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We report on the fragile site expression in lymphocytes from 16 Down syndrome (DS) men aged 24 to 52 years. Among rare fragile sites, 16q22 has been reported to be induced or enhanced by alpha-interferon. Since DS cells have three copies of the receptor for alpha-interferon, we hypothesized a possible enhancement of 16q22 expression. This fragile site has also been related to a specific rearrangement in M4 acute nonlymphocytic leukemia. In view of the high incidence of acute leukemia in DS subjects, we studied the expression of 16q22 in lymphocyte cultures treated with 5-bromodeoxyuridine or alpha-interferon. We also studied whether the repair deficiency of DS cells could affect the expression of aphidicolin-induced fragile sites. The level of chromosomal aberrations was compared with that found in aphidicolin-treated cultures from 12 normal subjects of the same age. We found neither spontaneous or BrdU-induced fragility at 16q22 nor induction by alpha-interferon. Chromosomal breakage rate was increased in alpha-interferon-treated cultures in comparison with control cultures of the same subjects. Aphidicolin-induced fragile sites expression in DS patients did not differ significantly from that found in the lymphocyte cultures from control subjects.

The present study concerns the monitoring of children from the Byelorussian, Ukrainian and Russian republics exposed to the fall-out of the Chernobyl accident. Cytogenetic analyses have been performed on 41 children coming from different areas and exhibiting varying amounts of 137Cs internal contamination, as evaluated by whole-body counter (WBC) analysis. On a total of 28,670 metaphases scored, radiation-induced chromosome damage is still present, although at a very low frequency. Due to the very low fraction of dicentrics, because of the time elapsed from the accident and the relatively low doses of exposure, radiobiological dosimetry is not possible for these children. However, considering that the WBC data indicate that the children are still exposed to 137Cs contamination, the observed occurrence of stable chromosome rearrangements and breaks may represent the persisting effect of continuous low doses of radiation. The present study also indicates that the parallel use of internal contamination dosimetry and cytogenetics could be usefully employed to monitor individual exposure to radiation and to define further management measures.

Isolated chondrocytes from mouse ribs have been put in culture and maintained for several weeks, till confluence. They retain differentiation, and preliminary data of cells characterization and growth are reported. Electron microscope observations of the cellsin vitro grown are superimposable to those performed on chondrocytes derived from live animals. Mouse chondrocytes, grownin vitro, represent a promising system for the study of bone differentiation, growth and regeneration, also considering the several mutations affecting skeleton formation known in mice, like cn/cn (achondroplasia).

Pgm allele frequencies of 383 individuals were determined in a sample of Drosophila melanogaster from three laboratory Sardinian populations, using the techniques of standard electrophoresis, heat denaturation, and isoelectric focusing. The analysis of the progeny obtained from informative crosses showed that the isoelectric focusing patterns segregate in a Mendelian way. The Pgm1.00 and Pgm0.70 electrophoretic alleles displayed different isoelectric points, whereas the Pgm1.00,tr and Pgm1.00,ts isoelectrophoretic alleles could not be differentiated when tested by isoelectric focusing. Moreover, the Pgm0.70,ts allele was split into two classes, with isoelectric points of pH 6.4 and pH 6.6.

In this paper, the optimal sequencing of aircraft in the near terminal area with a single runway for both landings and take-offs, is considered. This problem is imbedded in the class of problems related to sequencing n jobs (either landings or take-offs) on one machine (the runway). A difference immediately arises, since the jobs are not simultaneously available and once begun must be fully completed. A branch and bound algorithm is developed, by making use of some peculiar properties which hold in this particular case.

The frequency and distribution of aphidicolin (APC)-induced common fragile sites (cfs) were analyzed in human embryonic cells of different origins. Embryonic lung fibroblasts (MRC-5), amniocytes (AMINO) and embryonic retina cells (HERO790) are as sensitive to the APC-induced clastogenic effect as peripheral lymphocytes, whereas embryonic kidney cells (HEK) seem more resistant to the induction of chromosomal gaps and breaks by the drug. Analysis of the distribution of fragile sites confirmed that the expression of specific APC-induced cfs varies in different cells and that the embryonic cell strains show a greater similarity among themselves than to lymphocytes. In addition, HEK, MRC-5, HERO790 and AMINO cells show specific APC induction of the cfs at the 1p31.2 chromosomal band, which seems to be a distinctive feature of the embryonic stage of cells.

We have sub localized to the region between 1p22 and lp33 a total of 14 yeast artificial chromosomes previously assigned to a broader area of human chromosome 1p. Our purpose was to map DNA sequences that could be used for the molecular characterization of the two common fragile sites present in bands 1p31.2 and 1p32, the expression of which is increased in patients with neuroblastomas.

Mammalian DNA topoisomerase II represents the cellular target of many antitumor drugs, such as epipodophyllotoxin VP-16 (etoposide). The mechanism by which VP-16 exerts its cytotoxic and antineoplastic actions has not yet been firmly established, although the unique correlation between sensitivity to ionizing radiation and to topoisomerase II inhibitors suggest the involvement of DNA double-strand breaks. In the present study we analyzed the chromosomal sensitivity of lymphoblastoid cell lines derived from ataxia telangiectasia (AT) patients to low concentrations of the drug. Our results indicate that AT derived cells are hypersensitive to the clastogenic activity of VP-16 either when the drug is present for the whole duration of the cell cycle or specifically in the G2 phase, confirming that the induction of DNA double strand breaks, to which AT cells seem typically sensitive, could have an important role in the biological activity of VP-16.

Cytogenetic studies with high-resolution banding were performed on specimens from 132 consecutive patients with de novo acute myeloid leukemia (AML). All patients were treated according to therapeutic protocols in the same institution. Clonal abnormalities were detected in 97 of the 124 patients in whom an adequate number of mitoses was obtained (78.2%). Neither sex, FAB classification, WBC, or the extent of bone marrow infiltrate affected the rate of chromosomal aberrations, whereas patients younger than 40 years had a greater proportion of normal karyotypes (p = 0.047). Two different chromosomal classifications were evaluated: the presence of normal and abnormal metaphases (NN-AN-AA classification), and a classification in cytogenetic categories, the latter being based on the frequency of cytogenetic abnormalities. Both classifications were found to correlate significantly with the clinical outcome. They also showed independent prognostic significance when age, sex, and FAB morphology were considered in a multivariate analysis. Two abnormalities were closely associated with specific clinical-pathologic subsets of AML. All the 15 patients with t(15;17) had acute promyelocytic leukemia; this translocation was not found in any other subset of AML. Eight of the nine patients presenting rearrangements at 11q23 belonged to a FAB subset with monocytic differentiation (M4 and M5). Our data suggest that cytogenetic findings should influence the therapeutic approach to AML. In particular, young patients with karyotypes associated with poor responses may be considered for more eradicating treatments, including allogenic bone marrow transplantation.

Chromosomal instability has been described in patients affected by various tumors. We previously reported a high sensitivity to fragile sites induction by aphidicolin in lymphocytes from patients affected by neuroblastoma and in those from their parents. In the search for the most suitable clastogenic agent to enhance the possible differences between healthy controls and patients affected by tumors, we have now tested two other drugs: bleomycin, a radiomimetic agent already used in vitro on chromosomes of patients affected by other tumors and arabinoside cytosine, an inhibitor of DNA polymerases alfa and beta. We observed a high sensitivity to bleomycin both in patients and in their parents, but to arabinoside cytosine only in NB patients. Moreover, the two drugs induced more fragile sites in 1p in patients and in their parents than in healthy controls. This phenomenon, which we already observed after treatment with aphidicolin, might be related to the frequent deletions and loss of heterozigosity in 1p in neuroblastoma cells.

In a previous study we demonstrated spontaneous fragility and hypersensitivity to fragile site induction by aphidicolin in lymphocytes from some neuroblastoma patients and their parents. Here we report data based on a total of 40 patients and 37 families. Possible correlations between higher sensitivity to aphidicolin and a variety of personal and clinical characteristics were verified. Patients with a poor prognosis generally proved to be more susceptible to fragile site induction.

Chromosome fragile sites are inducible by aphidicolin in cultured human lymphocytes. To assess the frequency and distribution of these common fragile sites in the general population, a cytogenetic survey was performed on 126 subjects, 59 males and 67 females, whose age ranged from 1 day to 72 years. Common fragile sites, induced by aphidicolin, were widespread and showed a remarkably different sensitivity among individuals; age influenced the overall frequency of fragile sites. Moreover, both age and sex seemed to modulate the expression of specific fragile sites. In our population, the most common fragile sites were: 3p14, 16q23, Xp22, 6q26, 1p31, 4q31, 1p22, 7q22, 2q33, 3q27, 2q31, 7q32, 14q24, 10q22, 5q31, 2q37, 6p21.

Infection of human embryonic kidney cells with adenoviruses results in the induction of gaps and breaks in cell chromosomes. With adenovirus type 12, cytogenetic damage is known to occur primarily at fragile sites on chromosomes 1 and 17. We have mapped adenovirus type 5-induced breaks and have observed that, although they occur on all chromosomes, they are localized primarily on bands where fragile sites have been mapped. The susceptibility of fragile sites to adenovirus led us to investigate their expression upon combined treatments with virus and aphidicolin, a frequently used inducer of fragile sites. Under these experimental conditions, the frequency of damage at all sites was found to increase significantly, and the magnitude of such increases indicated a synergistic effect between drug and virus.

Restriction endonucleases have been shown to induce chromosome damage in a variety of cultured cells. We recently reported the coincidence between Msp I-induced breakage and the location of common fragile sites. We have extended our study to Hpa II, which induced a 4.5-fold increase in total breakage compared to controls. It appeared that a major contribution was given by stable chromosome rearrangements, which were present at a 14-fold increased frequency in comparison to the spontaneous levels. Moreover, several chromosome bands were involved in rearrangements in different cultures from different donors. Notably, Hpa II-induced breakage occurred in the same bands where breakpoints of constitutional and neoplastic rearrangements are located.

The distribution of chromosome breaks induced by the antitumor drug cis-diamine-dichloroplatinum (II) in lymphocyte cultures from Fanconi anemia patients was analyzed. Breakpoints occurred nonrandomly over an arbitrarily defined human karyotype of 319 bands. These bands were classified according to either their banding pattern or their fragile site status (whether or not a fragile site of a given type is located at a chromosomal band). A significant involvement of G-light and fragile site bands was detected. The preferential occurrence of breaks at fragile site bands was limited to common fragile site bands (essentially of the aphidicolin-type).

We recently demonstrated an increased expression of fragile sites, induced by aphidicolin, in lymphocytes of neuroblastoma patients. We have now extended our studies to parents of affected children with neuroblastoma to verify if this characteristic may be genetically transmitted. We have examined 20 families. In most of them, the hypersensitivity to aphidicolin was found in the affected child and in at least one parent. Moreover, some of the parents showed an increase in the expression of the fragile sites 1p32, 1p13, or both that are preferentially expressed in neuroblastoma patients. The possible relations between the hypersensitivity to aphidicolin and the inheritance of predisposition to neuroblastoma must be clarified.

The Segregation Distortion (SD) phenomenon is a typical case of non-Mendelian segregation in Drosophila melanogaster, due to the dysfunction of sperm bearing a non-SD homologous chromosome. In nature, several factors involved in the expression of the SD phenomenon have been described; among these, a genetic modifier carried by chromosome 3, which enhances the distortion effect of the SD chromosomes. The analysis of natural Sardinian populations, carried out in order to evaluate the presence of chromosome 3 bearing these enhancer factors, has enabled us to ascertain that (a) also in these populations chromosomes 3 with enhancer factors are present, although with frequencies lower than those previously reported in other publications; (b) among these enhancer chromosomes 3, some increase the k of certain chromosomes 2 from values of chromosomes considered non-distorting (k less than or equal to 0.66) to value typical of SD chromosomes. The data obtained also allow us to put forward some considerations regarding the dynamics of the SD phenomenon in Sardinian populations, where the frequency of SD chromosomes is fairly elevated.

We have conducted a study on the spontaneous and UV-A-induced frequency of chromosomal breaks and sister-chromatid exchanges (SCE) in purified lymphocytes from normal donors and from systemic lupus erythematosus (SLE) patients who were in clinical remission at the time of the study. Our results show that although SLE lymphocytes exhibit a higher frequency of spontaneous SCEs than controls, the rate of chromosomal breakage is comparable in the 2 groups. In both controls and patients, irradiation with UV-A (320–400 nm) increases the SCE values but does not significantly affect the frequency of chromosomal aberrations.

ZusammenfassungBei 20 Kindern mit Neuroblastom (davon 9 Sauglinge) und deren Eltern wurden Chromosomenanalysen aus dem peripheren Blut durchgefuhrt. Die Chromosomenbruchigkeit («breaks», «gaps», % bee

The report, few years ago, of some growth hormone-deficient children having developed leukemia following therapy with human growth hormone, raised concern about a possible stimulatory effect of this therapy on tumor development. Since it is known that proneness to cancer is related to chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy might increase chromosome fragility. Ten short-normal children (age: 6-11 yrs. mean height: −2.5 SD; mean growth rate: 4.1 cm/yr; mean bone age: −2.5 SD) were studied. Lymphocytes were collected at 0, 6 and 12 months of therapy, and the rate of spontaneous chromosome aberrations, the frequency of sister chromatid exchanges, the proiterative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomicin (BLM) were assessed. The mean frequency of BLM-induced chromosome aberrations increased from the pretherapy 0.11 breaks/cell (b/c) value to 0.23 b/c at 6 months of therapy (p

A modified form of the Discrete Maximum Principle (DMP) is derived for systems with finite memory. It is shown that this form of the DMP may be used for the optimal control of nonlinear continuous dynamics systems, when the control policies are bound to be piecewise constant. In this case the modified DMP allows one to determine, in an optimal way, both the control vectors and the switching points. A computational procedure for practical applications is presented. A numerical example is given relative to the computation of the optimal temperature sequence in a completely mixed batch reactor where two consecutive irreversible reactions are taking place.

We have analyzed the distribution of bleomycin-induced breaks in a subline of the ATL9 lymphoblastoid line, derived from peripheral lymphocytes of an ataxia telangiectasia patient, transformed in vitro by Epstein-Barr virus (EBV). As reported elsewhere (Caporossi et al., 1988), the major feature of this subline, ATL9/g, is a stable achromatic gap at lp32 in one of the chromosomes 1, overlapping a preferential site of EBV localization. The results of this paper show that this gap is highly sensitive to bleomycin-induced damage. In addition, the breaks induced by bleomycin in ATL9 cells are distributed nonrandomly and are preferentially localized in bands where fragile sites have been mapped.

In this paper the air traffic flow control is approached as a constrained optimization problem on a multicommodity network. The proposed dynamic mathematical model, by means of a suitable time discretization, has been changed into a “static” one, in order to use static network flow algorithms while taking into account the “unsteady” nature of the air traffic congestion problems. The complexity of the model requires some preliminary effort, such as the identification of some characteristic parameters of the system. In this paper, the network theory is applied to evaluate the influence of the time discretization interval on the model significancy with respect to the actual traffic situation. In particular, a computational example concerning the Rome air traffic control region is presented and the relative results are discussed.

A method is presented for estimating parameters of chemical reactor models. It is assumed that the process can be represented by a system of quasilinear partial differential equations, with two-point boundary values. The Green's function is used to transform the differential to integral equations. The unknown coefficients can then be identified by gradient search. The algorithm of the Fast Fourier Transform may be used to numerically compute some of the integrals involved. The FFT, sharply reducing the computation time, makes the method effective. Numerical applications are dealt with in detail, showing that the method is promising.

Some mathematical models for supporting the development of semi/ fully automated air traffic control systems are discussed. Particularly, the flow control problem is approached as a constrained optimization problem on a multicommodity network. The proposed mathematical model, by means of a suitable time discretization, is initially changed into a “static” one. Then a multicommodity algorithm, based on the resource directive decomposition method, is used for the actual computation of the optimal flow in the network. The method is evaluated from the point of view of its practical implementation and its capability to take into account the peculiar aspects of the problem. An application, relative to the Rome air traffic control region, is discussed.

Flow control is that part of an air traffic management system, in which control actions to avoid traffic congestion are considered. The aim is to redistribute traffic flows so as to fit air traffic demand to the system capacity and in the same time to minimize the possibility of unsafe conditions, incovenience and costs. Different levels of intervention can be defined according to the size of the area interested by the demand overload and to the time interval of the forecasted congestion. As a consequence, a flow control system generally proves to be a multi-level system acting on a large network of routes. In this paper, a model of an automated flow control system is considered and a particular mathematical approach is proposed. Then a linear constrained optimization problem on a multicommodity flow network is defined. To solve the resulting large-scale problem, a suitable decomposition technique is used. Finally, the model and the algorithm are tested on a case-study and the results are discussed.

UV-repair activity was studied in two sibs affected by XP showing different clinical symptoms. Complementation studies indicated that both patients fit into complementation group A. The levels of UV-induced 3H-thymidine incorporation, in fibroblasts and in lymphocytes, are different in the two patients: residual level of repair DNA synthesis in the sister is higher than in the brother. In one of the cell samples analyzed UDS analysis showed that in the sister a low proportion of cells with normal repair synthesis is present.

The 1-p-(3-methyltriazeno) benzoic acid potassium salt (MTBA) is a triazeno analogue of dacarbazine, an antineoplastic agent capable of mediating the appearance of new antigenic specificities on cancer cells in mice, a phenomenon described as 'chemical xenogenization' (CX). Recently we reported the clastogenic potential of MTBA on human lymphocytes. Since sister-chromatid exchange (SCE) assay is more sensitive than clastogenic tests, at least at low drug concentrations, we assessed SCE frequencies induced by MTBA on human lymphocytes stimulated by PHA. Drug treatment at 2-500 micrograms/ml was performed in vitro prior to or after PHA addition. SCE values increased significantly in a dose-dependent manner up to 200 micrograms/ml. However, SCE frequencies, as well as chromosome breaks, did not increase dramatically. These data indicate that MTBA concentrations used for CX do not cause severe cytogenetic damage to immune cells at least in vitro.

The restriction endonuclease MspI (cleavage site C/CGG) induces chromosomal breaks in human lymphocytes. The breakpoints are distributed non-randomly along the chromosomes and the pattern of MspI-induced breakage depends on the recovery time (20 h or 6 h). Chromosomal bands preferentially involved in breakage are likely to coincide with bands where common fragile sites are located.

A computer algorithm is described for the optimization of discrete-time pulse frequency modulated systems with state and control constraints. The algorithm, based on a modified maximum principle [1], leads to the solution of a Boolean linear programming problem, for which many computer codes are available commercially. An application to a time-shared sampled-data control system is presented. Numerical examples are given.

To clarify the possible relationship between fragile site expression and cancer, we examined lymphocytes from patients affected by neuroblastoma. This neoplasia may be inherited in some cases and is often characterized by a specific chromosomal aberration: deletion of the short arm of chromosome 1. We found a higher expression of fragile sites after aphidicolin and, to a lesser extent, after methotrexate treatment in lymphocytes from neuroblastoma patients as compared with those of normal donors. The analysis of fragile site distribution pointed out the increase in the expression of fragile site 1p32 in the patients. We believe that this finding might be relevant because this fragile site is located in the same region where breakpoints and rearrangements frequently occur in neuroblastoma cells.

This paper deals with a general method for the optimization of multivariable systems with non-uniform sampling chosen in an optimal way. The algorithm is based on Dynamic Programming and is applied to extend the Kalman-Koepcke optimization method for a linear dynamic system, with a quadratic performance index. In the general multivariable case, the method implies the solution of a two-point boundary value problem. In the scalar case, which has only one input and one output, the sampling periods may be found separately from the control law. The computational difficulties connected with the implementation of the method are discussed and simplifications, possible for discretized continuous systems, are derived. Numerical examples are given.

Summary Darwinian fitness, considered from the standpoints of fecundity, fertility, hatchability and rate of development, has been studied both in the natural and laboratory populations of Drosophila melanogaster. The AA. have tested laboratory populations Oregon-R isogenic, Oregon-R, mass colture, wild population (Perugia) and reciprocal crosses between Oregon-R and wild Perugia. Darwinian fitness is higher in the which show a high degree of heterosis for this character, and is followed immediately by wild Perugia and Oregon-R. A highly reduced Darwinian fitness is shown by Oregon-R isogenic. These results suggest a direct relation between the degree of heterozygosis and Darwinian fitness. The AA. emphazise that the same difficulties arise in the exact determination of the rate of development due to the rythmicity of emergency in Lrosophila. With respect to the trait rate of development, the heterozygotes are less variable than inbred populations and therefore are more buffered to environment...

Summary The AA. demonstrate the existence of sexual selection, under certain experimental conditions against individuals of the mutant strain ssa (autosomic mutation concerning the III segment of the antennae: tarsuslike aristae). The results of the experiments show that when a normal male and a mutant male are left together for 24h in competition for a mutant female (or a heterezigous fenale), then the mutant male is usually not favoured. In another series of experiments in which a normal female and a mutant female were left together with only one male, normal or mutant, then a preference was shown towards the normal individuals. According to Mayr the antennae play a very important role in mating discrimination. Moreover it would seem that most authors have accepted the viewpoint that females are responsible for sexual selection. On the basis of the results obtained, the present experiments would suggest that a sexual selection is a result of a selection operated on individuals able to reach the necessar...

A general method is described for approximating a specified curve with a continuous sequence of arcs in such a way to minimize a suitable norm of the distance between the two over the approximation interval. The arcs, pieced together continuously, may belong to any curve which satisfies a linear differential equation of general type, with forcing functions taken constant in each interval. By a suitable application of the principle of optimality, a computer algorithm is derived to find the values of the breakpoints and forcing functions. The computational difficulties are discussed; several simplifications in various cases of interest are derived, and numerical examples are given.

Necessary and sufficient conditions for the optimization of multivariable discrete systems containing pure delays in dynamics, in performance index, and in constraints are investigated. Using nonlinear programming, it is shown that a discrete maximum principle similar to the one derived by Pearson and Sridhar [1] is valid for a subclass of these problems, that is, systems with linear dynamics, convex inequality constraints, and convex performance index.

A given curve is approximated by a sequence of arcs pieced together continuously in such a way that each arc satisfies a linear differential equation of a general type with input vector constant in each interval. A computer algorithm based on a modified version of the discrete maximum principle for the optimal determination of the switching points and input vectors is outlined.