Improving performance of 3D speckle tracking in arterial hypertension and paroxysmal atrial fibrillation by using novel strain parameters.

The function of left atrium (LA) is closely related to LA remodeling and one of the most important mechanisms is an increased deposition of fibrous tissue that often is the basis for LA electro-mechanical changes before the onset of atrial fibrillation (AF). This study evaluated LA shape and function, by investigating standard and novel strain parameters calculated by a new approach based on homologous times derived from 3D speckle tracking echocardiography (3DSTE) in hypertensive (HT) and paroxysmal atrial fibrillation (PAF) patients with or without left ventricular hypertrophy (LVH), compared to control (C) subjects. LA function was assessed using homologous times to compare strain variables among different individuals, acquired at different physiological time periods. Standard global longitudinal (GLS) and circumferential (GCS) strains were measured at peak of atrial diastole, while longitudinal and circumferential strains (GLSh, GCSh), strain rate (GLSr, GCSr), volume (Vh) and volume rate (Vr) were measured during the atrial telediastolic phase (fifth homologous time) and atrial pre-active phase (tenth homologous time). Using ANOVA, we found an impaired LA deformation detected by standard, interpolated strains and strain rates in both HT and PAF groups compared to C. We also performed ROC analysis to identify different performances of each parameter to discriminate groups (GLSr10 + GCSr10: C vs PAF 0.935; C vs PAF_LVH 0.924; C vs HT_LVH 0.844; C vs HT 0.756). Our study showed anatomical and functional LA remodeling in patients with PAF and HT. 3D strains and strain rates derived from the homologous times approach provide more functional information with improved performance to identify among the explored groups, in particular PAF patients.

The conceptual framework of ontogenetic trajectories: parallel transport allows the recognition and visualization of pure deformation patterns.

Ontogeny is usually studied by analyzing a deformation series spanning over juvenile to adult shapes. In geometric morphometrics, this approach implies applying generalized Procrustes analysis coupled with principal component analysis on multiple individuals or multiple species datasets. The trouble with such a procedure is that it mixes intra- and inter-group variation. While MANCOVA models are relevant statistical/mathematical tools to draw inferences about the similarities of trajectories, if one wants to observe and interpret the morphological deformation alone by filtering inter-group variability, a particular tool, namely parallel transport, is necessary. In the context of ontogenetic trajectories, one should firstly perform separate multivariate regressions between shape and size, using regression predictions to estimate within-group deformations relative to the smallest individuals. These deformations are then applied to a common reference (the mean of per-group smallest individuals). The estimation of deformations can be performed on the Riemannian manifold by using sophisticated connection metrics. Nevertheless, parallel transport can be effectively achieved by estimating deformations in the Euclidean space via ordinary Procrustes analysis. This approach proved very useful in comparing ontogenetic trajectories of species presenting large morphological differences at early developmental stages.

Non-invasive assessment of functional strain lines in the real human left ventricle via speckle tracking echocardiography.

A mechanics-based analysis of data from three-dimensional speckle tracking echocardiography is proposed, aimed at investigating deformations in myocardium and at assessing shape and function of distinct strain lines corresponding to the principal strain lines of the cardiac tissue. The analysis is based on the application of a protocol of measurement of the endocardial and epicardial principal strain lines, which was already tested on simulated left ventricles. In contrast with similar studies, it is established that endocardial principal strain lines cannot be identified with any structural fibers, not even along the systolic phase and is suggested that it is due to the capacity of the endocardial surface to contrast the dilation of the left ventricle.

The evolution of allergen immunotherapy from empirical desensitization to immunological treatment.

In its century-long history, allergen immunotherapy (AIT), has shown continuous evolution in terms of the materials and the treatment schedules used, the adequate duration, and the mechanisms of action underlying its clinical efficacy. The passage from the empirical phase of AIT to the era of evidence-based medicine (EBM) was associated with achievement of the highest levels of evidence. This regarded both forms of AIT currently used, represented by subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). In particular, SLIT tablet preparations of pharmaceutical quality provided physicians and patients a treatment whose efficacy had been confirmed with the highest level of scientific evidence and improved the credibility of AIT for the entire medical field. However, further advances are needed for AIT in terms of optimal patient selection and the required dosage, as well as the quality and composition of the allergen extracts, factors favouring compliance, and the most appropriate duration capable of maintaining the clinical benefit over time.

Rapid action in the Palaeogene, the relationship between phenotypic and taxonomic diversification in Coenozoic mammals.

A classic question in evolutionary biology concerns the tempo and mode of lineage evolution. Considered variously in relation to resource utilization, intrinsic constraints or hierarchic level, the question of how evolutionary change occurs in general has continued to draw the attention of the field for over a century and a half. Here we use the largest species-level phylogeny of Coenozoic fossil mammals (1031 species) ever assembled and their body size estimates, to show that body size and taxonomic diversification rates declined from the origin of placentals towards the present, and very probably correlate to each other. These findings suggest that morphological and taxic diversifications of mammals occurred hierarchically, with major shifts in body size coinciding with the birth of large clades, followed by taxonomic diversification within these newly formed clades. As the clades expanded, rates of taxonomic diversification proceeded independently of phenotypic evolution. Such a dynamic is consistent with the idea, central to the Modern Synthesis, that mammals radiated adaptively, with the filling of adaptive zones following the radiation.

Testing convergent and parallel adaptations in talpids humeral mechanical performance by means of geometric morphometrics and finite element analysis.

The shape and mechanical performance in Talpidae humeri were studied by means of Geometric Morphometrics and Finite Element Analysis, including both extinct and extant taxa. The aim of this study was to test whether the ability to dig, quantified by humerus mechanical performance, was characterized by convergent or parallel adaptations in different clades of complex tunnel digger within Talpidae, that is, Talpinae+Condylura (monophyletic) and some complex tunnel diggers not belonging to this clade. Our results suggest that the pattern underlying Talpidae humerus evolution is evolutionary parallelism. However, this insight changed to true convergence when we tested an alternative phylogeny based on molecular data, with Condylura moved to a more basal phylogenetic position. Shape and performance analyses, as well as specific comparative methods, provided strong evidence that the ability to dig complex tunnels reached a functional optimum in distantly related taxa. This was also confirmed by the lower phenotypic variance in complex tunnel digger taxa, compared to non-complex tunnel diggers. Evolutionary rates of phenotypic change showed a smooth deceleration in correspondence with the most recent common ancestor of the Talpinae+Condylura clade.

The role of post-natal ontogeny in the evolution of phenotypic diversity in Podarcis lizards.

Understanding the role of the developmental pathways in shaping phenotypic diversity allows appreciating in full the processes influencing and constraining morphological change. Podarcis lizards demonstrate extraordinary morphological variability that likely originated in short evolutionary time. Using geometric morphometrics and a broad suite of statistical tests, we explored the role of developmental mechanisms such as growth rate change, ontogenetic divergence/convergence/parallelism as well as morphological expression of heterochronic processes in mediating the formation of their phenotypic diversity during the post-natal ontogeny. We identified hypermorphosis - the prolongation of growth along the same trajectory - as the process responsible for both intersexual and interspecific morphological differentiation. Albeit the common allometric pattern observed in both sexes of any species constrains and canalizes their cephalic scales variation in a fixed portion of the phenotypic space, the extended growth experienced by males and some species allows them to achieve peramorphic morphologies. Conversely, the intrasexual phenotypic diversity is accounted for by non-allometric processes that drive the extensive morphological dispersion throughout their ontogenetic trajectories. This study suggests a model of how simple heterochronic perturbations can produce phenotypic variation, and thus potential for further evolutionary change, even within a strictly constrained developmental pathway.

The solitary fibrous malignant tumour of the kidney: clinical and pathological considerations on a case revisiting the literature.

The solitary fibrous tumours (SFT) are rare spindle cell neoplasms which generally originate from the pleura; also described are cases of SFT in other locations, included the genital-urinary tract. Described in the ambit the kidney are 19 cases of SFT and such rarity of localisation makes rather unknown the histogenesis and the prognosis of the lesion. We report the case of a 72 year old lady who attended our Unit for a mass which was clinically palpable at the level of the left hemiabdomen. Following an abdominal ultrasound scan a neoformation was highlighted which a successive tomodensitographic test indicated as being of likely pertinence of the middle third of the left kidney; the mass had a diameter of approximately 19 cm. A radical nephrectomy has been conducted. The histological examen highlighted a solitary fibrous tumour: the presence of hypercellularity, of cellular pleiomorphism and of a high number of mitosis has led to a histopathological diagnosis of malignancy of the neoplasm under examination. Departing from this case a review of the literature is carried out. The SFT of the kidney can have an aggressive character and more the present has hystopathological characters and clinical results are still rather unknown.

Low cadmium concentration in whole blood from residents of northern Sardinia (Italy) with special reference to smoking habits.

INTRODUCTION: The present study was initiated to investigate the cadmium concentrations in whole blood of Northern Sardinian, non-occupationally exposed adult subjects. Sardinia is a large Italian island which differs genetically and environmentally from other mainland Italian areas. METHODS: Two hundred and forty-three adults (157 females and 86 males) were selected in the study area from subjects who were undergoing blood collection for laboratory analysis during the period January 2005-May 2005. Whole blood was analysed by graphite furnace atomic absorption spectrometer equipped with a Zeeman-effect background corrector (Perkin Elmer ZLS5100) and an auto sampler. The adopted analytical procedure uses the Stabilized Platform Temperature Furnace (STPF) technique. RESULTS: The mean value of Blood Cadmium Concentration (BCdC), expressed as Geometric Mean, was 0.32 pg/l (CI 95%: 0.31-0.34 l) in non-smokers to 034 pg/l (CI 95%: 0.30-0.39 pg/l) in ex-smokers up to 0.47 gg/ll(CI 95%: 0.42-0.53 pg/l) in smokers (p < 0.0001). DISCUSSION: The results show that BCdC levels in Northern Sardinian non-occupationally exposed adults are lower than levels found in many other regions, including those within Italy. Nevertheless, similar values have been detected in other European countries and cities. CONCLUSIONS: In relation to other reports in which data were analysed by strata for smoking habit and age, we found similar BCdC values among non smokers. However, Sardinian smokers seem to show lower levels of blood cadmium.

Testing evolutionary stasis and trends in first lower molar shape of extinct Italian populations of Terricola savii (Arvicolidae, Rodentia) by means of geometric morphometrics.

Extinct populations of Terricola savii have been investigated in order to analyse evolutionary stasis and correlation of first lower molar shape with climatic proxies by means of geometric morphometrics. Evolutionary stasis, its recognition and explanation are central topics in evolutionary paleobiology. In this study, tooth shape variation of the arvicolid T. savii has been analysed through time. In addition to explicit multivariate tests of stasis based on landmark and semi-landmark geometric morphometrics, first lower molar M(1) shape has been decomposed in orthogonal axes of variation and tested for correlation with climate changes. Multivariate tests were consistent with evolutionary stasis. Yet, according to univariate tests, the dominant dimension of shape variation shows a temporal trend well correlated with a climatic proxy, i.e. delta(18)O. The remaining variation does not show any trend. Adaptation to current climatic condition might occur even without affecting shape as a whole. Phenotypic plasticity of this species could be invoked to explain evolutionary stasis, as a long time pattern.

[Solitary fibrous tumor of the kidney. A propos of a case].

Solitary Fibrous Tumors (SFT) are rare spindle cell neoplasm that typically originate from the pleura. However, cases of the SFT are described with origin in other organs, including the urinary and genital apparatus. Within the kidney, except from the renal pelvis, only 19 cases of SFT are described and such rarity of localization makes the histogenesis and the prognosis of the tumor rather unknown. We report the case of a 72-year-old lady who attended our Unit for a mass that was clinically palpable at the level of the left hemiabdomen. The tomodensitographic test indicated a 19cm-diameter mass of likely pertinence of the middle bystender of the left kidney. She had undergone left radical nephrectomy. The histological examination highlighted a solitary fibrous tumor (SFT): the presence of hypercellularity, of cellular pleiomorphism and of a high number of mitosis has led to a histological diagnosis of malignancy for the neoplasm analyzed. The SFT are of rare clinical comparison: this does not allow for a deep knowledge of the lesion histogenesis and prognosis; moreover, the clinical behavior should be more precisely defined.

[Scrotal masses: considerations on two cases of epididymal tumors].

The scrotum is a fibromuscular sac that contains the testis, epididymis, spermatic cord and the associated fibrous coatings. All these components can be affected by different variety of pathologic phenomena, including congenital, inflammatory and neoplastic events. When a scrotal mass is observed, there are two basic questions to be answered, i.e. if the mass is intratesticular or extratesticular, and if it is of cystic or solid nature. Apart from a few rare exceptions, intratesticular solid masses should be considered malignant, while extratesticular masses with liquid content are generally benign. CASE REPORTS. Two cases of tumor are hereby presented: they originated from the epididymis, and their clinical presentations did not allow making a differential diagnosis between benign and malignant tumor during the preoperative examinations. After presenting the diagnostic doubts to patients, and once obtained their informed consent, surgeries were performed allowing for a precise histological diagnosis, and at the same time, proving to be also valid therapeutic tools.

First direct detection of rickettsial pathogens and a new rickettsia, 'Candidatus Rickettsia barbariae', in ticks from Sardinia, Italy.

The present study evaluated the molecular detection and identification of Rickettsia species in 83 ticks collected in Sardinia, Italy. Fifteen ticks were PCR-positive using gltA-specific and ompA-specific primers, leading to the identification of Rickettsia aeschlimannii in Hyalomma marginatum marginatum, R. massiliae in Rhipicephalus turanicus and in Rhipicephalus sanguineus, and a new rickettsia, previously referred to as PoTiRb169 in Portugal, in four Rhipicephalus turanicus. This new species was further characterized by amplification and sequencing of three additional genes (ompB, sca4 and rrs). Using the current criteria to name a rickettsia, this uncultivated rickettsia can be given a Candidatus status, and we propose to call it 'Candidatus Rickettsia barbariae'. The detection of three tick-borne rickettsiae in Sardinia raises the possibility that many cases of spotted fever considered by clinicians and health authorities as Mediterranean spotted fever due to R. conorii could, in fact, be due to other rickettsiae, including those found in this study. Analysing skin biopsies of inoculation eschars in patients with spotted fever would be, together with continuing entomological surveys, the best way to increase our knowledge of tick-borne rickettsioses in Sardinia and more generally in the Mediterranean basin.

[A case of particular diffusion of prostate cancer].

Neoplastic diffusion can occur due to dissemination, continuity, through lymphatic or haematic vessels, or, more rarely originate from surgical instruments. We report a particular case of prostate cancer spread. A 64-year-old man was diagnosed with undifferentiated prostate cancer through prostate biopsy. The patient was treated with a total androgenic block allowing a decrease in PSA blood level. The patient, wishing to regain his sexual activity compromised by hormonal therapy, interrupted the treatment spontaneously and unchecked. 19 months later he contacted us again: we had to hospitalize him due to a 12-hour anuresis. A urgent right transcutaneous nephrostomy was carried out, yielding an improvement in the patient's condition. A descending pyelography carried out by means of nephrostomy revealed a completely reduced urethral lumen. During the following surgery for transcutaneous urinary derivation we observed the two ureters entangled in whitish tissue, spreading bilaterally up to the renal pelvis. The histological examination of tissue samples showed the presence of neoplastic metastasis of prostatic origin. We assume that this neoplastic diffusion has occurred due to permeability through the lymphatic vessels of the urethral wall, producing a subsequent neoplasm growth: this has been limited by the urethral connective sheath, thus preventing its wide diffusion to the surrounding tissues, but fostering its spreading upwards along the ureter pathway.

Pharmacoeconomics of subcutaneous allergen immunotherapy.

The current burden of allergic diseases, estimated by both direct and indirect costs, is very relevant. In fact the cost estimation for rhinitis amount globally to 4-10 billion dollars/year in the U.S. and to an average annual cost of 1089 euros per child/adolescent and 1543 euros per adult in Europe. The estimated annual costs in Northern America for asthma amounted to 14 billion dollars. Consequently, preventive strategies aimed at reducing the clinical severity of allergy are potentially able to reduce its costs. Among them, specific immunotherapy (SIT) joins to the preventive capacity the carryover effect once treatment is discontinued. A number of studies, mainly conducted in the US and Germany demonstrated a favourable cost-benefit balance. In the nineties, most surveys on patients with allergic rhinitis and asthma reported significant reductions of the direct and indirect costs in subjects treated with SIT compared to those treated with symptomatic drugs. This is fully confirmed in recent studies conducted in European countries: in Denmark the direct cost per patient/year of the standard care was more than halved following SIT; in Italy a study on Parietaria allergic patients demonstrated a significant difference in favor of SIT plus drug treatment for three years versus drug treatment alone, with a cost reduction starting from the 2nd year and increasing to 48% at the 3rd year, with a highly statistical significance which was maintained up to the 6th year, i.e. 3 years after stopping immunotherapy, corresponding to a net saving for each patient at the final evaluation of 623 euros per year; in France a cost/efficacy analysis comparing SIT and current symptomatic treatment in adults and children with dust mite and pollen allergy showed remarkable savings with SIT for both allergies in adults and children.

Economic evaluation of sublingual immunotherapy: an analysis of literature.

Allergic rhinitis and asthma constitute a global health problem because of their very high prevalence and the consequent burden of disease, concerning medical and economical issues. Among the treatments of allergy, specific immunotherapy has the capacity to favourably alter the natural history of the disease both during and after its performance and thus to reduce the direct and indirect costs of allergic rhinitis and asthma. A number of studies reported such cost reduction for traditional, subcutaneous immunotherapy and recent data demonstrate that also sublingual immunotherapy (SLIT) is associated to economic advantages and/or monetary savings, specifically in terms of reduction of disease economic burden. Only few formal economic assessments of SLIT have been carried out so far, this article will present and discuss the published studies addressed to this issue. The data obtained, although the number of studies is still limited, provide preliminary evidence supporting a SLIT effect on sparing costs for respiratory allergy.

Practice parameters for sublingual immunotherapy.

The efficacy and safety of sublingual immunotherapy (SLIT) are currently supported by clinical trials, meta-analysis and post-marketing surveys. Practice parameters for clinical use of SLIT are proposed here by a panel of Italian specialists, with reference to evidence based criteria. Indications to SLIT include allergic rhinoconjunctivitis, asthma, and isolated conjunctivitis (strength of recommendation: grade A). As to severity of the disease, SLIT is indicated in moderate/severe intermittent rhinitis, persistent rhinitis and mild to moderate asthma (grade D). SLIT may be safely prescribed also in children aged three to five years (grade B), and its use in subjects aged more than 60 years is not prevented when the indications and contraindication are ascertained (grade D). The choice of the allergen to be employed for SLIT should be made in accordance with the combination of clinical history and results of skin prick tests (grade D). Polysensitisation, i.e. the occurrence of multiple positive response does not exclude SLIT, which may be done with the clinically most important allergens (grade D). As to practical administration, co-seasonal, pre co-seasonal, and continuous schedules are available, being the latter recommended for perennial allergens or for pollens with particularly prolonged pollination, such as Parietaria (grade D). For pollens with relatively short pollination, such as grasses and trees (cypress, birch, alder, hazelnut, olive) the pre co-seasonal and perennial schedules are preferred (grade C). The build-up phases suggested by manufacturers can be safely used (grade A), but they can be modified according to the patient's tolerance (grade C). A duration of SLIT of 3-5 years is recommended to ensure a long-lasting clinical effect after the treatment has been terminated (grade C).

[Anti-HLA antibodies in nephropathic patients]. / Rilevazione di anticorpi anti HLA con nuova metodica citofluorimetrica in una casistica di pazienti nefropatici candidati al trapianto.

BACKGROUND: The presence of anti-human leukocyte antigen (HLA) alloantibodies in nephropathic patients is due to immunogenic stimuli such as transfusions, pregnancies, and transplantations. These stimuli can be highlighted using a classic aspecific serologic technique, such as complement-dependent cytotoxicity (CDC) or using more recent and specific techniques, such as cytofluorimetrics or enzyme linked immunoabsorbant assay (ELISA). Because the presence of anti-HLA preformed antibodies is linked to the largest incidence of both acute and chronic rejection, it seems appropriate to re-evaluate that data obtained using aspecific classic serological analysis techniques by using the more specific cytofluorimetric technique. To aid in the possible prevention of ant-HLA antibody formation, it is also appropriate to analyze the influence of immunogenic stimuli on the development of these antibodies. METHODS: We studied 116 patients (37 women and 79 men). Anti-HLA antibodies were detected using microlymphotoxic technique after separation of B and T lymphocytes. This separation was obtained using magnetic balls. We used a 30-cell panel. We also used a recent cytofluorimetric test (Flow Pra screening; One Lambda Inc., 21001 Kittridge St., Canoga Park, California, U.S.A.) with a panel of micrograins covered with class I and class II purified antigens. Statistical analysis was performed using chi-square analysis or Fischer s exact test. For each test, sensibility, specificity, and positive and negative value were measured. RESULTS: Among 33 patients testing positive using the classic CDC-PRA technique (17 positive for B-lymphocytes and 16 positive for both B and T lymphocytes), using cytometry, 25 were positive for anti-HLA-specific antibodies (10 among the B lymphocyte-positive patients and 15 among the B + T lymphocyte-positive patients). Two patients were shown positive only using the cytofluorimetric method. Of the 27 patients positive at cytometry, 18 were positive for class I and class II, 4 for class I, and 5 for class II. FLOW-PRA screening results were less sensitive and more specific. The results obtained by the two methods are comparable(p<0.0001). The immunogenic stimuli found responsible for immunization were: transfusion in 10 of 25 patients, pregnancies in 3/9 patients, transplant in 4/8 patients, and different immunogenic stimuli in 10/12 patients. The results were not statistically significant (p>0.05). CONCLUSIONS: Data show that positivity for B lymphocytes obtained using CDC-PRA is not always linked to the development of anti-HLA antibodies, whereas positivity for B+T lymphocytes, obtained using CDC -PRA, is often linked to specific antibody development. Immune response is more often directed against class I and II antibodies. The specific detection of HLA antibodies using the cytofluorimetric method allows us to identify patients at risk for rejection, and it suggests that red cells should be filtrated to prevent anti-HLA immunization secondary to transfusion in transplantation candidates.

First stereocontrolled synthesis of (S)-cleonin and related cyclopropyl-substituted amino acids.

[reaction: see text]. Enantiomerically pure (S)-cleonin, a key component of the antitumor antibiotic cleomycin, was prepared starting from (R)-serine. The Kulinkovich cyclopropanation of the methyl ester of N-Cbz serine acetonide gave the hydroxycyclopropyl moiety. The amino alcohol region was further oxidized to amino acid. The Kulinkovich cyclopropanation allowed also the preparation of other non-natural substituted cyclopropylglycines.