SINERELY, … I AN’T GIVE UP - PharmacologyOnLine | …...Paola, a psychiatrist living and working away from home in Novi Ligure (Piedmont), brought her dog. Silvy saw a rat at thebottom

Newsletter • 2015 • vol.3 • 8-33

SINCERELY, … I CAN’T GIVE UP

Rossini, L.

Department of Neuroscience, Service of Clinical Pharmacology and Toxicology, and Section of Human Pharmacotoxicology, I.M.O. Interuniversity Center, Medical School, Polytechnic University of Ancona, Italy

Via Tronto 10 A, Ancona 60100, Italy

[email protected]

SUMMARYA narration diary of some key periods in my life.

“Multitudo non est sequenda”(Augustine of Hippo)

Dedicated to Prof. Lorenzo Maniscalco, MD, PhD, a world renowned surgeon with Doctors Without Borders.

Keywords: Life artifacts, Basic decisions, Education and first steps in competition, Home anectodes and “in the new world”: US and Canada, B ack toItaly, Multiple joint foundations in biomathematics, chemical physiology, and in vitro, in situ, in vivo physio-pharmacotoxicological non-invasive read-outs, World pharmacotoxicological epidemiology and monitoring. Final plea to the Authorities.

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http://pharmacologyonline.silae.it

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December 30, 2015

mailto:[email protected]

IntroductionObligations toward family, students, and friends

(Thursday 29th October, 2015)Yes, I feel the need to write down some of my

memories. Now 83, it is quite clear that I don'tknow whether I'll have or want to stop.This endeavor stems from the suggestion, or betterthe reiterated request in favor of students, by agroup that was undoubtedly a community ofexcellence, teaching and research at the time whenits name was Università di Ancona. It is nowUniversità Politecnica delle Marche, becausenobody then felt up to opposing the name change -in favor of technology and engineering - advocatedby Marco Pacetti, who has been Chancellor formany years.I have taken up this invitation to honor the last,great friend I had the luck to make in Ancona,Lorenzo Maniscalco, a surgeon 11 years my junior,who retired early from his hospital job. Well, atleast over the last 3-4 years, after I retired as late aswas allowed in Italy, and after suffering severehumiliation during the time I was doyen, I metLorenzo on October 31th, 2008 at the Passettopublic swimming pool in Ancona. I was swimming torecover from a bad fall. During one of her short andincreasingly rare week end visits, my daughterPaola, a psychiatrist living and working away fromhome in Novi Ligure (Piedmont), brought her dog.Silvy saw a rat at the bottom of our swimming pool,which was empty and undergoing repair, andjumped in, breaking a leg. I climbed down as Paolaheld the ladder, but when I climbed back up the lasttime, I did not realize that she was tending to herdog and was no longer holding it. I thus fell backfrom a height of 2.5 m like a sack. A cry and thenunconsciousness. When I came to, a short whilelater, I had to find the strength to climb back up.Two days later I was examined at the ED by a teamof internal medicine doctors, orthopedic surgeons,neurologists and radiologists, at a time when the CTmachine was not yet available. After at least 5hours of tests and consultations, feeling increasingand spreading pain, I was told that there wasnothing the matter with me, that I could go back toplaying tennis, and that I could take tramadol asneeded. But in fact I had to self-inject morphine fora week - all of this without ever neglecting my work.Then one day, as I was walking like a monkey alonga corridor of Torrette hospitaI, I accidentally metMaurizio Ricci, who then headed the rehabilitationservice. He was so alarmed that he examined methen and there. He took my shirt out of the trousersand as I leaned against the wall he prodded the

protruding spinous processes. “Get yourself wheeledto the Radiology department at once" he said"because I'm sure you've broken some vertebrae. Inthe mean time I'll call GianMarco Giuseppetti, a veryexperienced radiologist from the hospital". The lattersaid that he could not carry out the imaging studiesrequired, which would have to be done at theNeurosurgery department, then coordinated by Prof.Ugo Salvolini, but sent me to the Gynecological andMaternity Hospital, where a resident was waiting forme. She attentively followed my CT scan andeventually based her dissertation thesis on my case,where I was of course anonymized. The diagnosiswas “full, oblique comminuted fracture of L3 and L5vertebral bodies, with large free fragments”. Thescans were terrifying. I risked being confined to awheelchair for life. There are unfortunately more ofthese stories that have come to my knowledge, andwhich may be instructive to tell, maybe later.Back to Lorenzo Maniscalco. While I swam my 14-16daily laps (each 33 m), he did exercises to counterthe late sequelae of a fall down the hospital stairs,made slippery by a wash with a common rag. Hesuffered a fracture requiring cervical laminectomy.What are two pensioners to do in Italy if they havenot nurtured other professional or different interests? We had both been completely absorbed in ourwork, which in his case included night shifts. As formyself, in the seven North-American universitieswhere I had worked (5 in the US and 2 in Canada),retired researchers can no longer apply for grants,but are given an office, sometimes the services of asecretary, and access to labs and other services.However, I had left North America to become aProfessor in Ancona. It is really an inexcusable wasteof free teaching and research experience. I wentback to my philately; if I took care not to be too loud- and before my osteoarthritis, I could also practiceon the Steinway baby grand I had bought with all mysavings when I was at Siena (before it was attackedby moths). After the oxidized chords had beenreplaced, I could finally follow Barenboim in all thesonatas of my beloved Schubert, performed by twos,at the Piccola Scala. I also read, commented in themargin, and annotated the major works of the 38greatest philosophers of all times and of the 15greatest universal poets. In turn, Lorenzo offered hishelp to Doctors Without Frontiers, and participatedin several three-month stages in countries such asYemen, Somaliland and, repeatedly, Haiti. Then, as Iwrote to the Director of the Ancona local paper:

October 3rd, 2015:

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PhOL Rossini 9 (8-33)

“Doctors Without Frontiers are deeply saddened bythe sudden death of colleague and friend, Prof.Lorenzo Maniscalco, surgeon and aid worker, attheir Bikenge hospital, Democratic Republic of theCongo. After a long career in Italy as a surgeon anduniversity professor, in 2012 he'd placed hisexperience at the service of DWF and theirbeneficiaries in conflict areas such as Yemen,Central African Republic, Somaliland, Haiti, and theDemocratic Republic of the Congo, where he hadbeen only three weeks. The DWF family, thehumanitarian workers, the staff, and the voluntaryworkers are all deeply affected by Lorenzo's demiseand their thoughts are with his loved ones”, saidGabriele Eminente, general director of DWF.Lorenzo had a heart attack at our Bikenge hospitalwhile tending to his patients as usual. We'llremember him with affection and will always begrateful for the passionate, enthusiastic anddedicated work he donated to us in these valuableyears together. DWF began working in Bikengehospital in March 2015. Bikenge is a remote miningvillage in the eastern province of Maniena, wherepeople live in extreme health conditions and DWFare the sole possibility of access to care”. It isespecially for Lorenzo, to remember hisexceptionally lucid and accepting character, that Imust follow him here, in telling some facts of ourexistence and our often obscure battles, sometimesbecause of shyness or fear, when one tries to keephigh the spirit of research and service without eventhinking of asking for remuneration”.

1.Disbandment of an internationally competitiveresearch group, with a waste of millions of Eurosof public money, while the competent controlAuthorities turn a blind eye

(Still Thursday 29th October, 2015)Yesterday I read at 12:33 (updated at 12:51):Ancona, mass flight of ward directors fromTorrette hospital. This is the other side of thebudget balance achieved by the regional healthservice. The President of the regional government,Ceriscioli, replies to the question of councilorsZaffiri, Malaigia, and Zura Puntaroni (NorthernLeague) on the exodus of high-profile physiciansfrom Torrette Regional Hospital. Budgetaryconstraints and a reduction of activities, aimed atcost containment, have resulted in the massdeparture of valuable professionals, includingTorraca and Cascinu. (Not to mention Muzzonigroand Salvolini, who have retired in recent and lessrecent times). This is what Ceriscioli said to the

assembly: “Budgetary constraints have involvedsacrifices from personnel, and production has sloweddown, which for Torrette is the worst thing thatcould be done. This " added Ceriscioli " hasgenerated passive mobility. We thus need a strategicplan, focusing on the structures that can operate atfull capacity and reduce passive mobility". I can readbetween the lines the willingness to make changes atthe top of the hospital management, to restoreTorrette to its place as a regional excellence. Butreally, also Muzzonigro, my former Director, who hasmounted an exhibition of old urological instrumentsin my former study! His Director followed the Dean,Prof. Corsi, who was always accurate, impeccable,really unique and admirable with everybody and astickler to form. He suggested entrusting themultinuclear spectrometer, which enabled 13-C, 19-F, and, initially 31-P analyses, exclusively to hisyoung, brilliant pathologist, a great fan of motorcycleworld championship races. I agreed that he wouldmanage the future of that lab, unique in Italy, whichhosted optical, surface fluorescence, and massspectrometry apparatuses (He divorced his beautifulwife, who was later diagnosed with breast cancer ata very young age; I have no idea where either hasended up). Then came Polito, who began byappropriating my sole radiology technician, who wasforced to become an operating room x-ray technicianovernight, whereas he was an excellent NMRspectroscopist and an expert cardio-coronary physio-pharmacological technician, at least for Langendorffpreparations. The Dean ad interim approved theabuse - really a Far West story of arrogance and highhandedness - in the teeth of national regulations. Inthe meantime Lamberto Re, a medical assistant, hadrefused a collaboration with the hospital to devotehimself to electrophysiology, including unicellularelectrophysiology, honed with the group of theHeidelberg Nobel laureate. He also worked with thetrailblazer Vittorio Erspamer, but ended up dealingmostly with ozone therapy, ignoring the stimulicoming from Ferid Murad's physiological chemistryand working also with Camerano and Dubai, besidesour Science faculty. The excellent graduatetechnician Cecilia Tonnini did not accept theunanimous decision of the Consiglio di Istituto, whohad assigned her to the ongoing NMR spectrometryresearch, and opted for a position in the Hematologyclinic. Should I really write my memoirs, as Lorenzosuggested? But then who would publish them? Whatabout making them a free instant book? No, they willbe published as a Note in the online journal of ourItalian Society of Pharmacology.During my latest ED visit, last month, they missed my_______________________________________


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left rib fracture as they concentrated on the rightscapular fracture. The injuries are due to a fall,facilitated by my chronic lower limb polyneuritis. Ihave radiculopathy and a beginning of axonotmesis,late complications of the fall into the empty pool Ihave mentioned above. What can one do if he hasto spend the night in an armchair? How can onehelp remember, during one's sleepless hours, thatPortonovo faculty meeting not so many years ago,when Ancona Medical School offered a post to thisnew, extraordinary pharmacologist? He was foistedon us, against my strenuous opposition, by theDean (later Chancellor) of Napoli University, withthe blessing of our long-time Dean. The move wasrelated to the earlier offer of a post, in Naples, to acolleague from our University. Our faculty then hadno choice but to accept this person, who had beenwaiting for a position for years, and whose state ofacademic eligibility was close to expiry, since noother university had offered one. However, verysoon the then department head Muzzonigro andthe newly arrived pharmacologist fell out, andMuzzonigro lost to the wily fighter of universitybattles. He had also appropriated my secretary, arelative of the elusive Re. The latter did nothowever pay her the compliment of ignoring herfaults, and honestly acknowledged her scarceprofessional value, a feature that she shared withmost of the people hired at the time of theinstitution of the new Medical School. And if I didnot fall sick then, it was because I was relentlesslyteaching and doing exams. (Oral examinations havesince been replaced by tables of numbers and signsthat are to be completed in less than an hour, everytrimester, by all students. The answers are partiallyconsistent with being arranged in advance with thestudents. These examinations replace thediscussions of at least one and a half/two hours thatI had adopted, asking random and exclusively oralquestions.) This was the time when the lab hostingthe mass, optical, and UV fluorescencespectrometers, and especially the multinuclearNMR apparatus, became a storing place for thebikes of the new occupants. To this day, itsphotographic records have apparently been ignoredby the internal and external, local and nationalcontrol bodies, which had formally been notified.This at the very least negligent course could not butlead to the scrapping of equipment that had costseveral millions to acquire, some of which wasoriginal and had been built over years of hard,dedicated application by different inventors.Another apparatus was the fully accessorizedBrϋker spectrometer, still featuring in the current

product list: our residents traveled to Munich, allexpense paid, to learn its basic functioning; as for thegroup of technicians, whose voluntary experiencewith it had been excellent, it was disbanded andassigned elsewhere to banal administrative tasks, forwhich they were not trained. And today we learnthat a regional and possibly even national orinternational excellence - at least according to thePresident of the Marche government - has stoppedbeing so and that the top dogs are fleeing en masse.But I'd like to stress another question of topicalinterest. Today some arithmologists have published anote (1) describing the successful application, andthe safety of any side effects, of their antitachycardiaprotocol in patients with ventricular tachycardia andfast ventricular tachycardia. Well, it is widelyaccepted that clinical risks would have been reducedif the trial had been preceded by preclinicalexperimentation in animal models, for instance withLangendorff preparations of common rodents suchas rat, Guinea pig, and mouse. Indeed, there are 499published papers on the subject, one of which I haveco-authored in 2006 (2). Application of non-invasivecontinuous monitoring - or monitoring throughcollection, according to Wollenberger - of PCr,creatine, ATP, ADP, AMP, adenosine, inosine, Pi,NO/CO/O2/CO2, HbO2/Hb, and possibly thecomponents of the central glycolytic and oxidativepathways (Krebs and G6P cycles) and of coenzymeredox levels in different compartments, at leastNAD(P) (as in our experiments involving Cyto b andselective flavoproteins (3)), would definitely havecontributed useful data to be correlated to theincrease and decrease of amplitudes andfrequencies, as well as to the time of application ofthe antitahycardia protocol, thus enablingoptimization of the correlations obtained. Maybe -and this is critical for us - to define the mechanism of(metabolic) activation in a diagnostic and therapeuticmodel - through detection, for instance, of metabolicand electric uncoupling in the relevant pacemakers,and of conduction syncytia capable of being isolated,not to mention any interference with the models ofpreconditioned hypoxia/ischemia adaptation,whether related or unrelated, which today areamong the best explored (again 2, 4).

References:1. Landolina M, Lunati M, Boriani G, Ricci RP, Proclemer A,

Facchin D, Rordorf G, Maines M, Gasparini G, Molon G,Turrini P, Gasparini M, ClinicalService cardiological centres.Ventricular Antitachycardia Pacing Therapy in Heart FailurePatients with Cardiac Resynchronisation TherapyDefibrillators: Efficacy, safety and impact on mortality.Heart Rhythm 2015 Oct 15. Pii 51547-5271(15)013°3X.

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2. Luigi Rossini, Bozena Kuzio, Roxanne Deslauriers, Craig WJohnson, Epicardial autofluorescence NAD(P)H kinetics inthe ischemically preconditioned Langendorff rat heart.Effects of capsaicin, Part 1. Pharmacologyonline 3: 125.176(2005); Luigi Rossini, Carlo Violet, Paola Rossini, Craig WJohnson. Epicardial autofluorescence and NAD(P)Hkinetics in the ischemically preconditioned Langendorff ratheart. Effects of Capsaicin, Part 2. Pharmacologyonline 3:18-63 (2006);

3. Luigi Rossini, Paola Rossini, Britton Chance, Continuousread-out of cytochrome b, flavin and pyridine nucleotideoxido-reduction processes in the perfused frog heart andcontracting skeletal muscle. Pharmacol Res 23, 4: 349-365(1991);

4. Rajesh K Kharbanda, Torsten Toftgard Nielsen, Andrew NRedington, Translation of remote ischaemicpreconditioning into clinical practice. Review, Lancet 374:1557-65 (2009).

2.When a chronic protocol does not envisage thenecessary follow-up monitoring

(Friday 30th October, 2015)It has become accepted that genetics does not exerta decisive influence by itself, and that a much largerrole is played by the epigenetics of selectivelyinvolved histones and of simple and complex,methylated, acetylated, phosphorylated, nitrousand nitrated, glycosylated, formylated and otherproteins, directly and through modifications of theconformational traits that are most prone toselection and change by the “thousand forms” ofthe nucleic acids of double helix DNA with athymine nucleobase, or of single helix RNA with auracil, not thymine, nucleobase. According to thewobble base pair hypothesis, the latter constitutethe guanyl-uracil, hypoxanthine-adenine andhypoxanthine-cytosine RNA pairs, hypoxanthinebeing the nucleobase of inosine (5). Notably,besides adenine, thymine, cytosine and guanine,DNA can stably be constituted at least of 5-formylcytosine (6). This affects with growingintensity the development of individuals and ethnicgroups and increasingly large populations. We haverecently addressed the placebo effects - eitherstable and acquired through adaptation and/ordependence - in the framework of physiologicalchemistry and molecular pharmacology. Despite thenew insights into the functional details obtained forthe latter (7), it has not sufficiently been realizedthat - besides the dynamics of the mechanisms thatare in mass equilibrium in ranges of concentrationsthat can be linearized exponentially as S functions(which can be defined by the slope of min-maxeffect relationships according to general theories,chiefly based on the central doses and theirrelationships) - the construct does not in fact

include the different and never uniform effects ofionic and/or radical molecules, characterized byirreversible kinetics of their active interactingresidues, which are consumed down to the lastcomponent… . A typical case that has largely eludeddescription in selectivity experiments, including myown, and the general statistical analyses carried outin clinical trials, including phase IV post-marketingtrials, are the useful relatively stable block of plateletprostaglandin endoperoxide synthase, cyclo-oxygenase (COX-1), which is non selectively inhibitedby chronic aspirin, even at low dose. This results in agreater amount of COX-1, thromboxane A2, which byinhibiting platelet aggregation has been found to behighly effective in secondary prevention ofmyocardial infarction and ischemic stroke, havingcontributed to detect the selective inhibition ofmultiple proteases by the same salicylate, as noted inmy first work in Hoppe-Seiler Zeischrift fϋrPhysiologische Chemie of 1969 (8), a line so originalthat it has given origin to a rich, enduring school (9).Yes Lorenzo, I remember that long long ago, on theedge of the swimming pool, you did mention thedangers of aspirin, also in connection with surgery. Ididn't know then that the daily dose of 100 mg(Cardioaspirin), which I've taken as CV prevention formany years, since well before I retired, was capableof causing the severe damage it did to me. We didn'telaborate then, it's my fault! However, I've alwayshad some doubt about its chronic preventiveadministration, albeit at low dose. Clinical trials werecarried out first of all by the Chieti pharmacologist,who obtained international consensus, andsubsequently by numerous papers in journals such asthe New England Journal of Medicine, which I havealways followed and cited during my lectures. I havealways been concerned with the use of “irreversiblebinders”, which prevent establishing clearly hownecessary are the equilibria of the key mass law forany pharmaco-toxicological interaction. In fact, eachaspirin molecule does not react in equilibrium, albeitnot always in an irreversible way, making itimpossible to study in detail the pharmaco-toxicokinetic fate of each molecule, although this isabsolutely necessary. It is clearly impossible to applyto it the linear theory, the theoretical reference baseof pharmaco-toxicokinetics. I have investigated indepth the in vitro interactions of human (and bovineand rodent) serum albumin, isolated in the nativestate hence unfortunately in the impure state inwhich the molecule survives in the circulation, fromwhich it is isolated by methods that are not per sedenaturating. In contrast, I have done much lesswork on in vivo interactions, and then only in

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rodents, since this requires ad hoc labeledmolecules. Albumin of human serum from adultdonors, of bovine serum from abattoirs, and ofadult, genetically standardized lab rodent, hence of"mixed" blood, contains several molecules variouslyand stably bound also to all the other residues ofirreversible binders to which it is exposed in its half-life, “native” molecules that are pure only in termsof their crystallization, which can be verified, butare in fact always different, like the other moleculeson which aspirin (including isotope-labeled aspirin),and respectively non acetylated salicylate forcontrols, were made to interact (clearly byacetylating irreversibly, “artificially” in the lab in acontrolled fashion) with the sole aspirin theresidues of the various amino acid chains that werestill free. In this way I have defined the various“specifically denaturated” forms. These aredifferently digested – see “younger” molecules -and also easier to acetylate on even freer residues,all determined to be free or not free in controls,amines of arginine and lysine at positions numberedon the basis of known sequences, made lessdigestible because further acetylation (which in thelab is even greater) blocks to a greater extent theselective pepsin binding sites. This is different fromwhat is observed in chymotrypsin (which forinstance recognizes them only if they are close to atyrosine residue), papain, etc, toward “older”molecules that are more “denaturated in vivo”, ofdigestion for controls already more inhibited, andanyway still more inhibitable in percentage with thefurther irreversible block of the less numerous freeresidues that have remained so when subjected incontrol experiments to additional, less selective invitro acetylation. Digestion is therefore moreinhibited in percent terms, but lower in absoluteterms ... . Clearly, in vitro digestion is applied as amodel of in vivo turnover, of pool renewal ... . Inshort, since my earliest work in Hoppe-Seyler’sZeitschrift fϋr Physiologische Chemie, I have tried toassess the risk of its utilization ... in a personal waythat has remained confined to biology, and to thebest of my knowledge this has never again beenexplored in depth in human medicine. This is all. Icould add, with hindsight (acquired in Ferid Murad'slab at Houston Medical Center) that the argininefree groups, when acetylated, can no longer beused for NO synthesis and other purposes. How willthis apply to degenerative conditions such asAlzheimer's disease, and how will it affect theetiopathogenesis of the so-called “excess (which?)senile oxidation …?”. I remember that much morerecently my contemporary, Silvio Garattini, said in a

TV interview that he had become opposed to thechronic administration of many drugs, also because itdoes not envisage close monitoring, but just checks“when it occurs to one”. Below I report theconfirmation by the Maestro, who also said, Iremember it well, that he too took very aspirin at thelowest doses, but...

“Dear Rossini,Thanks for the information you kindly sent.I myself have not taken preventive aspirin for manyyears exactly for the reasons you mention.Kind regards and best wishes.

Silvio GarattiniFrom: "Rossini Luigi" <[email protected]>To: "silvio garattini" <[email protected]>Sent: Tuesday 13th January 2015, 18:45:05Re: A short report of the effect of chronic aspirin onCV prevention.

Dear Professor Garattini,I'm writing to report information, that I deem useful,with regard to the clinical course of a condition fromwhich I have suffered, that has now ostensiblyresolved. In brief, in January 2014 I began toexperience respiratory problems both duringexercise and at rest (even while speaking). My bloodHb was down from 14 to 7.5, and the hematologistprescribed Fe2+ (Niferex UCB, 100 mg, 3capsules/day), which I did not take ex juvantibus. Acomplete colonoscopy and gastroduodenoscopyprescribed by the surgeon I consulted, performed inJune, gave the following results: the former wasnormal, whereas the latter demonstratedhemorrhagic gastroduodenitis. The condition wasascribed to the chronic use, for many years, of thesole drug I had been taking: aspirin 100 mg/day(Bayer's Cardioaspirin) for CV prevention. However,there had never been any adverse effects,esophageal or GI tract symptoms, or occult fecalblood. I was immediately placed on Tiklid Sanofi'sCardioaspirin 2 tablets/day (250 mg of ticlopidinechlorhydrate). Oral iron supplements restored Hb to14 and my respiratory insufficiency resolved. Clearly,I'm well aware of the risks associated with aspirin,salicylates, and anti-inflammatories, on gastricmucosa. These effects are mostly seen in the elderly,but I trusted that the doses recommended by the CVprevention protocols and guidelines would not be soharmful as to lead to the condition I mentioned. Themost surprising thing was that all the endoscopists Ihave consulted since then are well aware of the highfrequency of gastro-duodenal hemorrhage in_______________________________________


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subjects taking "preventive" aspirin (even at lowdoses), while the CV prevention specialists largelyfail to mention the risks, or the need for the workupI eventually required, and prescribe chronictreatment without gastroprotective agents (egprostaglandins), and symptomatic treatments forconditions they do not consider as side effectswithout prescribing a workup. Do you think I'vebeen a fool in this case? I remember that in a TVdebate you stated that, luckily, you did not takedrugs, except low-dose preventive aspirin,"whenever I happen to remember".

Kind regards,

Luigi Rossini

Dear Lorenzo, the surgeon who prescribed me theendoscopic examination before the unwarrantedadministration of drugs ex-juvantibus was indeedyou, and I will acknowledge it forever!Warmest regards,Luigi Rossini

References5. Sarah Harris, The structural diversity of supercoiled DNA,

[email protected] Science News, 12 October 2015,Supercomputer DNA simulations at the UK University ofLeeds, and Researchers at the Baylor College of Medicinein the US; Francis Crick, Codon-anticodon pairing: thewobble hypothesis. J Mol Biol 19 (2): 548-555 (1955);

6. Martin Bachman, Nature Chemical Biology, Science News,University of Cambridge, 27 October 2015; RichardLewontin, Il sogno del genoma umano e altre illusionidella scienza, Traduzione di Michel Sampaolo, EditoriLaterza (2004) 1- 288;

7. Luigi Rossini and Paola Rossini, Requirements for theassessment of pharmacokinetic, pharmacodynamic andmixed population models and some topicalconsiderations; A seminar, PharmacologyonlineNewsletter 2:48-72(2007); Id, Id, Pharmacotherapeuticreceptor specificities and selectivity classes, and placeboeffects; A perspective: Pharmacologyonline 2: 206-235(2006);

8. Luigi Rossini, Hemmung der trytischen albumin spaltungdurch 2,4-Dinitrophenol, Hoppe-Seyler’ Zeitschrift fϋrphysiologische Chemie 33, S: 1-4 (1963).

9. George Bonewell, Luigi Rossini, Kinetics of 2,4-Dinitrophenol inhibition of tryptic, chymotryptic, andpronase digestion of native bovine serum albumin. The It JBiochem 19: 457-486 (1969).

3.Collaboration with my friends, physicists at Siena university

(Friday 30th October, 2015)Lorenzo: “But how did it come about that, at theage you had then, you set up a radiopharmacologylab (!) for non-invasive imaging including

multinuclear NMR spectrometry, which elsewhere isexclusively managed by specialists? What anunforgivable mistake!”The most interesting period of my life after my stayin the US and Canada was the time I spent with theSienese physicists, Pier Giorgio Bergamini, FrancescoPiantelli, and our director, Mario Rigato.

The Pharmacology Institute, like the Physics Institute,which became departments, and together with thehospital were moved out of town, occupied the topfloor of a building just uphill of the Palio square, inthe historical town center, and had a uniqueambiance conferred by the view and the atmosphereof that fascinating medieval city. Moreover, as myfamily remained in Turin, I was free to enjoy the verypersonal luxury of a devoting my timewholeheartedly to my professional interests:pharmacology, which has been defined by the Nobelprize winner Otto Loewe as “Grentzgebiete” -between medicine and biology - and basicmathematics, chemistry, and physics.In the company of my incomparable, cool friendFrancesco Periti, we clean forgot the hour of the day(and night) as we did in Camerino, and workedfuriously with the computer center at our fulldisposal. Oh, those moonlit nights spent behind thetall hedge listening, in complete absorption, to thealready unrivaled beauty of Martha Argerich! Shepractised for hours on end in a villa in the country,the windows open, while we devised theories ofalgorithms... . In Camerino the center had beenfounded and developed for him alone, and dealt withmodels of genetic information reversibility to thecomplex protein receptor. I was bothered byproblems that had followed me from Turin to the USand the Canadian universities, from physiologicalchemistry to neurophysiopharmacology. I could nowundertake, with critical help from the new friends,the physicists, the design and construction ofprototypes for the observation of macromolecules,cells and increasingly complex organisms, trying to gobeyond the absurd generalizations of irrationallystandardized preclinical in vitro and ex vivo research,and conduct human translational studies, which Ilater performed at the new Ancona Medical School.It was an exceptional period of free and wide-rangingresearch, with findings that evolved continuously.We heavily relied on Franco's exceptional abilities,engineering and manual skills, and attitude for laband even DIY work, which made it possible to makeapparatuses that, especially, today, I wonder whythey were not patented and marketed by Sienauniversity, which was heavily affected by the

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economic collapse of Monte dei Paschi. In this sadstory, wily politicians received double salaries andhad access to financing that was out of the reacheven of the Directors of Institutes and Departments.And here I'd like to add a recent record of anexceptionally objective, lucid, irreprehensible andincorruptible colleague, friend, and poet:

Paradigms#1, PHYSICS DEPT. - Merged with two other departments andgrown into a hypertrophic structure in different, scatteredbuildings, it is now paralyzed. The Director is ignored and faraway, the teaching staff are absent, the frustrated technicianswould prefer working to doing nothing. In sum, immobility,rage, and salaries paid without work being done.#2, COURTHOUSE - I go there with my solicitor, to deposit apetition. The clerk of the court hands us the dossier. We godownstairs and photocopy it. Back up to the clerk, he takes thepetition and declares it accepted. "But it's incredible, we couldhave changed all the documents, and the judge has not evensee our petition". Explanation: the judge comes to signdocuments every 20 days. The one who considers and decidesis the clerk of the court.#3, Siena PHILOSOPHY DEPT. - I go there to seek an interviewwith a Professor and ask for her office hours. I'm told: "Thereare no office hours". "I'll meet her after class then, when willshe be teaching next?". "Classes have not resumed yet". "Inmid-January?!". "You can call her on the phone ". "Well then,thank you. Can you please call her for me?". The usher givesme the Professor's telephone number and warns me: "Notfrom here, from an outside phone". It is a Rome number, thepractice and residence of her physician husband. TheProfessoressa gets paid her salary and lives at home”.

A poem by Mario Rigato:“OSCURAMENTO”

C'ERA UNA VOLTA UN PICCOL SOGNATORECHE NEL VEDER TANTO DISTORTO IL MONDOCONCLUSE CHE IL RIFARLO GIUSTO E TONDO

FOSSE UN'IMPRESA DEGNA DEL SUO ARDORE.

SI MISE DUNQUE ALL’OPERA CON LENAMA PRESTO PICCHIÒ IL NASO CONTRO UN MURO

CHE I GENI GLI OPPONEVAN TANTO DURODA TRADURRE IL SUO ARDORE IN VANA PENA.

DOVETTE ALLOR AMMETTERE DELUSOCHE I GENI IN GRUPPO RIESCON SPROVVEDUTI

COSÌ COME ASSOMMANDO ANGOLI ACUTISI VA A COMPORRE UN RISULTANTE OTTUSO.

IL MURO COLLEGIAL DUNQUE PROTEGGETANTE CAZZATE CHE NESSUNO PAGA

MENTRE IL PIGRO BUONISMO CHE DILAGALE CONFONDE CON OBBLIGHI DI LEGGE.

I'll make no further comments and additions, which could certainly be numerous, mine included.

In vitro and in vivo stability, which I've mentionedabove when discussing the controlled digestion ofalbumin prototypes, has become significant also forplasma volume expanders (Hetastarch), and hasbeen generalized with ad hoc apparatuses (10, 11) atthe time when a new technique for thedetermination of ionizing radiation microdoses wasbeing developed (12). It was especially myexperience with the exceptional Britton Chance (13)while a Fulbright scholar (and with my now three-some family), in the neurophysiology lab of thebulky, hyperenergizing visionary, Carlo Terzuolo inMinnesota (14), who had sent me to Chance (15),that I undertook a new project, still unique in theworld, that was carried out, moved, and sadlydestroyed during the Ancona earthquake (16). It wasan apparatus whose acquisition had involved thewhole Siena Physics Institute, and also fundsacquired thanks to the farsightedness of CNR, fromthe eclectic Rita Levi Montalcini, and fromFondazione Fidia. Such equipment should bedeveloped in any biophysics, physiological chemistry,and pharmaco-toxicology lab, including private(industrial) ones, best in association with optical, UVsurface and near infrared, and multinuclear NMR,contrast-enhanced imaging with radioisotopes, andmolecular imaging also in vivo, in human andveterinary clinical practice … In Ancona, I alsoaddressed muscle evoked potentials and the,similarly non-invasive, study of pacemaker frequencyin vitro and in vivo (17). But Franco again helped mein establishing the way, which had never beenevidence with 31P-NMR spectrometry, to resolve anoriginal topic that had obsessed me even before mydegrees: the observation of the activation by lowouabain doses of its receptor in vitro as well as invivo, which could be accompanied (or not) by theclinical activity of digoxin, commonly detected inchronic heart congestion and insufficiency: in brief, inthe metabolic flow (oscillating? Definitely yes, to theextent that this has been ascertained, one of themost extraordinary and fascinating topics I'veaddressed, I still shiver at the thought), some labeledelements were activated, within a generalframework, where others were clearly inhibited athigher, clearly toxic doses (18). These observationswere fully in line with the generalphysiopharmacological theory of hormesis, where itis not excluded that at low threshold values also theantagonists give rise to agonist power spectra andvice versa: this is the my main, initial contribution topharmacology (19). Well, with my forced move toAncona, the collaboration with the Sienesecolleagues suffered, even though I did maintain my_______________________________________


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commitments toward the development of theshared Center (20). Moreover, Franco had becomeentangled in cold fusion, at least according to thewell-known chemistry researchers from my wife'sWaldense valley, M Fleishmann and S Pons. I hadalready reported to him my meeting with them,which had taken place at the research center theyhad set up in Utah, after a paper in Nature which heconsidered not devoid of mistakes, and his model ofhydrogen (and helium) saturation activation alsomagneto-constrictive where the central nickelelectrode worked uninterruptedly, producing extraheat for years, as, stunned, we observed it together(the interested reader is referred to (21) for a studyof the issue by other researchers). Our friendshipdid not suffer, since I cut short by saying: “DearFranco I, unlike you, am not competent. Only youare capable of studying the theory. I thus invite youto do so and to write a timely report, by yourself,because it is clear to me that you can't deal withother topics, which albeit less demanding, would bea waste of time for you”.And then I abruptly left to go to the Canadian NRCin Ottawa, then to Winnipeg (Manitoba), at the newBiodiagnostics Institute, a short distance fromMinneapolis (Minnesota), where my daughter Paolahad been born. I still hoped to be able to live withmy family. I went to learn, there too, non-invasiveNMR, where the best physicists, mathematiciansand engineers of the Country were gathering. Theywere directed by a Hungarian physicist, a formerassistant of Einstein's in Princeton, who had beencalled expressly, and adequately financed, tocoordinate and develop diagnostic andspectroscopic and imaging techniques for allCanadian hospital and university facilities,competitive techniques that should rival those byBrϋcker, UK-Oxford Ltd and, especially, GeneralElectric-US. He later married the Quebec biologistRoxanne Deslauriers, who had invited me to thecapital. Finally, I'd like to mention the latest reportby the incredible Francesco Piantelli and to make acomment: he says that, over the 25 years or sosince he began to study the topics I've summarizedabove, he's achieved a description of thephenomenon that has become his main interestthat is neither complete nor satisfactory, but he'salready identified 22 parameters. In my opinion, atleast according to Jordan Ellenberg's "How not to bewrong" (pages 35-136 of the Italian translationpublished by Ponte delle Grazie, 2015), this meansthat he has reached a very good point if we acceptfrom Kepler - for the 12 plane face-polyhedrons ofpomegranate seeds - the evolution provided by

John Leech's odd reticulum lattice (1960) of 24-dimension spheres, where each interferes 196,560times with the adjacent spheres. According to HenryCohn and Abhinav Kumar (2003), the furthermeasurement precision that can be achieved - shoulda denser reticulum exist - is merely 1.165 x 10-32.“Letter by Franco Piantelli to Mario Rigato (whichMario forwarded to me) 3. 9. 2015.Dear Gigi, I'm enclosing ample (very ample)information. Be sure to read the P.S. (!).Ciao ciao. MarioFrom: Francesco Piantelli <[email protected]>Date: 03 September 2015 17:10:36 GMT+02:00To: Mario Rigato <[email protected]>RE: i casini

My dear Mario,My life is down to a whisper and I don't know if I'll beable to complete this complex research work. Justthink that the parameters identified have nowbecome 22, and they may not even be all those thatare required. I apologize for my wordiness below, butgiven the interest in the question I've tried tosummarize, although I've not really condensed it, theabnormal phenomenon that I'm trying to understandand test experimentally.Best regardsFrancoP.S.: Try to comfort our good Luigi, who has sufferedgreat injustice at the hands of those he had helpedmost. The ungrateful are legion.

References10. A. Al Savair, F. Bonsignore, V. Moretti, F. Piantelli, L.Re, L.

Rossini, A spectrometric analysis of thermal stability ohHetastarch, ventennale dell’ Universita’ degli studi diAncona, Nuovo Boll. Farmacol. Clinica 12: 123-129 (1989);

11. P.G. Bergamini, G. Palmas, F. Piantelli, L. Rossini, Unastrumentazione e una metodologia per la determinazionedei limiti di stabilita’ di molecole sottoposte a gradienti ditemperatura o radiazioni UV-VIS e IR. Atti Accad. FisiocriticiSiena XV, Tomo X: 267-374 (1991);

12. P.G.Bergamini, M. Mengoni, G. Palmas, F. Piantelli, L.Rossini, G. Tonnini, Una nuova tecnica per ladeterminazione di microdosi di radiazioni ionizzanti. AttiAccad. Fisiocratici Siena, XV, Tomo VIII: 119-127 (1989);

13. Britton Chance (1913-2010), Retrospective in Prospectives,Science 330: 1642 (2010);

14. C.A. Terzuolo, E.J. Handelman, L. Rossini, An isolatedcrustacean neuron preparation for metabolic andpharmacological studies. In: Invertebrate Neuron System, C.A. G. Wiersma, Ed., USA: 55-64 (1967); L. Rossini, H.P.Cohen, E. Hendelman, S. Lin, C.A. Terzuolo, Measurementsin oxido-reduction processes and ATP levels in an isolatedcrustacean neuron, Ann. N.Y.Ac Sci. 137: 864-876 (1966);

15. C.A. Terzuolo, B. Chance, E. Hendelman. L. Rossini, P.Schmelzer. Measurements of reduced pyridine nucleotidesin a single neuron, Biochimica Biophysica Acta 126: 361-372(1966); Chance B. Mayer D. Rossini L. A time sharing_______________________________________


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instrument for direct read-out of oxidation-reductionstates in intracellular compartments of cardiac tissue. RevSci Instr 41: 11-114 (1970); L. Rossini, J. Larner,Conformational transytions of glycogen synthase formsstudied with fluorescent probes, Atti Accad FisiocriticiSiena Serie XIV, Vol 9: 53-75 (1977); Luigi Rossini, PaolaRossini, Britton Chance, Continuous read-out ofcytochrome b, flavin and pyridine nucleotide oxido-reduction processes in the perfused frog heart andcontracting skeletal muscle. Pharmacological Research 23,n 4: 349-365 (1991); L. Rossini, Cinetica dei processi diossido-riduzione delle codeidrogenasi in vivo, Progressi inBiochimica III, Minerva Medica, Torino: 1-24 (1965-66);

16. P.G. Bergamini, G. Palmas, F. Piantelli, M. Sani, and M.L.Cingolani, L. Leone, L. Re, G. Roda, L. Rossini, A multi -λdevice for bioluminescence measurements in vivo. Chem.Biomed. and Environ. Instrumentation 10 (3): 289-309(1980);

17. L. Re, V. Moretti, L. Rossini, P. Giusti, Sodium-activatedpotassium current in mouse diaphragm, FEBS Letters 270,1-2: 195-197 (1990); L. Rossini, Domini del tempo e difrequenza in fenomeni biomedici, I°, Lettere dalla Facolta’,Parte 2, 6: 21-25 (1999); Parte 2 , 9, 9: 23-26 (1999); LuigiRossini, Marina Bernardi, Gerardo Galeazzi, Luca Moroni,Franco Pettinari, Paola Pigini, Paola Rossini, CeciliaTonnini, Giorgio Vagionis, Carlo Violet. Domini del tempoe di frequenza in fenomeni biomedici, II, Proc. Acc. March.Scienze, Lettere ed Arti, Ancona, XXXVIII: 187-232 (2006);

18. M. Bernardi, G. Galeazzi, E. Lamura, F. Piantelli, J. Rendell,L. Rossini, P. Rossini. (Ecto)nucleotidase kinetics observedby 31P-NMR spectroscopy: Resolutions of signals.Pharmacological Research 36, 5: 1997, 353-361 (1997); P.Dal Pra, P. Periti, L. Rossini, Ouabain effects on the levelsof nucleotide phosphates in frog heart perfusate.Pharmacol Res Commun 4, 4: 287-304 (1973); P. Dal Pra, L.Rossini, G. Segre, The kinetics of ouabain uptake in frogheart in relation to the kinetics of inotropic effect and tothe activation of transport ATP-ases, Pharmacol ResCommun 2, 3: 177-191 (1970);

19. L. Rossini, Antagonismo della isoprenalina verso alcunesostanze ad azioni adrenergiche e colinergiche. ArchivioItaliano Scienze Farmacologiche III, XIV, 2: 3-24 (Aprile1964);

20. Bernardino Di Sarra, Franco Piantelli, Vincenzo Moretti,Lamberto Re, Luigi Rossini, Cecilia Tonnini. Physio-pharmaco-toxicological in vivo read-out: an interuniversityintegrated analytical center. Issues, results andprospectives. Quaderni Marchigiani Medicina, SpecialIssue 20th Anniversary of Ancona University 5: 183-185(1989).

21. Roberto Germano, Fusione fredda, Bibliopolis (2003) 1-198;

22. J. W. K. Lee, L. Rossini, J. K. Sanders, R. Deslauriers,Seasonal variation in isolated perfused Xenopus laevisheart as characterized by 31-P and 13-C MR Spectroscopy.A new digitalis effect. Vol V, Proceedings Int Soc Magn Res/European Soc Magn Res, Nice: 19.25: 82 (August, 1995).

4.This part tells some facts and things that havehappened to me, my family, acquaintances,colleagues, and friends at different times andplaces: at GassinoTorinese (Italy); during primaryschool, high school, and university in Turin (Italy);at the Institutes and/or Departments of Human

and General Physiology, Biological Chemistry,General Pathology, Pharmacology andPharmacognosy in Turin; in Minnesota and at theJohnson Research Foundation (Philadelphia,Pennsylvania); in Camerino and Macerata (Italy); inVirginia and Utah; in Ottawa and Winnipeg(Canada), in Houston (Texas), Siena and Ancona(Italy); at Turin San Giovanni Battista hospital (theold hospital) as an intern while I was a voluntaryassistant in Physiology; as a patient at San GiovanniBattista / Molinette hospital, or on holiday inValtournenche (Italy)

(From Monday 2nd to Tuesday 4th November 2015) Last summer, Lorenzo told me once again: “In ourusual cultural meetings by the Passetto swimmingpool, we have discussed some initial propedeutictopics, but the narration of our personal stories mayalso be of some interest, based as they are on ourlives, which have centered on investigation andprofessional research. They involve widely differentfields from surgery, and these will perhaps requiremy telling them. But the readers may find otheranecdotes from your long life amusing, and learnfrom them…”.

1.Home..........We lived in GassinoTorinese, where I was born.My mother was Lucia Ozella – a housewife from SanFrancesco al Campo whose family owned a cottonmill that made them rich during the Great Warthanks to the patent of a filter that enabled usingunrefined fuels; her brother, an engineer, foundedFIAT's Centro Studi. My father was ordered to runaway from the hydroelectric power station on theriver Toce and narrowly escaped being struck bylightning outside it. He went on to become thetechnical manager of a stocking factory, CalzificioSobrero, built on ground donated by themunicipality. The factory grew hugely at first, thencollapsed when, at the dawning of democracy in ourcountry, the five brothers who owned it went intopolitics with the Italian Communist Party (PCI). Ourtwo-floor house stood close to the factory. Under acherry tree there was a large woodshed, where thepartisans hid, and rooms at the back, wherechickens, rabbits and a goat were reared by mygrandfather, together with a pig, when we had one.The house was surrounded by lawns and by a gardenand a large vegetable garden, which were fenced.When I was at primary school, I used to collectstamps, and remember quite well being fiercelybeaten by the brutal petty boss of the opposed side.Soon I had to learn to go about nearly always alone.

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On Friday nights, my mother would prepare thePiedmontese cakes for which our guest FatherPiovano had a weakness. He was a greatconnoisseur of Saint Paul and used to talk to meabout him. I started playing the piano with Mrs.Prelle. We had an upright piano in the sitting room.For the rest of my life I essentially taught myself,attending concerts, and setting up a huge musiclibrary of vinyl recordings, ultrasensitive tapes, andup-to-date CDs from all over the world, mainlyperformances of solo piano or its precursor, theharpsichord. My passion, which had always beenoverriding, reached its climax when in Siena I usedall my savings to buy a Steinway baby grand. Myknowledge of music was so extensive, since I usedto listen to music throughout the day and also atwork, that I was able to recognize a piece, and ofteneven the performer, from the very first notes.However, last year I had to give up the concerts of“Amici della Musica” due to bilateral hypoacusia. Ihave now entrusted my piano to the specialist,master Roberto Valli - who has tended to it foryears, replacing the chords oxidized by the sea airwith new original ones every 15 or 20 years - to killoff moths by saturation with pure CO2.My parents started a stocking factory of their ownin Corso Casale, Turin. My only, dearest brother,Dario, and his family also worked there, while Itried, unasked, to contribute by promoting ourproducts abroad, always with poor financial results.My father was an excellent technician. The onlyfactory producing vertical circular machines forknitting seamless men’s stockings, in Chemnitz, hadbeen destroyed by Allied bombs. My fathersucceeded in engineering and building faster andsafer machines for the cams of the thousandrotating needles, at the “Monterosa” FIATworkshop, by changing the steel-cam, heat-sensitive adjustment mechanism of the needles,into an oleo-pneumatic coordination. Like me,though, he was no businessman.Each day, traveling from Gassino on a SATTI train, Iarrived in Turin at 11:30 a.m., often clinging to thecarriage doors outside. The cars were so crowdedthat I preferred to cycle whenever the weatherpermitted. Classes in high school started at 1:30p.m., so I had time to stroll under the arcades of ViaPo and Piazza Vittorio, discussing all kinds ofsubjects with my friends. I even met a veryknowledgeable theologian in the church in front ofthe street where the high school, Liceo ScientificoGalileo Ferraris, was located. Exhaustive discussionswith him sometimes went on through theafternoon, meaning that I skipped class. During all

five high school years I shared a desk with the heir ofthe Cirio family of goldsmiths, who had worked forthe Savoys. They owned at least two floors of theskyscraper in Piazza San Carlo, one of which housedtheir collection of works by the most renownedcontemporary painters and sculptors. He farmedpearls (black ones too) on an island in the East, andevery year traveled to South America and India tobuy emeralds and rubies. I’ve always admired sucharts. My friend even asked my daughter, already apsychiatrist in Novi Ligure (Piedmont), to work fulltime in his workshop, but she didn't accept. At myschool where, regretfully, Latin was not taught welland Greek not at all (not to mention the mainmodern languages!), I luckily met an excellent historyand philosophy teacher, whose advice was “never behappy with just reading Lisier's and Lamanna'stextbooks: study the original texts in depth!". Thus Ibecame aware of the way British, French, andGerman historians narrated the Italian independecewars and our Risorgimento!After I passed my school-leaving examination, myparents presented me with a Frejus racing bicycle,the bike of the winners of the latest tours, includingthe Giro d'Italia. Sometimes I was also allowed to usemy father’s Lambretta. Since my very first years ingraduate school, I had been accepted at the night EDof hospital San Giovanni Battista (the old one), whereI had a bedroom all to myself. Beside classes, Iregularly attended the Physiology labs, and theswimming pool too, where I became infatuated witha beautiful, dark-haired fellow student, a champion.We used to study together at her place and one dayshe actually assaulted and undressed me. As wewere chatting during a class of the course ofChemistry and Biology, which was still taught by theDirector of the Physiology Institute, Anna Maria DiGiorgio accused us of irresponsible inattention andthrew us out of the lecture hall, threateningvengeance on the upcoming examination. She didn’tforget, and she grilled me for the whole morning.Then she gave me full marks cum laude and invitedme to attend the Institute as an intern to prepare mygraduation thesis. We worked together for the nextfour years, and my dissertation on conditioned andunconditioned, spinal and thermal reflexes (Cf: 23,24) earned me a first-class honors degree. My thesiswas published and won the International Pfizer Prizeas best graduation thesis of the year. Those wereextraordinary, critical years and I still regret that Icouldn’t specialize as a chemist-physiologist due to alack of places. Later, again at the swimming pool, Imet attractive Maria, who immediately aftergraduation was hired as an assistant at the clinical

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hospital of Ophthalmology, while Anna Mariaadvised me to continue my voluntary work at thePhysiology institute, but to specialize as anoccupational physician, in hopes of being assigned apaid hour as a health insurance doctor. However,the doctor in charge wanted me to spend half of thetime with him at the clinic. This saved me fromanother thesis in physiology. This I was supposed todevelop by breathing through the mask andcylinders associated with the Benedict apparatus,comparing the “typically women’s” job of cleaningthe Institute with a men’s job, since the AnnaMaria, a constitutional feminist, was persuaded thatthe energy metabolism was differently influencedand more easily sustainable. Then Rittenberg’s pupil(in the UK) talked me into administering to myself amass of unstable emitting isotopes, to evaluate thehemoglobin metabolism, in the presence ofcontrolled, early-stage lead poisoning. This wasanother excellent, highly successful pioneeringthesis. However, after I recovered from an eyecondition treated by Maria, who was by then myfiancée, only my cousin Cornelio Valetto, thePresident of Turin's Federation of Industrialists,offered me a job as a specialist in one of hisfactories (in Ciriè). We realized that theremuneration there amounted to less than half theone of Prof. Scansetti, Rubino’s assistant, who hadwon the post by an open competition. So I movedto biochemistry and to Prof. Camillo Lenti, whoasked me to take a chemistry degree. This turnedout to be a very tiring endeavor, also because Saini,the Chemical Physics professor - whom I later metin his hometown Camerino - maintained that aphysician could not hope to enter into the requiredmindset. Anyway, I qualified for teachingBiochemistry, then Pharmacology andPharmacognosy, and lastly General Physiology.Since I had no chances of paid employment in Turin,I tried Human Genetics with Director Ceppellini(who later gave me a teaching job at Siena School ofMedicine), and then I tried again with Di Macco, theGeneral Pathology Director. Of the latter Iremember that he had elaborated a curious imageof sexuality, including human sexuality, which hesaw as being distributed on the two sides of a right-angled triangle: this could evolve from an isoscelesinto its opposite, the obtuse-angled triangle, andinto the geometric squaring of the Pythagoreancircle and the inscribed (or non-inscribed) squares.In the meantime, I spent my nights as a first aidphysician of the Red Cross, visiting patients in theirhomes. I wasn’t paid: it was the surviving patientswho were supposed to do so. The experience was

extremely interesting anyway, and I tried to qualify itby identifying at least the patients I had sent tohospital, to make sure that the diagnoses andtreatments applied wouldn’t make me the onlyculprit. Finally, we managed to get myself hired byFarmitalia Monte-Edison in Milan, Via Gracchi, in thelaboratory of Prof. Vittorio Erspamer, who thentaught in Parma (or was it Bari?), in thecardiovascular section directed by Glässer. Eachweek I would go back, also to see my girlfriend, aftersleeping in a nearby slummy guesthouse... At the endof this leg of my journey, Prof. Emilio Beccari, of theBologna school, accepted me as an assistant throughthe introduction of a junior doctor I had met in theBiochemistry, General Pathology, and MedicalInstitute (Prof. Bastai, Rubino’s colleague in charge ofOccupational Medicine). When I resigned from theMilan factory I had to sign a document stating that Icould not be hired again there. However, over thenext two years I worked hard and published manyabsolutely original articles (Cf. 19, 25). Yet no opencompetition was in sight. Finally, without breakingwith Prof. Beccari, but with his permission, I dashedto the US and the Neurophysiology Department ofCarlo Terzuolo, who was from Turin but alreadycollaborated with the physiologist Moruzzi in Pisa. …A final non-professional parenthesis: one night I wenthome exhausted after one hour of intense physicalactivity that was excessive for a student of the lastyear of high school. I fainted at the gate and wasimmediately admitted to the new San GiovanniMolinette hospital, in the ward of Moracchini andVolterra, with the rupture of a subpleural bulla andconsequent right pneumothorax. I never ran atemperature and was given the newly-developedstreptomycin without any bacteriological tests. Itsprotracted administration eventually caused vertigoattacks (and hearing impairment…). In the cinema,located in the hospital basement, with a collapsedlung, I developed left pneumothorax and had anarrow escape… Then, as soon as the lung hadexpanded again, I survived a make it or break it climbto the peak of Mont Blanc, where a friend drove meright after my discharge. (While ascending, I piercedmy left hand with the ice ax I was holding in my righthand, which resulted in copious bleeding). Thenthere were the races as a sprinter on my Frejus, andthe climbing, enjoyed for several summers, to thehut of Laboratorio Angelo Mosso on Mount Olen, tothe Gnifetti refuge, the Dufour peak, and the northface of Liskamm, from the Capanna Margherita huton the top of Mount Rosa or via the Signal crest.Always well, maybe God wanted it this way, but thathospital stay in the last year of high school persuaded

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me that I should try to become a physician, not anengineer. Also, awesome skiing all over the Alps,even going to Sestrière and back the same day,after skiing down the most difficult slopes for hourson end, the two of us riding a Lambretta with theskis fastened upright, on roads where the ice hadn’talways been removed. So we made the second bigdecision, that is moving to the US. I left by myself,as a Fulbright scholar, then I was joined by my wifewho was on pregnancy leave.

2.First stays in the US and CanadaI used to spend the whole day in the lab, in the coldroom, dissecting under the microscope slowadapting neurons and comparing them with fastadapting neurons, placing them in the gasmicrochamber, monitoring them, isolating themotor plate nerve fibers, the accessory (GABAergic)inhibitory fibers where the neurons go back into themuscle, and centripetal ventral ganglia afferents,testing them through the quartz base of thechamber by electrophysiological andpharmacological approaches as well as using cellmicrofluorescence in optical chemistry and micro-physiopharmacology tests (14, 15). It was reallytotally absorbing and exciting, but it prevented mefrom following what happened in the rest of thelab, where the Director kept losing his temper withcolleagues Edwards and Ajala. The latter was theson of the Director of the Rome Opera House,whose American wife, married in Italy, eventuallywent back to the States with their children and twocontainers full of paintings by Guttuso and antiquePalermitan furniture. Edwards was thrown out,whereas Ajala was admitted to a psychiatric clinicand became a clinical neurologist. He had publisheda paper in Science on epilepsy induced by penicillinfiltered through the meninges, in rodents andhumans. When the family decided to live in Italy forgood their containers, even fuller than the firsttime, disappeared somewhere between Rome andPalermo. As for myself, good old Carlo (Terzuolo)made me write papers several times and then torethem up. Most nights I didn’t sleep at the lab butwas, instead, a guest at his villa and worked withhim. There, too, I began to seek an independentrole by associating with Lowry’s pupil, NelsonGoldberg, a microanalysis specialist (forPharmacology), and then making friends with twobiochemists who were there at the time: CarlosVillar Palasi, the brother of Spain's Minister ofEducation, and, especially, Joseph Larner. The latterwas a Czechoslovakian pupil of the two Nobels Cori,

who had been a high official of the secret central USchemistry and biological war labs during the war. Hewent on to became the undisputed master in thatfield and the teacher, as a pharmacologist in Virginia,of five Nobel laureates including Alfred GoodmanGilman Junior and Ferid Murad. During the summer,Carlo went back to Italy with his family, and askedme to mow the lawn in the garden and in front of thehouse. I didn't, and when he came back he couldn’tgo in because the weeds had grown waisthigh…Conditions were worse at Christmas, when mywife arrived. She was seven months pregnant andsuffered from severe gestosis. Temperatures fell aslow as -35°C, and our beautiful cottage on the edgesof the golf course, on the Mississippi River bank, wascovered in meters of snow, just like my VW, and thewindows had turned into ice sheets. The colleagueliving on the upper floor, a remarkable architect,used to spend his weekends getting drunk and endedup shooting himself. The police broke down the doorof our apartment, where Maria lived with Paola,because they hadn’t opened since they couldn’tunderstand the order; clearly they were terrified.Besides, whenever those half-Swedes from the Northspotted them at the supermarket, they would saywords like “mafia” out loud. On January 8th (1965),we celebrated Paola’s happy birth with the typicallocal cakes looking all alike. We received thecongratulations of Emilio Beccari, who also took theoccasion to write that he had decided to retire andtherefore, if I wished to go back to Italy, I should turnto Giorgio Segre, who had won the chair inCamerino. After risking to rent an airplane instead ofbuying a TV set, which I had ordered on the phone asa stroller, one terrible day my old Wols with myselfat the wheel, Giovanni Ajala on the passenger seat,and Paola in a baby basket on the back seat, was runinto by a big Cadillac at an icy crossroads. The carwas crushed as flat as a cookie. Ajala’s ribs and rightclavicle were fractured, but the lesions were missedat Minnesota Hospital ED and he was discharged andhad to go right back to work. Luckily, my daughterjust took a fright. By then we had made our decision:after about three months, mother and daughter fledto Italy. I stayed on a few more months, but inPhiladelphia, at the Johnson Research Foundation forBiomedical Physics, as an assistant to itsextraordinary founder, the engineer Britton Chance(again (13)). He used to cycle by around 4:30 a.m. tocheck the diagrams lying on the desks, and to write indetail the tasks to be carried out the next day. Thenhe cycled away to go training on a boat on theDelaware river – at the time he was already anOlympic sailing champion.

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Before closing, I'd like to tell an anecdote aboutBritton Chance, who was very rich. I had removedthe ventral ganglia from a mountain of freshwaterdecapod crustaceans. We needed the ganglia toextract cytochrome b5, which contributes torespiration also in the presence of carbon oxide andcyanide, and is needed in considerable amounts tobe studied by liquid nitrogen spectrometry. I wasabout to throw away the remaining tissues when hearrived and said: “Hey, no! Please, have themcollected and cooked” (for the weekly dinner towhich at least 150 members of the staff used to beinvited on his model farm). A unique man (13, 3,15)! Each time, his guests, gathered around thetable in the salon, were expected to present“spontaneously”, in turn, their best contributions.Similarly, during my last, long training periods atHouston Medical Center, Integrated Department ofBiology, Physiology and Pharmacology, the recentAlbanian Nobel laureate and former junior clinicalpharmacologist of Joseph Larner, Ferid Murad,wanted (with me by his side) all researchers of hislab to write a report and discuss it in depth: everyMonday morning of every week, as he returnedfrom a weekend spent on the greens of theGrenadines or in one of his other institutes, maybein Hong Kong.

References23. L. Rossini, riflessi condizionati da stimoli termici nella

cavia. I. Effetti della narcosi, dell’ ipotermia e di farmacipsicotropi. Archivio scienze Biologiche 46: 356-369 (1962);

24. A. M. Di Giorgio, L. Rossini, Fenomeni di disinibizione nell’animale spinale, Boll Soc It Biol Sper 20: 128-129 (1958); L.Rossini, Tasso catecol-enteraminico e reazioni didisinibizione d’ indole termica, Boll Soc It Biol Sper 40:673-676 (1964);

25. G. Rolla, L. Rossini, Fenomeni di rimbalzo farmacologicoosservati nel dotto deferente isolato di cavia con certesostanze anti-β. Boll Soc It Biol Sper XL, 12: 676-679(1964).

3.Back to Italy, south of the deep South (in the wordsof the S.I.F. President),then SienaWhile in the North no door opened for me, myfamily was in Turin. My wife rushed from the eyeclinic to the various health insurances, includingFIAT’s, once risking to be tipped over in her car byviolent strikers as she broke the strike. Paola wasbeing taken care of by grandpa Giovanni, owner ofa big Norton motorcycle. He was an apparentlygrumpy man who had been an extraordinarymaster builder of roads, bridges, and railroads inthe Belgian Congo and subsequently in Val d’Aosta

and Sicily where, in his words, “I met the mostdebauched workers, so dangerous even for my lifethat I had to give up the job”. I decided to make anew start as a graduated technician at the School ofPharmacy in Camerino, where I was welcomed at thedoor by first assistant Giorgio Giorgi: “You're warnedthat I am the professor here, and you have arrivedafter me”. My only answer was a shove with myshoulder as I took in my two giant suitcases full ofbooks. Life as a single was egoistically better than the“nothing of indifference” described by Moravia.Director Giorgio Segre showed up very rarely, oftendriven in a Ferrari to the meetings of national drugcommittees, the ISS (Istituto Superiore di Sanità), andthe ministries in Rome by the former Perugiagastroenterologist Francesco Orlandi, who laterparticipated in the foundation of the new universityand School of Medicine in Ancona. From my desk infront of the window – all I had been equipped with –overlooking the marvelous wooded valley, we usedto peer at him with powerful binoculars, as hemoved in and out of the tent with lively Franca, whohad taken her Pharmacy degree in Turin. The thirdcomer, a physician and highly knowledgeablemathematician from Piacenza, Francesco Periti, keptup with him: he would interrupt a lunch for a quickiejust because he had played footsie with the studentsitting in front of him. I drove down from Turin everyweek in my OSCA Pininfarina, then in the VW 914, orin a Fiat 500, often getting lost in the fog atColfiorito, travelling nearly always by night, at a timewhen the motorway was just Turin to Milan, andlater Turin to Bologna. I left Camerino on Saturdaysat 1 p.m., after the last class scheduled by theDirector, and on Monday mornings I left Turin to getback in time for the first lesson, which began at 8:30a.m. In the winter everything was frozen, and fromCastelraimondo to Camerino you could meet hungrywolves on the roads…. I was a fairly good driver andamong my passengers I boasted the Chancellor,Professor of Jurisprudence, and director of a sectionof the Alfa Romeo factory in Milan. I will never forgetthe way he'd circle the car to check the tires’conditions before getting in. There I took my thirddegree, in Pharmacy, after the terrible professor ofPharmaceutical Chemistry, Mrs. Steiner, had tried tofail me by asking me the phases of the synthesis ofseveral β-lactams, penicillins and cephalosporins offungal and artificial origin in the smallest detail.Before the opening of the new facility out of town, Ilived in a period building in the old town. My agedlandlady didn’t hesitate to enter my bedroom to useher antique Singer or Necchi treadle sewing machineto sew and embroider even as I was sleeping. I

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regularly played my Steinway, now moved to anabandoned church. At other times, Periti drove thetwo of us down to the valley, where he gluttedhimself with beer, repeatedly recounting hisdreams of successful research, and I had to put himto bed after driving us back in his Ford. We veryoften traveled in Giorgio Segre’s Giulietta, drovingto meetings chiefly in Pavia (the headquarters of bigshot Mascherpa), or Perugia, Genoa, Florence,Naples, Ferrara, Verona, and Rome (to the ISS). Wewere a competitive group, and the cofounders ofthe Italian Society of Molecular Biology. Camerinowas a top university, especially the chemistrysection, which also included Antonini, who diedyoung, Brunori, and Cerletti (Jr.), all of them fromRome's Biochemistry. We soon learned that, atOlivetti in Ivrea, Director Giorgio Segre haddesigned and developed an early industrialpharmacology research lab, which preceded theone set up by Silvio Garattini, in Via Negri, Milan.Our good father, boss, and master Giorgio Segreoften took us to lunch, sometimes even to Piacenzaor Turin, and always chose certain places wherehe'd systematically refuse the proffered wine,which was actually excellent. Once as I went to therestroom to wash my hands a waiter came out ofthe kitchen carrying a steaming plate of risotto, andafter saying “For the Jew”, he spat on it. When Iwent back to the table, I said nothing and neverknew who had been served that plate.With time, I got tired of going back to Turin everyweekend. I used to travel by train in a second classcar with Segre, but it was always overcrowded withmigrants and their bloated suitcases, typically tiedup with string to prevent them from breaking open.Instead of getting a mistress, on Sundays I began toattend a flight training course at the former militaryairport in Foligno, to get a pilot license (which I got)for the Macchino. The aircraft had a 6-meterwingspan and was riddled with the holes of thebullets it had received in the battles it had won. Myflight instructor was crazy: he used to make theaircraft stall at a high altitude also over built-upareas, and once ended up nosing over in a ploughedfield with a full reserve tank that he had completelyforgotten about –a double mistake that was reallyunforgivable and convinced me that I had to quit.When Paolo Mantegazza was recalled from Siena toMilan, soon becoming the Chancellor of the fourdepartments of that megalopolis, which was theactual capital of Europe, Segre was called to Siena.The political party for which Giorgi had acted as hiselectioneer settled him in the town of the Palio,where he collaborated with bank Monte dei Paschi.

The Dean of Camerino, the general physiologistTedeschi, asked me to accept an appointment asDirector. I accepted it, only to live in a nighmarethrough the worst three months of my career. “Youcouldn't know that Marches are the preserve ofRome's School. You’ll find yourself alone and lose theopen competition, and first of all your Pharmacologyteaching job, if you don’t come to Siena with meright away..." advised Giorgio Segre. Even though Ihad a degree in both general and human physiology,I was too afraid of not being allowed to go back toTurin, so I gave in. Moreover, a very bitter event hadtroubled my otherwise privileged existence there. Iwas attending a congress when, at least two daysafter the fact, I learned that while my wife wasworking at the hospital, our housemaid had left Paolaalone, waiting for her grandpa, and had thoroughlysearched the flat and stolen everything we had,including the silver dollars we had saved in the USand the family jewels. She had a lover, a thief shehad just met, who had talked her into cleaning ourplace out. We never managed to get anything back –we had no insurance and the jewels, which had beenpurchased from Cirio and in America, were meltedand lost for good. We didn’t report the theft and welet our maid have her employment card when shehad already fled abroad, but we informed her newemployer. In Siena we soon lost the excellent Periti.Without his knowledge, his parents had gone toSegre, asking him to favor their son. Francesco gotmad at them but also at Segre, whom he called “aNazi”. That was really too much, and earned him theexclusion from every job. Francesco, whose fatherwas the head of the psychiatry dept in Piacenza anda Mason, was soon proposed as a professor ofGeneral Pathology in Pavia, but he preferred todevote himself to his wife and daughter, working as aradiologist. Once he called me and together wecycled by the restaurants and buildings that hadbelonged to him. He told me that he had beendisinherited because he had got married without hisparents’ consent. He also confided that he had self-diagnosed some, by then untreatable, metastases ofa prostate cancer. He died shortly afterwards. Everyyear we call his wonderful widow, a teacher, and hisdaughter, two extraordinary persons of unparalleled,crystal-clear honesty just like my dear, irreplaceable,esteemed colleague. Meanwhile, as Segre foughtwith the old pharmacologist of the School ofPharmacy, Italo Taddei, I neglected all the rest andworked alone -I could (26) - or with his excellenttechnician Carlo Arezzini (27), then with FrancescoPeriti and with the equally keen, younger assistantPaolo Dal Pra (18), who also died very young. I no

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longer drove a car, but rode, enjoying especially thesharp turns of the Genova-Serravalle and SanGimignano roads, a brand-new, three-cylinder, two-stroke Kawasaki, up to and over 15,000 rpm, a realCagniard de La Tour siren. . I later learned that itwas called “the human coffin”, but that is not whathappened to me: while I was riding at about 245km/h in the vicinity of the Monteriggioni straightstretch on the Siena-Florence, the engine seized. Iwasn’t fast enough to disengage the clutch and wasshot forward, rolling on the clearway. Sand enteredthrough my skin into all my joints down to the bone,even though none broke. I fainted only when I wastaken back to my lodging, in a tower along the townwalls, where a radiologist colleague also lived.Actually she was driving in the opposite directionwhen, as I fell, my bike pushed me into the oppositelane, and she nearly run me over. She then droveme to my lodgings, put me in the shower and left,and there I fainted. But worse was to come, sincewhen she dressed my wounds with penicillin-medicated gauze I developed an allergy in littlemore than a week and one night, when I was aloneagain, I woke up breathing heavily and realized thatI had acute Quincke's edema, close to choking. Imanaged to drag myself down to the centralpharmacy, where the chemist on duty saved my lifeby injecting just antihistamines, no cortisone and/oradrenaline. All this happened while my family wasat the seaside in Sestri Levante: I told them that Iwas busy and would join them in two more weeks.Work was obsessing and took up all my time. Oneday I got a call from my brother in Turin: “Today Inoticed that Dad talks and discusses everythingcorrectly, but doesn’t realize that there is a word hecan't say, which he drops systematically; moreover,he does multiplications and divisions correctly, butmiscalculates simple sums by millions”. I called Dad,who greeted me cheerfully. I said “I’m coming over,on my bike”. Talking about this and that, we wenttogether up to the fourth floor of the Neurologicalclinic of Molinette hospital, where he was examinedby two acquaintances Bergamini and Schiffer, whowere puzzled but didn’t find any additional deficits.I accompanied him down to the basement and wasthere during his cerebral arteriography: as soon asthe iodinated agent spread he gave a sort of startand lost consciousness, never to regain it. My poorDad, lost at 63 years of age. His brain wascompletely riddled and was immediately consideredinoperable by Maspes, a Milan neurosurgeon, andby a luminary in Zurich. All we could do was to placehim, at home, into the care of my contemporary,the ECG specialist Riccio, who a few days after I had

gone back to work certified his death. I recountedthis highly distressing fact to the neurologists ofSiena and Ancona, who however did not offer anyplausible explanation for my father's mathematicaland linguistic behavior, the only apparent, conclusivesign of a functional and organic impairment.

References26. L. Rossini, Noradrenaline reversal of papaverine, Pharmacol

Res Commun 2: 121-126 (1971);27. C. Arezzini, L. Rossini, G. Segre, Effects of group Selective

reagents on the receptors for histamine and acethylcholinein Guinea pig ileum. Pharmacol Res Commun 1,3: 295-302(1969).

4.Siena and AnconaEventually also the construction work for the newpreclinical facilities of the Medical School began, notin Camerino, but in Ancona, where the engineeringfaculty had already been founded. The MedicalSchool was founded by the mayor (and laterChristian Democratic senator Alfredo Trifogli); thesurgeon Gian Carlo Castiglioni from Rome's CatholicUniversity of the Sacred Heart in Piacenza; theSicilian microbiologist Michele La Placa (of theRepublican party and a follower of Giorgio La Malfa)from Bologna university; the pharmacologist GiorgioSegre, whom I have defined an aspiring socialist; andthe gastroenterologist Francesco Orlandi, formerly inPerugia and well known in Camerino. Segre, while Ibelieved I was being supported by thepharmacologist, and after I had advanced mycandidature for the third year of the degree course,wanted me to remain in Siena as his assistant toshare, as I did, the teaching burden and to shoulderthe further specialist courses. However, after hisheart attack, he supported the assignment toOrlandi's wife, Ms Anna Marie Jezequel, a well-known Belgian researcher, of the hospital's Liver andDrugs Center, while I waited in vain to be appointedto Clinical Pharmacology and Toxicology. I had theluck of being able to block her assignation to CellPharmacology, a subject that I didn't know was upfor appointment, and which would otherwise havebeen swiftly given to her by the faculty. The Deanwas the neurologist, and later Chancellor, FrancoAngeleri, who once said that in his life he haddiscovered a single protester within the faculty.Orlandi went on to become a good academic andgastroenterologist and his former assistant Benedettidisrupted the sequence of expected Deans. The nextwas the current Dean, hygienist Marcello MarioD’Errico. At the time when the Medical School wasfounded, the academics, and especially the technicaland administrative staff, were informally "appointed”_______________________________________


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by politicians.The building in Posatora, which was later assignedto the Agricultural faculty, grew in the shadow asthe tall, modernist building of the Engineeringfaculty already towered on the highest of the hillsaround Ancona. The Biology dept was far removedand awaited the move with the inauguration of theAzienda Ospedaliera Clinica Generale Regionale atTorrette, which was very distant from the citycenter. The Medical School was designed and builtin a muddy depression that may have been part ofthe historical landslide area. Be as it may, after thefirst earthquake tremor it was inundated and theground floor, including the pharmacology lab, wasswamped. I lost my whole library, including my ownbooks, the recently completed equipment of theCNR and my own, which I had taken with me fromthe US, Turin, and Siena. I also lost the archives, allcurrent research records, and the material for thescheduled lab sessions, which involved theresearchers, technicians, and interns (thus trainingthem in the basic notions that would later help theirresearch work). I was never refunded or offeredreplacements, something that I had to achieve withexternal funding that I procured myself (for thecomplete story the reader is referred to (28)). WhileI was waiting to be offered tenure in the US, I hadaccepted the appointment from Ancona MedicalSchool to start not only the course of GeneralBiological Pharmacology, but also the clinicalbranch, as Toxicology. But neither the initialcontract nor the subsequent changes wererespected, even when we moved to the newTorrette buildings, and this regarded only us. Somuch so that in November 2013 I closed, sayinggoodbye to my colleagues and also sending a formalletter to the local and higher control bodies (29)(together with the list of the works published wellafter my retirement). I have never received a reply,but any chance of coherent development of theSections has been delayed without justification. Allof this prompted me to try and go back to Canada,hoping to convince my family to live there, but Icouldn't. I used to follow the construction work atfirst from lodgings in Falconara. There, I was offeredthe opportunity of purchasing for the negligible sumof 30 million the 17th century villa Domini, built on ahilltop, with a double row of cypress treesbordering the avenue leading to it, as in Bolgheri(the first researcher I was assigned, the enthusiasticDr. Cingolani Belli, was a relative of the Director ofthe Fine Arts dept and, unasked endorsed thepurchase). It had an immense hall with wonderfulfrescoes and antique furniture (that I later saw in

the shop windows of the antique dealers along viaFlaminia), a central chapel and two apartments atthe sides. One would have been sufficient, and itsrestoration would have been partially paid for by theFine Arts Superintendence if I agreed to keep it opento visitors one day a week. The other could haveserved to accommodate the increasing number ofour guests, who came to conduct research and teachin Ancona. We didn't buy it, also to avoid being tiedup by this agreement, and opted for a two-bedroomflat, where I moved by Steinway, but I managed tohost the geneticist and pianist, and renownedenzymologist Charles Walter from Houston, withwhom I co-authored a chapter in the Proceedings ofthe First Portonovo Biomathematics Conference. Mywife came in the summer, although we also met inSestri Levante or at Monterosso (Liguria). Moreover,the first earthquake tremors, not an uncommonevent in Ancona, contributed to her decision to goback to Piedmont, to her maternal and professionalduties. I finally found a property along the panoramicroad that connects Ancona to the seaside area ofPortonovo. It was a ruined house standing high onthe cliff at a height of 120 m, with a pinewood thatextended down to the beach. On the beach thefishermen had dug 18 caves into the face of the clifffor their boats and equipment. We beganrestructuring the house and were sued no less thanseven times by the neighbors (these are penaloffenses in Italy). All suits eventually resolved and Iwas finally awarded the three year test period(straordinariato), last among the 12 academics of theMedical School. The restoration work at home was soslow that we had to sleep on the second floor terracein a tent, before we were granted permission to buildthe roof and an attic. Recently, on November 5th,2015, we tested and finished the PV plant that, withthe acquisition of the newest batteries, will shortlymake us independent of our utility, which buys fromus the excess power and sells it back at 100foldprices. I'm still bothered by the institution of theParco del Conero, where our house is included. ThePark dispossessed us of the pinewood, with morethan 3000 trees, and has since neglected it, not eventending to the underwood. In the past I used to godown the path early in the morning, before going tothe lab around 8 am. I used to swim in the open sea,and I had trained my first two Alsatians to swim withme and tow me back if I needed it. The third, Sancho,only ever learned to float upright, but he's muchmore affectionate. The first one day swam backbefore me and smelled a large barbecue where thefishermen were roasting spider crabs. When theysaw him he had already eaten them all. That incident

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started a cold war with the "cave people", whosecaves were unauthorized, but who were extremelyarrogant, potentially dangerous, spiteful andmenacing. We had to build a large rainwaterreservoir with a pump and two nozzles, since in thecase of a fire we would have to keep the fire at bayuntil the fire brigade arrived... . Nice people: theyhave now become owners, through positive (albeitcontroversial) prescription, of these picturesqueand unique caves, which we have never been ableto enjoy, as if pretending we were survivors on adesert island. Moreover, they clearly never obeyedthe mayoral ban (no. 11 of 16.7.2006) and theHarbor Police ban (no. 37 of 1996) forbiddingaccess and stopping over along the coast, nor didthey accept our offer of September 5, 1986, whicheallowed them to remain provided they left one cavefor our use. Nevertheless, they invoked positiveprescription, which contrasts with the above bans.It is however a scandal that the park managers firstsized our 4.84 hectares of wood and then justabandoned them. Yet a ministerial decree (of30.10.2007, GU n. 40, 15.2.2008) clearly states thatthe wood should be at least disinfested ofprocessionary moths (Traumatocampapityocampa), a pest whose nests severely damagethe pines, and which I have to remove annually, atleast as long as I can afford it. Moreover, theyproduce a terrible toxin and our third Alsatian wasnearly killed when he ate one as a puppy. Thepoison induces mucosal necrosis and he survivedonly because for months I fed him liquid fooddirectly into the mouth every couple of hours, dayand night. The new Dean, and later Chancellor, theclinical surgeon Salvatore Occhipinti, referred me toTrabucchi in Milan, an unexpected help and onethat was offered without strings attached by a realgentleman that I remember with great humility.This is not because my mentor abandoned me.Indeed, years later he visited my wife, who had bythen moved to Ancona, asking if she agreed tomove the family to Rome: at the Istituto Superioredi Sanità, where he had been offered the chair, orat the Catholic University, where he had beenoffered the direction of the Pharmacology dept,which later went to Preziosi from Naples (incrediblefor the Catholic university: a non-practicing Jew andan openly anticlerical one to boot), but nothingcame of it. That for me was a period of intensework and interesting results in new fields, at least inpharmacology, that I have mentioned above. In (30)there are a few more, but I'm prepared to discussthem only with interested readers. Events thatcannot be described as other than bewildering

happened, too, and here I want to tell about one,without comment. Maria had never found the timeto devote herself to gastronomic biochemistry, butshe soon became a much sought after hostess andcook for faculty members, gate crashers, presidentsand heads of national bodies, colleagues, foreignguests and visitors from the WHO, all of whompraised her immensely (”the best restaurant inAncona”, sic the impudent, if this is a merit).Chairman Joseph Larner came with his wife, who wasdelighted by the school of Marche cuisine; so was theclinical pharmacologist Ferid Murad, later a Nobelprize winner, from his new department in Virginia,who contributed to the discussion - also bypresenting his work (31) - of the Second PortonovoBiomathematics Conference, which centered on ourtopics (32). Soon Larner was able to forget thatduring his visit to Naples his uninsured Rollei haddisappeared from the taxi. After a meeting withVittorio Erspamer, he presented to the 19th Congressof the SIF and Associates his latest review (33), togreat acclaim and - as he confessed to me - intensepersonal satisfaction. The medical clinician Carlo DeMartinis, co-organizer of the Congress and co-founder of the Ancona Institute of Experimental andClinical Medicine, was a frequent guest andsometimes brought fresh crustaceans and fish thatwe cooked together. One day we decided to prepareas a surprise an omelet with "French onions", whichgrew in the garden and we dried in the sun, thinkingit was shallot. In fact it was a case of severepoisoning that ended with us vomiting grey materialreminiscent of an unsuccessful Exorcist. We calledstraightway the Sienese colleague Taddei, apharmacognosist and toxicologist, who confirmedthe etiological diagnosis of potentially lethalscillaridine poisoning, since the plant was actuallyScilla maritima and required an emergency gastriclavage. De Martinis, who was eventually offered achair at the first university of Rome, refused thelavage on the grounds that he'd find his assistant(who was later hired in Teramo and next at Ancona'sINRCA) on duty at the ED. These are anecdotes thatremain in one's mind even though they have norelation to work. Like the case of our student, whoduring a pause of a local motocross competitioninadvertently ate some Atropa belladonna fruits. Thetwo motorcycle-mounted Carabinieri who werecarrying the antidote, neostigmine, from Rome(because it was out of supply in Ancona) had anaccident due to the rain, but the patient made it.Maria finally won a public competition in Macerata,and was offered a position at the Ancona obstetricgynecological hospital, where her 20 year experience

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as a specialist surgeon was never exploited in theambulatory visits she was assigned to. Much latershe was transferred to the General Hospital, where- after being an academic in Turin - she was at leastno longer required to do also research andteaching. A very negative and disagreeable battlewas undertaken by Extraordinary Director,radiologist Alfio Montesi, who after calling the firstRegional Healthcare Service Conference (Loreto, 21-22.6, 2001; (34)), in which the Service of ClinicalPharmacology and Toxicology clearly participated,surreptitiously tried to cancel it with an infamousadministrative and penal measure that was neverupheld by the board of directors and that had beeninspired by the Chancellor, who to his shame lostthe rich, useful and well-organized ToxicologyService. Montesi was later appointed a (powerless)coordinator of MRI magnet purchases in Marcheand had an early retirement. Even worse for theInstitute and the Services was the position offeredto the physicist Aldo Rescigno, a mistake I mademyself, since the offer should have beenconditioned to specific programs, requirement andresults, which I didn't set. Although he took part in afew summer courses, he never systematicallytaught his biomathematics and laterpharmacokinetic courses (two complementarysubjects), for which he had been offered theposition and for which he was exceptionallyqualified in terms of skills and teaching andacademic degrees. Similarly, he refused to sit onexamination boards and to vote the purchase of anypiece of equipment; he even opposed theacquisition by others of indispensable equipment.He clearly could not sustain the teaching load ofPharmacology I and II or of Clinical Pharmacology orExperimental and Clinical Toxicology. Rich only intheoretical knowledge, he never followed a singlestudent's thesis of specialist dissertation, nor did hemanage to convince the founding members tofollow him to a hypothetical department of theBiology or the Engineering faculties. Supported byour only associate professor, Luciana Leone, heproposed his candidature as Institute Director,proving only as an element of rupture and chaos,and was luckily away most of the time. His modelsand theories have never agreed with any of theexperimental results we have obtained. I havenever expressed an opinion before: hispharmacokinetic is now well known all over theworld but it never worked while he was with us,and I'm unable to assess his competence andoriginality, since I've always dealt with thepharmacokinetics of power spectra of time series

(35). Always a guest, he never even looked for criticalsupport from Giorgio Segre (who had indeed advisedme against him) and myself, for his future academiccareer, and disappeared.Nearly every year, I used to go back to the veryactive foreign labs where I had worked, spendingthree months (once six, for several reasons), withLarner in Virginia (1970-1977), with Deslauriers inCanada (1984-2003), at Utah university (2004), andtwice at Texas university in Houston (2004, 2005).These facts are dealt with below.

References28. L. Rossini, Didattica vissuta e aggiornamento della “Nuova

Tabella XVIII”, Proc, Acc March Scienze, Lettere Arti Ancona38: 123-142 (2005);

29. Statement to the Authorities 4 November 2013, and list ofpapers written after retirement, below, after my CV;

30. L. Rossini, Reclassifying cholinergic receptors, TrendsPharmacol Sci, Editorial 3, 9: I-V (1981); L. Leone, L. Rossini,B. Lumachi, B. Valsecchi, G. Coppi, The therapeutic use ofcholinergic drugs acting on the Vegetative Nervous System,Il Farmaco 36, 10: 827-837 (1981); L. Re, M. L. Cingolani, C.Concettoni, L. Rossini, Cholinergic effects of cimetidine andranitidine, Pharmacol Res Commun 15, 5: 485-527 (1983); D.Bradu, M. L. Cingolani, L. Ferrante, L. Re, A. Rescigno, L.Rossini. A contribution to the advancement of thecomputational procedures as applied to the classification ofdrug and receptor congeners. In: Highlights in receptorchemistry, C. Melchiorre, M, Giannella Edts, Elsevier Sci PubB.V. (1984) 251-294; D. Bradu, B. Di Sarra, V. Moretti, L. Re,An alternative to ANOVA: a maximum likelihood approach,Quaderni didattici ERSU 15: 5-22 (1984); M. L. Cingolani, L.Re, L. Rossini, The usefulness, in pharmacologicalclassification, of complementary pattern-recognitiontechniques and structure modelling, as afforded by theiterative collation of multiple-trial data in data banks,Pharmacol Res Commun 17- 1: 1-22 (1985); D. Bradu, B. diSarra, C. Concettoni, V. Moretti, P. Pagelli, L. Re, L. Rossini,C. Tonnini, Characterization of the rabbit aortaendothelium-dependent cholinergic receptor by agonistequipoptent molar doses, J Pharmacol Methods 22, 4: 219-231 (1980); P. Rossini, L. Rossini, Evoluzione di alcuneconoscenze base in tema di tossicoassunzioni etossicomanie. Quinquennio 1998-2003, Lettere dallaFacoltà, 8, 7-8: 19-26 (1095); L. Rossini, Global recurrentclassification in experimental and clinicalpharmacotoxicology, Pharmacologyonline Newsletter 3: 12-15 (2012);

31. F. Murad, Role of cyclic nucleotides and feedback system toregulate cyclic AMP accumulation and action, 1st PortonovoConference, On endocrine pharmacology: Compartmentalmodels and control systems, Cofese Ed Palermo, Piccin IntEd (1974): 107-114;

32. L. Rossini, P. Bastianelli, M. L. Cingolani, G. Gamba, M.Giannella, F. Gualtieri, L. Leone, F. Martorana, C.Melchiorre, V. Moretti, P. F, Periti, M. and P. Pigini, L. Re, G.Roda, S. Tuccella, Pattern recognition in profilingpharmacological receptors. In: 2nd Portonovo ConferenceOn biomathematics, Cofese Ed Palermo, Piccin Int Ed,September 27-28 (1978): 257-290;

33. J. Larner, J. C. Lawrence, J. P. Roach, A. A. De Paoli-Roach, R.J. Walkenbach, J. Guinovart, R. J. Hazen, Two biochemical_______________________________________


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mechanism of action of insulin to control glycogensynthesis. In: Volume of the contributions, Proc. of the XIXCongress of the Italian Pharmacological Society, andassociated National Scientific Societies, 1st Joint Meetingof Yugoslav and Italian Pharmacologists, (Ancona, 24-27September 1978): 205-243;

34. L. Rossini, Unita’ Operativa Farmacologia clinica eTossicologia: Attivita’ peculiari, di eccellenza,programmatiche ed in corso. Prot F 297, Ia Conferenzasulla sanita’. Realizzazioni, problemi aperti, ed indicazioni,Loreto, 21-22 giugno 2001;

35. M. Bernardi, R. Deslauriers, I. Docherty, C. Rossi, L. Rossini,P. Rossini, C. Tonnini, Spectral analysis of intercycle heartfluctuations in Xenopus laevis, conscious or spinalized,treated with calcium channel blockers, Part 1- GenPharmacol 29, 3: 477-481 (1997); M Bernardi, RDeslauriers, J Docherty, G Galeazzi, L Rossini, P. Rossini.Spectral analysis of intercycle heart fluctuations in thediethyl-ether-anesthetized or pithed rat treated withl.hyoscyamine. J Autonomic Pharmacology, 17: 27-34(1997); M. Bernardi, R. Deslauriers, J. Docherty, C. Rossi, L.Rossini, P. Rossini, C. Tonnini. Spectral analysis ofintercycle heart fluctuations in the diethyl-ether-anesthetized or pithed rat treated with prazosin, dl-propranolol, endothelin-1, α-r atriopeptin and ACE-inhibitors, J Autonomic Pharmacol 18: 1-10 (1998).

5.VISITING PROFESSOR IN VIRGINIA, UTAH,WINNIPEG, AND HOUSTON1. Back to mentor LarnerSince the time of my first stay in Minnesota, I hadcontinued to keep in touch with the lab that hasnurtured five Nobel laureates in Medicine, assistingJoseph Larner and Villar Palasi in their work. In thenext room, one day the lab technician of FeridMurad, who was then in the Pharmacology sectionof the new hospital, was using nitroprusside toobtain inhibition in an in vitro test, but in fact noteddilation and activation. Larner said: the salt is verypure, recrystallized, and well preserved, it musttherefore be a new effect. It was the first case ofNO-induced activation of guanylate cyclase, thesystem that Ferid then isolated and for which heearned the Nobel prize of “the three NOs” forMedicine in 1988 together with Furchgott andIgnarro. Larner, who in the UK had honed thetechnique developed by Sanger for insulin, askedme to study the amino acid sequences of thedependent and independent forms of glycogensynthase (UDPG: glycogen α-4-glucosyltransferase,EC 2.4.I.II), activated or not activated by G6P, thevery first example of allosteric regulation heanalyzed. For me this involved spending nearly allmy three-month vacation from Italy again in thecold room digesting peptides modified by thespecific reaction of the amino acid sequencesstudied with Segre in the mentioned receptors (27),separating then by high-voltage electrophoresis

according to Sanger. A first paper, describing theselectivity of the aromatic tyrosine hydroxyl, blockedby nitrating tetranitromethane, a key residue forcatalysis, not for allostery, together with a host ofother specific or selective reagents, was publishedbefore my return to Italy (36). Two further papers bymyself alone did not persuade the suspicious Larner,and were put aside awaiting my return (37).Incidentally, when I was accepted in Houston in2004-5, Murad asked me to study the nitration oftyrosine residues of his NO synthase, as well as tocomplete the work on glycogen synthase, extendingit to "his” enzyme. This could not be done, becausemy wife and daughter could no longer bear thelength of our migrations.

References36. Larner, D. Benjamin, L. Rossini, Effects of group selective

reagents on Rabbit muscle glycogen synthase. Molecular &Cellular Biochemistry 6: 65-70 (1975); L. Rossini, J. Larner,The inhibition of UDPG-glycogen synthase activity in vivoand in vitro, by Cinchona alkaloids, Pharm Res Commun 3:21-35 (1971);

37. L. Rossini, J. Larner, C. Villar Palasi, An “in vitro”cycle ofmodulation of glycogen-synthase activity from skeletalmuscle. Submitted to the Chairman 1-18 (1975); L. Rossini,J. Larner, C Villar Palasi, Unprimed UDPG incorporation byan highly purified glycogen synthase from rabbit skeletalmuscle. Submitted to the Chairman 1-19 (1975).

2. A parenthesis at Utah UniversityThe Mormons, those of the strange traditions, chosefor themselves a magnificent valley, and as rumorhad it Utah university paid lower salaries because theplace was very attractive in itself, with theenchanting houses in woods visited by deer, thenearby ski slopes, and the heated swimming pools onthe rooftops. Nothing of this was true, but mydaughter and I had a splendid accommodation in aguesthouse with a Viennese grand piano at theentrance. However, I practically lived in thePharmacy department lab, where Martin Schweizer,who had been a contract teacher in Ancona,managed the still only NMR spectrometer, which heemployed to resolve micro-RNA strands. I proceededby systematically learning to use it every day andnight, while in my leisure time I exploited the nearbypresence of the best known specialist in liquidchromatography-mass spectrometry in the US. Ioccasionally met the two chemistry researchers frommy wife's Waldense valley, who had been involved inthe controversial beginning of cold fusion. This timePaola had been very sad about leaving Italy for aplace where I would gladly have moved my family forgood, a place that was more interesting also inwinter, compared with icy Minnesota and Manitoba.

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The city was ordered, modern and well kept, exceptfor the peculiar temples. The acoustics in theconcert hall and the direction of the choir wereexceptional; and the five nationals parks - there are25 in the US! - the mighty five, Arches, Bryce,Canyon Lands, Capitol Reef, and Zion - werefantastic. Paola, a neoAmerican, had by thenforgotten the time when in Tokyo she had beenexpelled from the country after only 5 days, and onher first turn around the world had been celebratedin Canberra and Sydney. My promising student Dr.Marina Bernardi, who had had to postpone herItalian wedding by three months, to be in the USlong enough to master those no less than extremetechniques, was not equally amused.

3. Back to WinnipegWhile we were in Manitoba, Paola went back tovisit nearby Minneapolis, where she had been born,then flew with her mother to Churchill Bay, to seethe annual return of the bears from the pack for theArctic winter, an unforgettable sight. I lived in thecomfortable 5 star downtown hotel and regularlyswam in the Olympic swimming pool, devoting therest of my leisure time to honing my belovedBeethoven's Op. 101 and Rachmaninoff's variationson a Theme of Corelli. I had my own office and lab,and watched together with the engineers andphysicists the design, construction, and biomedicalapplications of clinical MR scanners, including theoriginal titanium device that could be moved to theneurosurgery theater. I hoped to bring back toAncona an NMR (micro)spectrometer, maybe alsoan infrared one. At last, the General Directoroffered me for Ancona the most advancedapparatus used by the clinicians, and another formy lab, with a 50% discount including maintenance,cryogens and upgradings for five years. I gave thequote to the Chancellor, Angeleri, asking him toinvite the Director for a lecture, maybe offering anhonorary degree, but he forgot to reply to thequote, and I was left with egg on my face. I'mPiedmontese and obstinate, and bought a 300 mcBrϋker apparatus with the research funds of 15years, but after a while I could no longer support itsoperating cost alone, even though it had beenapproved and financed by the RegionalGovernment with an ad hoc measure. All mycolleagues know that my successor has authorizedthe scrapping of the apparatus despite the fact thatit was still competitive, functioning, and even stillon the catalog, a shameful event that I have notshared before. All of this notwithstanding, Isuccessfully applied my favorite preparation after

the one of Minnesota to the heart and muscle ofXenopus laevis, and to finalize my research ondigitalis that was presented in Nice, France (22),where samples had been subjected to magnetizationtransfer with results that were absolutely original.Unlike Britton Chance's data on heterothermicdecapod crustaceans, employed and proposed withCarlo Terzuolo in Minnesota, my data remainedunpublished, because it was impossible to establishwhether the tissue was damaged by the heatgenerated by this staggering technique. After myretirement I tried to go back at least to the NationalBiodiagnostics Institute, to conclude the researchwork I had been forced to interrupt in Ancona, whichinvolved the observation, at least by 31P-NMR, ofretrogradely perfused rodent heart (Cf: 2). However,I discovered that the facility was in disuse and thewonderful group of the Director had been moved,and she was now head of Waterloo UniversityThunder Bay Regional Research Institute, now moregenerously funded (the interested reader is referredto the 269 papers by Roxanne Deslauriers, includingours, easily found by Google).

4. Last two escapes to Houston..........In the US, Larner introduced me to Murad,who welcomed me kindly. At the time he was verybusy in his three capacities as Chairman of threemerged departments (Biology, Physiology andPharmacology), head of the Institute of MolecularMedicine, and head of the Chinese University inHong Kong. I lived in the exceptionally well-appointed guesthouse, where I had room for myfamily, and I was the sole full professor helping himout in the discussions with his researchers, whichwere held on Monday mornings around theDirector's oval table. For two years I workedintensely with the technician Meng Zhong incollaboration with Emil Martin's group, on theepigenetic significance of the nitration of the varioushydroxyl, aromatic, tyrosine (38) - where I laterfound a clerical mistake in the published text in thenames of the two inhibitors used (not their doses) -and non-aromatic residues. I filled two notebookswith data, most of which preliminary - due to theinvolvement of the serine and threonine residues,which were detected at first with selective antibodiesand subsequently with chemical analyticaltechniques. These notebooks, the sole repositories ofthese data, I was authorized by the Director to takewith me to Italy. In sum, I was again on the spotwhen the decision between analytical, especiallyNMR, non-invasive or invasive spectrometry,including isotope mass spectrometry, and the

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neonate proteomics was being made. I then had togo back to Italy because my family needed me … .As I mentioned above, it may be significant thatchronic aspirin blocks irreversibly all the free–NH2guanidinium groups of arginine, resulting in NOsynthesis inhibition. The issue warrants furtherexploration, for example with DFMO(difluoromethylornithine), which can be measurednon-invasively in vivo (38); the block of arginine canbe explored in rat models of Alzheimer's disease.Today I called Houston: Dr Alan Frazer, Ph.D., is thenew head of the Pharmacology department of theUniversity of Texas Health Science Center MedicalCollege, while Dr. Emil Martin has moved toVascular Surgery, but neither replies. All facts of thisworld that take place there, too.

References38. L. Rossini, E Martin, M. Zhong, Nitration of inducible nitric

oxide synthase tyrosine residues in Raw 264.7macrophages, Pharmacologyonline 2: 1-23 (2005);

39. S. Bompadre, M.L. Cingolani, B. Di Sarra, V. Moretti,P. Pigini, L. Re, L. Rossini, C. Tonnini,Spettrometria NMRdei farmaci e metaboliti fluorurati. Atti XXXVI Congressonazionale AiPAC, II Congresso internazionale (Ancona, 21-24 May, 1986):441-452.

Letter to the Research Student(Sunday, 9th November, 2015)

Summing up Lorenzo's invitations and hopes, andafter stressing the salient points that regardteaching in (28), I feel I must to write a letter to theResearch Student. “Always observe closely” and“You see what you know” are the researcher'stenets, although they do not always agree. Indeed,Eugenio Meda called Camillo Lenti's attention onme when, at Angelo Mosso (Colle dell’Olen, MountRosa), I mixed sugar and water in a cup and said tomyself ”there's something odd, there are bubbleshere”. I've always felt that it was not worth learningtoo much of the work of others, unless it was tostudy and reproduce it based on original papers. Itherefore suggested to the students who came,asking to write their dissertation thesis inPharmacology, to spend two years to becomecompetent on a topic they found interesting todevelop. Then we'd decide together, first of allwhether they could be sent to the lab of theresarchers currently studying the topic in question,to work first with them; then we would meet againto find some unpublished aspects of the issue. It isuseful for a public employee with a stable job to beso lucky as to find an original theme that can bedeveloped for years. The topic may be foundserendipitously, but the find won't be accidental ifone subtracts it to a colleague, maybe even one

who is more deserving. In addition, if one has gothold of a topic that becomes increasingly interestingduring one's lifetime, one is more confident of beingable to develop it over time. Interesting topics areendless, unless one wants to change university,running after new public and private funders. Amodel has to be developed, it is a key step, but itdoes not have to be mathematical. I've often foundthat mathematicians tend to ignore experimentalresults that do not fit, confiding that they'll be able toaccount for them theorically. Against the constantadvice to go farther, I say that one should not forgetthat reinforcing a complex system of separate,discordant data is useful in itself. I'd like to recall apoem by C.P. Cavafy, which here is not dedicated tohis mother, Anna Dassené, or to his wife or thedaughter he could not have, but is appropriate forany couple of researchers:In the golden bull that Alexios Comnenos issuedTo prominently honor his motherthe very sagacious Lady Anna Dalassené,distinguished in her works, in her waysthere are many words of praise:here let us convey of thema beautiful, noble phrase"Those cold words "mine" or "yours" were neverspoken”.Source:http://users.hol.gr/~barbanis/cavafy/anna.html

7.1. Luigi Rossini, Curriculum vitae et studiorumBorn in Turin, Italy, on July 27th, 1933, married MariaFranchino M.D., Ph.D., Ophthalmologist in 1963. Onedaughter, Paola, born in Minneapolis, Minnesota,January 8th, 1965.First degree: Medicine, University of Torino, magnacum laudre (1957); second degree: Chemistry,University of Torino (until 1963), interrupted due tomove to Camerino; third degree: Pharmacy,University of Camerino, magna cum laude (1968).Specializations: Occupational Medicine, University ofTorino, magna cum laude (1959).1st Ph.D. degree equivalent: General Physiology(Ministerial Decree 20.9.1963); 2nd Ph.D. degree.equivalent: Pharmacology and Pharmacognosy (MD20-2.1969), and 3rd Ph.D. degree equivalent:Biochemistry (MD 1.9.1971).Fulbright Scholar, Research Fellow, and thenResearch Associate at the Laboratory ofNeurophysiology, University of Minnesota (Head:Carlo Terzuolo) 1964-1965; Research Associate,Department of Biophysics and Physical Biochemistry,University of Pennsylvania (Head: Britton Chance)1965-1966; Visiting Professor, Department of

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Pharmacology, University of Virginia School ofMedicine (Head: Joseph Larner) 1970-1977, usuallythree-month stages each year; Faculty of Pharmacy,Laboratory of Magnetic Resonance Spectroscopy,University of Utah (Head: Martin Schweizer) 1978-1980; National Research Council Canada, MagneticResonance Spectroscopy Laboratory, Ottawa,Ontario (Head: Roxanne Deslauriers) 1983; NRC,Canada, Institute of Biodiagnostics, WinnipegManitoba, Section of Biology (Head: RoxanneDeslauriers, co-founder, Section of Pharmacology)1984-2000, usually three-month stages each year;University of Texas, Houston Medical Center,Department of Integrative Biology, Physiology andPharmacology (Chairman: Ferid Murad) 2004, 2005.Assistant Professor of Physiology, then inBiochemistry, next in human Genetics, and later inPharmacology at the University of Torino;thereafter assistant in Pharmacology and Toxicologyat the Universities of Torino, Camerino, Siena, andAncona (Italy). Professor of PhysiologicalTechniques at the Science Faculty, University ofTorino, 1964; Professor of Pharmacometrics at theUniversity of Camerino (since 1965), of HumanGenetics at the University of Siena (1969), andPharmacology, and Pharmacology, Toxicology andClinical Pharmacology (since 1972) at thecofounded Ancona Medical School, laterPolytechnic University of Marche, Ancona. Since1973, the cofounded Institute of Experimental andClinical Medicine (IECM) had been under the ClinicalPharmacology and Toxicological Hospital Service ofRegione Marche, as were the Analyticalinterdisciplinary units of gas, HPLC, mass and NMRin vitro-in vivo spectroscopy. In 1974 I wasappointed Official WHO Adviser, and delegated toset up the National Collaborative WHO-ITA/ITA-OMS Office, designated by the WHO GeneralAssembly as a National Drug Monitoring Center,affiliated to WHO-Geneva and to the InternationalUppsala Monitoring Center. Since 1975, the WHO-ITA/ITA-OMS Center had been the sole NationalItalian center officially responsible for setting upand developing pharmatoxicovigilance research andpractice in Italy, as designated and delegated by theHealth Minister (M.D. 230/36.40/4.10.14, 26.3.75).Based on an Official WHO declaration, this Centerwas in charge of the interactive network connectingAncona University, WHO HQ, the UppsalaInternational Collaborating Center, and the otherNational participating Centers. In 1978, the NationalCongress of the Italian National PharmacologicalSociety, the National Italian Society of ClinicalPharmacology, the National Italian Society of

Chemotherapy, the National Italian Society ofToxicology, the National Italian Society of Pharmacy,and the Italian National Society of Clinical Pharmacy,held their First Joint Meeting with the YugoslavPharmacological Society, organized by the IMSC atAncona University, in association with the 1st

Portonovo Congress of Biomathematics andEndocrinology. In 1982, the 5th International Meetingof the then 23 countries participating in the WHO-International Drug Monitoring Program was held atthe same venue, together with the the 2nd

Portonovo Conference on Biomathematics andAutoclassification Statistics.Since 1982: Coordinator, Research Doctorate onPharmacological Sciences “Biomedical Modeling:Pharmacokinetics and Bioengineering”; since 1988:Promoter and Co-organizer of the InteruniversityInterdepartmental Center for the Study ofBiophysical and Biochemical Interactions withinMolecules and Organisms (IMO, first the cofoundersAncona and Siena Universities, then Bologna andCagliari Universities too).More than 400 personal papers published; morethan 300 co-authored papers published by theResearch and Collaborative Staff of the new IECM,including researchers and associate professors PietroGiusti, Chemotherapy; Luciana Leone, ClinicalPharmacology and Giorgio Roda, GeneralPharmacology) and full professors SalvatoreAmoroso, Pharmacology II, and the late AldoRescigno, Biomathematics & Pharmacokinetics.Contract professors each year taught more than 25lectures, mostly on Statistics (Dan Bradu), Magneticresonance spectroscopy and imaging (MartinSchweizer), Drug abuse and analytical clinicalpharmacy (Vincenzo Moretti), Integrated massspectrometry and chromatography (Charles GardinerEdmonds). Basic research largely addressed bio-physiochemical and pharmacotoxicological in vitroand in vivo readout, pattern recognition techniquesapplied to classification of drug analogs and iso-receptors (ongoing collaboration, up to 2012, withDan Bradu, initially with the University of SouthAfrica at Witwatersrand); and in epidemiologicalclinical pharmacotoxicology.The final list contains the 291 papers by Luigi Rossiniand those of the Collaborators, at the time of theIMSC foundation (1974) until those accepted in 1993.In the same period, 203 Communications and Posterswere presented to National and InternationalCongresses. During my 6-month sabbatical before myretirement on October 31, 2008, conferences andlectures had been presented at the Universities ofRoma, Torino, Milano, Siena, Firenze, Napoli, E.

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Maiorana Center (Trapani), Paris, London, Berlin,Tokyo, Canberra, and UNAM, Utah, JohnsonResearch Foundation (Philadelphia, Pennsylvania),Houston (Texas), Winnipeg (Manitoba), Manova(Hawai), Columbia, Minnesota, Stanford(Massachussets), and Virginia.We continue to maintain updated the closecollaboration network now involving 150 nationalCollaborating Centers, as our contribution, at allAnnual Meetings of the Representatives of theseCenters, as summed up at the Ottawa Meeting (15-17 September, 1992) by live discussion of 10Communications on different topics, which werestated to be developed throughout the ongoingInternational Research Program. With the late Prof.Dan Bradu, at the University of Tel Aviv (Israel), in2010-2012 I drew up an objective autoclassificationProgram that we distributed to all currentparticipating Centers with a view to developinguniformly and evaluating national and regionalstudies in drug monitoring, associated butindependent of those worked out at Geneva andUppsala. A list of the last related 6 co-authoredpapers, and of other 23 from the finalcollaborations within the Medical School and theIMO, is reported in (29). 2. Reference # 29, Agoodbye to Colleagues and Formal statement tothe competent Authorities (sent November 4,2013)To the Honorable Minister of University, Researchand Education, ROMETo the Honorable Health Minister, ROMETo the Court of Auditors, ANCONA,To the Chancellor and Board of Administrators,Polytechnic University of Marche, ANCONATo the Dean and Faculty of Polytechnic University ofMarche Medical School, ANCONATo the President of Marche Government, the HealthCouncilor, and the Collegiate Bodies, ANCONATo the General Director and Administrative andHealthcare Bodies, Azienda Ospedali Riuniti diAncona, ANCONATo the General Director and Administrative andHealthcare Bodies, I.N.R.C.A., ANCONAand c/c tothe President and Board of Accademia MarchigianaScienze, Lettere ed Arti, Ancona; ColleaguesProfessors Paolo Bruni, Saverio Cinti, GiovanniDanieli, Mario Governa, Rodolfo Montironi, LeandroProvinciali, Antonio Procopio, Alessandro Rappelli,Paolo Russo, Ugo Salvolini, Vincenzo Suraci, AdrianoTagliabracci, and Ivano Testa.RE: Transmission of the copy of papers.The list, written at the behest of the Dean, of

the communications presented and accepted morethan 13 years ago by invitation from the AccademiaMarchigiana has finally been published, after beingannounced in 2012 (3 references in the paper andreference list).I left my teaching and research work in the US(Universities in Minnesota, Virginia, Utah, and Texas)and Canada (National Research Council, Ontario andManitoba) to respond to the invitation to set up thenew Medical School in Ancona and its ClinicalPharmacology and Toxicology Service, and work fulltime there.The Toxicology Service was originally the first in theList of the Founding Document of 3.7.1985. It wasplanned here with collaborators, who were trainedover time. The plan included the acquisition ofcomplex, unique and highly expensive equipmentusing exclusively public, specifically allocated fundsapproved on different occasions by the RegionalGovernment. This is a unique case, not only becausenot even the tiniest ad hoc operative space wasever provided, in the same way to all colleagues andresearchers, including those that I later called,meeting their legitimate professional requests alsoby voting in Faculty meetings, but also without everexhaustively discussing what I had been offered byINRCA, Ancona (Cf: Villa Gusso; Agreement draftedby University of Ancona Central Administration, sentto the Faculty Proceedings by Chancellor PaoloBruni), with undeniable, growing and irreversibledamage, both of general professionalism and ofnormal, confident expectations, which have alwaysbeen respected by the operators. I'd also like tostress here that the same initial foundingdocument, containing the agreement, clearlydescribed the refunds that the hospital was toprovide to the university for failing to providespaces for healthcare services in buildings belongingto the university. This has never been upheld forthe Clinical Pharmacology and Toxicology that I hadfounded and developed.Significantly, the original documentation of the morerecent activities, entrusted exclusively to thisAcademy, which provided updates on the ongoingdevelopments, has not yet been published after sixyears.It should also be noted that the university andhospital staff that had been allocated to the above-mentioned program were never even completelyprovided, on the contrary (!), and that the Service Ihave set up and developed has been excludedwithout any formal reason from the subdivision ofthe funds ( which were then assigned to others) thatthe Azienda ospedaliera had duly set aside, no less

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than 5%, for personnel teaching full time, asenvisaged by the C.C.N.L. 8.6.2000, arts. 57-70. Iteven happened that my full time position (forinstance in 2000-2004, but other periods, too) wasnot recognized, unilaterally and without anycommunication of the fact. In addition, I was neverrefunded the small documented expenses, both forthe university and for items that were included inthe yearly budgets with a 100% rating by the ad hocofficial joint committees, for instance for the lastthree years I was in service, 2005-2008, and forthose minimum but essential expenses incurred formedical assistance. Moreover, still without anyreason, we failed to receive the first 60 million Liratranche that had been approved by the Minister on26.11.1993 for the continuation of a set ofexperiments that had already been decided,financed, and successfully completed, money thatwas subsequently assigned by the Health MinistryStudy Center (Cf: CS/413/FARM/93/AG/1526). As ifthis were not enough, the perfectly functioningand highly accessorized 7 Tesla NMR apparatuswas inexplicably and absurdly scrapped when itcould have easily been sold, since it was still beingproduced and was in the catalog of Brϋker, theworld renowned manufacturer.The case calls for an overdue, necessary in depthanalysis of whether the basic principles of goodadministration were violated, documented andnever consistently and coherently equal againstcommon sense and common management ofconstitutional action and failed control. This is nothot air: I believe that it is impossible to refrain fromcontinue, if we are to be protected from therepetition of similar behaviors, which cannot butbring severe and irreversible harm to all, with thedenial, if not the disappearance, of institutionaldignity and rationale.I'm available for any question and clarification.Luigi Rossini, Via Conero 115 A, 60129 Ancona.Documents not reported, but formally included inthe statement were: Report in extenso on theactivity provided for the hospital, asked by theDean: Ist , 2nd and 3rd part, cited there; List of the141 national specialist Centers from the 137member Countries, that received the Calculationprogram with reference to the last six paperspublishedwith colleague Dan Bradu in theframework of the voluntary collaboration offeredto the WHO DRUG MONITORING Program, ofwhich the ITA-OMS/WHO-ITA, NationalCollaboration Center was a founder together withfive other Countries, by appointment of the ItalianHealth Minister, which was confirmed at the WHO

world meeting. Moreover, copy of the documentfrom the Faculty meeting of 15.5.1979 mentioningthe Medical School's commitment (which was neverthen honored) to set up and structure the Toxicologyservice, and recent report on the Services of ClinicalPharmacology and Toxicology in Italy, generally inthe wake of the Italian (and European) trailblazer.Moreover

3. List of the 29 papers published after myretirement, or without university funding (ref. # 29)1. Rossini L. Global recurrent classifications in experimental

and clinical pharmaco-toxicology. PharmacologyonlineNewsletter 3:12-15 (2012);

2. Bradu D, Rossini L. December 25, 2011. Letter to the Editorin Chief, Pharmacologyonline Newsletter.Pharmacologyonline Newsletter 3, 99: 991-992 (2011);

3. Rossini P, Rossini L. Postherpetic neuralgia in the elderly; anupdate. Pharmacologyonline Newsletter 3, 82: 826-847(2011);

4. Bradu D, Rossini L. Contrast agents – Full list of the 30iodinated products for which reports have been sent overthe first 40 years of the WHO Pharmacovigilance System,subdivided into two 20-year periods. Fourth WHO-ITA/ITA-OMS 2010-2011 contribution on the 30 basic aggregatedWHO system-organ class disorders (SOCDs), and suspected+

adverse reactions and event preferred names (SADRs+).Pharmacologyonline Newsletter 2, 64: 701-836 (2011);

5. Bradu D, Rossini L. Biosimilar branded iodinated contrastagents related to the largest number of reports to theWHO-Pharmacovigilance system over the first 40 years ofthe Programnme. Fifth WHO-ITA/ITA-OS 2010-2011contribution. Pharmacologyonline Newsletter 2, 78: 929-962 (2011);

6. Bradu D, Rossini L. 4,436 reports from Italy, accepted in theWHO-UPM Collaborating Centre Thesaurus vs 181,744globally collected reports from other participating Countriesof same 33 monitored contrast agent-products over the first40 years of the Programme. Sixth WHO-ITA/ITA-OMS 2010-2011 contribution. Pharmacologyonline Newsletter 2, 98:1140-1160 (2011);

7. Bradu D, Rossini L. Contrast agents – paramagneticgadolinium and manganese chelates andsuperparamagnetic iron-based products. Third WHO-ITA/ITA/OMS 2010 contribution using WHO system organclass disorders (SOCDs) and adverse reaction and eventpreferred names (ADRs). Pharmacologyonline Newsletter3:728-781 (2010);

8. Bradu D, Rossini L. Contrast agents – Iodinate products.Second WHO-ITA/ITA-OMS 2010 contribution on aggregateWHO system-organ class disorders and/or clustering basedon reported adverse reactions/events. PharmacologyonlineNewsletter 2:727-753 (2010);

9. Bernardi M, Bradu D, Di Sarra B, Galeazzi G, Marcucci M,Montecchiani G, Moretti V, Moroni L, Re L, Rossini L, RossiniP, Tonnini C. Ionic and nonionic contrast agents. Acontribution by WHO-ITA and the Drug Documentation andInformation Centre of Regione Marche.Pharmacologyonline Newsletter 2:497-517 (2019);

10. De Martinis C, Rossini L. Some internal medicine andpharmacotoxicological clinical views and perspectives onglobal essentials, regionally protected, brand-name orunbranded equivalents, off-label and “me-too”, neglected,repurposed, complementary, prescribed and/or distributed_______________________________________


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over-the-counter, differently marketed available or notcounterfeit diagnostic, preventive and therapeuticmedicinal products. Pharmacologyonline Newsletter2:475-496 (2010);

11. Rossini L, Rossini P. After the new “year of Darwin”.Pharmacologyonline Newsletter 1:754-771(2010);

12. Rossini P, Rossini L. Experimental and clinicalpharmacology 2009. Narrative upgradings mostly relatedto cognitive neurosciences. PharmacologyonlineNewsletter 3:443-457 (2009);

Other papers not financed by the university,written in the last few years before retirement:13. Rossini L, Rossini P. Medical pharmacotoxicology today.

Pharmacologyonline Newsletter 3:85-108 (2008);14. Rossini L. Pre- and post-marketing pharmacovigilance:

The myths of the placebo effects and of the off-label useof drugs. Pharmacologyonline Newsletter 2:80-94 (2008)

15. Rossini L, Rossini P. Requirements for the assessment ofpharmacokinetic, pharmacodynamic and mixedpopulation models and some topical considerations: Aseminar. Pharmacologyonline Newsletter 2:48-72 (2007);

16. Rossini L, Violet C, Rossini P, Johnson CW. Epicardial auto-fluorescence NAD(P)H kinetics in ischemicallypreconditioned Langendorff rat heart. Effects of capsaicin.Part 2. Pharmacologyonline 3:18-63 (2006);

17. Rossini L, Rossini P. Pharmacotherapeutic receptorspecificity and selectivity classes, and placebo effects: Aperspective. Pharmacologyonline 2:206-235 (2006);

18. Rossini L, Kuzio B, Deslauriers R, Johnson CV. Epicardialautofluorescence NAD(P)H kinetics in the ischemicallypreconditioned Langendorff rat heart. Effects of capsaicin.Part 1. Pharmacologyonline 3:125-176 (2005);

19. Rossini L, Martin E, Zhong M. Nitration of inducible nitricoxide synthase tyrosine residues in Raw 264.7macrophages. Pharmacologyonline 2:1-23 (2005);

20. Rossini L. Drugs and the future. Pharmacologyonline 1:12-44 (2005);

21. Rossini P, Rossini L. Evoluzione di alcune conoscenze basein tema di tossicoassunzioni e tossicomanie. Quinquennio

1998-2003. Lettere dalla Faccolta’ VIII, 7/8:19-26 (2005);22. Rossini L, Bernardi M, Galeazzi G, Moroni L, Pettinari F, et al.

Domini del tempo e di frequenza in fenomeni biomedici. II°.Relazione sugli sviluppi del primo trentennio della lineadelle ricerche coordinate per il Settore Disciplinare ex E07X,Bio-14, Area Biologica-05, Facolta’ medica dell’ Universita’di Ancona. Memorie Atti Acc March Sci Lett Arti Ancona38:211-256 (2005);

23. Rossini L. Didattica vissuta e aggiornamento della nuovatabella XVIII, Settore scientifico disciplinare Farmacologia.Memorie Atti Acc March Sci Lett Arti Ancona 38:323-342(2005);

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25. Rossini L, Gatti G, Galeazzi G, Moroni L, Pettinari F, Violet C.Regione Marche, il Polo universitario ospedaliero dorico, II.Il Servizio di Farmacologia clinica e Tossicologia: Sviluppipiu’ recenti di aspetti del monitoraggio diagnostico e delleverifiche preventive, terapeutiche e riabilitative farmacotossicologiche. Memorie Atti Acc March Sci Lett ArtiAncona. Accepted, Lettera del Presidente Prot 21, 2.2.2007;

26. Rossini L, Galeazzi G, Gatti G, Moroni L, Pettinari F, et al.Regione Marche, Il Polo universitario-ospedaliero dorico,III°. Il Servizio di Farmacologia clinica e Tossicologia. Altrisviluppi degli aspetti post-genomici del monitoraggiodiagnostico e delle verifiche preventive, terapeutiche eriabilitative: coinvolgimenti farmaco tossicologici analiticied esplorativi proteomici-metabolomici strutturali.Memorie Atti Acc March Sci Lett Arti Ancona. Accettato perle stampe, Lettera del Presidente Prot 21, 2.2.2007;

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