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The year 2022 will mark the 150th anniversary of the death of Giuseppe Mazzini, the spiritual father of the Italian Republic and one of the best political minds of the nineteenth century. In this review, we revisit the events surrounding Mazzini's death, based on a report published in 1872 by Dr. Giovanni Rossini, the Italian physician who cared for him during his last days in Pisa. The detailed clinical information provided by Dr. Rossini suggests quite strongly that Mazzini's most likely cause of death was gastroesophageal cancer complicated by aspiration pneumonia. Surprisingly, there are no published medline entries concerning the cause of death of this Italian patriot and revolutionary, who spent 41 years of his life in exile, was admired by Dickens, Meredith and Carlyle, and is considered not only one of the founding fathers of Italy but also one of the visionaries behind the idea of a United Europe.

The invasion of the ancient Ethiopian empire perpetrated by the Italian fascist regime in 1935-1936 deserves all the blame due to a war of aggression, a belated colonial enterprise and a bullying act of a totalitarian regime. Yet there is one aspect of that war that aroused universal admiration among contemporaries and which still deserves to be analysed today: the healthcare of troops. The Italian army, which came close to half a million men, was the largest European army that had ever fought in tropical or sub-tropical territories. Many Cassandras expected a health catastrophe, even more than a military one. But Mussolini decided to entrust Sir Aldo Castellani, the famous tropicalist doctor who had been living between Italy and England for years, with the role of Inspector General of Military and Civilian Health Services for East Africa. At the end of the seven-month victorious military campaign, the very low number of casualties recorded due to illness or injury evoked amazement and admiration. This was not just propaganda, as proved by the uncountable invitations from military and health authorities all over the world (including some of the nations that had imposed economic sanctions against Italy a few months earlier) for Castellani to reveal his secret through lectures, articles and conferences. Even US President Franklyn D. Roosevelt, who as a polio sufferer was particularly sensitive to public health issues, asked for and obtained a long private interview with Castellani, the "man who won the war".

C4 photosynthesis concentrates CO2 around Rubisco in the bundle sheath, favouring carboxylation over oxygenation and decreasing photorespiration. This complex trait evolved independently in >60 angiosperm lineages. Its evolution can be investigated in genera such as Flaveria (Asteraceae) that contain species representing intermediate stages between C3 and C4 photosynthesis. Previous studies have indicated that the first major change in metabolism probably involved relocation of glycine decarboxylase and photorespiratory CO2 release to the bundle sheath and establishment of intercellular shuttles to maintain nitrogen stoichiometry. This was followed by selection for a CO2-concentrating cycle between phosphoenolpyruvate carboxylase in the mesophyll and decarboxylases in the bundle sheath, and relocation of Rubisco to the latter. We have profiled 52 metabolites in nine Flaveria species and analysed 13CO2 labelling patterns for four species. Our results point to operation of multiple shuttles, including movement of aspartate in C3–C4 intermediates and a switch towards a malate/pyruvate shuttle in C4-like species. The malate/pyruvate shuttle increases from C4-like to complete C4 species, accompanied by a rise in ancillary organic acid pools. Our findings support current models and uncover further modifications of metabolism along the evolutionary path to C4 photosynthesis in the genus Flaveria.

John Keats (1795-1821), besides being the famous English poet, was a student of medicine at the United Hospitals in London. On the occasion of the bicentenary of his death, we would like to pay tribute to this versatile figure with a photographic itinerary of his medical life. This article, in connection with the project “Himetop – The History of Medicine Topographical Database”, retraces objects and places where the poet lived, studied, worked, and prematurely died, showing the importance of material culture. The photographic journey starts in London with the birthplace of the poet and continues through the places of his infancy and youth, the school in Enfield, the lodgings at 8 St. Thomas Street, the United Hospitals, etc. After giving up medicine to devote to poetry, the itinerary proceeds in the Hampstead and, as the ultimate destination, in Rome, where John Keats spent his last months of life due to tuberculosis. To conclude the path at the Protestant Cemetery in Rome, where he was buried, surrounded by grass and flowers. The material memories left by John Keats, as well as preserving his memory, take on a significant educational and inspirational role for everybody and, in particular, literary people and medical students., Osim što je slavni engleski pjesnik, John Keats (1795. – 1821.) bio je i student medicine na londonskom sveučilištu. Fotografskim putopisom njegova medicinskog života želimo odati počast ovome svestranom čovjeku u povodu dvjestote obljetnice njegove smrti. Ovaj članak, u suradnji s projektom Himetop – topografska baza podataka povijesti medicine (eng. Himetop – The History of Medicine Topographical Database) pokazuje važnost materijalne kulture prateći objekte i mjesta na kojima je pjesnik živio, studirao, radio i prerano umro. Ovo fotografsko putovanje počinje u Londonu, njegovu rodnome mjestu, i nastavlja put kroz mjesta njegova djetinjstva i mladosti – škola u Enfieldu, prebivalište na broju 8 Ulice St. Thomas, Ujedinjene bolnice itd. Nakon što je odustao od medicine kako bi se posvetio poeziji, putopis se nastavlja u Hampsteadu i vodi do Rima gdje je John Keats, zbog tuberkuloze, proveo posljednje mjesece svoga života. Putovanje završava na protestantskom groblju u Rimu gdje je pokopan okružen travom i cvijećem. Materijalne uspomene koje je ostavio, osim što čuvaju uspomenu na njega, imaju značajnu obrazovnu i inspirativnu ulogu za sve, a posebice za ljude koji se bave književnošću i studente medicine.

Italian born and long term resident in England, Sir Aldo Castellani (1874–1971), is usually credited with “several discoveries of great importance in tropical medicine”, most notably for his role in determining the aetiology of sleeping sickness and yaws. This contribution tries to highlight his role in the history of vaccinology as a pioneer in the design and use of combined and polyvalent vaccines. In the light of existing data, while acting as Director of the Bacteriological Institute of Colombo (Ceylon) in the decade before the First World War, Castellani was the first to experiment with both different strains of “antigens belonging to the same group” like in his typhoid-paratyphoid vaccine (TAB), as well as the simultaneous use of more pathogens, or part of them, for protection against different diseases, like in his “tetravaccine” (TAB + cholera) and “pentavaccine” (TAB + cholera + Malta fever). At the beginning of the War, based on the results of thousands of vaccinations, he strongly maintained that those combined or mixed vaccines were harmless and effective. The Allied Armies became more and more interested in Castellani’s methods. His TAB vaccine was extensively used among the soldiers and his contributions were largely acknowledged especially in the Anglo-Saxon world in the following years, when it was plainly stated that “to Castellani is due the credit of having first proposed, prepared, and used, combined vaccines”. The path to widespread use of combination and polyvalent vaccines - which is usually dated back only to the late 1940s - was still long and winding. Castellani himself abandoned that field of research after the War and this is probably why that early history is nowadays often forgotten.

The kaleidoscopic figure of Giovanni Maria Lancisi (1654-1720), one of the most remarkable physicians, scientists and scholars in modern Italy, can be a lucky gateway into eighteenth-century Rome – a surprising place for its intellectual vivacity, sometimes unprejudiced and always open to the most innovative expectations. The Medical Library he founded, one of the oldest and most important in the world, is only the most concrete among the many contributions that Lancisi gave to the dissemination and growth of medical knowledge of his time. His studies in the field of hygiene and the fight against malaria, his efforts to eradicate fears and popular superstitions caused by the ‘sudden deaths’, the enhancement of new forms of teaching such as the use of anatomical theatres, the active participation to the life of scientific and literary academies of Europe, are all revealing features, which make Lancisi a figure of lasting and widespread interest three centuries after his death. A figure who, according to his first biographer, was so outstanding «in the knowledge of sciences, and in the competence to explain them» that he aroused «the applause, even among the commoners, and the young people».

Metabolite profiling has uncovered unexpected diversity of Calvin–Benson cycle operation in C3 species, but also conserved features that may be important in the fluctuating conditions found in the field., Improving photosynthesis is a promising avenue to increase crop yield. This will be aided by better understanding of natural variance in photosynthesis. Profiling of Calvin–Benson cycle (CBC) metabolites provides a top-down strategy to uncover interspecies diversity in CBC operation. In a study of four C4 and five C3 species, principal components analysis separated C4 species from C3 species and also separated different C4 species. These separations were driven by metabolites that reflect known species differences in their biochemistry and pathways. Unexpectedly, there was also considerable diversity between the C3 species. Falling atmospheric CO2 and changing temperature, nitrogen, and water availability have driven evolution of C4 photosynthesis in multiple lineages. We propose that analogous selective pressures drove lineage-dependent evolution of the CBC in C3 species. Examples of species-dependent variation include differences in the balance between the CBC and the light reactions, and in the balance between regulated steps in the CBC. Metabolite profiles also reveal conserved features including inactivation of enzymes in low irradiance, and maintenance of CBC metabolites at relatively high levels in the absence of net CO2 fixation. These features may be important for photosynthetic efficiency in low light, fluctuating irradiance, and when stomata close due to low water availability.

Summary Introduction of a C4 photosynthetic mechanism into C3 crops offers an opportunity to improve photosynthetic efficiency, biomass and yield in addition to potentially improving nitrogen and water use efficiency. To create a two‐cell metabolic prototype for an NADP‐malic enzyme type C4 rice, we transformed Oryza sativa spp. japonica cultivar Kitaake with a single construct containing the coding regions of carbonic anhydrase, phosphoenolpyruvate (PEP) carboxylase, NADP‐malate dehydrogenase, pyruvate orthophosphate dikinase and NADP‐malic enzyme from Zea mays, driven by cell‐preferential promoters. Gene expression, protein accumulation and enzyme activity were confirmed for all five transgenes, and intercellular localization of proteins was analysed. 13CO2 labelling demonstrated a 10‐fold increase in flux though PEP carboxylase, exceeding the increase in measured in vitro enzyme activity, and estimated to be about 2% of the maize photosynthetic flux. Flux from malate via pyruvate to PEP remained low, commensurate with the low NADP‐malic enzyme activity observed in the transgenic lines. Physiological perturbations were minor and RNA sequencing revealed no substantive effects of transgene expression on other endogenous rice transcripts associated with photosynthesis. These results provide promise that, with enhanced levels of the C4 proteins introduced thus far, a functional C4 pathway is achievable in rice.

Photorespiration is essential for maintaining high rates of C4 photosynthesis by preventing the 2-phosphoglycolate-mediated inhibition of carbon utilization efficiency., Photorespiration is indispensable for oxygenic photosynthesis since it detoxifies and recycles 2-phosphoglycolate (2PG), which is the primary oxygenation product of Rubisco. However, C4 plant species typically display very low rates of photorespiration due to their efficient biochemical carbon-concentrating mechanism. Thus, the broader relevance of photorespiration in these organisms remains unclear. In this study, we assessed the importance of a functional photorespiratory pathway in the C4 plant Flaveria bidentis using knockdown of the first enzymatic step, namely 2PG phosphatase (PGLP). The isolated RNAi lines showed strongly reduced amounts of PGLP protein, but distinct signs of the photorespiratory phenotype only emerged below 5% residual PGLP protein. Lines with this characteristic were stunted in growth, had strongly increased 2PG content, exhibited accelerated leaf senescence, and accumulated high amounts of branched-chain and aromatic amino acids, which are both characteristics of incipient carbon starvation. Oxygen-dependent gas-exchange measurements consistently suggested the cumulative impairment of ribulose-1,5-bisphosphate regeneration with increased photorespiratory pressure. Our results indicate that photorespiration is essential for maintaining high rates of C4 photosynthesis by preventing the 2PG-mediated inhibition of carbon utilization efficiency. However, considerably higher 2PG accumulation can be tolerated compared to equivalent lines of C3 plants due to the differential distribution of specific enzymatic steps between the mesophyll and bundle sheath cells.

Introduction of a C4 photosynthetic mechanism into C3 crops offers an opportunity to improve photosynthetic efficiency, biomass and yield in addition to potentially improving nitrogen and water use efficiency. To create a two-cell metabolic prototype for an NADP-malic enzyme type C4 rice, we transformed Oryza sativa spp. japonica cultivar Kitaake with a single construct containing the coding regions of carbonic anhydrase, phosphoenolpyruvate (PEP) carboxylase, NADP-malate dehydrogenase, pyruvate orthophosphate dikinase and NADP-malic enzyme from Zea mays, driven by cell-preferential promoters. Gene expression, protein accumulation and enzyme activity were confirmed for all five transgenes, and intercellular localisation of proteins was analysed. 13 CO2 labelling demonstrated a 10-fold increase in flux though PEP carboxylase, exceeding the increase in measured in vitro enzyme activity, and estimated to be about 2% of the maize photosynthetic flux. Flux from malate via pyruvate to PEP remained low, commensurate with the low NADP-malic enzyme activity observed in the transgenic lines. Physiological perturbations were minor and RNA sequencing revealed no substantive effects of transgene expression on other endogenous rice transcripts associated with photosynthesis. These results provide promise that, with enhanced levels of the C4 proteins introduced thus far, a functional C4 pathway is achievable in rice.

Interspecific divergence in metabolite profiles in C3 and C4 species points to differing evolutionary trajectories of the Calvin–Benson cycle in different seed plant lineages, Low atmospheric CO2 in recent geological time led to the evolution of carbon-concentrating mechanisms (CCMs) such as C4 photosynthesis in >65 terrestrial plant lineages. We know little about the impact of low CO2 on the Calvin–Benson cycle (CBC) in C3 species that did not evolve CCMs, representing >90% of terrestrial plant species. Metabolite profiling provides a top-down strategy to investigate the operational balance in a pathway. We profiled CBC intermediates in a panel of C4 (Zea mays, Setaria viridis, Flaveria bidentis, and F. trinervia) and C3 species (Oryza sativa, Triticium aestivum, Arabidopsis thaliana, Nicotiana tabacum, and Manihot esculenta). Principal component analysis revealed differences between C4 and C3 species that were driven by many metabolites, including lower ribulose 1,5-bisphosphate in C4 species. Strikingly, there was also considerable variation between C3 species. This was partly due to different chlorophyll and protein contents, but mainly to differences in relative levels of metabolites. Correlation analysis indicated that one contributory factor was the balance between fructose-1,6-bisphosphatase, sedoheptulose-1,7-bisphosphatase, phosphoribulokinase, and Rubisco. Our results point to the CBC having experienced different evolutionary trajectories in C3 species since the ancestors of modern plant lineages diverged. They underline the need to understand CBC operation in a wide range of species.

Calvin–Benson cycle intermediate profiling in Arabidopsis and rice reveals interspecies differences in pathway operation at moderate irradiance, and shared features that minimize inefficiency in low light and low CO2., Metabolite profiles provide a top-down overview of the balance between the reactions in a pathway. We compared Calvin–Benson cycle (CBC) intermediate profiles in different conditions in Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) to learn which features of CBC regulation differ and which are shared between these model eudicot and monocot C3 species. Principal component analysis revealed that CBC intermediate profiles follow different trajectories in Arabidopsis and rice as irradiance increases. The balance between subprocesses or reactions differed, with 3-phosphoglycerate reduction being favoured in Arabidopsis and ribulose 1,5-bisphosphate regeneration in rice, and sedoheptulose-1,7-bisphosphatase being favoured in Arabidopsis compared with fructose-1,6-bisphosphatase in rice. Photosynthesis rates rose in parallel with ribulose 1,5-bisphosphate levels in Arabidopsis, but not in rice. Nevertheless, some responses were shared between Arabidopsis and rice. Fructose 1,6-bisphosphate and sedoheptulose-1,7-bisphosphate were high or peaked at very low irradiance in both species. Incomplete activation of fructose-1,6-bisphosphatase and sedoheptulose-1,7-bisphosphatase may prevent wasteful futile cycles in low irradiance. End-product synthesis is inhibited and high levels of CBC intermediates are maintained in low light or in low CO2 in both species. This may improve photosynthetic efficiency in fluctuating irradiance, and facilitate rapid CBC flux to support photorespiration and energy dissipation in low CO2.

Leopold Auenbrugger (1722-1809), the inventor of percussion, joins René Laennec as the father of modern physical examination. On the occasion of the bicentennial of the invention of the stethoscope (1816), I went in search of the material footprints left by Auenbrugger in his homeland, Austria. This attempt led me to construct a rather fragmented picture, with some disillusionment (e.g. about his tomb) and some pleasant surprise (e.g. a new interpretation of the extant iconography). Apparently, posterity has not been sufficiently mindful of or grateful towards this great innovator of medical science. All the more reason for knowing and protecting what is left of him: buildings, monuments, portraits… Anyway, Leopold Auenbrugger is honored and implicitly remembered today, as he was in the past, every time a doctor practices the percussion on the chest of a patient (i.e. billions of times each year)., Leopold Auenbrugger (1722. – 1809.), izumitelj perkusije, pridružuje se Renéu Laennecu, ocu suvremenoga fizikalnog pregleda. U povodu dvjestote godišnjice izuma stetoskopa (1816.) tražio sam materijalne tragove Auenbruggera u njegovoj domovini Austriji. Taj je pokušaj doveo do stvaranja prilično fragmentirane slike, s ponekim razočaranjem (npr. oko njegova groba) i ponekim ugodnim iznenađenjem (npr. novo tumačenje postojeće ikonografije). Očigledno, potomci nisu bili dovoljno zahvalni ili pažljivi prema ovom velikom inovatoru medicinske znanosti, što nam pruža više razloga za bolje poznavanje i veću zaštitu onoga što je ostalo nakon njega: zgrade, spomenici, portreti... Svakako, Leopold Auenbrugger je poštovan i implicitno se pamti danas, kao i u prošlosti, svaki put kad liječnik prakticira perkusiju na grudnom košu pacijenta (tj. milijardu puta svake godine).

A 2014 American-German war movie directed by and starring George Clooney (Actor, Screenwriter, Film Director, and Producer; Los Angeles, California and Laglio, Italy) (1961-current) popularized the work of a special United States Army unit devoted to the rescue of art treasures stolen or hidden by the Nazis during World War II. A similar story occurred in Paris to a curious little monument closely linked to the history of Anesthesia. This happened about 70 years ago, in December 1944.

Dementia is a terminal disease, associated with great suffering and difficult decisions in the severe stage. The decision-making process is characterized by uncertainty because of lack of scientific evidence in treatments and by the need to reconcile conflicting points of view. In intercurrent diseases, aggressive interventions are used without consideration of its futility; in comparison with cancer, several consequences of physicians' attitude not to consider dementia as a terminal disease have been reported, especially concerning pain relief. Lack of evidence of artificial nutrition and hydration effectiveness makes advance care planning relevant.

During photosynthesis of higher plants, absorbed light energy is converted into chemical energy that, in part, is accumulated in the form of transitory starch within chloroplasts. In the following night, transitory starch is mobilized to sustain the heterotrophic metabolism of the plant. β-amylases are glucan hydrolases that cleave α-1,4-glycosidic bonds of starch and release maltose units from the non-reducing end of the polysaccharide chain. In Arabidopsis, nocturnal degradation of transitory starch involves mainly β-amylase-3 (BAM3). A second β-amylase isoform, β-amylase-1 (BAM1), is involved in diurnal starch degradation in guard cells, a process that sustains stomata opening. However, BAM1 also contributes to diurnal starch turnover in mesophyll cells under osmotic stress. With the aim of dissecting the role of β-amylases in osmotic stress responses in Arabidopsis, mutant plants lacking either BAM1 or BAM3 were subject to a mild (150mM mannitol) and prolonged (up to one week) osmotic stress. We show here that leaves of osmotically-stressed bam1 plants accumulated more starch and fewer soluble sugars than both wild-type and bam3 plants during the day. Moreover, bam1 mutants were impaired in proline accumulation and suffered from stronger lipid peroxidation, compared with both wild-type and bam3 plants. Taken together, these data strongly suggest that carbon skeletons deriving from BAM1 diurnal degradation of transitory starch support the biosynthesis of proline required to face the osmotic stress. We propose the transitory-starch/proline interplay as an interesting trait to be tackled by breeding technologies aimingto improve drought tolerance in relevant crops.

The document deals with some ethical issues raised by the treatment of demented people. In particular the conceptual and empirical aspects of the assessment of awareness and competence of these patients are analysed, as well as the dilemmas related to the treatment of behavioral disorders.

Le tecniche di neurostimolazione e neuromodulazione cerebrale, mediante elettrodi collegati a stimolatori elettrici sottocutanei, vanno progressivamente consolidandosi come una delle più promettenti branche della neurochirurgia. Alle indicazioni terapeutiche tradizionali riguardanti il Parkinson e altri disturbi motori, se ne vanno aggiungendo di nuove che spaziano dai disturbi della coscienza alla terapia del dolore, dall’epilessia a numerose patologie neuropsichiatriche. È ormai frequente l’accostamento di tali tecniche alla problematica esperienza della psicochirurgia, dalla quale tuttavia esse sembrano distinguersi per l’assenza del principale inconveniente di quella che, com’è noto, era l’irreversibilità degli effetti negativi. Ma “modulare” artificialmente il sistema nervoso vuol dire in qualche modo “modulare” la mente umana, ovvero curarla innanzitutto, ma anche saggiarne i limiti, potenziarla, trasformarla. Una tale possibilità “manipolatoria” di ciò che costituisce il nucleo distintivo della persona umana non può prescindere da un’attenta valutazione etica, che tenga conto non solo delle applicazioni attuali di questa tecnologia ma anche delle sue potenzialità future. La sperimentazione e l’utilizzo clinico di tali tecniche sono stati invece finora accompagnati solo da sporadiche, ancorché interessanti, riflessioni etiche, quasi sempre a carico degli stessi scienziati che se ne occupavano. Il presente contributo cerca di fornire gli elementi necessari per avviare un’approfondita riflessione bioetica su questo argomento che, per le ragioni accennate, appare particolarmente urgente.

Triumphant medicine in the late nineteenth and in the first half of the twentieth centuries involved increasing amounts of technology and engineering skills. The present contribution gives an example of such a momentous and irreversible convergence between two specific fields: surgery and mechanical engineering. In less than 50 years (c.1930–1980) several “scientific couples” (usually a visionary surgeon and an above-average-skilled engineer) had made a reality of a long dreamed “impossibility” of modern medicine such as open-heart surgery. This contribution will focus not only on technical details but also on the “human factor” which was the hallmark of the protagonists of this revolution.

Luigi Carlo Farini (1812-1866) was one of the leading figures in the Italian unification, the Risorgimento. As a physician he always took care of the health problems of its people with a broadminded attitude, promoting for example extensive campaigns of Jennerian vaccination or experimenting the effects of electricity on tetanus. As a political leader - he was proclaimed “Dictator” in 1859 - he made possible the annexation of the Adriatic regions of Emilia and Romagna to the Kingdom of Vittorio Emanuele II of Savoy that later, in March 1861, was to become the new Kingdom of Italy. This article, in connection with the project “Himetop - The History of Medicine Topographical Database”, offers a brief photographic survey of the location and condition of the monuments and memories of the physician-dictator in his homeland, two hundred years after his birth. Not only the tormented history of his monument in Ravenna, but also his birthplace, hospital, tomb, etc., testify that Farini’s memory is well preserved among the people he served as a physician and as a statesman., Luigi Carlo Farini (1812.–1866.) bio je vodeća ličnost u pokretu ujedinjena Italije, tzv. Risorgimentu. Kao liječnik, uvijek se širokogrudno brinuo za zdravlje svog naroda, promičući kampanje poput Jennerova cijepljenja ili ispitujući djelovanje električne struje na tetanus. Kao politički vođa – 1859. proglašen je “Diktatorom” – omogućio je pripojenje jadranskih područja Emilije i Romagne kraljevstvu Viktora Emanuela II. od Savoje, koje je poslije, u ožujku 1861., postalo Kraljevina Italija. Ovaj članak, povezan s projektom pod nazivom “Himetop – topografska baza podataka povijesti medicine”, daje kratki fotografski pregled lokacija i stanja spomenika i uspomena posvećenih ovom liječniku-diktatoru u domovini dvjesto godina nakon njegova rođenja. Nesretni događaji vezani uz njegov spomenik u Ravenni, njegovo rodno mjesto, bolnica i grob već dovoljno svjedoče koliko je očuvano sjećanje na Farinija među narodom kojem je služio kao liječnik i državnik.