Rate of entropy model for irreversible processes in living systems.

In living systems, it is crucial to study the exchange of entropy that plays a fundamental role in the understanding of irreversible chemical reactions. However, there are not yet works able to describe in a systematic way the rate of entropy production associated to irreversible processes. Hence, here we develop a theoretical model to compute the rate of entropy in the minimum living system. In particular, we apply the model to the most interesting and relevant case of metabolic network, the glucose catabolism in normal and cancer cells. We show, (i) the rate of internal entropy is mainly due to irreversible chemical reactions, and (ii) the rate of external entropy is mostly correlated to the heat flow towards the intercellular environment. The future applications of our model could be of fundamental importance for a more complete understanding of self-renewal and physiopatologic processes and could potentially be a support for cancer detection.

Spin-Hall nano-oscillator with oblique magnetization and Dzyaloshinskii-Moriya interaction as generator of skyrmions and nonreciprocal spin-waves.

Spin-Hall oscillators (SHO) are promising sources of spin-wave signals for magnonics applications, and can serve as building blocks for magnonic logic in ultralow power computation devices. Thin magnetic layers used as "free" layers in SHO are in contact with heavy metals having large spin-orbital interaction, and, therefore, could be subject to the spin-Hall effect (SHE) and the interfacial Dzyaloshinskii-Moriya interaction (i-DMI), which may lead to the nonreciprocity of the excited spin waves and other unusual effects. Here, we analytically and micromagnetically study magnetization dynamics excited in an SHO with oblique magnetization when the SHE and i-DMI act simultaneously. Our key results are: (i) excitation of nonreciprocal spin-waves propagating perpendicularly to the in-plane projection of the static magnetization; (ii) skyrmions generation by pure spin-current; (iii) excitation of a new spin-wave mode with a spiral spatial profile originating from a gyrotropic rotation of a dynamical skyrmion. These results demonstrate that SHOs can be used as generators of magnetic skyrmions and different types of propagating spin-waves for magnetic data storage and signal processing applications.

Magnetic Radial Vortex Stabilization and Efficient Manipulation Driven by the Dzyaloshinskii-Moriya Interaction and Spin-Transfer Torque.

Solitons are very promising for the design of the next generation of ultralow power devices for storage and computation. The key ingredient to achieving this goal is the fundamental understanding of their stabilization and manipulation. Here, we show how the interfacial Dzyaloshinskii-Moriya Interaction (IDMI) is able to lift the energy degeneracy of a magnetic vortex state by stabilizing a topological soliton with radial chirality, hereafter called radial vortex. It has a noninteger Skyrmion number S (0.5<|S|<1) due to both the vortex core polarity and the magnetization tilting induced by the IDMI boundary conditions. Micromagnetic simulations predict that a magnetoresistive memory based on the radial vortex state in both free and polarizer layers can be efficiently switched by a threshold current density smaller than 10^{6} A/cm^{2}. The switching processes occur via the nucleation of topologically connected vortices and vortex-antivortex pairs, followed by spin-wave emissions due to vortex-antivortex annihilations.

Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma.

BACKGROUND: This expansion cohort of a multicenter, dose-escalation, phase I study (NCT00557856) evaluated safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamic effects of the anti-activin receptor-like kinase-1 (ALK-1) monoclonal antibody PF-03446962 in advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with HCC and disease progression after prior antiangiogenic therapy or intolerance to treatment received PF-03446962 7 mg/kg intravenously biweekly, as recommended in the dose-escalation part of the study. RESULTS: Twenty-four patients received PF-03446962. The most frequent treatment-related adverse events (AEs) were thrombocytopenia (33.3%), asthenia (29.2), and chills (16.7%). Two patients experienced treatment-related telangiectasia, suggesting an in vivo knockout of ALK-1 function through ALK-1 pathway inhibition. Overall, treatment-related grade 3-4 AEs were reported in eight patients (33.3%). Treatment-related grade 3-4 thrombocytopenia was noted in four patients. No complete or partial responses were reported. Twelve (50%) patients achieved stable disease, which lasted ≥12 weeks in seven (29.2%) patients. The median time to progression was 3 months. Biomarker analyses showed higher mean tumor expression of c-tumor mesenchymal-epithelial transition factor and higher mean serum levels of bone morphogenetic protein-9 in patients with disease control (DC) for ≥12 weeks versus patients with disease progression. Conversely, lower mean serum transforming growth factor-ß and vascular endothelial growth factor receptor-3 levels were detected in patients with DC versus patients with progression. CONCLUSIONS: The observed safety, tolerability, pharmacokinetic profile, and clinical activity support further evaluation of PF-03446962 in patients with HCC and other solid malignancies, as single agent or in combination with other antiangiogenic, chemotherapeutic, or immunotherapeutic agents. TRIAL REGISTRATION NUMBER: NCT00557856.

A strategy for the design of skyrmion racetrack memories.

Magnetic storage based on racetrack memory is very promising for the design of ultra-dense, low-cost and low-power storage technology. Information can be coded in a magnetic region between two domain walls or, as predicted recently, in topological magnetic objects known as skyrmions. Here, we show the technological advantages and limitations of using Bloch and Néel skyrmions manipulated by spin current generated within the ferromagnet or via the spin-Hall effect arising from a non-magnetic heavy metal underlayer. We found that the Néel skyrmion moved by the spin-Hall effect is a very promising strategy for technological implementation of the next generation of skyrmion racetrack memories (zero field, high thermal stability, and ultra-dense storage). We employed micromagnetics reinforced with an analytical formulation of skyrmion dynamics that we developed from the Thiele equation. We identified that the excitation, at high currents, of a breathing mode of the skyrmion limits the maximal velocity of the memory.

Outpatient parenteral antibiotic therapy in the elderly: an Italian observational multicenter study.

Bacterial infections are the most frequent cause of hospitalization in elderly patients. In the early eighties, the advantages of Outpatient parenteral Antibiotic therapy (OPAT) were identified in the United States, and suitable therapeutic programs were established. In order to understand the different ways of managing OPAT, a National OPAT Registry was set up in 2003 in Italy. This study analyzes data concerning bacterial infections in 176 elderly patients including demographics, therapeutic management, clinical response, and side-effects. Bone and joint infections (48.9%) and skin and soft tissue infections (27.8%) were the most common infections treated with OPAT. Teicoplanin (28.9%) and ceftriaxone (22.1%) were the top two antibiotics chosen. OPAT was mainly performed at a hospital infusion center (52.8%). The clinical success rate was high and side-effects were low (12.6% of cases). Management of bacterial infections in the elderly with an outpatient program is effective and safe.

Outpatient parenteral antibiotic therapy for bone and joint infections: an italian multicenter study.

In the early eighties, the advantages of outpatient parenteral antibiotic therapy (OPAT) (reduced costs, no hospitalization trauma in children, no immobilization syndrome in elderly, reduction in nosocomial infections by multiresistant organisms) were identified in the United States, and suitable therapeutic programs were established. Currently, more than 250,000 patients per year are treated according to an OPAT program. In order to understand the different ways of managing OPAT and its results, a National OPAT Registry was set up in 2003 in Italy. Analysis of data concerning osteomyelitis, septic arthritis, prosthetic joint infection and spondylodiskitis, allowed information to be acquired about 239 cases of bone and joint infections, with particular concern to demographics, therapeutic management, clinical response, and possible side effects. Combination therapy was the first-line choice in 66.9% of cases and frequently intravenous antibiotics were combined with oral ones. Teicoplanin (38%) and ceftriaxone (14.7%), whose pharmacokinetic/pharmacodynamic properties permit once-a-day administration, were the two top antibiotics chosen; fluoroquinolones (ciprofloxacin and levofloxacin) were the most frequently utilized oral drugs. Clinical success, as well as patients' and doctors' satisfaction with the OPAT regimen was high. Side-effects were mild and occurred in 11% of cases. These data confirm that the management of bone and joint infections in an outpatient setting is suitable, effective and safe.

Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial.

BACKGROUND: Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. METHODS: 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. RESULTS: After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded. CONCLUSIONS: Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.

Birthweight centiles in preterm infants. A new approach.

BACKGROUND: To analyze the birth weight of preterm infants developing a new methodology in order to efficiently collect data. METHODS: We have analyzed the birthweight of 2,482 preterm babies with a gestational age between 24 and 36 weeks admitted to a Neonatal Intensive Care Unit from 1991 to 1998. The gestational age was determined from obstetric data. No selections were performed at the earlier stages of the study by excluding newborns with congenital defects, sepsis, intrauterine growth retardation or obstetric pathologies. More selective criteria were applied at the final stage by using statistical tests. The anomalous and extreme weights for every gestational age were identified with Box and Whisker graphs. The clinical records of these cases were analyzed and their characteristics described but these weights were excluded from the calculation of the percentiles. For each gestational age we evaluated if the weight distribution was assimilable to normal distribution by calculating the kurtosis, asymmetry by applying the Kolmogorov-Smirnov and Shapiro test. RESULTS: In the majority of cases we found a normal weight distribution. CONCLUSIONS: The proposed methodology seems useful in making data collection for preterm centiles calculation simpler. A study of the clinical characteristics of the SGA and LGA identified with the normal procedure or with the proposed method might be useful in validating our approach to the definition of the percentiles.

[Cytomegalovirus infection in the adult]. / Infezione da Cytomegalovirus nell'adulto.

Aim of this report is to review the epidemiological and clinical features of HCMV infection in the adult. In all geographical areas high diffusion of HCMV infection involving all socioeconomic groups is observed; significant most elevated seroprevalence in North African and Asian ethnic groups is compared to Western populations is pointed out; besides, HCMV is absolutely the virus most frequently transmitted in the perinatal period. In the immunocompetent host, the HCMV infection is symptomless in the great majority of cases; in the symptomatic cases it shows the clinical features of a self-limited mononucleosis-like syndrome. In the immunocompromised patients, either in subjects infected with HIV or in onco-hematologic patients or recipients of solid organ or bone marrow transplants patients, HCMV infection leads to serious illness. The most frequent clinical pictures are: pneumonia, retinitis, hepatitis, polyradiculopathy, encephalitis, gastrointestinal tract disease, adrenal involvement; cases of myocarditis, pancreatitis, genitourinary localizations are less frequent. The clinical pictures are different in the different clinical groups: retinitis, in subjects with HIV infection and pneumonia in recipients of transplants, are respectively the main clinical manifestations; the mechanisms of such differences are not clearly defined. A to the diagnosis, the serological tests (evidence of IgM activity, IgG avidity) are useful in the immunocompetent host; whereas, in the immunocompromised host cytological detection (demonstration of typical cytological aspects and positive immunohistology for HCMV antigens) and/or virological detection (isolation of virus or evidence of viral antigens or viral DNA) are needed. The most used therapeutical choices are ganciclovir, foscarnet and cidofovir; these three drugs have similar antiviral effectiveness, but they show different outlines of toxicity and praticality of use.

Cranioectodermal dysplasia: a new patient with an inapparent, subtle phenotype.

Cranioectodermal dysplasia is a rare syndrome characterized by craniofacial and skeletal anomalies and ectodermal dysplasia. Life-threatening associated conditions (i.e., kidney failure and abnormal regulation of the parathyroid-bone axis) can also develop. We report a patient whose features are suggestive of an inapparent, subtle phenotype of the syndrome. The patient is a 4-year-old girl with only dolichocephaly and clinodactyly; microdontia, hypodontia, and taurodontia (i.e., cone-shaped teeth); anteverted nares, full cheeks, and everted lower lip; epicanthal folds, hypertelorism and hyperopia; and corpus callosum hypoplasia. She has no rhizomelic limb shortening or hair abnormalities. In view of the rarity of the cranioectodermal dysplasias, the variability of the phenotype, and the uncertain outcome of some previously described patients, we believe this inapparent, subtle case should reported to enable better understanding and treatment of this rare syndrome.

A genetic model: analysis and application to MAXSAT.

In this paper, a genetic model based on the operations of recombination and mutation is studied and applied to combinatorial optimization problems. Results are: 1. The equations of the deterministic dynamics in the thermodynamic limit (infinite populations) are derived and, for a sufficiently small mutation rate, the attractors are characterized; 2. A general approximation algorithm for combinatorial optimization problems is designed. The algorithm is applied to the Max Ek-Sat problem, and the quality of the solution is analyzed. It is proved to be optimal for k > or = 3 with respect to the worst case analysis; for Max E3-Sat the average case performances are experimentally compared with other optimization techniques.

Autonomic dysfunction in children with Hirschsprung's disease.

During embryogenesis, two different transmembrane receptors, Ret and Ednrb, together with their ligands, respective, GDNF and endothelin-3, are involved in the migration and differentiation of enteric ganglion cells, sympathetic neurons and melanocytes from the neural crest. Mutations in these genes have been found in a number of human and murine neurocristopathies, including Hirschsprung's disease. RET and GDNF knockouts suggest that they are involved in a correct autonomic nervous system formation. The aim of this study is the evaluation of the autonomic nervous system in patients with Hirschsprung's disease. Seventeen children (mean age: 8.6 years) with Hirschsprung's disease and 19 age- and sex-matched control children (mean age: 9.9 years) underwent pupillary and cardiovascular testing of sympathetic adrenergic and cholinergic function and cardiovagal cholinergic function. Seven of 17 patients with Hirschsprung's disease were affected by autonomic dysfunction. Three of seven patients had evidence of sympathetic denervation, two showed a parasympathetic dysfunction, whereas the remaining two had dysfunction of both sympathetic and parasympathetic tests. Our data in a small number of patients with Hirschsprung's disease show that a subset of these patients exhibits measurable autonomic dysfunction. A RET mutation has been found in one of them. As for the absence of the enteric ganglion cells, autonomic dysfunction in these subjects seems to be polygenic.

Cell-specific transcriptional regulation and reactivation of galectin-1 gene expression are controlled by DNA methylation of the promoter region.

The galectin-1 gene is developmentally regulated gene whose activity is strongly modulated during cell differentiation and transformation. We have previously shown that galectin-1 promoter constructs are highly active when transiently transfected in cells both expressing and not expressing the endogenous gene and that the basal activity is determined by a small region encompassing the transcription start site (from positions -50 to +50). We have now investigated the role of DNA methylation in galectin-1 gene expression. Southern blot analysis with HpaII and MspI endonucleases and sodium bisulfite analysis of genomic DNA from expressing and nonexpressing cell lines and cell hybrids showed a close correlation between gene activity and demethylation of the 5' region of the galectin-1 gene. We found that the galectin-1 promoter region is fully methylated, at every CpG site on both strands, in nonexpressing differentiated rat liver (FAO) and thyroid (PC C13) cells and unmethylated in the expressing undifferentiated liver (BRL3A) and thyroid transformed (PC myc/raf) cell lines. In addition, reactivation of the silent FAO alleles in FAO-human osteosarcoma (143tk-) hybrid cells is accompanied by a complete demethylation of the promoter region. Finally, when galectin-1 chloramphenicol acetyltransferase (CAT) promoter constructs were methylated in vitro by SssI methylase at every cytosine residue of the CpG doublets and transfected into mouse fibroblasts, the transcription of the CAT reporter gene was strongly inhibited.

[Posterior cranial fossa hemorrhage in term newborn infants: clinical and ultrasonographic aspects in 2 cases]. / L'emorragia della fossa cranica posteriore nel neonato a termine: aspetti clinici ed ecografici di due casi.

Haemorrhages of the posterior cranial fossa were diagnosed by cerebral sonography, sometimes these lesions were misinterpreted by the examination. We report two cases of posterior fossa haemorrhages in the term newborn without ultrasonography signs of this pathology. In a case some days after haemorrhagical damage, the signs of past haemorrhage were demonstrated.

A study of the effects of rifabutin on isoniazid pharmacokinetics and metabolism in healthy volunteers.

The effect of repeated administration of rifabutin on the pharmacokinetics and metabolism of isoniazid was evaluated in 6 healthy volunteers. The subjects received on day 1 and 9 a single oral dose of 300 mg isoniazid and from day 2 to 8 a single daily oral dose of 300 mg rifabutin. Two out of 6 subjects were shown to be rapid acetylators. No significant modification of the plasma pharmacokinetic profiles of isoniazid and acetylisoniazid was found. Evidence exists in the present study for autoinduction of rifabutin metabolism; this is shown by the lower plasma concentrations obtained 24 h after the seventh dose as compared to the theoretical concentrations.

Effect of ergolines on neurotransmitter systems in the rat brain.

The interaction of nicergoline with various monoaminergic receptors and its effects on monoamine turnover were studied in specific rat brain areas in comparison with those of its metabolites, 10-methoxy-1,6-dimethyl-ergoline-8 beta-methanol (MMDL) and 10-methoxy-6-methyl-ergoline-8 beta-methanol (MDL). Nicergoline showed marked in vitro affinity for alpha 1-noradrenergic receptors (IC50 = 0.2 nM), less for alpha 2, S1 and S2 (IC50 about 10(-7) M). Its strong interaction with alpha 1-receptors was confirmed in vivo. The affinity of the other ergolines for alpha 1-receptors was lower than that of nicergoline. The level of monoamine metabolites (HVA and DOPAC for dopamine, MOPEG-SO4 for noradrenaline and 5-HIAA for serotonin) was taken as a measure of their turnover in the rat brain. A single dose of nicergoline (20 mg/kg, s.c.) strongly enhanced noradrenaline turnover, less that of dopamine. These effects, probably due to the interaction with alpha-receptors, were more marked after parenteral than oral administration. MMDL shared nicergoline's effect on dopamine and MDL that on noradrenaline, but they were less active than the parent compound. The most interesting results were obtained after chronic treatment (6-7 weeks) with rather low doses: 5 mg/kg b.i.d. of nicergoline and equimolar doses of the metabolites. Nicergoline and MMDL both enhanced dopamine turnover, especially in mesolimbic areas. In conclusion, the present report confirms and extends previous results on nicergoline's effects on catecholamine turnover and shows that its metabolite MMDL shares its effects on dopamine. Finally, it is particularly interesting that both ergolines were more effective in old than in young rats.

Receptor adaptive responsiveness in disease models: 6-OHDA lesioned and spontaneously hypertensive rats.

We have examined the adaptive modifications of brain monoamine receptors in response to pathophysiological processes in animal disease models: 6-OHDA lesioned and spontaneously hypertensive rats (SHR). The two models share a similar increase in D-1 receptor densities, while noradrenergic receptors are affected in different way: alpha-1 and beta are supersensitive in 6-OHDA lesioned rats and only alpha-2 are increased in SHR. S-1 receptors too are up-regulated in SHR. We must notice that though receptor hypersensitivity in the 6-OHDA model is linked to massive decreases in neurotransmitter levels, this mechanism seems not to exist in the SHR model.