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In 1981, Weinsier and Krumdieck described death resulting from overzealous total parenteral nutrition in two chronically malnourished, but stable, patients given aggressive total parenteral nutrition. This was the birth of what is now called the refeeding syndrome, a nutrition-related disorder associated with severe electrolyte disturbances. The purpose of this work is to demonstrate that refeeding syndrome was first described medically in Florence by Antonio Benivieni in 1507 in his book On Some Hidden and Remarkable Causes of Diseases and Cures. What we now know as refeeding syndrome was described in Report No. LVII of that book. The condition occurred as a result of the famine that affected Florence in 1496. The report documents (i) death due to starvation, (ii) death due to ingestion of deteriorated/toxic foods (inevitable in times of famine when healthy food is scarce), (iii) death caused by excessive food ingestion after forced, prolonged abstinence from food in adults, (iv) the death of breast-fed children and of their starved mothers eating to satiety and (v) the more favourable clinical outcome of those admitted to hospitals. It is possible that Benivieni was inspired by the description of the deaths of starved deserters in the book The Jewish War (70 AD) by the Romano-Jewish historian Flavius Josephus. Nevertheless, Benivieni wrote the first medical account of the central clinical features of refeeding syndrome. The main, broad clinical aspects of refeeding syndrome, described by Weinsier and Krumdieck in 1981, had been documented in medical literature four centuries earlier by Benivieni.

The aim of this work is to refer on the death due to crush syndrome in 1277 of Pope John XXI, philosopher, logician, anatomist, physician scientist, university professor of medicine at the university of Siena and author of books adopted for nearly 4 centuries in universities in the Middle Ages. The Pope died crushed by the ceiling of his office which had been built in rush to meet his need for a quiet and warm place, his need of light and nature. There he attended to his duties of governing the church, studied fine theological questions, inspected the stars, made experiments and discussed with the renowned ophthalmologists who in those days made Viterbo the center of the study on vision. Following the fall of the ceiling of his apartment, John XXI was extracted alive from among the pieces of wood and stones. However, a few days after the disaster, he died in bad conditions (miserabiliter). He experienced a typical death due to crush syndrome which was described for the first time by Antonino D’Antona, following the Messina-Reggio Calabria 1908 earthquake. He was born (c. 1210–1220) in Lisbon as Pedro Hispano (Peter of Spain). He had regular trivium and quadrivium courses at the University of Paris under Albertus Magnus, a talented naturalist. He became Master of Arts, then studied medicine out of Paris (probably Montpellier or Salerno). He wrote three treatises (On the eye (De oculo), The Treasury of Medicines for the Poor (Thesaurus Pauperum) and Little Summaries of Logic (Summulae Logicales)) which were used in the European universities from the 13th to the beginning of the 18th century. Pedro Hispano was advisor of King Alphonso III for affairs inherent to the Church, bishop of Braga and then Cardinal Bishop of Tusculum and Pope as John XXI. He was buried in the Cathedral of Viterbo, the city where he had settled the seat of the Pontiff.

Background and Aims The history of popes is an untapped treasure for historian of medicine for many reasons including i. number, ii. richness of documents available on their lives, iii. gender homogeneity, iiii. Long lasting lives, v. their affluence, vi. number of archiaters and personal physicians and surgeon of high professional level, viii. lived for many years in the same environment (Rome). Taking into consideration the availability of documents from 1100 onward (10 centuries of European history), popes represent good models to study a. the diseases of popes, b. social medicine, c. history of European universities and beyond, d. the history of hospitals, e. the history of archiaters, and f. the diseases of power. We are studying renal stone disease in popes from St Peter to John Paul II (34-2005). Preliminary results on gouty popes have been presented at ERA-EDTA Congress in Budapest and Milan pointing that out 20 gouty pontiffs 12 were stone formers or died because of its complications and 6 popes died because of non-gouty renal stones. The goal of this study is to provide an historical outline on renal stone disease in gouty and not gouty popes reigning in the years 537-1830 (from Vigilius―the 1st stone former pope―to Pius VIII, the last gouty pope). Methods We have studied history of popes on many books including those authored by von Ranke, von Pastor, de Novaes, Henrion, Paravicini Bagliani, Reardon, Rendina, Ceccarelli and Cosmacini. We have also studied the histories of archiaters of Platina and Marini. Results 25 out 193 popes were found gouty. Their mean age at start of pontiff was 64.6 and 70.6 at death, that nearly correspond to the time-course decline of age-related uric acid excretion. Thirteen of these popes had histories, signs, symptoms, and /or postmortem examination compatible with a diagnosis of renal stone disease. Six of them died with uremia, 4 were hydropics, 6 died because of stroke. In addition we have also outlined the narratives of 14 non gouty popes who had renal stone disease. The last pope affected by renal stone disease was Pius VI (1775-1779) , the last gouty popes was Pius VIII (1829-1830). Conclusion We have excluded from gouty popes Alexander VII erroneously defined gouty by Giuseppe De Novaes in 1815 and also excluded John IX since his gout―hypothesized by Wendy J Reardon in 1971―is not supported by documents. There are a few available specific data on the topic. A fundamental contribution was published by Lorenzo Gualino in 1934. He reported on 19 gouty popes, 12 of whom with histories or signs, or symptoms, and/or postmortem examination confirming renal stone diseaase. He also reported on 8 non gouty popes suffering from or died of renal stone disease. The findings should be matched also with those of Giovanni Ceccarelli (2001) who reported on 11 gouty popes 6 presenting with signs of stones and five dying anuric and/or hydropic. This paper includes on all popes with renal stone disease. Stroke and heart failure in gouty popes are a priority. In the last 2 centuries renal stone disease was no more a papal disease.

The aim of this work is to refer on the death due to crush syndrome in 1277 of Pope John XXI, philosopher, logician, anatomist, physician scientist, university professor of medicine at the university of Siena and author of books adopted for nearly 4 centuries in universities in the Middle Ages. The Pope died crushed by the ceiling of his office which had been built in rush to meet his need for a quiet and warm place, his need of light and nature. There he attended to his duties of governing the church, studied fine theological questions, inspected the stars, made experiments and discussed with the renowned ophthalmologists who in those days made Viterbo the center of the study on vision. Following the fall of the ceiling of his apartment, John XXI was extracted alive from among the pieces of wood and stones. However, a few days after the disaster, he died in bad conditions (miserabiliter). He experienced a typical death due to crush syndrome which was described for the first time by Antonino D'Antona, following the Messina-Reggio Calabria 1908 earthquake. He was born (c. 1210-1220) in Lisbon as Pedro Hispano (Peter of Spain). He had regular trivium and quadrivium courses at the University of Paris under Albertus Magnus, a talented naturalist. He became Master of Arts, then studied medicine out of Paris (probably Montpellier or Salerno). He wrote three treatises (On the eye (De oculo), The Treasury of Medicines for the Poor (Thesaurus Pauperum) and Little Summaries of Logic (Summulae Logicales)) which were used in the European universities from the 13th to the beginning of the 18th century. Pedro Hispano was advisor of King Alphonso III for affairs inherent to the Church, bishop of Braga and then Cardinal Bishop of Tusculum and Pope as John XXI. He was buried in the Cathedral of Viterbo, the city where he had settled the seat of the Pontiff.

Background and Aims Pope Gregory I (Magnus)―born c.540 AD, Pope 580-604 AD―in a letter to Bishop Venanzio ofLuni (later venerated as a saint) wrote “I have been confined to bed for the last eleven months, because of pain and malaise and suffer because of goutand my life has been turned into a penitence for my sins thus I am waiting death as a physician who will give me health”. He was the first Pope to suffer of gout and opens a list including in the years 20 pontiffs that includes Sisinnius, (b.650, pope 21 day in 708); Boniface VI (b. 806, Pope 15 days in 886), Honorius IV (b.1210, Pope 1285-1287); Boniface VIII (b. 1230, Pope 1294-1303); Clement VI (b.1281,Pope 1342-1352), Nicholas V (b.1387, Pope 1447-1455); Pius II( b. 1405, Pope 1458-1464); Sixtus IV (b. 1414, Pope 1471-1474); Pius III (b.1440, Pope 26 days in 1503); Pius IV (b. 1499, Pope 1559-1565); Julius II (b. 1443, Pope 1503-1516); Julius III (b.1481, Pope 1550-1555); Clement VIII (b. 1536, Pope 1592- 1605); Clement X (b.1581, Pope 1670-1676); Innocent XI (b.1681, Pope 1676-1689); Innocent XII (b.1649, Pope 1676-2692); Innocent XIII (b.1655, Pope 1721-1724); Benedict XIV (b. 1765, Pope 1740-1758), and Pius VIII (b.1761, Pope 1829-1830). Their mean age at death was 69.4 years, the youngest being Sisinnius (59 years), the oldest being Clement X (96 years). Results Some popes were strong eaters like Boniface VIII. He was chronically affected by gout and renal stone disease and by the fear for death, and the search for therapies capable to prolong life. Cosmacini says “podagroso e gottoso”… the Pope is affected by arthritis and renal disease due to overalimentation very rich (straricca) in meat”. He enrolled various archiaters among them Taddeo Alderotti (1223-1295), Pietro da Abano (1257-1315), Anselmo da Bergamo (artisphysicae professor), Simone of Genova (author of Clavissanationis), Accursino from Pistoia, Manzia from Fabriano, Gugliemo da Brescia, Angelo da Camerino and Campano da Novara (Magister Campanus), the naturalist he too affected by renal stone disease. Julius III too was a strong eater (he loved fatty foods seasoned with garlic) as was Pius IV, the hard worker who everyday used to take a nap after lunch and a long walk later in the day. By contrast Nicholas V (his Pontiff saw in 1453 the Fall of Costantinople and the end of the Hundred Years War) was a sober eater and drinker as were Pius II who made use of simple common foods, little wine and slept up to 5-6 hours. Probably Nicholas V died uremic since his pale natural color switched into yellowish-brown (itaque ex naturali et subcandido in croceumsubcinericiumque color suusconversusest). Pius III “was a sober eater and drinker and used to dine every two days. Some of the above popes were patrons of universities (Boniface VIII, Nicholas V, Pius II), some were patrons of arts and science (Nicholas V, Sixtus IV). Boniface VIII is remembered for the Bulla detestandeferitatis (against dismemberment and evisceration of cadavers), issued on September 27, 1299). For thatBulla, during the subsequent centuries he was wrongly accused even by Herman Boerhaave and Albrecht von Haller to have retarded the advancement of medicine by impeding anatomical dissections. By contrast Sixtus IV is remembered not only for modernizing Rome and embelling it, but for the 1482 Breve to the University of Tubingen allowing―for teaching purposes ―dissection of dead bodies of people sentenced to death.

BackgroundThe antidiuretic hormone (ADH) or arginine vasopressin (AVP) regulates the body's water balance. Recently, modifications in AVP levels have been related to osteoporosis during ageing and microgravity/bed rest. Therefore the present study was devised to assess whether the absence of AVP, as in patients with central diabetes insipidus (CDI), modulates renal calcium excretion.MethodsWe retrospectively analysed data from 12 patients with CDI with measured 24-h urinary excretion levels of calcium. Data were available at the moment of the diagnosis when patients were drug-free and after therapy with dDAVP, an analog of AVP. Hypercalciuria was defined as 24-h urinary Ca2+ >275 mg/day in males and >250 mg/day in females and a urinary calcium (Ca):creatinine (Cr) ratio >0.20 mg/mg.ResultsUntreated CDI patients had a daily urinary Ca2+ excretion of 383 ± 47 mg/day and a urinary Ca:Cr ratio of 0.26 ± 0.38 mg/mg. The urine osmolarity significantly increased after the administration of dDAVP by 210% and the urinary flow decreased by 72%. Furthermore, the estimated glomerular filtration rate (eGFR) increased by 7%, which did not reach statistical significance. dDAVP treatment did not significantly modify the urinary Ca2+ concentration; however, the daily calcium excretion and the urinary Ca:Cr ratio were significantly decreased (160 ± 27 mg/day and 0.11 ± 0.02 mg/mg, respectively).ConclusionsPatients with CDI show hypercalciuria even though urine is more diluted than normal controls, and dDAVP reverses this effect. These data support the intriguing relationship between AVP and osteoporosis in ageing and microgravity/bed rest.

RESUME La difference de creativite entre hommes de science et artistes assumee par Charles P. Snow en 1959 n’est pas certaine. Les prix Nobel Albert Einstein, Karl Polanyi et Rita Levi Montalcini ont une opinion opposee. Les professeurs en retraite sont des bibliotheques ambulantes ; ils ont personnellement vecu l’emergence de la quasi totalite des connaissances les plus importantes dans leur domaine de recherche. Nous avons etudie l’activite des professeurs universitaires cliniciens, emerites ou en retraite et en avons demontre le nombre, l’originalite et l’impact. Recemment Ehrich, Nwaneri et De Santo ont suivi l’activite des professeurs de pediatrie emerites ou retraites (J Peds, 2017) dans presque 300 ecoles de specialisation post-universitaires. 50 % d’entre eux etaient engages dans des activites relatives a la protection de la sante de l’enfant. Cette etude soutient l’idee que ces professeurs constituent une reserve de competence a utiliser dans les pays souffrant d’un deficit en services de pediatrie. Beaucoup d’artistes comme Michel Ange, David Bailly, Rembrandt, Katsushika Hokusai, Henry Moore, Oscar Niemeyer ont produit des chefs-d’œuvres a un âge avance. La production de textes sur la vieillesse est abondante. Elle a commence avec Corneille (« vieillesse ennemie ! », Le Cid). La liste continue avec Carl-Henning Wijmark, Julian Barnes, Lynne Segal, Remo Bodei, Martin Amis. Ce dernier a peur du « tsunami argente » des personnes âgees et propose pour elles l’ouverture de kiosques ou l’on introduit quelques piecettes de menue monnaie afin d’obtenir un martini et un cocktail mortel. L’âge des contributions des hommes de science a une distribution aleatoire. Aux Etats-Unis les chercheurs seniors recoivent la plupart de leurs financements des National Institutes of Health. Nuccio Ordine a ecrit entre-temps (Les Belles Lettres, Paris, 2015) L’utilite de l’inutile, un livre qui nous aide a reflechir sur le role des chercheurs universitaires pour qui « publier ou perir » ne saurait etre un imperatif.

Aim: Different factors have been hypothesized to play a role in the cascade of events associated with the protein-induced glomerular response. However, scant data are available on the possible functional effect of vasopressin (VP) on the glomerular filtration rate (GFR) in humans with central diabetes insipidus (CDI), which was the aim of the present study. Method: Renal function was studied under fasting conditions (baseline) and after a meat meal in 16 patients with CDI before and after treatment with desmopressin (DDAVP) and in 16 control subjects. GFR was measured by the inulin method. Results: At baseline, the GFR was lower in patients with CDI. Treatment with DDAVP resulted in an insignificant increase in GFR, which was not statistically different from untreated patients. After an acute oral protein load, the GFR increased, peaking at 45min post meal in controls, and at 135min post meal in treated and untreated CDI patients. Conclusion: After a meat meal, the peak GFR response is delayed in CDI patients suggesting that VP might indirectly affect tubule-glomerular feedback.

Transplantation represents modernity thus the laws regulating the procedure should be continuously renovated and remodeled in order to take full advantage of progress. The debate is about Law no. 219, December 22, 2017 and on Law no. 222, April 1, 1999. The quests are a) about the possibility to modify the first so that people deciding on how they want to die, may also decide about their willingness to allow the removal of their organs for transplantation and b) the possibility for donor families and recipients to have contacts after transplantation in the case both sides agree. Questions were emailed to the constitutionalist Francesco Paolo Casavola, immediate Past President of the National Committee for Bioethics, and to the philosophers Remo Bodei and Aldo Masullo. Their answers received by September 16, support the idea a) to include in the Law no. 219, 2017 the possibility to decide not only on the modality one wants to die but also on the possibility to allow his own organs to be removed for transplantation and b) to liberalize contacts between donor families and recipients when both side agree. For both changes there is enough evidence of their feasibility-necessity. The answers related to contacts between donor families and recipients support the decision of the National Committee for Bioethics on September 27, 2018. Professor Casavola also suggests that contacts should organized and supervised by the ethical committees of the hospitals where the transplantation procedure is accomplished.

In the last decade many guidelines and report have been published about the optimal restriction of sodium intake for blood pressure control which deserve to be discussed in the medical community at large. The list includes i. the 2005 Dietary Guidelines of the Department of Health and Human Services and US Department of Agriculture; ii. The 2010 Dietary Guidelines for Americans; iii. The 2011 Presidential Statement of American Heart Association; iiii. The 2012 WHO guidelines on sodium intake in adults and children, v. The 2013 Report of the Institute of Medicine of the National Academies of the United States. All of them support the efficacy and feasibility of sodium restriction for blood pressure control.

Background/Aims: Little information is available about the tubular functions and the renal adjustments that take place in obese subjects after a protein meal. How the excess fat may affect renal response to dietary proteins is currently only partially understood. This paper aims to address (i) whether severe obesity, in the absence of other comorbidities, is responsible of kidney dysfunction at either the glomerular or the tubular level and (ii) whether it compromises renal adaptations to a large protein meal. Methods: Twenty-eight obese subjects without albuminuria, along with 20 control subjects, age and gender matched, have been studied. The glomerular filtration rate (GFR; inulin clearance), renal plasma flow (p-aminohippurate clearance), the proximal tubular function (lithium clearance), the fractional excretion of sodium (FPRNa) have been measured at the basal level (steady state) and after a protein meal (perturbation). Results: Under steady state conditions, filtration fraction, proximal tubular sodium handling and the FPRNa were not significantly different in non proteinuric obese subjects compared with controls. However, a protein meal led to a delayed glomerular hyperfiltration in obese patients compared with controls. Conclusion: This study shows that obese patients, in the absence of significant comorbidities, have a normal proximal tubule Na+ absorption at basal; conversely, these subjects showed a different response to a protein meal compared with normal subjects in terms of changes of GFR. Overall, these results suggest that the modified hemodynamic response to a protein meal might be the earliest hallmark of future kidney dysfunction in obese subjects.

IntroductionMaximum time-to-rescue has been studied accurately for many earthquakes in the years 1985-2004. No study is available for historical quakes.Hypothesis/ProblemThis study aimed to evaluate long-term survivors (from the fifth day after the quake) of the Messina-Reggio Calabria earthquake (1908; Italy), which is considered, historically, to be the worst seismic event in Europe.MethodsAccurate readings of 11 national newspapers from the fifth day after the quake looking for rescued persons and transferring, to an ad hoc form, all data relating to each rescued person.ResultsThe maximum time-to rescue was 20 days. There were 225 survivors, among them 51 children (22.6 %). For 23 out 225 rescued persons, there was evidence of availability of foods and drinkable fluids while under the rubble.ConclusionThe maximum time-to-rescue under the debris following this historical earthquake far exceeds that of all other quakes that occurred in the years 1985-2004. The long survival under debris was probably due to the lack of an order to stop search and rescue. Recent strategies reducing the time for search and rescue carry the risk of missing survivors.De SantoNG,BisacciaC,De SantoLS.Maximum time-to-rescue after the 1908 Messina-Reggio Calabria Earthquake was 20 days: hints for disaster planning?Prehosp Disaster Med.2017;32(3):249–252.

Nowadays, there is a renewed interest in bone changes in experimental and clinical nephrology. However, the need for understanding the peculiarity of bone can be traced back to the 5th century BC, when Empedocles of Acragas put forward a theory of a world made of air, water, fire, and earth governed by love and hate. By observing the various body tissues, he strove to demonstrate that they consisted of 4 elements assembled with different mathematical ratios (logos). Blood is considered the most perfect tissue, because the ratio between elements is one. Bone is a very unusual tissue because it is made of 2 parts of earth, 2 parts of water, and 4 parts of fire. This kind of reasoning could be considered the first cry in the birth of quantitative chemistry.

Hydrogen sulfide (H(2)S) is a poisonous gas which can be lethal. However, it is also produced endogenously, thus belonging to the family of gasotransmitters along with nitric oxide and carbon monoxide. H(2)S is in fact involved in mediating several signaling and cytoprotective functions, for example in the nervous, cardiovascular, and gastrointestinal systems, such as neuronal transmission, blood pressure regulation and insulin release, among others. When increased, it can mediate inflammation and apoptosis, with a role in shock. When decreased, it can be involved in atherosclerosis, hypertension, myocardial infarction, diabetes, sexual dysfunction, and gastric ulcer; it notably interacts with the other gaseous mediators. Cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase are the principal enzymes involved in H(2)S production. We have recently studied H(2)S metabolism in the plasma of chronic hemodialysis patients and reported that its levels are significantly decreased. The plausible mechanism lies in the transcription inhibition of the cystathionine γ-lyase gene. The finding could be of importance considering that hypertension and high cardiovascular mortality are characteristic in these patients. Hydrogen sulfide (H2S) is a poisonous gas which can be lethal. However, it is also produced endogenously, thus belonging to the family of gasotransmitters along with nitric oxide and carbon monoxide. H2S is in fact involved in mediating several signaling and cytoprotective functions, for example in the nervous, cardiovascular, and gastrointestinal systems, such as neuronal transmission, blood pressure regulation and insulin release, among others. When increased, it can mediate inflammation and apoptosis, with a role in shock. When decreased, it can be involved in atherosclerosis, hypertension, myocardial infarction, diabetes, sexual dysfunction, and gastric ulcer; it notably interacts with the other gaseous mediators. Cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase are the principal enzymes involved in H2S production. We have recently studied H2S metabolism in the plasma of chronic hemodialysis patients and reported that its levels are significantly decreased. The plausible mechanism lies in the transcription inhibition of the cystathionine γ-lyase gene. The finding could be of importance considering that hypertension and high cardiovascular mortality are characteristic in these patients. Copyright © 2011 S. Karger AG, Basel.

On July 1, 1751, the royal Parisian printer Le Breton published the first volume of the Encyclopédie of Diderot and d'Alembert, a rational dictionary, in folio and in alphabetical order, sold by subscription. The whole work was completed in 1780 (a total of 35 volumes, of which 12 were of illustrations, 4 of supplements and 2 of indices). In 1782 it was followed by the Encyclopédie méthodique, printed by Panckoucke, which ended in 1832 with volume number 166. The frontispiece of the first volume, designed by Charles-Nicolas Cochin Jr. and engraved by Benoît-Louis Prévost showed the columns of an Ionic temple where the Truth appears between Reason and Philosophy. Reason is shown trying to break the veil of Truth, and Philosophy trying to embellish it. Below are the philosophers, their eyes fixed on Truth. Theology is on his knees with his back facing Truth, and seems to receive light from the top. The subsequent chain of figures depicts Memory, Ancient History, Modern History, Geometry, Astronomy and Physics. Below are Optics, Botany, Chemistry and Agriculture. On the bottom line one finds the representatives of arts and professions derived from science. In a 42-page preface ("Discours préliminaire") d'Alembert discussed the path to new knowledge as one "based on what we receive through senses. Ideas depend on senses." The medical collaborators were, or became, famous. Medicine was considered to be rooted in experiment, in patients and in measurements. Functions started to be described with numbers. It was the birth of determinism which was later reinforced by Magendie and Claude Bernard. Albrecht Haller, president of the Academy of Science at Göttingen, as well as a member of all European academies, wrote seminal entries. New accurate definitions appeared for life, disease, death, infections, plague, epidemics, hygiene, fevers and edema. Semiology, the study of signs, became the visible explanation of deranged function, diagnosis and prognosis.

Hydrogen sulfide, H2S, is the third endogenous gas with cardiovascular properties, after nitric oxide and carbon monoxide. H2S is a potent vasorelaxant, and its deficiency is implicated in the pathogenesis of hypertension and atherosclerosis. Cystathionine beta-synthase, cystathionine gamma- lyase, and 3-mercaptopyruvate sulfurtransferase catalyze H2S formation. Chronic kidney disease is characterized by high prevalence of hyperhomocysteinemia, hypertension, and high cardiovascular mortality, especially in hemodialysis patients. H2S levels are decreased in hemodialysis patients through transcriptional deregulation of genes encoding for the H2S-producing enzymes. Potential implications relate to the pathogenesis of the manifestations of the uremic syndrome, such as hypertension and atherosclerosis. (C) 2010 by the National Kidney Foundation, Inc. All rights reserved.

Hyperhomocysteinemia is an independent cardiovascular risk factor, according to most observational studies and to studies using the Mendelian randomization approach, utilizing the common polymorphism C677T of methylene tetrahydrofolate reductase. In contrast, the most recent secondary preventive intervention studies, in the general population and in chronic kidney disease (CKD) and uremia, which are all negative (with the possible notable exception of stroke), point to other directions. However, all trials use folic acid in various dosages as a means to reduce homocysteine levels, with the addition of vitamins B6 and B12. It is possible that folic acid has negative effects, which offset the benefits; alternatively, homocysteine could be an innocent by-stander, or a surrogate of the real culprit. The latter possibility leads us to the search for potential candidates. First, the accumulation of homocysteine in blood leads to an intracellular increase of S-adenosylhomocysteine (AdoHcy), a powerful competitive methyltransferase inhibitor, which by itself is considered a predictor of cardiovascular events. DNA methyltransferases are among the principal targets of hyperhomocysteinemia, as studies in several cell culture and animal models, as well as in humans, show. In CKD and in uremia, hyperhomocysteinemia and high intracellular AdoHcy are present and are associated with abnormal allelic expression of genes regulated through methylation, such as imprinted genes, and pseudoautosomal genes, thus pointing to epigenetic dysregulation. These alterations are susceptible to reversal upon homocysteine-lowering therapy obtained through folate administration. Second, it has to be kept in mind that homocysteine is mainly protein-bound, and its effects could be linked therefore to protein homocysteinylation. In this respect, increased protein homocysteinylation has been found in uremia, leading to alterations in protein function. © 2009 Wiley Periodicals, Inc.

Item does not contain fulltext BACKGROUND AND OBJECTIVES: Evaluation of renal function by estimation of the glomerular filtration rate (GFR) is very important for the diagnosis and treatment of patients with chronic kidney disease (CKD). The Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulas are the most commonly used estimations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Estimated GFR values by each formula were compared with measured GFR (mGFR) by renal inulin clearance in 2208 European adults (46% women, 1.4% Caribbean blacks), with and without CKD, and mean mGFR 72.4 +/- 39.0 (range 2.2 to 177.2) ml/min/1.73 m(2). RESULTS: Overall, the CG and MDRD formulas showed bias (mean difference) -3.5 ml/min/1.73 m(2) (5.3%), P < 0.001, and -9.8 ml/min/1.73 m(2) (-6.4%), P < 0.001; precision (SD of bias) 21.5 ml/min/1.73 m(2) (43.1%) and 20.0 ml/min/1.73 m(2) (33.0%); limits of agreement (2 SD by Bland-Altman method) 39.5 to -46.5 (range 86.0) ml/min/1.73 m(2) and 30.2 to -49.8 (range 80.0) ml/min/1.73 m(2); and accuracy within +/-30% of mGFR 70.8 and 69.0%, respectively. Both formulas showed a trend for decreasing accuracy with lower mGFR levels. According to the Kidney Disease Outcomes Quality Initiative (K/DOQI)-CKD classification's five GFR groups, the CG and MDRD formulas properly assigned 61.6 and 57.1% of the entire population and had a range of positive predictive values 42.6 to 81.8% and 39.6 to 85.2% and of negative predictive values 81.7 to 96.6% and 76.4 to 97.5%, respectively. CONCLUSIONS: The CG and MDRD formulas had some limitations for proper GFR estimation and K/DOQI-CKD classification by GFR levels alone.

Immobilization-induced bone loss is usually greater in the epiphyses than in the diaphyses. The larger fraction of trabecular bone in the epiphyses than in the diaphyses offers an intuitive explanation to account for this phenomenon. However, recent evidence contradicts this notion and suggests that immobilization-induced bone loss from the distal tibia epiphysis is mainly from the cortical compartment. The aim of this study was to establish whether this pattern of bone loss was a general rule during immobilization. We monitored various skeletal sites with different tissue composition during 5 weeks of immobilization. Ten healthy male volunteers with mean age of 24.3 years (SD 2.6 years) underwent strict horizontal bed rest. Bone scans were obtained during baseline data collection, at the end of bed rest and after 14 days of recovery by peripheral Quantitative Computed Tomography (pQCT). Sectional images were obtained from the distal tibia epiphysis (at 4% of the tibia's length), from the diaphysis (at 38%), from the proximal metaphysis (at 93%) and from the proximal epiphysis (at 98%), as well as from the distal femur epiphysis (at 4% of the femur's length) and from the patella. Relative bone losses were largest at the patella, where they amounted to − 3.2% (SD 1.8%, p < 0.001) of the baseline values, and smallest at the tibia diaphysis, where they amounted to − 0.7% (SD 1.0%, p = 0.019). The relative losses were generally larger from cortical than from trabecular compartments (p = 0.004), and whilst all skeletal sites depicted such cortical losses, substantial trabecular losses were found only from the proximal tibia epiphysis. Results confirm that the differential losses from the various skeletal sites cannot be explained on the basis of trabecular vs. cortical tissue composition differences, but that endocortical circumference can account for the different amounts of bone loss in the tibia. The present study therefore supports the suggestion of the subendocortical layer as a transitional zone, which can readily be transformed into trabecular bone in response to immobilization. The latter will lead to cortical thinning, a factor that has been associated with the risk of fracture and with osteoarthritis.

The studies on the relation between Na intake and blood pressure were started at the Brookhaven National Laboratories in Upton (New York) by Lewis K Dahl in 1961, however the story goes back to our hunter-gatherer predecessors who, between 750,000 and 10,000 years ago, ate diets proving a Na intake of 690 mg/day. The relevance of this finding became evident when the data of the studies on Yanomamo Indians of Brazil and Venezuela (living in the tropical forest) became available. They showed that in these populations sodium intake averages 1.34±2.01 mEq/24 hours,and that their blood pressure increases from the first to the second decade of life and then tapers down. Studies inc himpanzees, a species genetically similar to humans, the DASH Trial, the Intersalt Study, various meta-analyses, the data in persons with stroke, the blood pressure profile of newborns on low Na intake, and various studies in hypertensives with and without Chronic Kidney Disease, have demonstrated the beneficial effects of a restricted low salt intake alone or as an adjunct to drug therapy on blood pressure profiles.

In patients with end-stage renal disease on maintenance hemodialysis, coagulation abnormalities such as hypercoagulability and thrombosis are common. Thrombotic complications in uremic patients are frequent and include those occurring at the vascular access and in the coronary, cerebral, and retinal arteries. Data do not entirely clarify the mechanisms involved and further investigations are necessary. Here we show a summary of coagulation and fibrinolytic disorders in uremia and the novelties foreseen in molecular biology.

The intravascular volume consists of 40% to 45% red cells. Their production is controlled predominantly by erythropoietin (EPO), a hormone that is secreted particularly when tissue hypoxia is present. Because of this high percentage of the total intravascular volume the question comes to mind that, in addition to hypoxia, can volume-regulation mechanisms, known to be responsible for the maintenance of plasma volume, modulate EPO secretion when the total vascular volume changes? Indeed, there is evidence that in situations in which the intravascular volume or specifically the intrathoracic volume is altered, EPO secretion is affected. EPO secretion increases when the intrathoracic volume decreases 24 hours after water immersion or after endurance exercise when a negative water balance prevails. A head-down tilt on the other side induces central engorgement leading to a decrease of EPO concentrations. Under these experimental conditions no hypoxia was seen, supporting the idea that a Volume stimulus outgoing from intrathoracic parts of the circulation modulated EPO secretion. Further observations from the clinical side are needed to support these ideas and the consequences need to be implemented into clinical practice.

This article gathers the data on the plants used for the treatment of pathologies of kidneys and the urinary tract from the most ancient medical texts of classical antiquity, the Corpus Hippocraticum , the Aristotelian Problems , and De Materia Medica by Dioscorides. If hippocratic information is scant and practical, aristotelian are of a more theoretical nature and propose an explanation of the action of drugs on the urinary tract. De Materia Medica , coming after a possible research activity in the Alexandrian School, reports the action of many drugs. The work had a deep influence on the subsequent centuries, up to the birth of modern pharmacochemistry.

This article reviews bone adaptation to microgravity, during manned space missions, in humans undergoing Head Down Tilt (HDT) and in Hind-Limb-Suspended Rats. Under microgravity conditions, bone loss occurs in association with hypercalciuria, which in turn modulates Aquaporin 2 (AQP2) excretion in urine, thus avoiding stone forming in space. This report discloses the need to prevent bone loss in order to prepare for long stays at lunar bases or voyages to Mars. (C) 2005 by the National Kidney Foundation, Inc.

Plasma proteins in hemodialysis patients display a significant increase in deamidated/isomerized Asx (asparagine and aspartic acid) content, a marker of protein fatigue damage. This has been linked to the toxic effects of hyperhomocysteinemia in uremic erythrocytes; however, treatment aimed at abating homocysteine levels did not lead to significant reductions in plasma protein damage. The hypothesis that lack of reduction in protein damage could be due to protein increased intrinsic instability, as result of interference with the uremic milieu rather than to hyperhomocysteinemia, was put forward. The deamidated/isomerized Asx content of normal plasma incubated with several uremic toxins for 24 h, 72 h, and 7 d was measured, identifying a group of toxins that were able to elicit this kind of damage. Uremic toxins were also incubated with purified human albumin, and dose-response experiments with the two most toxic agents in terms of protein damage (guanidine and guanidinopropionic acid) were carried out. The effect of the hemodialysis procedure on protein damage was evaluated. For investigating also the consequences of these alterations, human albumin was treated in vitro to produce an increase in deamidated/isomerized Asx residues, and the effects of albumin deamidation on protein binding were evaluated. Among the uremic toxins that are able to elicit protein damage, guanidine produced a dose-dependent increase in protein damage. No difference was found after a hemodialysis session. Deamidated albumin shows normal binding capacity to warfarin, salicylic acid, or diazepam but reduced binding to homocysteine. In conclusion, uremic toxins, especially guanidine, display an ability to induce significant protein damage, which can in turn have functional consequences. Plasma proteins in hemodialysis patients display a significant increase in deamidated/isomerized Asx (asparagine and aspartic acid) content, a marker of protein fatigue damage. This has been linked to the toxic effects of hyperhomocysteinemia in uremic erythrocytes; however, treatment aimed at abating homocysteine levels did not lead to significant reductions in plasma protein damage. The hypothesis that lack of reduction in protein damage could be due to protein increased intrinsic instability, as result of interference with the uremic milieu rather than to hyperhomocysteinemia, was put forward. The deamidated/isomerized Asx content of normal plasma incubated with several uremic toxins for 24 h, 72 h, and 7 d was measured, identifying a group of toxins that were able to elicit this kind of damage. Uremic toxins were also incubated with purified human albumin, and dose-response experiments with the two most toxic agents in terms of protein damage (guanidine and guanidinopropionic acid) were carried out. The effect of the hemodialysis procedure on protein damage was evaluated. For investigating also the consequences of these alterations, human albumin was treated in vitro to produce an increase in deamidated/isomerized Asx residues, and the effects of albumin deamidation on protein binding were evaluated. Among the uremic toxins that are able to elicit protein damage, guanidine produced a dose-dependent increase in protein damage. No difference was found after a hemodialysis session. Deamidated albumin shows normal binding capacity to warfarin, salicylic acid, or diazepam but reduced binding to homocysteine. In conclusion, uremic toxins, especially guanidine, display an ability to induce significant protein damage, which can in turn have functional consequences. Copyright & 2004 by the American Society of Nephrology.

Background: Female gender is associated with high erythropoietin (EPO) resistance in end-stage renal disease. The aim of our study was to investigate the roles of age and menstrual status in this relationship. Methods: Cross-sectional analysis of registry data for 3,224 hemodialysis adults treated with EPO. Data collection included gender, age, weight, height, dialytic age, hemoglobin, EPO dose, and, for women with ages 25–44 only, also information on menstrual status and iron homeostasis. EPO resistance index (ERI) was calculated as EPO dose per kilogram BW/hemoglobin. Results: Men and women had not significantly different hemoglobin and significantly different EPO dose per kilogram weight (women vs. men, +18.2%, p < 0.001). Thus, ERI was higher in women than in men (+19.5%, p < 0.001). The gender-associated difference in ERI linearly decreased along age groups: +30.9% for ages 25–44, +23.2% for ages 45–64, and +14.2% for ages 65–84 (p < 0.05 for interaction between age and gender-associated difference in ERI). Within the subgroup of women with ages 25–44, women with menses in comparison to women without had 44.6% higher ERI (p < 0.01) due to combination of lower hemoglobin (p < 0.05) with higher EPO dose (p < 0.001). Women with menses had also lower serum iron, transferrin saturation, and serum ferritin (p < 0.001). Conclusion: The gender-associated difference in ERI is lower with increasing patients’ age. The large difference between young men and women is due to women with menses who have iron deficiency more frequently than women without periods.

Purpose of reviewThis review focuses on recent findings (June 2002-July 2003) on the topic of homocysteine, a sulfur amino acid associated with cardiovascular disease, and its metabolism in renal failure, a condition with a high prevalence of both hyperhomocysteinemia and cardiovascular disease.Recent findingsA large meta-analysis of prospective studies in the general population established that hyperhomocysteinemia is a risk factor for cardiovascular disease. The results of intervention trials, once available, will also have to be tested in a meta-analysis, because of predicted problems with their statistical power. In kidney patients, intervention trials, still in the recruiting stage, target transplant patients, because of their unique characteristics related to folate responsiveness. As for the cause of hyperhomocysteinemia, new findings show that in humans, renal metabolic extraction depends on renal plasma flow in the post-absorptive state. Folate absorption or interconversion seems not to be affected. Riboflavin is a determinant of plasma homocysteine levels in uraemia. The consequences of hyperhomocysteinemia in uraemia are DNA hypomethylation and altered gene expression.SummaryThe causes of hyperhomocysteinemia in renal failure are still not clear. However, the possibilities include defective renal or extrarenal metabolism as a result of uraemic toxicity. Renal plasma flow is important in homocysteine renal metabolism. Among the consequences of hyperhomocysteinemia in renal failure are impaired protein and DNA methylation, with an alteration in the allelic expression of genes regulated through methylation. Intervention trials are under way to test whether hyperhomocysteinemia is causally related to cardiovascular disease in this patient population.

Functioning of the hypothalamic-neurohypophyseal-vasopressin axis is altered in aging, and the pathway may represent a plausible target to slow the process of aging. Arginine vasopressin, a nine-amino acid peptide that is secreted from the posterior pituitary in response to high plasma osmolality and hypotension, is central in this pathway. Vasopressin has important roles in circulatory and water homoeostasis mediated by vasopressin receptor subtypes V1a (vascular), V1b (pituitary), and V2 (vascular, renal). A dysfunction in this pathway as a result of aging can result in multiple abnormalities in several physiological systems. In addition, vasopressin plasma concentration is significantly higher in males than in females and vasopressin-mediated effects on renal and vascular targets are more pronounced in males than in females. These findings may be caused by sex differences in vasopressin secretion and action, making men more susceptible than females to diseases like hypertension, cardiovascular and chronic kidney diseases, and urolithiasis. Recently the availability of new, potent, orally active vasopressin receptor antagonists, the vaptans, has strongly increased the interest on vasopressin and its receptors as a new target for prevention of age-related diseases associated with its receptor-altered signaling. This review summarizes the recent literature in the field of vasopressin signaling in age-dependent abnormalities in kidney, cardiovascular function, and bone function.

BackgroundBed-rest experiments are designed for investigation on catabolic effects of hypokinetic conditions and/or for microgravity simulation in on-ground aerospace research. Bed-rest effects include a reduction in fat-free mass and muscle mass. Urea and creatinine are catabolites of endogenous protein and of muscular energetic metabolism which are excreted mainly by the kidney. The study investigated on urea, creatinine, and kidney function during bed-rest.MethodsTwenty healthy young men underwent a 7-day adaptation period (day-6 to day-0) and a 35-day bed-rest experiment (day1 to day35) during normocaloric diet. Urine were collected from day-3 to day0 (baseline) and from day1 to day35. Blood samples and anthropometrical data were collected at day0 (baseline) and bed-rest days 7, 14, 21, 28, and 35.ResultsBed-rest reduced plasma volume, weight, fat-free mass, and muscle mass (PConclusionsStudy results shows that urea is a marker of catabolic conditions secondary to hypokinetic conditions.