Coronary microvascular dysfunction correlates with the new onset of cardiac allograft vasculopathy in heart transplant patients with normal coronary angiography.

Coronary microvascular dysfunction is emerging as a strong predictor of outcome in heart transplantation (HT). We assessed the validity of microvascular dysfunction, defined by means of a reduced coronary flow reserve (CFR), as a factor associated with new onset epicardial cardiac allograft vasculopathy (CAV) or death. We studied 105 patients at 4 ± 1 years post-HT with a normal coronary angiography (CA). New onset CAV was assessed by CA. CFR was assessed in the left anterior descending (LAD) coronary artery by transthoracic Doppler echocardiography and calculated as the ratio of hyperaemic to basal blood flow velocity. A CFR ≤ 2.5 was considered abnormal. Epicardial CAV onset or death was assessed during a follow-up of 10 years. New onset CAV was diagnosed in 30 patients (28.6%) (Group A), and the CA was normal in the remaining 75 patients (71.4%) (Group B). Group A had reduced CFR compared with group B (2.4 ± 0.6 vs. 3.2 ± 0.7, p < 0.0001). A CFR ≤ 2.5 was independently associated with a higher probability of new onset CAV (p < 0.0001) and a higher probability of death, regardless of CAV onset (p < 0.01). Microvascular dysfunction is independently associated with the onset of epicardial CAV, and associated with a higher risk of death, regardless of CAV onset.

Inflammatory cell burden and phenotype in endomyocardial biopsies with antibody-mediated rejection (AMR): a multicenter pilot study from the AECVP.

This multicenter case-controlled pilot study evaluated myocardial inflammatory burden (IB) and phenotype in endomyocardial biopsies (EMBs) with and without pathologic antibody-mediated rejection (pAMR). Sixty-five EMBs from five European heart transplant centers were centrally reviewed as positive (grade 2, n = 28), suspicious (grade 1, n = 7) or negative (n = 30) for pAMR. Absolute counts of total, intravascular (IV) and extravascular (EV) immunophenotyped mononuclear cells were correlated with pAMR grade, capillary C4d deposition, donor specific antibody (DSA) status and acute cellular rejection (ACR). In pAMR+ biopsies, equivalent number of IV CD3+ T lymphocytes (23 ± 4/0.225 mm(2) ) and CD68+ macrophages (21 ± 4/0.225 mm(2) ) were seen. IB and cell phenotype correlated with pAMR grade, C4d positivity and DSA positivity (p < 0.0001). High numbers of IV T lymphocytes were associated with low grade ACR (p = 0.002). In late-occurring AMR EV plasma cells occurring in 34% of pAMR+ EMBs were associated with higher IB. The IB in AMR correlated with pAMR+, C4d positivity and DSA positivity. In pAMR+ equivalent numbers of IV T lymphocytes and macrophages were found. The presence of plasma cells was associated with a higher IB and occurrence of pAMR late after transplantation.

Everolimus prevents coronary microvasculopathy in heart transplant recipients with normal coronary angiograms: an anatomo-functional study.

BACKGROUND: Coronary allograft vasculopathy (CAV) involves both epicardial vessels and coronary microcirculation. Little is known about the effect of everolimus on coronary microvasculopathy in heart transplantation (HT). The aim of our study was to assess the pathological substrate of coronary flow reserve (CFR) impairment in HT patients and the effect of everolimus on microvascular remodeling and CFR. METHODS: We studied 28 HT patients with normal coronary angiograms (25 male, age at HT 54±10 years). Immunosuppressive regimen consisted of cyclosporine and everolimus (10 patients) or mycophenolate mophetil (18 patients). They were evaluated with digital microscopy for morphometric analysis of fibrosis and microvascular remodeling. Coronary flow velocity in the left anterior descending coronary artery was detected using transthoracic Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperaemic diastolic flow velocity (DFV) to resting DFV. A CFR≤2.5 was considered abnormal and sign of coronary microvascular dysfunction. RESULTS: In patients with CFR≤2.5 the thickness of the tunica media of intramyocardial arterioles was greater than in patients with CFR>2.5 (39±2 vs 17±3 µm; P=.02). Microvascular remodeling was significantly higher in patients with CFR≤2.5 (72.7±2.4 vs 50.4±8.4%; P<.007). Capillary density and fibrosis were comparable between groups (157.2±42.4 vs 175.7±42.4 capillaries/mm2; P=.3; and 6.8±5 vs 8.3±4.9%; P=.4, respectively). The thickness of the tunica media of intramyocardial arterioles was lower in patients whose therapy included everolimus (15±2 vs 32±4 µm, P=.03) and CFR was higher (3.2±0.5 vs 2.8±0.9; P=.03). CONCLUSION: The pathological substrate of reduced CFR in HT patients seems to be a hypertrophic remodeling of coronary arterioles. Everolimus appears to prevent such microvascular remodeling and preserve coronary flow reserve.

Intraplaque hemorrhage in cardiac allograft vasculopathy.

Plaque hemorrhage, inflammation and microvessel density are key determinants of plaque vulnerability in native coronary atherosclerosis (ATS). This study investigates the role of intraplaque hemorrhage (IPH) and its relation with inflammation and microvessels in cardiac allograft vasculopathy (CAV) in posttransplanted patients. Seventy coronary plaques were obtained from 12 patients who died because of CAV. For each patient we collected both native heart and the allograft, at the time of transplantation and autopsy, respectively. Intralesion inflammation, microvessels and IPH were assessed semi-quantitatively. IPH was observed in 21/35 (60%) CAV lesions and in 8/35 (22.9%) native ATS plaques, with a strong association between fibrocellular lesions and IPH (p = 0.0142). Microvessels were detected in 26/35 (74.3%) of CAV lesions with perivascular leakage as sign of endothelial damage in 18/26 (69.2%). IPH was strongly associated with microvessels (p < 0.0001). Inflammation was present in 31/35 (88.6%) of CAV lesions. CAV IPH+ lesions were characterized by presence of both fresh and old hemorrhage in 12/21 (57.1%). IPH, associated with microvessel damage and inflammation, is an important feature of CAV. Fresh and old intralesion hemorrhage suggests ongoing remodeling processes promoting the lesion progression and vulnerability.

HLA-DRB1 typing by micro-bead array assay identifies the origin of early lymphoproliferative disorder in a heart transplant recipient.

We report the case of a 68-year-old woman who underwent heart transplantation for hypertrophic cardiomyopathy. Two months after the transplant she developed mild fever and dyspnea with a marked drop in left ventricle ejection fraction of 31%. Coronary angiography was negative for cardiac allograft vasculopathy. Endomyocardial biopsy revealed ischemic damage with no evidence of acute cellular rejection, antibody-mediated rejection or viral myocarditis. A neoplastic process was suspected even though full-body computerized tomography was negative for malignancy. The patient died 4 months after transplantation. The autopsy showed acute antero-septal myocardial infarction due to a nodular epicardial EBV-related posttransplant lymphoproliferative disorder (PTLD) infiltrating the left anterior descending coronary artery with occlusive neoplastic thrombosis. We highlight two major aspects of this case: (1) the unusual occurrence of early PTLD involving the cardiac allograft and causing a fatal outcome, (2) the application of an immunological technique for HLA-DRB1 typing to posttransplant paraffin-embedded autopsy material to identify the recipient origin of this early malignancy, thus excluding a possible donor-transmitted neoplasm.

Nonadherent behaviors after solid organ transplantation.

BACKGROUND AND AIM: The effectiveness of any treatment depends not only on the choice of therapy, but also, to a large extent, on the patient's active cooperation. Adherence to medical prescriptions and particularly to immunosuppressive therapy is crucial to prevent medical complications that negatively influence graft function and patient survival after organ transplantation. The aim of this study was to assess, among patients who underwent solid organ transplantation, nonadherent behaviors (NAB) to immunosuppressive therapy, to correct lifestyle, and to general medical prescriptions. MATERIALS AND METHODS: We evaluated patients who underwent solid organ transplantation from March 2008 to June 2009. All participants completed an anonymous 15-item questionnaire to assess NAB. RESULTS: We enrolled 218 organ transplant patients: 103 liver, 50 kidney, 52 heart, and 13 lung. There were 152 men and the overall age was 52.2 ± 0.8 years (mean ± standard deviation [SD]) time from transplantation, 83.6 ± 4.5 months (mean ± SD). Overall 37.9%, 38.8%, and 12.8% of patients reported nonadherence to immunosuppressive therapy, to correct lifestyle, and to general medical prescriptions, respectively. Considering nonadherence to immunosuppressive therapy and to general prescriptions, the percentage of kidney transplant patients who referred NAB was significantly lower compared with other organ transplant patients (P = .008 and P = .04, respectively). Nonadherent patients to immunosuppressive therapy and to general medical prescriptions displayed a longer interval from transplantation compared with adherent patients (P = .02 and P = .03, respectively). Among patients nonadherent to the correct lifestyle, the rates of men and of patients with disability pension were significantly higher compared to adherent patients (P = .001 and P = .002, respectively). CONCLUSIONS: Poor adherence to medical prescriptions and to adequate lifestyle is common among organ transplant patients, especially those who have undergone liver transplantation. Psychoeducational interventions for transplanted patients and their families are needed to improve adherence.

Coronary flow reserve by transthoracic echocardiography predicts epicardial intimal thickening in cardiac allograft vasculopathy.

Cardiac allograft vasculopathy (CAV) is the leading cause of morbidity and mortality in heart transplantation (HT). We sought to investigate the role of coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography (CE-TTE) in CAV diagnosis. CAV was defined as maximal intimal thickness (MIT) assessed by intravascular ultrasound (IVUS) > or =0.5 mm. CFR was assessed in the left anterior descending coronary artery in 22 HT recipients at 6 +/- 4 years post-HT. CAV was diagnosed in 10 patients (group A), 12 had normal coronaries (group B). The mean MIT was 0.7 +/- 0.1 mm (range 0.03-1.8). MIT was higher in group A (1.16 +/- 0.3 mm vs. 0.34 +/- 0.07 mm, p < 0.0001). CFR was 3.1 +/- 0.8 in all patients and lower in group A (2.5 +/- 0.6 vs. 3.7 +/- 0.3, p < 0.0001). CFR was inversely related with MIT (r =-0.774, p < 0.0001). A cut point of < or =2.9, identified as optimal by receiver operating characteristics analysis was 100% specific and 80% sensitive (PPV = 100%, NPV = 89%, Accuracy = 91%). CFR assessment by CE-TTE is a novel noninvasive diagnostic tool in the detection of CAV defined as MIT > or =0.5 mm. CFR by CE-TTE may reduce the need for routine IVUS in HT.

MRI in the assessment of muscular pathology: a comparison between limb-girdle muscular dystrophies, hyaline body myopathies and myotonic dystrophies.

PURPOSE: The continuous discovery of new subtypes of neuromuscular disorders demands more accurate imaging analyses. We set out to establish the specific patterns of muscular involution using magnetic resonance imaging (MRI). MATERIALS AND METHODS: A systematic clinical evaluation based on the Medical Research Council scale and MRI was completed in ten patients with calpainopathy [limb-girdle muscular dystrophy (LGMD)-2A], 16 with dysferlinopathy (LGMD-2B), ten with hyaline body myopathy (HBM), six with myotonic dystrophy (MD) types 1 and 5 with MD type 2. Severity of fibroadipose degeneration was specifically staged using T1-weighted sequences. Turbo inversion recovery magnitude (TIRM) sequences were used to assess oedema-like changes. RESULTS: T1 scans showed recurrent patterns of fibroadipose replacement, whereas TIRM images revealed differences in oedema-like changes between the various diseases. In LGMD, the posterior compartments are more vulnerable to degeneration. In HBM, fatty muscle degeneration and oedema are allocated to muscles of the posterior compartments of the leg. In MD, fatty muscle degeneration and oedematous changes are allocated to muscles of the anterior thigh and posterior lower leg. CONCLUSIONS: Imaging examination suggests a characteristic pattern of muscle involvement. MRI represents an important diagnostic technique useful in differential diagnosis, thanks to the distinctive patterns observed in the distribution of muscular changes between the different muscular diseases.

Morphometric analysis of the canal system of cortical bone: An experimental study in the rabbit femur carried out with standard histology and micro-CT.

The osteonal pattern of cortical bone is gradually built around the intracortical vessels by the progression of the cutting cones (secondary remodelling); therefore, the central canal size can be used as index of the remodelling activity. An experimental model in the rabbit femur was used to investigate, through central canal morphometry and frequency distribution analysis, the remodelling activity, comparing the middle of the diaphysis (mid-shaft) with the extremity (distal-shaft) and at the same level sectors and layers of the cortex in transversal sections. The study documented a higher density of canals in the mid-shaft than in the distal-shaft and a higher remodelling in the distal-shaft. There were no significant differences between dorsal, ventral, medial and lateral sectors at both mid-shaft and distal-shaft levels, while the number of canals was higher in the sub-periosteal layers than in the sub-endosteal. A lower threshold of 40 microm(2) was observed in the central canal area. Sealed osteons in the midshaft were 22.43% of the total number of osteons of the central canal area between 40 and 200 microm(2) and 0.44% of those of the distal-shaft. Micro-CT allowed a 3D reconstruction of the vascular canal system, which confirmed the branched network pattern rather than the trim architecture of the traditional representation. Some aspects like the lower threshold of the central canal size and the sealed osteons documented the plasticity of the system and its capacity for adaptation to changes in the haemodynamic conditions.

[Prevention and control of substance abuse in the workplace: a new and significant opportunity for the occupational physician]. / La prevenzione ed il controllo dell'assunzione di sostanze psicotrope o stupefacenti nei luoghi di lavoro: una nuova ed importante opportunità per i medici del lavoro.

OBJECTIVES: Substance abuse is nowadays a recurrent theme in the daily practice of occupational physicians (OP), mainly owing to recent legislation prescribing mandatory assessments for workers performing job tasks involving danger to third parties. While some degree of bureaucracy is inevitable and legislation seems to be inclined towards deterrence, it is recommended to take advantage of the opportunities offered for practical interventions which, in accordance with science and ethics, the OP can carry out in the workplace. Risk assessment, health surveillance, fitness for work, health promotion and cooperation in management issues are the areas of intervention required for the OP to fully accomplish his role in the practice of modern occupational health. CONCLUSIONS: We propose specific activities for the OP so as to highlight roles and obligations, based on available scientific evidence and established codes of ethics. Lastly, we wish to emphasize the overall role of the OP in taking on responsibilities shared jointly with all the parties and in the approach to the substance abuse problem in all workplaces with the ultimate goal of acting for the benefit of workers, enterprises and society in general.

[Consensus Document. Update on latex exposure and use of gloves in Italian health care settings]. / Documento di Consenso. Aggiornamenti in tema di esposizione a latice e impiego di guanti in ambito sanitario.

This consensus document was prepared by an Italian working group including occupational health professionals involved for many years in the management of glove- and latex-related problems in health care settings. The aim of this document was to address the most significant technical, epidemiological, clinical, environmental and prevention problems related to the use of gloves and latex. The group's recommendations are based on scientific evidence and practical experience but they cannot be considered as final. These topics need to be periodically revised. The following points should be taken into account: glove quality seems to have improved considerably but the information on glove features provided by the manufacturers is often still inaccurate or incomplete; the regulations in force provide that the manufacturers perform tests to supply evidence for the quality of the products but they do not indicate which analytical method should be used and they do not require that the results be reported in the technical data sheets. Thus the manufacturers have only to declare that their products are "in accordance with the rules"; therefore, purchasers should require the manufacturing companies to supply detailed information and verify their reliability. Moreover, the rules should be adapted to higher quality standards; occupational physicians must be involved for the correct choice and purchase of protective gloves; the use of gloves (in particular latex gloves) and latex devices in health care settings should be based on specific criteria: procedures must be available stating which kind of gloves are suitable for specific tasks. When exposure to latex cannot be avoided it is necessary to choose products that have good biocompatibility (e.g., powder free-gloves with low allergen content); once and for all latex powdered gloves should no longer be commercially available! labels for latex devices (including gloves) should report the extractable latex allergen content. Limit values for extractable latex allergens should be established; the use of synthetic rubber gloves should be encouraged since some materials (e.g., neoprene and nitrile rubber) appear to have physical properties and protective efficacy similar to latex, plus good biocompatibility; more studies should be promoted to verify the protective efficacy of new synthetic materials; health care workers should be informed about the advisability and usefulness of using materials other than latex; health care services should not cause additional risks but rather highlight the advantages for workers and patients if the use of latex gloves and devices is minimized.

Post-transplant lymphoproliferative disorders after heart or kidney transplantation at a single centre: presentation and response to treatment.

Post-transplant lymphoproliferative disorders (PTLD) is a serious complication after solid organ transplantation. Reduction of immunosuppression (RI) alone is not able to control the disease. We report a prospective analysis of 30 patients with PTLD after heart or kidney transplantation. Only 5 of 30 patients, treated solely with RI, obtained a complete response. Five patients were treated heterogeneously; in the remaining 20, the efficacy and safety of a weekly anthracycline-based chemotherapy were assessed. Sixteen patients obtained a complete remission. One death was related to treatment. With a median follow-up of 36 months, 3-year overall survival was 63.3% and 57% for the entire group and the chemotherapy-treated group, respectively. Moreover, 4 second neoplasms were observed in the chemotherapeutic group. In this study, we demonstrated that most PTLD need other treatment than RI and a weekly regimen is manageable and has a favourable impact on long-term survival.

[Gloves as medical devices or individual protection devices: current regulations and correct use in hospital environments]. / Guanti come dispositivi medici o come DPI: normativa vigente e corretto impiego in ambito sanitario.

BACKGROUND: Hospital work consists of the care and assistance of patients, who therefore constitute another group of individuals besides the workers, which is a completely different situation compared to other workplaces in manufacturing industries. OBJECTIVES: Health professionals must know how to use the right devices to protect both the patients and themselves. In the case of protection of the hands, health professionals must also know when to use gloves as "individual protection gloves" and when to use gloves as "medical devices", and comply with both Italian and European Community regulations. METHODS AND RESULTS: The Hospital of Vimercate (Milan) has drawn up technicalprocedures regarding the various types of gloves used in hospitals, which provide health care workers with accurate information on regulations and protocols, prevention guidelines, safety management recommendations, purchasing specifications, quality controls, correct uses of gloves and devices.

[Hearing function and solvent exposure: study of a worker population exposed to styrene]. / Udito ed esposizioni a solventi: studio di una popolazione di lavoratori esposti a stirene.

The aim of the study was to investigate the ototoxic effects of occupational styrene exposure, in absence of other risk factors. Pure-tone audiometric thresholds of 32 workers exposed to styrene, but not to noise, in fibreglass reinforced plastic boat manufacturing process were detected and compared to audiometric thresholds of a control unexposed group composed by 60 subjects. Exposure to styrene was measured by urinary mandelic + phenylglyoxylic acid (mean value 149 mg/g crea, SD 80 mg/g crea). For all the frequencies investigated (0,5-1-2-3-4-6-8 KHz) the exposed group showed slight higher mean (median) audiometric thresholds (p < 0.05) compared to controls matched by age and sex, except for 8 KHz in the right ear. The present experience seems to confirm the hypothesis that styrene exposure alone can determine a weak sensorineural high-frequency hearing loss. Such slight impairment, even if statistically significant, does not remarkably limit social hearing and do not involve legal medical aspects. Sample expansion and objective diagnostic tests (auditory brainstem evoked potentials, acoustic otoemissions) are needed.

Medullary sponge kidney (Lenarduzzi-Cacchi-Ricci disease): a Padua Medical School discovery in the 1930s.

The introduction of radiological contrast media and intravenous (i.v.) urography in clinical diagnostics in the 1930s enabled the discovery of several diseases, including the medullary sponge kidney (MSK). MSK is a renal malformation characterized by cystic anomalies of precalyceal ducts, which is frequently associated with nephrocalcinosis and renal stones. Although it was first recognized by G Lenarduzzi in 1939, its thorough description was the result of the ante litteram multidisciplinary cooperation between a radiologist (Lenarduzzi), a urologist (Cacchi), and a pathologist (Ricci), all at the Padua University Hospital. These authors 'established' the paradigm for its diagnosis that is still used today. I.v. urography is the gold standard for the diagnosis of MSK, but as the technique is used less and less, there is a concrete possibility of this renal condition being forgotten in the future. Although the pathogenesis of MSK has yet to be elucidated, its association with different malformative conditions supports the idea that it is a developmental disorder. Recent findings suggest that MSK may be the consequence of a disruption of the ureteral-bud/metanephric-blastema interface.

Imaging of primary sclerosing cholangitis: preliminary results by two new non-invasive techniques.

BACKGROUND: Magnetic resonance cholangiography is a new technique which has already gained a role in primary sclerosing cholangitis. Computerised tomographic cholangiography is another non-invasive technique which has been used in assessing abnormal biliary tree, but has never been applied to evaluating primary sclerosing cholangitis. AIMS: To evaluate the ability of both magnetic resonance cholangiography and computerised tomographic cholangiography to detect bile duct changes in primary sclerosing cholangitis. PATIENTS AND METHODS: Magnetic resonance cholangiography and computerised tomographic cholangiography were performed in 16 primary sclerosing cholangitis patients. The computerised tomographic cholangiography data set was transferred to a processing workstation to obtain tridimensional reconstructions. Magnetic resonance cholangiography and computerised tomographic cholangiography images were analysed blind by two radiologists to assess: primary sclerosing cholangitis involvement, quality of imaging and the radiologist's certainty in determining the presence and location of the disease. RESULTS: Mean imaging quality was significantly better with computerised tomographic cholangiography compared with magnetic resonance cholangiography. Primary sclerosing cholangitis was identified in 15 cases with computerised tomographic cholangiography and 10 with magnetic resonance cholangiography (P < 0.05). Sensitivity in diagnosing primary sclerosing cholangitis was 94% with computerised tomographic cholangiography versus 63% with magnetic resonance cholangiography. Intrahepatic location was found in 14 cases, definitely present in 10 cases with computerised tomographic cholangiography and five with magnetic resonance cholangiography. Extrahepatic location was found in 13 cases, definitely present in 11 cases with computerised tomographic cholangiography and four with magnetic resonance cholangiography (P < 0.05). Computerised tomographic cholangiography also offered dynamic information about biliary excretion. CONCLUSIONS: Computerised tomographic cholangiography enables more accurate detection and location of primary sclerosing cholangitis than magnetic resonance cholangiography. Since computerised tomographic cholangiography offers additional information about biliary excretion, it may be proposed as an integrative technique in the diagnosis and follow-up of patients with primary sclerosing cholangitis.

[Determination of interleukin-8 in induced sputum of workers exposed to low concentrations of asbestos]. / Determinazione dell'interleuchina-8 nell'espettorato indotto di lavoratori esposti a basse concentrazioni di asbesto.

The concentration of interleukin-8 (IL-8) in the induced sputum of 17 workers exposed to low airborne asbestos levels and of 10 controls was determined. IL-8 levels were statistically significantly increased in the asbestos exposed group compared to controls. This finding underlines the usefulness of the study of proinflammatory mediators as possible predictors of alveolar damage.

Fractal analysis of lumbar vertebral cancellous bone architecture.

Osteoporosis is characterized by bone mineral density (BMD) decreasing and spongy bone rearrangement with consequent loss of elasticity and increased bone fragility. Quantitative computed tomography (QCT) quantifies bone mineral content but does not describe spongy architecture. Analysis of trabecular pattern may provide additional information to evaluate osteoporosis. The aim of this study was to determine whether the fractal analysis of the microradiography of lumbar vertebrae provides a reliable assessment of bone texture, which correlates with the BMD. The lumbar segment of the spine was removed from 22 cadavers with no history of back pain and examined with standard x-ray, traditional tomography, and quantitative computed tomography to measure BMD. The fractal dimension, which quantifies the image fractal complexity, was calculated on microradiographs of axial sections of the fourth lumbar vertebra to determine its characteristic spongy network. The relationship between the values of the BMD and those of the fractal dimension was evaluated by linear regression and a statistically significant correlation (R = 0.96) was found. These findings suggest that the application of fractal analysis to radiological analyses can provide valuable information on the trabecular pattern of vertebrae. Thus, fractal dimensions of trabecular bone structure should be considered as a supplement to BMD evaluation in the assessment of osteoporosis.