Echocardiographic findings in apparently healthy Czechoslovakian wolfdogs.

INTRODUCTION: To echocardiographically evaluate a large number of apparently healthy Czechoslovakian wolfdogs (CWDs) to identify possible subclinical cardiac abnormalities and to generate reference intervals. ANIMALS: One-hundred and seventeen apparently healthy client-owned CWDs. MATERIALS AND METHODS: Standard two-dimensional, M-mode, and Doppler echocardiographic measurements were obtained on non-sedated, manually restrained standing dogs. Animals with no relevant echocardiographic abnormalities were used to generate reference intervals. Echocardiographic variables were compared between males and females and between dogs with and without mitral regurgitation (MR). RESULTS AND DISCUSSION: Among the 117 CWDs, 103 dogs were used to generate reference intervals. The 14 dogs with abnormalities had more than trivial MR (12 dogs), subaortic stenosis (one dog), and equivocal subaortic stenosis (one dog). The 44 males were heavier than 59 females (P<0.001) and had a larger maximum left atrial dimension (P=0.015), left ventricular internal dimension at end-diastole (P<0.001) and systole (P<0.001), and thicker interventricular septum thickness at end-diastole (P=0.016). A positive linear correlation was identified between bodyweight and aortic root and left atrial diameters and left ventricular dimensions and between age and aortic root and left atrial diameter and peak late transmitral flow velocity. A negative linear correlation was identified between age and peak early transmitral flow velocity and the ratio between peak early and late transmitral flow velocities. No differences in echocardiographic-derived cardiac dimensions were detected between healthy dogs and dogs with more than trivial MR. CONCLUSIONS: In this population of CWDs, subclinical cardiac abnormalities were uncommon, and they were mainly classified as MR.

A genome-wide association study identifies novel gene associations with facial skin wrinkling and mole count in Latin Americans.

BACKGROUND: Genome-wide association studies (GWASs) have identified genes influencing skin ageing and mole count in Europeans, but little is known about the relevance of these (or other genes) in non-Europeans. OBJECTIVES: To conduct a GWAS for facial skin ageing and mole count in adults < 40 years old, of mixed European, Native American and African ancestry, recruited in Latin America. METHODS: Skin ageing and mole count scores were obtained from facial photographs of over 6000 individuals. After quality control checks, three wrinkling traits and mole count were retained for genetic analyses. DNA samples were genotyped with Illumina's HumanOmniExpress chip. Association testing was performed on around 8 703 729 single-nucleotide polymorphisms (SNPs) across the autosomal genome. RESULTS: Genome-wide significant association was observed at four genome regions: two were associated with wrinkling (in 1p13·3 and 21q21·2), one with mole count (in 1q32·3) and one with both wrinkling and mole count (in 5p13·2). Associated SNPs in 5p13·2 and in 1p13·3 are intronic within SLC45A2 and VAV3, respectively, while SNPs in 1q32·3 are near the SLC30A1 gene, and those in 21q21·2 occur in a gene desert. Analyses of SNPs in IRF4 and MC1R are consistent with a role of these genes in skin ageing. CONCLUSIONS: We replicate the association of wrinkling with variants in SLC45A2, IRF4 and MC1R reported in Europeans. We identify VAV3 and SLC30A1 as two novel candidate genes impacting on wrinkling and mole count, respectively. We provide the first evidence that SLC45A2 influences mole count, in addition to variants in this gene affecting melanoma risk in Europeans.

SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis.

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.

Serum total tryptase level confirms itself as a more reliable marker of mast cells burden in mast cell leukaemia (aleukaemic variant).

Mast cell leukemia (MCL) is a very rare form of systemic mastocytosis (SM) with a short median survival of 6 months. We describe a case of a 65-year-old woman with aleukaemic variant of MCL with a very high serum total tryptase level of 2255 µg/L at diagnosis, which occurred following an episode of hypotensive shock. She fulfilled the diagnostic criteria of SM, with a bone marrow smear infiltration of 50-60% of atypical mast cells (MCs). She tested negative for the KIT D816V mutation, without any sign of organ damage (no B- or C-findings) and only few mediator-related symptoms. She was treated with antihistamine alone and then with imatinib for the appearance of anemia. She maintained stable tryptase level and a very indolent clinical course for twenty-two months; then, she suddenly progressed to acute MCL with a serum tryptase level up to 12960 µg/L. The patient died due to haemorrhagic diathesis twenty-four months after diagnosis. This clinical case maybe represents an example of the chronic form of mast cell leukemia, described as unpredictable disease, in which the serum total tryptase level has confirmed itself as a reliable marker of mast cells burden regardless of the presence of other signs or symptoms.

Synthesis and characterization of polyethylenimine-based iron oxide composites as novel contrast agents for MRI.

OBJECT: Use of polyethylenimines (PEIs) of different molecular weight and selected carboxylated-PEI derivatives (PEI-COOH) in the synthesis and stabilization of iron oxide nanoparticles, to obtain possible multifunctional contrast agents. MATERIALS AND METHODS: Oxidation of Fe(II) at slightly elevated pH and temperature resulted in the formation of highly soluble and stable nanocomposites of iron oxides and polymer. Composites were characterized and studied by atomic force microscopy (AFM), transmission electron microscopy (TEM), X-ray diffractometry, AC and DC magnetometry, NMR relaxometry and magnetic resonance imaging (MRI). RESULTS: From AFM the dimensions of the aggregates were found to be in the ~150-250 nm size region; the mean diameter of the magnetic core of the compounds named PEI-25, PEI-500 and PEI-COOH60 resulted d approximately 20 +/- 5 nm for PEI-25, d approximately 9.5 +/- 1.0 nm for PEI-500 and d approximately 6.8 +/- 1.0 nm for PEI-COOH60. In PEI-COOH60 TEM and X-ray diffractometry revealed small assemblies of mineral magnetic cores with clear indications that the main constituents are maghemite and/or magnetite as confirmed by AC and DC SQUID magnetometry. For PEI-COOH60, the study of NMR-dispersion profiles revealed r (1) and r (2) relaxivities comparable to superparamagnetic iron-oxide commercial compounds in the whole investigated frequency range 7 < or = nu < or = 212 MHz. CONCLUSION: PEI-25 was studied as possible MRI contrast agent (CA) to map the cerebral blood volume (CBV) and cerebral blood flow (CBF) in an animal model obtaining promising results. The reported compounds may be further functionalized to afford novel multifunctional systems for biomedical applications.

Fire-eater's pneumonitis.

The authors report a case of acute respiratory failure that fulfils the diagnostic criteria for fire-eater's pneumonitis; pathological features, usually described only in experimental works on animals, are also discussed.

Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children.

BACKGROUND: Asthma exacerbation is the most common cause of hospital admission in children. A study was undertaken to investigate the importance of allergen exposure in sensitised individuals in combination with viral infections and other potentially modifiable risk factors precipitating asthma hospital admission in children. METHODS: Eighty four children aged 3-17 years admitted to hospital over a 1 year period with an acute asthma exacerbation (AA) were matched for age and sex with two control groups: stable asthmatics (SA) and children admitted to hospital with non-respiratory conditions (IC). Risk factors were assessed by questionnaires and determination of allergen sensitisation, home allergen exposure, pollen exposure, and respiratory virus infection. RESULTS: Several non-modifiable factors (atopy, duration of asthma) were associated with increased risk. Among the modifiable factors, pet ownership, housing characteristics, and parental smoking did not differ between the groups. Regular inhaled corticosteroid treatment was significantly less common in the AA group than in the SA group (OR 0.2, 95% CI 0.1 to 0.6; p = 0.002). A significantly higher proportion of the AA group were virus infected (44%) and sensitised and highly exposed to sensitising allergen (76%) compared with the SA (18% and 48%) and IC groups (17% and 28%; both p<0.001). In a multiple conditional logistic regression (AA v SA), allergen sensitisation and exposure or virus detection alone were no longer independently associated with hospital admission. However, the combination of virus detection and sensitisation with high allergen exposure substantially increased the risk of admission to hospital (OR 19.4, 95% CI 3.7 to 101.5, p<0.001). CONCLUSIONS: Natural virus infection and real life allergen exposure in allergic asthmatic children increase the risk of hospital admission. Strategies for preventing exacerbations will need to address these factors.

Acute eosinophilic pneumonia with respiratory failure: a case likely triggered by cigarette smoking.

The authors report a case of acute respiratory failure that fulfils the diagnostic criteria for acute eosinophilic pneumonia. Bronchoalveolar lavage eosinophilia and eosinophilic lung diseases are also discussed. The pathogenetic events, including the role of IL-5, eotaxin 1 and 2 and VEGF are emphasised.

A simple method to correct aortic tube graft kinking without cardiopulmonary by-pass and aortic clamping.

A method for correcting the tube kinking after ascending aortic replacement for acute dissection is described. Its main advantage is the no need for cardiopulmonary by-pass (CPB) and aortic clamping to solve the problem.

The lung as a target organ in patients with hematologic disorders.

The lung is one of the organs most severely affected by complications during the course of hematologic disorders. In the last years an impressive amount of progress has been made in clarifying the pathogenesis of lung diseases, particularly those occurring in conditions of severe immunosuppression such as bone marrow transplantion, acquired immunodeficiency syndrome or leukemia. Peculiar anatomical characteristics render the lung parenchyma highly susceptible to infections, but the clinical outcome is due not only to the injury induced by the pathogens but also to their interactions with inflammatory cells and particularly to the effects of a wide network of secreted cytokines. Polymorphonuclear cells, macrophages, lymphocytes and structural pulmonary cells (epithelial cells, interstitial cells) generate a variety of cytokines and growth factors which, in turn, may be responsible for the majority of the clinical effects in response to infections, such as those of Pneumocystis carinii and cytomegalovirus, but also to certain drugs or to radiation. The pathogenesis of graft-versus-host disease (GVHD) is still poorly understood, but animal models seem to demonstrate the involvement of a number of cytokines and growth factors, together with toxic effects induced by conditioning regimens.

Aortobronchial fistula after aortic dissection type B.

Although rare, aortobronchial fistula complicates thoracic aortic surgery. Correct diagnosis and the infectious nature of the lesion are the most important conditions to define, for the following best therapy. We presented a case of non-infectious postsurgical aortobronchial fistula, revealed by computed-tomographic scan and angiography procedure, treated with prosthetic graft replacement and broad spectrum antibiotic therapy. In the case of infection our policy is homograft replacement. Computed tomography, being able to make diagnosis, should be performed as the initial technique.

Bjork-Shiley convexo-concave valve: is a prophylactic re-replacement justified?

BACKGROUND: The Bjork-Shiley convexo-concave (BS-CC) heart valves represent the improved model of the standard valve first introduced with a different design of the disc valve to ameliorate hemodynamic performances and reduce thromboembolic complications. About 86,000 BS-CC were implanted during 1979-1986 and of them a small number developed an intrinsic dysfunction resulting in sudden death. METHODS: From 1979 to 1986 we implanted in 117 patients (48 males, 69 females, mean age 46.35+/-12.47, range 8-65 years) 125 BS-CC. In 38.5% (45/117) of the cases heart valve replacement represented the second cardiac procedure after a previous closed heart digital commissurotomy. The mean size of the implanted prosthesis was 25.6+/-2.8 for aortic valve and 29.5+/-1.2 for mitral valve. RESULTS: Hospital mortality was 4.27% (5/117) and survival rate at 10 years is 71.4% and at 17 years 54.7% (Kaplan-Meier). At follow-up causes of death proved valve related in most of the patients but with no evidence of valve fracture. We had 1 case of sudden death in patients at high risk (largest size, aortic position) and 30 cases of death by unknown causes but they did not have an autopsy to confirm the cause of death. CONCLUSIONS: We conclude that in our population with BS-CC at the moment there is no indication for prophylactic replacement because of the higher risks of a reoperation (third or fourth in the 35.4% of our patients) than a strut fracture. Nevertheless we believe an autopsy mandatory in all these patients at risk, when sudden death occurs.

Surgical treatment of massive pulmonary embolism. A case report.

Pulmonary embolism is a serious complication following trauma and bed rest and it represents a challenge in the prompt diagnosis and medical or surgical therapy. We present a surgically treated patient with a massive pulmonary embolism (more than 50% of the vascular pulmonary bed) which occurred after an inferior leg trauma which required a prolonged bed immobilization. We believe surgical intervention is the treatment of choice in patients with massive pulmonary embolism who do not respond to fibrinolytic therapy. Moreover prompt surgical embolectomy is mandatory to have more chances to save the patient's life.

[Correlation between malfunction of a bioprosthesis and deformation of a valve stent. Comparison of three different vale models]. / Correlazione tra malfunzionamento di protesi biologiche e deformazione dello stent valvolare. Confronto tra diversi modelli di valvola.

BACKGROUND: Stent deformation seems to be effective in the long term performances of bioprostheses. METHODS: The Inward Banding Angle (IBA) of three different models of bioprostheses explanted during the period 1991-1992 at our Division of Cardiac Surgery in 45 different patients (26 males; 9 females; mean age 59.71 +/- 10.74, range 26-75) has been measured. Explanted valves were as follow: Hancock, (H = 13); Carpentier-Edwards (C = 14) e Xenomedica (X = 18). Primary tissue failure was the most common cause of re-operation (n = 30; 66.7%) but also endocarditis (n = 6; 13.3%) and paraprothetic leak (n = 10; 22.2%). A semi-quantitative score (0-4) was used to assess calcifications (1.51 +/- 1.56); tears (0.41 +/- 0.98); vegetation's (0.51 +/- 0.99) and fibrosis (2.7 +/- 1.27). The mean follow-up was 7.77 +/- 3.79 years (range 1.5 +/- 16 years). The mean IBA evaluated after explantation was 3.34 +/- 2.29 degrees. RESULTS: Statistical analysis showed a significance in term of IBA in the Hancock group vs Carpentier (P < 0.02); a less duration in the Xenomedica group vs H and C (p < 0.001) and an increased susceptibility to vegetation's and fibrosis in the Xvs C (p < 0.01) and H (p < 0.05) respectively. A suggestive correlation between IBA and time and between IBA and diameter was found but no statistical significance was observed. CONCLUSIONS: In conclusions, it is suggested that all materials tends to deform during time and a possible explanation of stent deformation can be the different material used in the stent fabrication. Moreover, mechanical stress and compression around the ring can be another mechanism of creep.

Adjuvant adoptive immunotherapy with tumour-infiltrating lymphocytes and modulated doses of interleukin-2 in 22 patients with melanoma, colorectal and renal cancer, after radical metastasectomy, and in 12 advanced patients.

Adoptive tumour infiltrating lymphocytes (TIL) in combination with a modulated dosage of interleukin-2 (IL-2) can be used with acceptable toxicity in the treatment of immunogenic tumours. Following an experience of reinfusion in advanced melanoma, colorectal and renal cancer patients, treatment was given to disease-free patients after metastasectomy. The high risk of relapse and favourable ratio between reinfused TIL and possible microscopic residual disease determined this choice of adjuvant treatment. A group of 12 patients with advanced disease (7 melanoma, 4 colorectal carcinoma, 1 kidney carcinoma) were treated with TIL (median 5.8 x 10(10) cells) and IL-2 (West's schedule) modulated towards a lower dosage (from 12 to 6 MIU/day) in order to maintain an acceptable level of toxicity. As treatment was well tolerated, it was offered to another 22 patients in an adjuvant setting after metastasectomy (11 melanoma, 10 colorectal carcinoma, 1 renal cancer), the median dose of TIL reinfused being 4.95 x 10(10) cells. No objective response was observed in advanced patients: all patients progressed after a median of 1.5 months (0-8 months) and median survival was 8 months (3-22+ months). Thirteen patients from the second group are still disease-free after a median of 23+ months (9+ - 47+ months). The remaining 9 patients relapsed after a median of 5 months (3-18 months). Toxicity was moderate as clinical and hepatic/renal function parameters were used to assess the need for dose reductions. Consequently, there was great diversity in IL-2 dosages administered. In particular, there seemed to be a difference in IL-2 doses administered between disease-free cases and those who progressed (17.5 MIU/day versus 7 MIU/day in melanoma patients; 11.2 MIU/day versus 7.1 MIU/day in colorectal cancer patients). By contrast, no differences were observed between number of TIL reinfused and clinical response. Phenotypical characteristics of reinfused TIL were similar to those reported in the literature: 97% were CD3 and 92% were CD8. Aspecific cytolytic activity was evaluated on 12 cases whereas, in 2 melanoma cases, autologous tumour tissue was available for the specific cytotoxicity test. Perforin levels in TIL measured at the end of culture were generally high or very high. Cytokine levels were measured on the supernatant at the end of culture, with an estreme variability in results. Finally, delta chain and p56lck were histologically assessed on the resected tissue from which TIL were cultivated. There were virtually none of the former and a complete absence of the latter, which concurs with data reported in the literature. The same immunocytochemical analysis was carried out on TIL at the end of culture. This time an almost complete restoration of both functions was seen, especially in melanoma patients, who are still free from disease. The study is on-going and it has been decided to focus on disease-free patients after metastasectomy in order to increase the number and possibility of clinical and histological correlations.