolating the results of randomized controlled clinical trials to the general patient population is not always straightforward. For instance, it is well known that patients who participate in clinical trials are highly selected and therefore somewhat unrepresentative. In addition, their numbers are limited and the treatment period is often much shorter than in routine management of a chronic disease. Finally, patients in clinical trials are monitored more closely than in routine practice. This is why we need post-marketing pharmacoepidemiological studies, in which cohorts of patients exposed to the treatment in question are monitored sufficiently long to determine the precise risk-benefit ratio. Controlled clinical trials are lacking in various fields of biomedical research, either because drug companies consider them unprofitable, or because they concern public health issues that are outside the scope of the private sector In such cases, controlled clinical trials must be undertaken and funded by the public sector Today, only North American institutions such as NIH and the National Heart Blood and Lung Institute are capable of sponsoring such trials. This creates a potential problem for extrapolation to European patient populations, which may be different. Large controlled clinical trials must start to be sponsored by public funding in Europe if European practitioners are to receive the evidence-based results they need to rationalize their medical practice.