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Eisenmenger syndrome (ES), first described by Victor Eisenmenger, was defined by Paul Wood in pathophysiologic terms as “pulmonary hypertension (PH) at systemic level, caused by a high pulmonary vascular resistance (PVR), with reversed or bidirectional shunt at aorto–pulmonary, ventricular, or atrial level.” It represents the most severe hemodynamic phenotype of pulmonary arterial hypertension (PAH) in association with congenital heart disease (CHD) and develops in the presence of large, unrepaired atrial or ventricular septal defects, arterial shunts, or complex forms of CHD. Although therapeutic management has rapidly advanced in recent years, these patients were not included in randomized controlled trials for specific pulmonary arterial hypertension drugs, except for bosentan. However, in clinical practice we apply treatment strategies combining drugs targeting multiple pathobiological pathways. The clinical case we describe is that of a 44–year–old patient, suffering from Down syndrome, with ES due to subaortic VSD and a a patency of Botallo duct, followed in our PH clinic of the "Ruggi D‘Aragona" University Hospital for about 9 years. The patient, on dual therapy with Macitentan 10 mg and Sildenafil 60 mg, was in the intermediate–high risk class, stationary. During the last two checks, there was a progressive worsening of the hemodynamic parameters, walking distance of only 100 meters, with SpO2 at baseline 90% and desaturation during the 6mwt. On cardiac color Doppler ultrasound evidence of TAPSE 18 mm, PAPS 100 mmHg, RAA 20 cm²; TAPSE/PAPS 0.18. The patient presented in WHO class 3. The only RCTs currently available concern the use of bosentan, but in clinical practice, initial monotherapy with an endothelin receptor antagonist or a phosphodiesterase type 5 inhibitor for symptomatic patients is proposed. Reassess and consider escalation to a double combination therapy in case of clinical worsening or inadequate clinical response. Consider uptitration with the addition of prostanoids when inadequate response and timely assess the eligibility for transplantation. For our patient therefore, in consideration of the impossibility of surgery, although there is little evidence on prospective observational studies based on cohorts of a few patients, we added selexipag 200 ug x 2/day to titrate therapy.This case opens the door to still unclear scenarios in which unfortunately the only weapon available remains the clinician‘s judgment and experience.

Systemic sclerosis is a connective tissue disease characterized by endothelial dysfunction, hyper reactivity of fibroblasts and immunity abnormality in both humoral and mediated cells. Clinically, in addition to the typical skin involvement, mainly the face and fingers, is frequent involvement of lungs, heart and kidneys. Cardiac involvement, in combination with lung involvement, is considered to be the most important determinant of the prognosis of these patients. Cardiac involvement occurs in 15– 35% of cases but in autopsy surveys the incidence reaches 80%. The case we present concerns a woman of 65 years, admitted in December at the Department of Cardiology of our AOU for an episode of low–output heart failure with epigastralgia, sweating, and breathlessness. The cardiological history was almost silent; instead, it presented a history of chronic thyroiditis and a recent infection with SARS COV 2. The objective examination presented hypokinesis of basal pulmonary fields and pitting edema. The blood tests showed an increase in myocardial necrosis, BNP, creatininemia and inflammatory indices (VES, PCR, beta 2 microglobulin, ferritin, fibrinogen), normocytic normochromic anemia, hypogammaglobulinemia, hyperuricemia and proteinuria and hematuria. The echocardiogram showed severe biventricular dysfunction and moderate–grade mitral insufficiency. A coronary examination was performed that showed epicardial coronary vessels free from significant injury. The cardiac magnetic resonance showed a widespread late enhancement subendocardial of the ventricular and atrial chambers with non–vascular distribution suggestive of pathology on an autoimmune basis. Upon closer examination, multiple small telangiectasias were observed in the face, slight hyperpigmentation of the chest and back, and swelling of the hands. The antibody panel showed positivity of ANA and anti Scl70. The patient was thus addressed to a multi–specialist management in which therefore cardiologist and rheumatologist compare and support the treatment of this pathology with the goal of reducing the high mortality and morbidity that characterizes systemic scleroderma with cardiac involvement.

The introduction of more effective and powerful antithrombotic therapies has allowed the progressive reduction of ischemic events associated however with an increase in haemorrhagic events. What we are describing is an example of how iatrogenic and non–iatrogenic complications can add up, making routine therapeutic management difficult during and after hospital stay.We are talking about a 50–year–old male patient, a smoker and with a history of dyslipidemia under treatment, who arrived at our cath–lab with a diagnosis of anterior SCA–STEMI, after loading ticagrelor 180 mg from the spoke center where he had gone for chest pain. At coronary angiography, evidence of critical disease of the median anterior interventricular artery treated by primary angioplasty and for the high thrombotic load by thromboaspiration, DES and Tirofiban bolus and 18–hour continuous infusion. Approximately 15 hours after the event, the patient appeared confused and aphasic. A brain CT scan with and without contrast agent was performed which documented the presence of a hemorrhagic focus in the atypical left temporal site, in the absence of arteriovenous malformations not susceptible to surgical therapy (BARC–3). Therefore, in view of the high risk of bleeding, de–escalation therapy with cardioaspirin and clopidogrel was practiced. Five days after the event, the clinical picture was complicated again by the finding of apical thrombosis on the transthoracic ultrasound. For this reason, given the stability of the haemorrhagic lesion on CT scans and control MRIs, Enoxaparin sodium 4000 IU was introduced in therapy once, with resolution of the formation in the imaging control after one month. The patient was then discharged with indication for short–DAPT in consideration of the high PRECISE–DAPT score. The arduous task of managing this case led us to reflect on the importance of the pre– and post–PCI clinical picture of the patient in order to seek the appropriate antithrombotic treatment by dynamically balancing the ischemic and haemorrhagic risk during hospitalization through numerous standardized tools at our disposal.

Pulmonary hypertension is a not–so–rare complication of connective tissue diseases and is usually related with an inauspicious prognosis.We present the case of a 67–years–old woman hospitalized for progressive dyspnea. Two–dimensional echocardiography showed numerous features related to pulmonary hypertension (PH) with moderate Mitral Regurgitation. The right cardiac catheterization confirmed mixed PH (pre and post capillary) without chest angio–TC evidence of pulmonary thromboembolism. Thanks to optimized medical therapy (B–Blocker, ACE–i and diuretics), there was a significant clinical improvement documented at discharge. After 1 year, due to recurrence of dyspnea, she was admitted to our medical unit. Her clinical examination showed some of the characteristics of a connective tissue disease. Compared to previous echocardiography, a moderate to mild reduction of MR was documented. Chest CT scan revealed interstitial lung disease likely related to patient’s underlying pathology. Immunological screening tests detected the presence of antinuclear (ANA) and anti–topoisomerase (ATA) antibodies. Right heart catheterization documented a worsening of PH with only pre–capillary component. On the basis of the above findings, a diagnosis of CREST syndrome complicated with PH was made, and the patient was started on oral combination of macitentan and riociguat. The frequency of this complication in connective tissue disease, the need for screening tests and different treatment approaches of pre and post capillary pulmonary hypertension is discussed.

Background: IGF‐1 is a potent mitogen for vascular smooth muscle cells, but exerts protective effects on endothelial cells that may trigger antiatherogenic mechanisms. Objectives: This study was designed to test the hypothesis that an IGF‐1 excess following arterial injury prevents neointima formation and vascular stenosis. Methods: Rats were subjected to carotid balloon injury and treated with IGF‐1 (1.2 mg kg−1per die) or saline for 10 days. Results: In IGF‐1 treated animals, high tissue levels of eNOS, Akt and its phosphorylated form were found, confirming activation of IGF‐1‐dependent signaling pathways. IGF‐1 markedly reduced neointima formation and post‐injury arterial stenosis. IGF‐1 exerted proliferative and anti‐apoptotic effects in the media of injured carotids, but inhibited mitotic activity and induced apoptosis in the neointima. Furthermore, IGF‐1 stimulated mobilization of progenitor endothelial cells and re‐endothelialization of the injured arteries. L‐NAME administration inhibited IGF‐1 vasculoprotective effects. Conclusions: IGF‐1 attenuates post‐injury carotid stenosis by exerting differential effects in the neointima and tunica media with regard to the key components of the response to injury. The data point to a novel role of IGF‐1 as a potent vasculoprotective factor.

The purpose of this study was to evaluate monorchid patients’ long-term hormone levels and sexual function.Materials and Methods Between September and December 2005, 20 patients were reassessed, having undergone orchiectomy for testicular tumors at the Policlinico and at the National Tumor Institute in Milan between 1986 and 1996. Four patients had seminoma, three of them underwent radiotherapy; 15 patients with embryonal carcinoma subsequently underwent retroperitoneal lymphadenectomy, and one of them underwent chemotherapy; one patient had a Leydig cell tumour. The patients’ case histories were analysed; they underwent urological examination, endocrine test, scrotal ultrasound, and blood samples were taken for testosterone, FSH, LH, prolactin, E2, total cholesterol, triglyceride, beta-HCG, alpha-FP and LDH assays. Body mass index was calculated. Patients were also asked to fill in the IIEF questionnaire.Results Patients’ mean age was 30.7 years at the time of orchiectomy, and 44.7 at the time of endocrine/sexology follow up. Case histories showed that 2 patients suffered from arterial hypertension, for which they were receiving treatment, 2 patients were obese, none of the patients suffered from endocrine disorders. Upon ultrasound evaluation, the remaining testicle mean volume was 22.04 mL. All patients presented testosterone levels at the lower limits of the normal range (mean value 3.3 ng/ml). In 5 patients values were below the lower limit, indicating marked hypogonadism. Only one patient suffered from moderate erectile dysfunction.Conclusions Twenty-five per cent of patients showed low testosterone levels. In view of the long life expectancy of patients suffering from testicular tumors, it is fundamental to consider the long-term problems that a mutilation such as orchiectomy can involve. Patients undergoing orchidectomy in general should be considered to be at higher risk of andropause.

Abstract: Puya raimondiiHarms is an outstanding giant rosette bromeliad found solely around 4000 m above sea level in the Andes. It flowers at the end of an 80 ‐ 100‐year or even longer life cycle and yields an enormous (4 ‐ 6 m tall) spike composed of from 15 000 to 20 000 flowers. It is endemic and currently endangered, with populations distributed from Peru to the north of Bolivia. A genomic DNA marker‐based analysis of the genetic structure of eight populations representative of the whole distribution of P. raimondiiin Peru is reported in this paper. As few as 14 genotypes out of 160 plants were detected. Only 5 and 18 of the 217 AFLP marker loci screened were polymorphic within and among these populations, respectively. Four populations were completely monomorphic, each of the others displayed only one to three polymorphic loci. Less than 4 % of the total genomic variation was within populations and genetic similarity among populations was as high as 98.3 %. Results for seven cpSSR marker loci were in agreement with the existence of a single progenitor. Flow cytometry of seed nuclear DNA content and RAPD marker segregation analysis of progeny plantlets demonstrated that the extremely uniform genome of P. raimondiipopulations is not compatible with agamospermy (apomixis), but consistent with an inbreeding reproductive strategy. There is an urgent need for a protection programme to save not only this precious, isolated species, but also the unique ecosystem depending on it.

Vaccinia virus is exceedingly stable, with an indicated half-life of many years at —70°C. It may lose virtually all infectivity (PFU) in the temperature range 56° to —20°C without loss in countable particles. In the range 37°C to —20°C the activation energy for the process is 14 K cal / mole, a value which is lower than that of most viruses and much lower than that for the reaction at 56°C. Apparently the process of degradation of the virus is quite different in the 2 temperature regions.

Infectivity of vesicular stomatitis virus was inactivated by suspending the virus in aqueous salt solutions that had previously been subjected to X-irradiation. This viral inactivation did not appear to be attributable to hydrogen peroxide or to long-lived free radicals generated by X-irradiation of the salt solutions. Indirect evidence suggested that the deleterious effects on the virus were caused by chemical species resulting from interaction of free water molecules with anions in the solution. Inactivation of infectivity was associated with distortion of the outer layer of the virion, as determined by electron microscopy, and with consequent impairment of adsorption to otherwise susceptible cells.

Heated vaccinia virus has been applied to cultures of L cells followed by active virus. Multiplicities, determined by electron microscope particle count, were 10 and 100 for heated virus and 10 for challenge, active virus. Delay times ranged from 0 to 21 1/2 hours. Substantial inhibition was observed with inoculation of heated virus at M = 10. At M = 100 the growth of a challenge inoculum applied 21 1/2 hours later was 94% suppressed. The consequences of these findings are discussed in connection with titration of residual virus in heat-treated virus preparations.The authors express appreciation of the excellent technical work of S. W. Wilburn. electron microscopist.

Galasso, G. J. (University of North Carolina School of Medicine, Chapel Hill), and D. G. Sharp. Effect of particle aggregation on the survival of irradiated vaccinia virus. J. Bacteriol. 90:1138–1142. 1965.—The survival curve (plaque titer versus time) of vaccinia virus irradiated with ultraviolet light was found to be strongly dependent, in both shape and general slope, on the degree of aggregation among the virus particles. When special care was taken to produce completely dispersed virus, a straight steep line resulted. Some severely aggregated preparations produced a straight line also, but of much less slope. Thus, the straight line, often taken as evidence of complete dispersion, is not a reliable measure for vaccinia virus. None of the experimental curves resembled the classical multihit curve predicted by the Poisson function for the behavior of uniformly aggregated virus. The aggregation was observed, by electron microscopy, to be nonuniform, and of such a distribution that the survival curves can be qualitatively accounted for in terms of multiplicity reactivation of irradiated virus within cells that receive groups of two or more particles. The greatly increased survival value of aggregates of virus, which indicates multiplicity reactivation, is worthy of note.

Analysis by means of the electron microscope of vaccinia virus released from infected L cells and dispersed by sonic waves has shown the percentage of single particles to be a linear function of the log concentration in the region 1.5 × 109to 1.5 × 107VP/ml. The extrapolated concentration at which the sonic waves should produce complete dispersion (all single particles) is 6.3 × 106VP/ml. Actual measurements made at 6.0 × 106VP/ml showed that it had indeed been achieved. Reaggregation at this concentration was barely perceptible but at the higher concentrations it was quite . rapid. Completely dispersed virus is essential in experiments on multiplicity dependent phenomena such as interference and multiplicity reactivation.The authors wish to acknowledge the excellent technical assistance of William Fyfe who made the electron micrographs.

Galasso, G. J. (University of North Carolina School of Medicine, Chapel Hill), and D. G. Sharp. Effects of heat on the infecting, antibody-absorbing, and interfering powers of vaccinia virus. J. Bacteriol. 89:611–616. 1965.—At 56 C the infectivity of vaccinia virus particles is destroyed rapidly, but even when it is reduced by a factor of 106the particles are capable of producing strong interference in L cells. The rate constant Kfor thermal inactivation of plaque-forming power is greater than that for interfering power by the factor e3.8or about 45 times. At 37 C both properties of the virus decline more slowly and at equal rates. The temperature coefficient of Kis discontinuous in the region of 40 C, indicating quite different activation energies for the reactions above and below this critical point. The degradation of interfering power exhibits a similar discontinuity, although less in magnitude, but none has been found in the antibody-reactive power of the virus, which is much more heat resistant.

Galasso, G. J. (University of North Carolina School of Medicine, Chapel Hill), and D. G. Sharp. Relative plaque-forming, cell-infecting, and interfering qualities of vaccinia virus. J. Bacteriol. 88:433–439. 1964.—The growth of vaccinia virus in slant cultures of L cells inoculated with different multiplicities of counted particles suggests a higher incidence of cell infection than can be accounted for by the number of plaque-forming units. From cultures containing antiserum or heated virus to limit the passage of progeny to uninfected cells, the data clearly indicate the ability of all the particles to infect cells even though the plaque titer is only one-tenth of this number. Analogous experiments show that an average of two heat-inactivated (56 C, 45 min) particles induce interference in L cells. There is nothing yet to show whether the few plaque-forming particles are different from the majority or whether they are just statistically fortunate in the complex process of plaque formation.

Sharp, D. G. (University of North Carolina School of Medicine, Chapel Hill), P. Sadhukhan, and G. J. Galasso. Quality changes in vaccinia virus during adaptation to growth in cultures of Earle's L cells. J. Bacteriol. 88:309–312. 1964.—Although particle production improves rapidly with passage of vaccinia (mouse neurotropic strain) virus in L cells, plaque production improves much more slowly. Beyond the passage when maximal particle yield was reached (18th), further improvement in plaquing quality of 1,000-fold was observed. Particle count and plaque titrations showed that plaquing efficiency improves at comparable rates in either plaque-to-plaque passage on plates or in tube cultures inoculated at high multiplicity. The host cell is probably exerting some influence in addition to that of the selection of mutants from the initial population.

Galasso, G. J. (University of North Carolina, Chapel Hill) and D. G. Sharp. Homologous inhibition, toxicity, and multiplicity reactivation with ultraviolet-irradiated vaccinia virus. J. Bacteriol. 85:1309–1314. 1963.—Vaccinia virus whose plaque-forming capacity had been destroyed by ultraviolet rays (2,537 A) was shown to retard the growth of L cells in tube cultures. At input multiplicities (M) of 0 < M < 10, no interference was detected, but at M ≧ 100 the irradiated virus particles exerted a strong toxic effect on the L cells in monolayer cultures, affecting the plaque formation by active virus which was added. Multiplicity reactivation occurs in sublethally irradiated vaccinia, as shown by virus particle counts via electron microscopy and plaque counts. It is clearly demonstrated in this system because there is no complicating interference. It sets in at a total virus particle multiplicity of about one, even though the multiplicity of the original plaque-forming particles is much below one.

Quality measurements (number of virions per plaque forming units) were made on vesicular stomatitis virus indicating a virion: p.f.u. ratio of approximately 1. This highly infectious virus was produced by careful control of the inoculum size to avoid the production of the small inhibitory particles associated with VSV. The effect of virus aggregation on titer was investigated, as well as the effect of the dispersal techniques on viral infectivity. Thermal inactivation studies at various temperatures ranging from −57°C to 56°C showed the virus to be relatively stable when stored as a cell lysate or diluted 1∶:10 in nutrient media.

Aims Patients with acute coronary syndromes (ACSs) who are managed without coronary revascularization represent a mixed and understudied population that seems to receive suboptimal pharmacological treatment. Methods and results We assessed patterns of antithrombotic therapies employed during the hospitalization and in-hospital clinical events of medically managed patients with ACS enrolled in the prospective, multicentre, nationwide EYESHOT (EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in iTalian cardiac care units) registry. Among the 2585 consecutive ACS patients enrolled in EYESHOT, 783 (30.3%) did not receive any revascularization during hospital admission. Of these, 478 (61.0%) underwent coronary angiography (CA), whereas 305 (39.0%) did not. The median GRACE and CRUSADE risk scores were significantly higher among patients who did not undergo CA compared with those who did (180 vs. 145, P < 0.0001 and 50 vs. 33, P < 0.0001, respectively). Antithrombotic therapies employed during hospitalization significantly differ between patients who received CA and those who did not with unfractioned heparin and novel P2Y12 inhibitors more frequently used in the first group, and low-molecular-weight heparins and clopidogrel in the latter group. During the index hospitalization, patients who did not receive CA presented a higher incidence of ischaemic cerebrovascular events and of mortality compared with those who underwent CA (1.6 vs. 0.2%, P = 0.04 and 7.9 vs. 2.7%, P = 0.0009, respectively). Conclusion Almost one-third of ACS patients are managed without revascularization during the index hospitalization. In this population, a lower use of recommended antiplatelet therapy and worse clinical outcome were observed in those who did not undergo CA when compared with those who did. Clinical Trial Registration Unique identifier: NCT02015624, http://www.clinicaltrials.gov.

Eighty-seven immunosuppressed patients (53 with localized and 34 with disseminated herpes zoster) from 10 institutions were enrolled in a controlled therapeutic trial of adenine arabinoside. A crossover design was employed; thus, 47 patients received drug for five days and then received placebo, and 40 were given the two substances in the opposite order. Resolution of acute pain and the cutaneous lesions were graded during a 10-day observation period. During the initial five-day period, treated patients showed a statistically significant resolution of pain and cutaneous lesions. Surprisingly, in many untreated patients, natural resolution occurred during this period so that crossover data could not be adequately assessed. Effects on visceral disease also could not be judged, because such disease was uncommon. Ratings of late complications such as postherpetic neuralgia were confused by the crossover design. Toxicity posed no problem. The data further emphasized the potential usefulness of adenine arabinoside as an antiviral chemotherapeutic agent, but also clearly indicated the need for a double-blind study to define this usefulness and to determine how it can most practically be used, if the risk-benefit factor remains favorable.

The potential antiviral activity of 6-azauridine and 5-iododeoxyuridine was evaluated in a coordinated study at five institutions. Experimental models in five species, the mouse, rabbit, swine, cat, and ferret, were established with use of 10 viruses: Herpesvirus hominis types 1 and 2, murine cytomegalovirus, vaccinia virus, Shope fibroma virus, transmissible gastroenteritis virus, swine influenza virus, feline viral rhinotracheitis virus, feline panleukopenia virus, and ferret distemper virus. Criteria for selection were: (1) representation from a number of major groups of viruses, (2) reproduction of natural routes of infection, and (3) simulation of potentially treatable viral infections of man. Antiviral activity was observed for 5-iododeoxyuridine in H. hominis infections in hairless mice and influenza in swine, and a slight degree of efficacy was noted in rabbits infected with Shope fibroma virus. Toxicity was also observed in most of the experimental models. There was a suggestion of antiviral activity with 6-azauridine in swine infected with transmissible gastroenteritis virus; however, enhancement of disease and some toxicity were seen in most of the other models. Efficacy of these two compounds was not well substantiated by these studies.

This report is a condensation of data from a collaborative study proposed and sponsored by the Antiviral Substances Program of NIAID. The individual reports were prepared by the following persons: S. Baron and M. Worthington, NIAID, NIH; A. Friedman-Kien, New York University College of Medicine; J. C. Duenwald, Washington State University, L. A. Glasgow, M. Harmon, B. Janis, E. Kern, J. C. Overall, Jr., C. B. Smith, D. A. Stringfellow, and S. Westerberg, University of Utah College of Medicine; B. C. Easterday and E. H. Weinberg, University of Wisconsin.* Recently there has been much interest in isoprinosine as a broad-spectrum antiviral compound. The activity of this substance was evaluated in a coordinated study at five institutions. Experimental models in five species of animals were established using 11 viruses. Criteria for selection were: (l) representation of most major groups of viruses, (2) reproduction of natural routes of infection, and (3) simulation of potentially treatable viral infections of man. No therapeutic effect could be demonstrated in infections with encephalomyocarditis virus, type 2 Herpesvirus hominis, influenza, and rabies viruses in mice; vaccinia virus in rabbits; rhinotracheitis and panleukopenia viruses in cats; distemper virus in ferrets; and influenza and transmissible gastroenteritis viruses in swine. The only antiviral activity observed in this extensive series of experiments was suppression of fibroma virus lesions in rabbits given 600 mg/ kg per day of isoprinosine. Although antiviral activity is not precluded in other viral infections in animals or in man, these results clearly fail to substantiate the potential of isoprinosine as a potent, broad-spectrum antiviral substance.