Long-Term Outcomes in Heart Transplanted Patients with Anderson-Fabry Disease: Effectiveness of a Combined Medical and Surgical Therapy.

BACKGROUND: Transplantation in the management of end-stage organ failure in patients with Anderson- Fabry disease is still a matter of debate due to a lack of data regarding long-term outcomes and prognosis. OBSERVATIONS: Most of the cases in the literature did not receive enzyme-replacement therapy (ERT), or received it only years after transplantation. Based on our experience, we describe here the long-term results of heart transplant in combination with early ERT. CONCLUSIONS: Transplantation combined with lifelong ERT should be considered to offer patients a chance of good long-term outcomes and quality of life.

Systemic doxycycline for pre-emptive treatment of anti-EGFR-related skin toxicity in patients with metastatic colorectal cancer receiving first-line panitumumab-based therapy: a post hoc analysis of the Valentino study.

INTRODUCTION: The combination of anti-EGFRs and doublet chemotherapy is considered the optimal upfront option for patients with RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC). The prophylactic or reactive treatment with tetracyclines for EGFR inhibitor-induced skin toxicity is currently clinical practice, though non-conclusive results are available. METHODS: We performed a post hoc analysis of the Valentino study that randomized RAS wild-type mCRC patients to two panitumumab-based maintenance regimens after the first-line induction, aimed at assessing the safety and efficacy of the administration of a pre-emptive doxycycline prophylaxis for anti-EGFR-related skin toxicity. We assessed the rate of treatment-related and panitumumab-related adverse events (AEs), treatment intensity, progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 226 patients, out of the 229 enrolled in the Valentino study, were eligible for the analysis. Overall, 143 (63%) and 83 (37%) patients received or not the antibiotic prophylaxis for skin toxicity. Any grade and G3/4 panitumumab-related AEs were reported in 89% versus 92% (p = 0.650) and 27% versus 27% (p = 1.000) patients who received or not the pre-emptive prophylaxis, respectively. Any grade and G3/4 skin rash occurred in 81% versus 90% (p = 0.085) and 27% versus 25% (p = 0.876) patients receiving or not the prophylaxis, respectively. No significant differences in terms of treatment duration, treatment delays or dose reductions, PFS, and OS were observed in the two sub-populations. CONCLUSION: The adequate management of anti-EGFR-related skin toxicity is fundamental to optimize the outcome of mCRC patients, balancing the survival benefit with patients' quality of life, especially in the first-line setting.

Mending hearts: A further strategy to improve cardiac donors availability.

Patients listed for heart transplantation are increasing annually worldwide, but the limited number of available donor hearts restricts this treatment to a small fraction of potential recipients. Attempts have, therefore, been made to expand the donor pool by recruiting donors who may not satisfy the standard criteria for organ donation. We reviewed our early experience by using three donor hearts which were successfully transplanted either after correction or not of pre-existing defects (Case #1: Coronary fistula; Case #2: Takayasu syndrome; Case #3: Percutaneously repaired atrial septal defect), demonstrating that structural cardiac abnormalities might not always be an absolute contraindication to donation candidacy.

Porcelain aorta: A surgical dilemma in orthotopic heart transplantation.

BACKGROUND: Circumferential calcification of the ascending aorta, known as porcelain aorta, in a patient candidate to a heart transplant, requires technically demanding and high-risk procedural adjustments. AIMS: This case report showed successful replacement of ascending aorta due to extensive calcification at time of heart transplantation. MATERIALS AND METHODS: In the operating theatre, after median sternotomy, cardiopulmonary bypass (CPB) was achieved via the right femoral artery and vein. Due to the impossibility of replacing the ascending aorta using safe aortic cross-clamping, a moderate hypothermia was established, and circulatory arrest was realized. According to Kazui protocol for selective anterograde cerebral perfusion via anonymous trunk and left carotid artery, ascending aorta was replaced with vascular prosthesis. RESULTS: Thanks to accurate pre-surgical planning, which included hypothermic circulatory arrest, ascending aorta replacement, before orthotopic heart implantation, we were able to perform the procedure successfully and prevent neurological events. DISCUSSION: Although different reports showed the feasibility of heart transplant combined to aortic replacement for aneurysmatic pathology, few cases were described for porcelain aorta, due to technically demanding procedure and prohibitive aortic cross-clamping. To avoid vascular embolization, dissection and mural laceration, aortic cross-clamping is not recommended. We performed aortic replacement at first, to reduce allograft ischemia. CONCLUSION: The use of hypothermic circulatory arrest technique with selective cerebral perfusion for aortic replacement, followed by vascular graft clamping to favour cardiac allograft implantation, could be considered a winning combination to guarantee procedural success and to reduce perioperative complications.

A comparison of quality of life and psychological distress in heart transplantation patients at adult and pediatric ages.

BACKGROUND: The aim of the current study was to evaluate and compare the quality of life (QOL) and psychological status of adult patients who underwent heart transplant (HTx) at pediatric or adult ages. METHODS: The population consisted of two groups: patients who received HTx after 18 years old and pediatrics who received HTx between the age of 1 and 18 years. At the time of the study, all patients were over 18 years old. QOL data were collected from patients using 36-item Short-Form Health Survey (SF-36) and psychological distress by the Symptom checklist 90-revised questionnaire (SCL-90-R). RESULTS: A total of 232 HTx patients were evaluated; 217 were transplanted at an adult age and 15 at a pediatric one. QOL improved significantly in pediatrics patients in the general health perceptions subscale and physical pain subscale than adult patients. The Global Index of the psychological distress did not differ in the two groups, but the pediatric patients registered statistically significant higher scores on the interpersonal sensitivity symptom subscale (adult group 36 ± 0.42 vs pediatric group 81 ± 0.79), the hostility subscale (adult group m 39 ± 0.44 vs pediatric group 73 ± 0.76) and the paranoid ideation subscale (adult group 46 ± 0.46 vs pediatric group 96 ± 1.02). CONCLUSION: The pediatric heart recipients showed better quality of life, but they show marked sensitivity, hostility and paranoid ideation which increases the risk of mental distress and therefore their adherence to medical treatment.

Pulmonary arteriopexy to prevent pulmonary artery kinking in orthotopic heart transplantation.

Heart transplantation is still the best treatment for patients with end-stage heart failure unresponsive to medical therapy or those treated with mechanical circulatory support. The surgical technique for heart transplantation is fraught with potential complications. One of these potential complications, kinking of the pulmonary artery after anastomosis of the recipient and donor pulmonary arteries, has been reported as a cause of acute right ventricular failure. We describe a technique to ensure proper configuration of the pulmonary artery after heart transplantation via a pulmonary arteriopexy to restore a physiologically appropriate angle of the great vessels.

Nonlocal effects: relevance for the spontaneous emission rates of quantum emitters coupled to plasmonic structures.

The spontaneous emission rate of dipole emitters close to plasmonic dimers are theoretically studied within a nonlocal hydrodynamic model. A nonlocal model has to be used since quantum emitters in the immediate environment of a metallic nanoparticle probe its electronic structure. Compared to local calculations, the emission rate is significantly reduced. The influence is mostly pronounced if the emitter is located close to sharp edges. We suggest to use quantum emitters to test nonlocal effects in experimentally feasible configurations.

Rituximab in recurrent idiopathic giant cell myocarditis after heart transplantation: a potential therapeutic approach.

Giant cell myocarditis (GCM) is a very aggressive form of myocardial inflammation. While immunosuppressive therapy is usually able to keep under control the disease and prolong the average transplant-free survival in many patients, effective therapeutic strategies to prevent or treat the recurrence of GCM in transplanted organs are still to be defined. We report the case of a young woman with idiopathic GCM who, despite immediate aggressive immunosuppressive therapy, rapidly progressed to irreversible heart failure and required urgent heart transplantation. Yet, 2 months later, the disease recurred in the transplanted heart, despite an intensive four-drug antirejection regimen. The introduction of rituximab, an anti-CD20 monoclonal antibody, 375 mg/m(2) /week i.v. for four consecutive weeks and then every 4 months as maintenance therapy, determined a complete and steady clinical remission of the disease. After nineteen months since rituximab administration, the patient is doing well and repeated follow-up endo-myocardial biopsies confirmed the complete resolution of myocardial inflammation. Our experience seems to suggest that rituximab can be a reasonably effective and safe therapeutic option in GCM recurring in transplanted organs.

The role of air relative humidity on the wettability of Pseudomonas fluorescens AR11 biofilms.

Biofilms are complex porous materials formed by microorganisms, polysaccharides, proteins, eDNA, inorganic matter, and water. They are ubiquitous in various environmental niches and are known to grow at solid-liquid, solid-air and air-liquid interfaces, often causing problems in several industrial and sanitary fields. Their removal is a challenge in many applications and numerous studies have been conducted to identify promising chemical species as cleaning agents. While these substances target specific components of biofilm structure, the role of water content in biofilm, and how it can influence wettability and detergent absorption have been quite neglected in the literature. Estimating water content in biofilm is a challenging task due to its heterogeneity in morphology and chemical composition. In this study, we controlled water content in Pseudomonas fluorescens AR 11 biofilms grown on submerged glass slides by regulating environmental relative humidity after drying. Interfacial properties of biofilm were investigated by measuring wetting of water and soybean oil. The morphology of biofilm structure was evaluated using Confocal Laser Scanning Microscopy and Scanning Electron Microscopy. The results showed that biofilm water content has a significant and measurable effect on its wettability, leading to the hypothesis that a preliminary control of water content can play a crucial role in biofilm removal process.

A Comprehensive Excursus of the Roles of Echocardiography in Heart Transplantation Follow-Up.

Current guidelines for the care of heart transplantation recipients recommend routine endomyocardial biopsy and invasive coronary angiography as the cornerstones in the surveillance for acute rejection (AR) and coronary allograft vasculopathy (CAV). Non-invasive tools, including coronary computed tomography angiography and cardiac magnetic resonance, have been introduced into guidelines without roles of their own as gold standards. These techniques also carry the risk of contrast-related kidney injury. There is a need to explore non-invasive approaches providing valuable information while minimizing risks and allowing their application independently of patient comorbidities. Echocardiographic examination can be performed at bedside, serially repeated, and does not carry the burden of contrast-related kidney injury and procedure-related risk. It provides comprehensive assessment of cardiac morphology and function. Advanced echocardiography techniques, including Doppler tissue imaging and strain imaging, may be sensitive tools for the detection of minor myocardial dysfunction, thus providing insight into early detection of AR and CAV. Stress echocardiography may offer a valuable tool in the detection of CAV, while the assessment of coronary flow reserve can unravel coronary microvascular impairment and add prognostic value to conventional stress echocardiography. The review highlights the role of Doppler echocardiography in heart transplantation follow-up, weighting advantages and limitations of the different techniques.

Long-term efficacy and safety of tailored immunosuppressive therapy in immune-mediated biopsy-proven myocarditis: A propensity-weighted study.

AIMS: Standardized immunosuppressive therapy (IS) had been previously investigated in biopsy-proven (BP) lymphocytic myocarditis with heart failure (HF). This study evaluated efficacy and safety of tailored IS in BP immune-mediated myocarditis, irrespective of histology and clinical presentation. METHODS AND RESULTS: Consecutive BP myocarditis patients treated with long-term tailored IS on top of optimal medical therapy (OMT), were compared with OMT non-IS controls using propensity-score weighting. The primary outcome was a composite of death or heart transplant, the secondary outcome was a composite of biventricular function, New York Heart Association (NYHA) class variation, and relapse. IS was managed by a multidisciplinary Cardioimmunology Team, involved a safety checklist and active patients' education. Ninety-one IS patients were compared with 267 non-IS patients. IS patients more frequently had systemic immune-mediated diseases (35% vs. 9.7%), lower baseline echocardiographic left ventricular ejection fraction (35% vs. 43%), lower right ventricular fractional area change (34% vs. 41%) and higher frequency of active lymphocytic, eosinophilic and giant cell myocarditis (71% vs. 58%, 12% vs. 1.1%, and 6.6% vs. 1.5%, respectively). At 5-year follow up, no difference was observed in the primary outcome (survival rate 93% in IS vs. 87% in non-IS), but IS patients had a higher relapse rate. Thus, IS patients, with a lower biventricular function and a higher risk profile at baseline, presented similar biventricular function and NYHA class to non-IS patients at follow-up. Minor adverse drug reactions occurred in 13% of patients, all resolved with therapy switch. CONCLUSIONS: Prolonged tailored IS is effective and safe in BP immune-mediated myocarditis irrespective of histology and clinical presentation.

Overcoming the Boundaries of Heart Warm Ischemia in Donation After Circulatory Death: The Padua Case.

A 45 year old male obese patient with a previous history of repaired congenital heart disease developed worsening heart failure making heart transplantation listing mandatory. Unfortunately, due to his anthropometric measures, the search for a suitable brain-dead donor was unsuccessful. For this reason, he accepted to be enrolled in the controlled donation after circulatory death (cDCD) program. According to the Italian Law regulating death declaration after cardiac arrest (no-touch period of 20 minutes-one of the longest in the world), we faced a 34 minute cardiac asystole, after which the heart was recovered through a thoraco-abdominal normothermic regional perfusion excluding the epiaortic vessels. The heart was then preserved by means of cold static storage. Heart transplantation was performed successfully without any signs of primary graft failure. Postoperative endomyocardial biopsies were negative for acute cellular and antibody-mediated rejection. Furthermore, echocardiographic and cardiac magnetic resonance evaluation of the heart did not show any functional abnormalities. The patient was discharged on post-operative day (POD) #39 in good clinical conditions.

Aerobic biodegradation of propylene glycol by soil bacteria.

Propylene glycol (PG) is a main component of aircraft deicing fluids and its extensive use in Northern airports is a source of soil and groundwater contamination. Bacterial consortia able to grow on PG as sole carbon and energy source were selected from soil samples taken along the runways of Oslo Airport Gardermoen site (Norway). DGGE analysis of enrichment cultures showed that PG-degrading populations were mainly composed by Pseudomonas species, although Bacteroidetes were found, as well. Nineteen bacterial strains, able to grow on PG as sole carbon and energy source, were isolated and identified as different Pseudomonas species. Maximum specific growth rate of mixed cultures in the absence of nutrient limitation was 0.014 h(-1) at 4 °C. Substrate C:N:P molar ratios calculated on the basis of measured growth yields are in good agreement with the suggested values for biostimulation reported in literature. Therefore, the addition of nutrients is suggested as a suitable technique to sustain PG aerobic degradation at the maximum rate by autochthonous microorganisms of unsaturated soil profile.

Nonischemic Donor Heart Preservation: New Milestone in Heart Transplantation History.

Heart transplantation is considered the gold standard for the treatment of advanced end-stage heart failure. However, standard donors after brain death are decreasing, whereas patients on the heart transplant waitlist are constantly rising. The introduction of the ex vivo machine perfusion device has been a turning point; in fact, these systems are able to significantly reduce ischemic times and have a potential effect on ischemia-related damage reduction. From a clinical standpoint, these machines show emerging results in terms of heart donor pool expansion, making marginal donors and donor grafts after circulatory death suitable for donation. This article aims to review mechanisms and preclinical and clinical outcomes of currently available ex vivo perfusion systems, and to explore the future fields of application of these technologies.

Nanoparticle Coatings on Glass Surfaces to Prevent Pseudomonas fluorescens AR 11 Biofilm Formation.

Microbial colonization of surfaces is a sanitary and industrial issue for many applications, leading to product contamination and human infections. When microorganisms closely interact with a surface, they start to produce an exo-polysaccaridic matrix to adhere to and protect themselves from adverse environmental conditions. This type of structure is called a biofilm. The aim of our work is to investigate novel technologies able to prevent biofilm formation by surface coatings. We coated glass surfaces with melanin-ZnO2, melanin-TiO2, and TiO2 hybrid nanoparticles. The functionalization was performed using cold plasma to activate glass-substrate-coated surfaces, that were characterized by performing water and soybean oil wetting tests. A quantitative characterization of the antibiofilm properties was done using Pseudomonas fluorescens AR 11 as a model organism. Biofilm morphologies were observed using confocal laser scanning microscopy and image analysis techniques were used to obtain quantitative morphological parameters. The results highlight the efficacy of the proposed surface coating to prevent biofilm formation. Melanin-TiO2 proved to be the most efficient among the particles investigated. Our results can be a valuable support for future implementation of the technique proposed here in an extended range of applications that may include further testing on other strains and other support materials.

Application of Near Infrared Spectroscopy for the Rapid Assessment of Nutritional Quality of Different Strawberry Cultivars.

Strawberry is the most cultivated berry fruit globally and it is really appreciated by consumers because of its characteristics, mainly bioactive compounds with antioxidant properties. During the breeding process, it is important to assess the quality characteristics of the fruits for a better selection of the material, but the conventional approaches involve long and destructive lab techniques. Near infrared spectroscopy (NIR) could be considered a valid alternative for speeding up the breeding process and is not destructive. In this study, a total of 216 strawberry fruits belonging to four different cultivars have been collected and analyzed with conventional lab analysis and NIR spectroscopy. In detail, soluble solid content, acidity, vitamin C, anthocyanin, and phenolic acid have been determined. Partial least squares discriminant analysis (PLS-DA) models have been developed to classify strawberry fruits belonging to the four genotypes according to their quality and nutritional properties. NIR spectroscopy could be considered a valid non-destructive phenotyping method for monitoring the nutritional parameters of the fruit and ensuring the fruit quality, speeding up the breeding program.

Coronary Collateral Circulation: A New Predictor of Mortality in Heart Transplant Recipients With Allograft Vasculopathy.

Coronary collateral arteries (CCAs) are anastomotic channels between vessels; although beneficial in atherosclerosis, their role in heart transplantation (HT) recipients is underinvestigated. CCAs initially develop as microcirculation and cardiac allograft vasculopathy (CAV), promoting immune-dependent proliferative angiogenic response, and play a role in their development. In our hypothesis, ischemia induced by coronary microvascular dysfunction (CMD) triggers the development of CCAs, which are, in turn, less functional as affected by CAV themselves. Methods: One hundred twenty-one patients receiving HT at our institution were retrospectively evaluated and were included if transthoracic echocardiography with coronary flow velocity reserve (CFVR) assessment and coronary angiography were performed. CMD was defined as CFVR of ≤2.5. Patients with CAV were enrolled, and their angiograms were reviewed to evaluate the presence of CCAs. Cardiovascular mortality was assessed as the main clinical outcome. Results: Forty patients were found to have CCAs. Patients with CCAs have lower CFVR than those without CCAs (2.22 ± 0.72 versus 2.69 ± 0.92;P = 0.003), reflecting in different rates of CMD in the 2 groups (72.5% versus 37%; P < 0.001). CMD is associated with higher CAV grades (P < 0.001), which are also associated with CCAs (P < 0.001). Patients with poorly developed CCAs have lower CFVR (P < 0.001). At multivariable analysis, CMD (P = 0.008) and higher CAV grades (P = 0.005) are independent predictors of CCAs. During the median follow-up time of 10.2 (6.6-13.3) y, patients with CCAs have been found to have higher mortality than those without CCAs (57.5% versus 32.1%; P = 0.007). CCAs are associated with a lower probability of survival also in patients with CMD (P < 0.001) and are independent predictors of mortality (P < 0.001). Conclusions: Our results demonstrate an interplay between CAV, CMD, and CCAs. We confirm that CAV is associated with CMD, and we show, for the first time, that CMD is associated with CCAs. CCAs are pathophysiologically associated with more severe graft vasculopathy and independently predict mortality after HT.

Clinical significance of circulating interleukin-23 as a prognostic factor in breast cancer patients.

Little is known about specific IL-23 alterations associated with breast cancer and the data available are still controversial. Therefore, the evaluation of changes in serum IL-23 levels may add further information on the role of this cytokine in breast cancer patients. The aim of this study was to evaluate prospectively the prognostic importance of circulating IL-23 in patients with untreated breast cancer, respect to healthy controls, and the association with clinico-pathological variables. The study involved 50 women diagnosed with stages I-IV breast cancer and 38 healthy controls. Of the 50 breast cancer patients, 37 women were recruited prior to their initial adjuvant chemotherapy and 13 prior to receive first line chemotherapy for metastatic disease. Adjuvant chemotherapy patients were at least in their 4th week post-surgery. IL-23 serum concentrations were measured by a quantitative enzyme immunoassay technique. We found a statistically significant higher systemic cytokine value in women with cancer in comparison with the control group (14.52±11.39 pg/ml vs. 6.35±4.63 pg/ml, P<0.0001). Patients with shorter overall survival presented higher IL-23 values, suggesting a negative prognostic correlation. There was no significant differences in IL-23 levels among patients according to the biomolecular characteristics, the different subtypes and the presence of metastatic disease. This work investigated, for the first time, the role of IL-23 in breast cancer patients showing a significant increase respect the control group. However, further validations are needed in larger studies to better investigate the implications of IL-23 increase in these patients.

Human cytomegalovirus-specific T-cell immune reconstitution in preemptively treated heart transplant recipients identifies subjects at critical risk for infection.

Human cytomegalovirus (CMV) infection represents a major threat for heart transplant recipients (HTXs). CMV-specific T cells effectively control virus infection, and thus, assessment of antiviral immune recovery may have clinical utility in identifying HTXs at risk of infection. In this study, 10 CMV-seropositive (R(+)) pretransplant patients and 48 preemptively treated R(+) HTXs were examined before and after 100 days posttransplant. Preemptive treatment is supposed to favor the immune recovery. CMV DNAemia and gamma interferon enzyme-linked immunosorbent spot (ELISPOT) assay were employed to assess the viremia and immune reconstitution. HTXs could be categorized into three groups characterized by high (>100), medium (50 to 100), and low (<50) spot levels. Early-identified high responders efficiently controlled the infection and also maintained high immunity levels after 100 days after transplant. No episodes of grade ≥2R rejection occurred in the high responders. Midresponders were identified as a group with heterogeneous trends of immune reconstitution. Low responders were 41% and 21% of HTXs before and after 100 days posttransplant, respectively. Low responders were associated with a higher incidence of infection. The effect of viremia on immune recovery was investigated: a statistically significant inverse correlation between magnitude of viremia and immune recovery emerged; in particular, each 10-fold increase in viremia (>4 log(10) DNAemia/ml) was associated with a 36% decrease of the ELISPOT assay spot levels. All episodes of high viremia (>4 log(10) DNAemia/ml) occurred from 1 to 60 days after transplant. Thus, the concomitant evaluation of viremia and CMV immune reconstitution has clinical utility in identifying HTXs at risk of infection and may represent a helpful guide in making therapeutic choices.

Modified field enhancement and extinction by plasmonic nanowire dimers due to nonlocal response.

We study the effect of nonlocal optical response on the optical properties of metallic nanowires, by numerically implementing the hydrodynamical Drude model for arbitrary nanowire geometries. We first demonstrate the accuracy of our frequency-domain finite-element implementation by benchmarking it in a wide frequency range against analytical results for the extinction cross section of a cylindrical plasmonic nanowire. Our main results concern more complex geometries, namely cylindrical and bow-tie nanowire dimers that can strongly enhance optical fields. For both types of dimers we find that nonlocal response can strongly affect both the field enhancement in between the dimers and their respective extinction cross sections. In particular, we give examples of blueshifted maximal field enhancements near hybridized plasmonic dimer resonances that are still large but nearly two times smaller than in the usual local-response description. For the same geometry at a fixed frequency, the field enhancement and cross section can also be significantly more enhanced in the nonlocal-response model.