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In this paper we address the multiple obnoxious facility location problem. In this problem p facilities need to be spread within the unit square in such a way that they are far enough from each other and that their minimal distance from n communities, with known positions within the unit square, is maximized. The problem has a combinatorial component, related to the key observation made in Drezner (Omega 87:105–116, 2019) about the role played by Voronoi points. We propose a new approach, which exploits both the combinatorial component of the problem and, through continuous local optimizations, also its continuous component. We also propose techniques to limit the impact on computation times of the number n of communities. The approach turns out to be quite competitive and is able to return 24 new best known solutions with respect to the best results reported in Kalczynski (Optim Lett 16:1153–1166, 2022). [ABSTRACT FROM AUTHOR]

The convex envelope value for a given function f over a region X at some point x ∈ X can be derived by searching for the largest value at that point among affine underestimators of f over X. This can be computed by solving a maximin problem, whose exact computation, however, may be a hard task. In this paper we show that by relaxation of the inner minimization problem, duality, and, in particular, by an enlargement of the class of underestimators (thus, not only affine ones) an easier derivation of good convex understimating functions, which can also be proved to be convex envelopes in some cases, is possible. The proposed approach is mainly applied to the derivation of convex underestimators (in fact, in some cases, convex envelopes) in the quadratic case. However, some results are also presented for polynomial, ratio of polynomials, and some other separable functions over regions defined by similarly defined separable functions. [ABSTRACT FROM AUTHOR]

In this work we present some exactness conditions for the Shor relaxation of diagonal (or, more generally, diagonalizable) QCQPs, which extend the conditions introduced in different recent papers about the same topic. It is shown that the Shor relaxation is equivalent to two convex quadratic relaxations. Then, sufficient conditions for the exactness of the relaxations are derived from their KKT systems. It will be shown that, in some cases, by this derivation previous conditions in the literature, which can be viewed as dual conditions, since they only involve the Lagrange multipliers appearing in the KKT systems, can be extended to primal-dual conditions, which also involve the primal variables appearing in the KKT systems. [ABSTRACT FROM AUTHOR]

We introduce a variant of the Shortest Path Problem (SPP), in which we impose additional constraints on the acceleration over the arcs, and call it Bounded Acceleration SPP (BASP). This variant is inspired by an industrial application: a vehicle needs to travel from its current position to a target one in minimum-time, following pre-defined geometric paths connecting positions within a facility, while satisfying some speed and acceleration constraints depending on the vehicle position along the currently traveled path. We characterize the complexity of BASP, proving its NP-hardness. We also show that, under additional hypotheses on problem data, the problem admits a pseudo-polynomial time-complexity algorithm. Moreover, we present an approximation algorithm with polynomial time-complexity with respect to the data of the original problem and the inverse of the approximation factor ϵ . Finally, we present some computational experiments to evaluate the performance of the proposed approximation algorithm. [ABSTRACT FROM AUTHOR]

In this paper we consider Quadratic Programming (QP) problems with general linear constraints. We show, through a computational investigation, that a careful selection of a suitable reformulation of such problems, together with the related relaxation, and an intensive application of bound tightening are simple but very effective ingredients in order to make a standard branch and bound approach very competitive and in some cases able to outperform even well known commercial solvers. [ABSTRACT FROM AUTHOR]

In this paper we describe how to derive the convex envelope of a function f over the n-dimensional unit simplex Δ n at different levels of detail, depending on the properties of function f, by starting from its definition as the supremum of all the affine underestimators of f over Δ n . At the first level we are able to derive the closed-form formula of the convex envelope. At the second level we are able to derive the exact value of the convex envelope at some point x ∈ Δ n , and a supporting hyperplane of the convex envelope itself at the same point, by solving a suitable convex optimization problem. Finally, at the third level we are able to derive an underestimating value which differs from the exact value of the convex envelope at some point x ∈ Δ n by at most a given threshold δ . The underestimation is obtained by solving a suitable LP problem and may lead also to a convex piecewise linear underestimator of f. [ABSTRACT FROM AUTHOR]

Metformin is the largest drug produced globally in metric tons. It has been reported in many water treatment plants and water resources. The analysis of metformin at trace level is important before supplying water to the communities. The present article describes solid-phase micromembrane tip extraction and capillary electrophoretic methods for the analysis of metformin in water using multi-walled carbon nanotubes as a sorbent in the sample preparation method. The maximum extraction of metformin was achieved at 10.0 mg/L metformin, 25 shaking time, 0.5 g/L CNTs dose, 7.0 sorption pH, 30-min desorption time and 12 desorption pH. The migration time of metformin was 8.4 min with 2.0 × 10–4, 1.35 × 10–4 and 15,600 as electrophoretic mobility (cm2V−1 s−1), electroosmotic mobility (cm2V−1 s−1) and the number of theoretical plates. These solid-phase micromembrane tip extraction and capillary electrophoretic methods were highly applicable to monitor metformin in the wastewater. The reported methods are efficient, reproducible and useful for the estimation of metformin in water and may be exploited for the analysis of the metformin water resource. [ABSTRACT FROM AUTHOR]

In this paper we address game theory problems arising in the context of network security. In traditional game theory problems, given a defender and an attacker, one searches for mixed strategies which minimize a linear payoff functional. In the problems addressed in this paper an additional quadratic term is added to the minimization problem. Such term represents switching costs, i.e., the costs for the defender of switching from a given strategy to another one at successive rounds of a Nash game. The resulting problems are nonconvex QP ones with linear constraints and turn out to be very challenging. We will show that the most recent approaches for the minimization of nonconvex QP functions over polytopes, including commercial solvers such as CPLEX and GUROBI, are unable to solve to optimality even test instances with n = 50 variables. For this reason, we propose to extend with them the current benchmark set of test instances for QP problems. We also present a spatial branch-and-bound approach for the solution of these problems, where a predominant role is played by an optimality-based domain reduction, with multiple solutions of LP problems at each node of the branch-and-bound tree. Of course, domain reductions are standard tools in spatial branch-and-bound approaches. However, our contribution lies in the observation that, from the computational point of view, a rather aggressive application of these tools appears to be the best way to tackle the proposed instances. Indeed, according to our experiments, while they make the computational cost per node high, this is largely compensated by the rather slow growth of the number of nodes in the branch-and-bound tree, so that the proposed approach strongly outperforms the existing solvers for QP problems. [ABSTRACT FROM AUTHOR]

Summary: We have calculated the biological variation (BV) of different bone metabolism biomarkers on a large, well-described cohort of subjects. BV is important to calculate reference change value (or least significant change) which allows evaluating if the difference observed between two consecutive measurements in a patient is biologically significant or not. Introduction: Within-subject (CVI) and between-subject (CVG) biological variation (BV) estimates are essential in determining both analytical performance specifications (APS) and reference change values (RCV). Previously published estimates of BV for bone metabolism biomarkers are generally not compliant with the most up-to-date quality criteria for BV studies. We calculated the BV and RCV for different bone metabolism markers, namely β-isomerized C-terminal telopeptide of type I collagen (β-CTX), N-terminal propeptide of type I collagen (PINP), osteocalcin (OC), intact fibroblast growth factor 23 (iFGF-23), and uncarboxylated-unphosphorylated Matrix-Gla Protein (uCuP-MGP) using samples from the European Biological Variation Study (EuBIVAS). Methods: In the EuBIVAS, 91 subjects were recruited from six European laboratories. Fasting blood samples were obtained weekly for ten consecutive weeks. The samples were run in duplicate on IDS iSYS or DiaSorin Liaison instruments. The results were subjected to outlier and variance homogeneity analysis before CV-ANOVA was used to obtain the BV estimates. Results: We found no effect of gender upon the CVI estimates. The following CVI estimates with 95% confidence intervals (95% CI) were obtained: β-CTX 15.1% (14.4–16.0%), PINP 8.8% (8.4–9.3%), OC 8.9% (8.5–9.4%), iFGF23 13.9% (13.2–14.7%), and uCuP-MGP 6.9% (6.1–7.3%). Conclusions: The EuBIVAS has provided updated BV estimates for bone markers, including iFGF23, which have not been previously published, facilitating the improved follow-up of patients being treated for metabolic bone disease. [ABSTRACT FROM AUTHOR]

The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS. [ABSTRACT FROM AUTHOR]

In western countries, the process of 'ageing of the population' is increasingly forcing clinical medicine to find answers for pathologies affecting the elder segments of our community. In this respect, pituitary adenomas often raise difficult questions on surgical indications, since little is known about postoperative morbidity and mortality in elderly patients. The transsphenoidal endonasal approach (TNS), which is considered the gold standard for surgical resection of the majority of functioning and non-functioning pituitary adenomas, is supposed to be a low morbidity and mortality procedure in adult patients. However, only a few contradicting data are available in the literature about elderly patients. In this paper we retrospectively analyze a cohort of 43 consecutive patients aged more than 65 years, operated on for pituitary adenomas at our Institution in the years 1998-2007. These patients were treated by transsphenoidal endonasal approach (TNS) for resection of non-functioning pituitary adenomas (n = 31), GH-secreting adenomas (n = 4) and ACTH-secreting adenomas (n = 8). Clinical records reported a macroadenoma with tumour-related mass symptoms in about 80 % of patients; single or multiple pituitary deficits were present in 44 % of patients. Regarding comorbidities, cardiac disease was the most frequently observed (86 %); assessment of anaesthesiological risk indicated a moderate to severe ASA score in most patients, 11 % showing a 4-5 score. On the basis of current criteria, our retrospective analysis revealed that cure was achieved in 54 % of patients. The outcome was similar to that observed in the general population of patients undergoing transphenoidal surgery in our centre, without differences in the rate of surgical and endocrinological cure, minor and major surgical complications and hospitalization duration. In particular, no significant anaesthesiological complications were observed and no patient developed either permanent diabetes insipidus or cerebrospinal fluid rhinorrhea. In conclusion, in specialized centres the surgical treatment of pituitary adenomas via the transsphenoidal route can be a safe and effective procedure even in elderly patients. [ABSTRACT FROM AUTHOR]

In this paper we consider a mathematical model for magmatic mixtures based on the Gibbs free energy. Different reformulations of the problem are presented and some theoretical results about the existence and number of solutions are derived. Finally, two homotopy methods and a global optimization one are introduced and computationally tested. One of the homotopy methods returns a single solution of the problem, while the other is able to return multiple solutions (often all of them). The global optimization method is a branch-and-reduce one with a theoretical guarantee of detecting all the solutions, although some numerical difficulties, resulting in a loss of a few of them, may have to be faced. [ABSTRACT FROM AUTHOR]

Rhabdomyosarcoma (RMS) is a paediatric soft-tissue sarcoma arising from skeletal muscle precursors coexpressing markers of proliferation and differentiation. Inducers of myogenic differentiation suppress RMS tumourigenic phenotype. The Notch target gene HES1 is upregulated in RMS and prevents tumour cell differentiation in a Notch-dependent manner. However, Notch receptors regulating this phenomenon are unknown. In agreement with data in RMS primary tumours, we show here that the Notch3 receptor is overexpressed in RMS cell lines versus normal myoblasts. Notch3-targeted downregulation in RMS cells induces hyper-phosphorylation of p38 and Akt essential for myogenesis, resulting in the differentiation of tumour cells into multinucleated myotubes expressing Myosin Heavy Chain. These phenomena are associated to a marked decrease in HES1 expression, an increase in p21Cip1 level and the accumulation of RMS cells in the G1 phase. HES1-forced overexpression in RMS cells reverses, at least in part, the pro-differentiative effects of Notch3 downregulation. Notch3 depletion also reduces the tumourigenic potential of RMS cells both in vitro and in vivo. These results indicate that downregulation of Notch3 is sufficient to force RMS cells into completing a correct full myogenic program providing evidence that it contributes, partially through HES1 sustained expression, to their malignant phenotype. Moreover, they suggest Notch3 as a novel potential target in human RMS. [ABSTRACT FROM AUTHOR]

In this paper we introduce the LeGO ( Learning for Global Optimization) approach for global optimization in which machine learning is used to predict the outcome of a computationally expensive global optimization run, based upon a suitable training performed by standard runs of the same global optimization method. We propose to use a Support Vector Machine (although different machine learning tools might be employed) to learn the relationship between the starting point of an algorithm and the final outcome (which is usually related to the function value at the point returned by the procedure). Numerical experiments performed both on classical test functions and on difficult space trajectory planning problems show that the proposed approach can be very effective in identifying good starting points for global optimization. [ABSTRACT FROM AUTHOR]

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The electrical conductivity of both as-deposited and annealed poly(α,α,α′,α′-tetrafluoro- p-xylylene) (PA-F) films has been investigated up to 400°C. The static conductivity ( σ) values of PA-F measured between 200°C and 340°C appear to be ∼2.5 orders of magnitude lower for annealed films than for as-deposited ones. This change is attributed to a strong increase in the crystallinity of the material occurring above 340°C. After annealing at 400°C in N, the σ value measured at 300°C, for instance, decreased from 3.8 × 10 Ω cm to 7.5 × 10 Ω cm. Physical interpretations of such an improvement are offered. [ABSTRACT FROM AUTHOR]

In this paper we propose a Monotonic Basin Hopping approach and its population-based variant Population Basin Hopping to solve the problem of packing equal and unequal circles within a circular container with minimum radius. Extensive computational experiments have been performed both to analyze the problem at hand, and to choose in an appropriate way the parameter values for the proposed methods. Different improvements with respect to the best results reported in the literature have been detected. [ABSTRACT FROM AUTHOR]

We discuss the complexity of a class of highly structured global optimization problems, namely the maximization of separable functions, with each one-dimensional component convex and nondecreasing, over polytopes defined by a 0-1 constraint matrix with at most two variables involved in each constraint. In particular, we prove some inapproximability and approximability results. [ABSTRACT FROM AUTHOR]

Epidermoid cysts are rare disontogenetic tumoral lesions in the cranial compartment (1% of all intracranial tumors) and are usually located in relation to the cranial sutures; the intradiploic location is the less frequent. We report a clinical case in which the post-traumatic etiology of a frontal intradiploic epidermoid is considered. The histological findings revealed the presence of an epidermoid tumor associated with a typical foreign body inflammatory reaction, after repeated head traumas at the site of the tumour. This is the first case in whom the association between this tumoral lesion and a tissue inflammatory reaction due to foreign bodies is demonstrated. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Established autoimmune mark- ers of type 1 diabetes, including islet cell autoantibodies (ICA) and auto antibodies to glutamic acid decarboxylase (GADA) have been used to screen people presenting with type 2 diabetes for latent autoimmune diabetes in adults. We have examined the prevalence of autoantibodies to protein tyro sine phosphatase iso forms IA-2 (IA-2A) and IA- 2(3/phogrin (IA-2(3A) in a cohort of adult UKPDS patients thought to have type 2 diabetes, and investigated the possible role of these automotive dies in predicting requirement for insulin therapy. Methods: IA-2A and IA-2(3A were measured by a validated radioimmunoassay with human recombinant autoantigens in 4,169 white Caucasian patients aged 25-65 years and newly diagnosed with type 2 diabetes. The clinical requirement for insulin therapy within 6 years was examined in 2,556 patients not insulin. Results: IA-2A and IA-2(3A were present in 2.2 and 1.4%, respectively, of these patients. IA-2A were more prevalent in younger patients (p for trend <0.00001), more often associated with the HLA-DR4 allele (26.3 vs 8.0%, p

In this paper we will discuss the multilevel structure of global optimization problems. Such problems can often be seen at different levels, the number of which varies from problem to problem. At each level different objects are observed, but all levels display a similar structure. The number of levels which can be recognized for a given optimization problem represents a more complete measure of the difficulty of the problem with respect to the standard measure given by the total number of local minima. Moreover, the subdivision in levels will also suggest the introduction of appropriate tools, which will be different for each level but, in accordance with the fact that all levels display a similar structure, will all be based on a common concept namely that of local move. Sonic computational experiments will reveal the effectiveness of such tools. [ABSTRACT FROM AUTHOR]

To test a new tool for the neurophysiological identification of the human subthalamic nucleus (STN) during stereotactic surgery for the implantation of deep-brain-stimulation (DBS) electrodes, we analysed off-line the intraoperative signals recorded from patients with Parkinson’s disease. We estimated the power spectral density (PSD) along each penetration track (8 patients, 13 sides) and determined the spatial correlation of the PSD with the target location estimated from neuroimaging procedures (“anatomical target”), and with the final target location derived from standard intraoperative neurophysiological procedures for STN localization (“clinical target”). At each step we recorded the ‘on-line’ signal for 120 seconds; because the PSD was estimated by calculating the periodogram for 6-second epochs of neural signal, we had 20 epochs at each step. When the electrode track crossed the STN, the PSD in the 0.25-2.5 kHz band increased, peaking on average <0.5 mm cranial to the clinical target and 1.00±1.51 mm caudal to the anatomical target. When the track was outside the nucleus, the PSD remained unchanged. Even on recordings with low signal-tonoise ratio, off-line PSD analysis of neural signals showed a good correspondence with the target indicated by the surgical team. On-line intraoperative estimation of the PSD may be a simple, reliable, rapid and complementary approach to electrophysiological monitoring during STN surgery for Parkinson’s disease. [ABSTRACT FROM AUTHOR]

Although high-dose methotrexate (HD-MTX) is the most effective drug against primary CNS lymphomas (PCNSL), outcome-determining variables related to its administration schedule have not been defined. The impact on toxicity and outcome of the area under the curve (AUCMTX), dose intensity (DIMTX) and infusion rate (IRMTX) of MTX and plasmatic creatinine clearance (CLcrea) was investigated in a retrospective series of 45 PCNSL patients treated with three different HD-MTX-based combinations. Anticonvulsants were administered in 31 pts (69%). Age >60 years, anticonvulsant therapy, slow IRMTX (?800?mgm-2h-1), and reduced DIMTX (?1000?mgm-2wk-1) were significantly correlated with low AUCMTX values. Seven patients (16%) experienced severe toxicity, which was independently associated with slow CLcrea. A total of 18 (40%) patients achieved complete remission after chemotherapy, which was independently associated with slow CLcrea. In all, 22 patients were alive at a median follow-up of 31 months, with a 3-year OS of 40±9%; slow CLcrea and AUCMTX >1100?µmol?hl-1 were independently associated with a better survival. Slow CLcrea and high AUCMTX are favourable outcome-determining factors in PCNSL, while slow CLcrea is significantly related to higher toxicity. AUCMTX significantly correlates with age, anticonvulsant therapy, IRMTX, and DIMTX. These findings, which seem to support the choice of an MTX dose ?3?gm-2 in a 4-6-h infusion, every 3-4 weeks, deserve to be assessed prospectively in future trials. MTX dose adjustments in patients with fast CLcrea should be investigated.British Journal of Cancer (2004) 90, 353-358. doi:10.1038/sj.bjc.6601472 www.bjcancer.com [ABSTRACT FROM AUTHOR]

The Raf-MEK-ERK signalling pathway controls fundamental cellular processes including proliferation, differentiation and survival. It remains enigmatic how this pathway can reliably convert a myriad of extracellular stimuli in specific biological responses. Recent results have shown that the Raf family isoforms A-Raf, B-Raf and Raf-1 have different physiological functions. Here we review how Raf isozyme diversity contributes to the specification of functional diversity, in particular regarding the role of Raf isozymes in cancer.British Journal of Cancer (2004) 90, 283-288. doi:10.1038/sj.bjc.6601488 www.bjcancer.com [ABSTRACT FROM AUTHOR]

In this paper simulated annealing algorithms for continuous global optimization are considered.Under the simplifying assumption of known optimal value, the convergence of the algorithms and an upper bound for the expected first hitting time, i.e. the expected number of iterations before reaching the global optimum value within accuracy ε, are established. The obtained results are compared with those for the ideal algorithm PAS (Pure Adaptive Search) and for the simple PRS (Pure Random Search) algorithm. [ABSTRACT FROM AUTHOR]

Summary Background. The treatment of choice in Cushing's disease is transsphenoidal adenomectomy with a recurrence rate ranging 9–23%. We investigated whether abnormal hormonal responses may predict the relapse in “operated” patients followed-up for a long period. Method. Sixty-eight surgically treated patients with Cushing's disease were followed-up for 12–252 months. Forty-eight patients underwent selective adenomectomy, 17 enlarged adenomectomy and 3 underwent total hypophysectomy. After surgery ACTH and cortisol levels were measured after stimulatory (desmopressin and CRH) and inhibitory tests (dexamethasone and loperamide). Findings. After operation 46 patients were cured (group A), 15 patients only normalized cortisol levels (group B), 7 patients were surgical failures. During the follow-up, a disease-free condition was maintained in 48 of 61 cases (79%), while a recurrence occurred in 13 patients (21%, 5 of group A and 8 of group B). In 5/13 patients who relapsed an absent inhibition after dexamethasone and an exaggerated response to CRH test preceded the recurrence. In 5 other patients the relapse was suspected by loperamide test. In the 3 remaining cases, positive responses to desmopressin preceded the recurrence. In 7/13 patients who relapsed the pituitary tumour was visualized by MRI/CT imaging. Interpretation. During the follow-up a careful assessment of ACTH dynamics is needed. Although no single test can reliably predict the late outcome, individual patients at risk for relapse may be identified by abnormal responses to desmopressin, CRH and loperamide tests; particularly, the persistent responsiveness to desmopressin may be a criterion of risk for recurrence in patients who only normalized cortisol levels after surgery. [ABSTRACT FROM AUTHOR]

In this paper a simulated annealing algorithm for continuous global optimization will be considered. The algorithm, in which a cooling schedule based on the distance between the function value in the current point and an estimate of the global optimum value is employed, has been first introduced in Bohachevsky, Johnson and Stein (1986) [2], but without any proof of convergence. Here it will be proved that, under suitable assumptions, the algorithm is convergent [ABSTRACT FROM AUTHOR]

The question of the finiteness of simplicial branch-and-bound algorithms employing only ω-subdivisions is considered. In Ref. 1, it was shown that this algorithm is convergent; here, it is proved that the algorithm is also finite if two assumptions are fulfilled. The first assumption requires the function values at vertices of the initial simplex to be lower than the optimal value of the problem. The second assumption requires each vertex of the initial simplex to violate at most one of the constraints defining the feasible polytope. The first assumption is mild from a theoretical point of view; the second assumption is strong, but holds always for instance when the feasible region is a hypercube. [ABSTRACT FROM AUTHOR]

The problem of minimizing a concave function over a polytope is considered. The simplicial branch-and-bound approach is presented and theoretical studies about the convergence of these algorithms are carried on. In particular, the convergence of the algorithm based on so-called ω-subdivisions is proved, which had been an open question for a long time. [ABSTRACT FROM AUTHOR]

Our aim was to study the activity and toxicity of the gemcitabine plus vinorelbine (Gem Vin) combination and to identify the optimal dose. Previously untreated patients aged < 70 years, with stage IV or IIIb (not candidates for radiotherapy) non-small cell lung cancer were eligible. Studied dose-levels of Gem Vin, administered on days 1 and 8 every 3 weeks, were (mg m[SUP-2]): level I = 1000/25; level II = 1200/25; level III = 1000/30; level IV = 1200/30. A feasibility study was performed at each dose-level, followed by a single-stage phase II study. Dose-level IV was unfeasible because of grade 4 neutropenia. Overall, out of 126 patients enrolled in phase II studies, there were one complete and 32 partial responses (response rate 26%: 95% CI 18-34%). Response rates were 27.9%, 21.4% and 29.3% at levels I, II and III, respectively. The treatment was well tolerated. Toxicity was less frequent and severe at level I. Overall median survival was 33 weeks (95% CI 28-40). Descriptive quality of life analysis showed that patients with a worse baseline global health status score tended to drop out of the study earlier than those with a better score. Gem Vin is feasible at different doses. It is sufficiently active and well tolerated. A phase III study to compare the effect on quality of life of Gem Vin (level I) vs cisplatin-based chemotherapy is ongoing. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate capabilities of pulse inversion harmonic imaging (PIHI) in characterization of unifocal liver lesions. We evaluated with PIHI (HDI5000, ATL, Bothell, Wash.) and spiral CT 46 consecutive patients with a single liver lesion identified by fundamental US [7 hepatocellular carcinomas (HCC), 2 cholangiocarcinomas, 7 focal nodular hyperplasias (FNH), 17 hemangiomas and 13 metastases]. The PIHI was performed before and 30 s, 2 and 4 min after bolus administration of Levovist (2.5 g, 300 mg/ml). Scans were digitally stored and reviewed using a dedicated software. Hepatocellular carcinoma was hyperechoic on 30-s scan, and hypoechoic (n = 5) or isoechoic (n = 2) on 2-min scan. Cholangiocarcinoma had inhomogeneous persistent enhancement. Focal nodular hyperplasia was hyperechoic (n = 5) or isoechoic (n = 2) on 30-s scan, hyperechoic (n = 4), isoechoic (n = 2) or slightly hypoechoic (n = 1) on 2-min scan. Large hemangioma revealed peripheral enhancement on 30-s scan which extended centripetally on 2-min scan. Small hemangioma appeared isoechoic on 2-min scan in all but two cases in which they were hypoechoic on 2-min scans and hyperechoic on 4-min scan. Metastasis was hypoechoic on all scans, 70 % with rim enhancement. Similar changes in enhancement pattern have been observed at spiral CT.¶ The 30-s and the 2-min scans revealed a conclusive importance in characterization of HCC, cholangiocarcinoma, and large hemangioma. The 2-min scan often furnished enough information for characterization of small hemangioma and metastasis. The 4-min scan allowed characterization of two hemangiomas which appeared hypoechoic on 2-min scans. In the other cases it did not provide further information. Diagnosis of FNH is usually reached with Colour Doppler US; PIHI should be used when colour Doppler is biased by artefacts or when colour Doppler findings are not characteristic. Our results seem to show that PIHI could be a valuable alternative diagnostic approach to spiral CT for unifocal liver lesion characterization. This hypothesis needs to be confirmed with an increased number of lesions. [ABSTRACT FROM AUTHOR]

Unlabelled: Increased serum concentrations of liver enzymes are sometimes observed, in the absence of clinical symptoms of liver disease, in patients with Turner syndrome. The purpose of this study was to evaluate, in our Turner patients, serum liver enzyme levels and to find a cause for their increase. In 70 Turner patients, serum AST, ALT, GGT levels were evaluated every 6 months during a period of 0. 8-21.9 years. In patients in whom increased values of liver enzymes were found, serological markers for infectious hepatitis, serum hepatitis C virus RNA and virus genotype, IgG and IgA antibodies to gliadin and endomysium, coeruloplasmin, copper, alpha(1)-antitrypsin, total proteins and electrophoresis, IgG, IgA, IgM, fibrinogen, prothrombin, alkaline phosphatase, creatine kinase and total and direct bilirubin were also determined. Antinuclear, anti-smooth muscle and anti-liver-kidney microsome antibodies together with antithyroglobulin and anti-thyroid peroxidase antibodies were determined in all patients and in 166 age-matched female controls. In 22 patients, increased liver enzymes were observed, not related to karyotype. Follow-up showed that the hepatic disorder did not worsen with the time. Serological markers of hepatitis C virus were positive in three patients. When the serum liver enzyme increase was first observed in the other 19 patients with high enzyme levels (group A), 14 patients had never been submitted to hormonal treatment, 4 were on oestrogen/gestagen treatment and 1 was being treated with both growth hormone and oestrogen. Coeliac disease, alpha(1)-antitrypsin deficiency and Wilson disease were ruled out by appropriate investigations. In 8/19 group A patients, antinuclear and/or anti-smooth muscle antibodies were present versus 6/48 of patients with normal liver enzymes (group B). Thyroid antibodies were found in 8/19 patients in group A and in 13/48 in group B. Weight excess SDS was significantly higher in Turner girls with liver enzyme increase. Ultrasonography, performed in 17 patients of group A, showed mild hepatomegaly in 4 and increased echogenicity with fatty infiltration in 6.Conclusion: Hepatic abnormalities in Turner syndrome are not progressive. Oestrogen should not be considered the main cause of increased liver enzymes in Turner syndrome since most of our patients with this finding had not been previously treated with oestrogens. An auto-immune pathogenesis might be considered in some cases, whereas the association with weight excess seems the most frequent cause of liver disorder in Turner syndrome. [ABSTRACT FROM AUTHOR]

In this paper, simulated annealing algorithms for continuous global optimization are considered. After a review of recent convergence results from the literature, a class of algorithms is presented for which strong convergence results can be proved without introducing assumptions which are too restrictive. The main idea of the paper is that of relating both the temperature value and the support dimension of the next candidate point, so that they are small at points with function value close to the current record and bounded away from zero otherwise. [ABSTRACT FROM AUTHOR]

Abstract. In this paper the problem of finding the global optimum of a concave function over a polytope is considered. A well-known class of algorithms for this problem is the class of conical algorithms. In particular, the conical algorithm based on the so called omega-subdivision strategy is considered. It is proved that, for any given accuracy epsilon > 0, this algorithm stops in a finite time by returning an e-optimal solution for the problem, while it is convergent for epsilon = 0. [ABSTRACT FROM AUTHOR]

The aim of this study is to evaluate capability of contrast enhanced ultrasonography (US) using pulse inversion harmonic imaging (PIHI) to detect liver metastases in comparison to fundamental B-mode ultrasound and spiral CT. Thirty-six consecutive patients with known malignancies and sonographically proved or suspicious liver metastases have been examined with fundamental B-mode US, with PIHI 2', 4' and 6' after Levovist injection and with four phase spiral-CT. Presence, conspicuity and number of lesions have been evaluated comparing PIHI with fundamental B-mode US and spiral-CT. A strong grey-scale enhancement of the liver parenchyma has been observed 2' and 4' after Levovist injection. The optimum parenchymal enhancement and contrast difference between liver and metastases was observed during the 2' measurements. PIHI revealed more lesions than fundamental B-mode US in 56 % of patients, while in 39 % and in 5 % revealed respectively the same number and fewer lesions. PIHI and spiral-CT were in agreement in 67 % of patients, while in 22 % and 11 % PIHI revealed respectively more and fewer lesions. PIHI accurancy presents restrictions in anterior superficial and in deep liver areas, whereas it may be superior to spiral-CT in studying sub-diaphragmatic liver regions. [ABSTRACT FROM AUTHOR]

In this paper Bayesian analysis and Wiener process are used in orderto build an algorithm to solve the problem of globaloptimization.The paper is divided in two main parts.In the first part an already known algorithm is considered: a new (Bayesian)stopping ruleis added to it and some results are given, such asan upper bound for the number of iterations under the new stopping rule.In the second part a new algorithm is introduced in which the Bayesianapproach is exploited not onlyin the choice of the Wiener model but also in the estimationof the parameter σ2 of the Wiener process, whose value appears to bequite crucial.Some results about this algorithm are also given. [ABSTRACT FROM AUTHOR]

Blood rheology alterations have often been reported in diabetic patients and may be associated with an increased risk for diabetic vascular disease. In this light a hemorheologic approach with pentoxifylline has been suggested in diabetic patients with hemorheological changes in order to improve the hemorheology approach and to evaluate the long-term effects of this treatment on the other clinical and metabolic variables. The study concerned a 10-year retrospective analysis of diabetic patients with hemorheologic alterations and angiopathic complications. Pentoxifylline (Trental 400) significantly reduced blood and plasma viscosity (at high and low shear-rates), fibrinogen and erythrocyte aggregation, and increased erythrocyte filterability throughout the study. The improvement of the hemorheologic pattern was obtained independently of the variation in glycometabolic control and body weight changes, whereas concomitant reductions of arterial blood pressure levels and of urinary excretion of albumin and total proteins was observed during the treatment. Pentoxifylline might therefore be successfully employed for long-term periods in the treatment of hemorheologic disorders in diabetic patients without effects on the metabolic pattern. [ABSTRACT FROM AUTHOR]

In two workers admitted to hospital because of a coma due to an accidental occupational exposure to a mixture of solvents, the level of toluene was respectively 823-1122 μg/1 in the blood and 53-38 μg/1 in the alveolar air on the second day of admission (36 h after the accidental exposure). On the fifth day, 112 h after exposure, the toluene level was 120-45 μg/l in the blood and 3-1 μg/l in the alveolar air. The urinary excretion of o-cresol, calculated as a toluene equivalent, was 0.8-0.9 mg on the second day and 1.7-1.6 mg on the third day. Urinary hippuric acid, as a toluene equivalent, was 1.7-1.4 g on the second day and 1.3-0.7 g on the third day. A half-life of between 19 and 21 h was calculated for toluene both in the blood and in the alveolar air. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor reporting evidences that show the prevalence of antibodies to Human herpesvirus 8 in children from Sardinia, Italy, and Croatia.

The temperature coefficient of the breakdown voltage of 6H-SiC p-n structures has been investigated. It is shown that the temperature dependence of the breakdown voltage can be explained by charge exchange on deep acceptor levels in the space charge layer. The computational results are in good agreement with the experimental data obtained for boron-doped 6H-SiC p-n structures. [ABSTRACT FROM AUTHOR]

The efficacy of deep brain stimulation of the subthalamic nucleus (STN) is dependent on the accuracy of targeting. In order to reduce the number of passes and, consequently, the duration of surgery and risk of bleeding, we have set up a new method based on direct magnetic resonance imaging (MRI) localisation of the STN. This procedure allows a short duration of the neurophysiological session (one or two initial tracks). Whenever a supplementary track is needed, the stimulation-induced side effects are analysed to choose from one of the remaining holes in Ben's gun. A good knowledge of anatomical structures surrounding the STN is mandatory to relate side effects to the actual position of the track. In our series of 11 patients (22 sides, 37 tracks), the most common and reproducible side effects were those characterised by motor, sensorial, oculomotor and vegetative signs and symptoms. Moreover, the therapeutic window (distance between the current intensity needed to obtain the best clinical effect and the intensity capable to induce side effects) predicted clinical efficacy in the long-term, and contributed to the choice of which among the examined tracks had to be implanted with the chronic macroelectrode. [ABSTRACT FROM AUTHOR]