Late effects in patients with Fanconi anemia following allogeneic hematopoietic stem cell transplantation from alternative donors.

Hematopoietic stem cell transplantation (HSCT) is curative for hematological manifestations of Fanconi anemia (FA). We performed a retrospective analysis of 22 patients with FA and aplastic anemia, myelodysplastic syndrome or acute myelogenous leukemia who underwent a HSCT at Memorial Sloan Kettering Cancer Center and survived at least 1 year post HSCT. Patients underwent either a TBI- (N=18) or busulfan- (N=4) based cytoreduction followed by T-cell-depleted transplants from alternative donors. Twenty patients were alive at time of the study with a 5- and 10-year overall survival of 100 and 84% and no evidence of chronic GvHD. Among the 18 patients receiving a TBI-based regimen, 11 (61%) had persistent hemochromatosis, 4 (22%) developed hypothyroidism, 7 (39%) had insulin resistance and 5 (27%) developed hypertriglyceridemia after transplant. Eleven of 16 evaluable patients (68%), receiving TBI, developed gonadal dysfunction. Two patients who received a TBI-based regimen died of squamous cell carcinoma. One patient developed hemochromatosis, hypothyroidism and gonadal dysfunction after busulfan-based cytoreduction. TBI appears to be a risk factor for malignant and endocrine late effects in the FA host. Multidisciplinary follow-up of patients with FA (including cancer screening) is essential for early detection and management of late complications, and improving long-term outcomes.

Observation of electromagnetically induced transparency and slow light in the dark state--bright state basis.

The quantum coherence phenomenon of electromagnetically induced transparency (EIT) is observed in a three-level system composed of an excited state and two coherent superpositions of the two ground-state levels. This peculiar ground state basis is composed of the so-called bright and dark states of the same atomic system in a standard coherent population trapping configuration. The characteristics of EIT, namely, width of the transmission window and reduced group velocity of light, in this unusual basis, are theoretically and experimentally investigated and are shown to be essentially identical to those of standard EIT in the same system.

Localization and delocalization of energy in a Peyrard-Bishop chain.

This paper studies energy localization conditions in lattices of the type proposed by Peyrard and Bishop. Homogeneous and inhomogeneous lattices are analyzed and the role of interfaces in the latter is emphasized. Simulations allowed us to identify critical energy values for the existence of localization. After a certain energy value, it is possible to observe the loss of energy localization along the chain.

A model coupling vibrational and rotational motion for the DNA molecule.

We investigate a mechanical model for the DNA molecule using an extension of the Peyrard and Bishop model. In the present model, there are two chains of oscillators linked by a Morse potential, which represent the hydrogen bonds. The rotational and vibrational motions of each base pair are considered and the coupling for these motions are introduced by a nonlinear combination of them in the Morse potential. In this context, thermodynamics and structural properties are discussed.

Energy localization in the phi4 oscillator chain.

We study energy localization in a finite one-dimensional phi(4) oscillator chain with initial energy in a single oscillator of the chain. We numerically calculate the effective number of degrees of freedom sharing the energy on the lattice as a function of time. We find that for energies smaller than a critical value, energy equipartition among the oscillators is reached in a relatively short time. On the other hand, above the critical energy, a decreasing number of particles sharing the energy is observed. We give an estimate of the effective number of degrees of freedom as a function of the energy. Our results suggest that localization is due to the appearance, above threshold, of a breather-like structure. Analytic arguments are given, based on the averaging theory and the analysis of a discrete nonlinear Schrödinger equation approximating the dynamics, to support and explain the numerical results.

Insomnia, fatigue, anxiety, depression, and quality of life of cancer patients undergoing chemotherapy.

The purposes of this study were to examine: (a) the relationships between the symptoms of insomnia and fatigue and the psychological factors of anxiety and depression, and; (b) the relationships between these psychological and symptom variables and quality of life in cancer patients who were receiving chemotherapy. The Theory of Unpleasant Symptoms was the framework for the study. A descriptive correlational design was used in a secondary analysis of data obtained from a sample of 263 cancer patients who were undergoing chemotherapy. Insomnia, fatigue, depression, and anxiety were positively correlated with one another (r = .26 to r = .69, p < .001) and negatively correlated with quality of life (r = -.28 to r = -.63, p < .001). Women had more anxiety and fatigue and poorer quality of life than did men. Older age was associated with better quality of life and less insomnia, fatigue, anxiety, and depression. Multiple regression analysis revealed that the symptoms and psychological variables explained 47% of the variance in quality of life, with the largest proportion of the variance explained by depression. Fatigue and insomnia explained only 4% of the variance in quality of life in excess of that contributed by the psychological factors. Although overall depression levels were low in this sample, these findings suggest that insomnia and fatigue are related to depression and that depression is more closely associated with quality of life than are insomnia and fatigue.

Levels of dissociation in detoxified substance abusers and their relationship to chronicity of alcohol and drug use.

This study compared the frequency and types of dissociative experiences reported by detoxified alcoholics and drug abusers, and examined the relationship between dissociation and recent and lifetime use of alcohol, cannabis, cocaine, and heroin. One hundred thirty-eight self-referred male veterans detoxified from alcohol (N=62) and drugs (N=76) on inpatient units at a Veterans Affairs hospital completed questionnaires including the Dissociative Experiences Scale. Three types of dissociative experiences were examined: amnesia, depersonalization/derealization, and absorption. Ninety-one of the patients were also given the Addiction Severity Index interview to determine their histories of recent (past 30 days) and lifetime drug and alcohol use. High levels of dissociation were found in both groups, with alcoholics reporting higher levels of all three types of dissociative experiences than drug addicts. Chronicity (lifetime years) of both alcohol and cocaine use was significantly correlated with dissociation scores. The amnestic effect of chronic cocaine use persisted even after controlling for the effects of chronic alcohol use. In contrast, no dissociative effects of recent (past month) use of alcohol or drugs were found. These findings suggest that dissociation may be a chronic residual effect of long-term substance abuse, including both alcohol and cocaine. Implications are discussed for the treatment of chronic substance abusers.

Conformational features of galacturonans. I. Structure and energy minimization of charged and uncharged galacturonan dimeric units.

Structural parameters (e.g. the geometry, partial charges and dipole moment) of the alpha-D-galacturonic residue have been calculated by using semi-empirical quantum mechanical methods on several combinations of either the uncharged or charged forms, GalAH and GalA-, respectively. Three residue types have been explored: (i) the isolated residue, termed GEO1 and GEO1C for GalAH and GalA-, respectively; (ii) the residue with a methyl group attached to the O4 and O1 positions (GEO2 and GEO2C); and (iii) the internal residue in a trimer, e.g. GalAH-GalAH-GalAH or the corresponding fully charged version (GEO3 and GEO3C). The presence of a charged group in the galacturonate residue and the distribution of the excess negative charge on the molecule lead to significant differences in the structural parameters in comparison with those of the uncharged galacturonic residue. These perceptible differences in internal coordinates of GalAH and GalA- residues appear to play a major role in the delimitation of the conformational space that is accessible to the dimers, as clearly seen by inspection of the conformational maps. Although the overall features seem alike, the maps show that the position of the minimum and the shape of the lower energy region significantly change if one or both residues in the dimer are charged. The relevance of these results for the conformational properties of polygalacturonate chains is discussed elsewhere (Ruggiero et al. Int. J. Biol. Macromol. 1995, 17, 213-218).

Conformational features of galacturonans. II. Configurational statistics of pectic polymers.

The unperturbed dimensions of poly-alpha-D-galacturonic acid (PGA) as a function of the degree of polymerization (n) and degree of ionization (%GalA-) have been determined by molecular mechanics and Monte Carlo methods. Chain extensions appear to depend substantially on contributions arising from local redistributions of charge on charged and uncharged galacturonic acid residues. Inclusion of methyl-esterified galacturonic acid units results in increased chain extensions. Incorporation of alpha-(1-->2)-L-rhamnose units causes abrupt changes in chain propagation and a reduction in calculated chain extension.

Initial reliability and validity of a new retrospective measure of child abuse and neglect.

OBJECTIVE: This report presents initial findings on the reliability and validity of a new retrospective measure of child abuse and neglect, the Childhood Trauma Questionnaire. METHOD: Two hundred eighty-six drug- or alcohol-dependent patients were given the Childhood Trauma Questionnaire as part of a larger test battery, and 40 of these patients were given the questionnaire again after an interval of 2 to 6 months. Sixty-eight of the patients were also given a structured interview for child abuse and neglect, the Childhood Trauma Interview, that was developed by the authors. RESULTS: Principal-components analysis of responses on the Childhood Trauma Questionnaire yielded four rotated orthogonal factors: physical and emotional abuse, emotional neglect, sexual abuse, and physical neglect. Cronbach's alpha for the factors ranged from 0.79 to 0.94, indicating high internal consistency. The Childhood Trauma Questionnaire also demonstrated good test-retest reliability over a 2- to 6-month interval (intraclass correlation = 0.88), as well as convergence with the Childhood Trauma Interview, indicating that patients' reports of child abuse and neglect based on the Childhood Trauma Questionnaire were highly stable, both over time and across type of instruments. CONCLUSIONS: These findings provide strong initial support for the reliability and validity of the Childhood Trauma Questionnaire.

Increased calcium affinity of a fucosylated chondroitin sulfate from sea cucumber.

Calcium binding and charge distribution on a fucosylated chondroitin sulfate and a standard chondroitin 6-sulfate have been studied using a metallochromic indicator and conductimetric titrations. The fucosylated chondroitin sulfate has a approximately 5-fold greater affinity for calcium ions than the standard chondroitin 6-sulfate. Possibly, this increased affinity for calcium ions is due to the branches on the fucosylated chondroitin sulfate, since the calcium affinity of an unbranched, sulfated fucan is similar to that of the standard chondroitin 6-sulfate. More charged groups per disaccharide unit (and a shorter distance between these groups) also distinguish the fucosylated chondroitin sulfate from standard chondroitin 6-sulfate. Comparison between native and chemically modified (desulfated or carboxyl-reduced) polysaccharides suggests that the sulfate esters are responsible for the increased charge density of the fucosylated chondroitin sulfate and that the presence of the fucose branches does not alter the length of the repetitive units which compose the central core of chondroitin from sea cucumber. These results are consistent with the chemical studies of these two polysaccharides.

Glutamate dehydrogenase from the hyperthermophile Pyrococcus furiosus. Thermal denaturation and activation.

Pyrococcus furiosus is a marine hyperthermophile that grows optimally at 100 degrees C. Glutamate dehydrogenase (GDH) from P. furiosus is a hexamer of identical subunits and has an M(r) = 270,000 +/- 5500 at 25 degrees C. Electron micrographs showed that the subunit arrangement is similar to that of GDH from bovine liver (i.e. 3/2 symmetry in the form of a triangular antiprism). However, GDH from P. furiosus is inactive at temperatures below 40 degrees C and undergoes heat activation above 40 degrees C. Both NAD+ and NADP+ are utilized as cofactors. Apparently the inactive enzyme also binds cofactors, since the enzyme maintains the ability to bind to an affinity column (Cibacron blue F3GA) and is specifically eluted with NADP+. Conformational changes that accompany activation and thermal denaturation were detected by precision differential scanning microcalorimetry. Thermal denaturation starts at 110 degrees C and is completed at 118 degrees C. delta(cal) = 414 Kcal [mol GDH]-1. Tm = 113 degrees C. This increase in heat capacity indicates an extensive irreversible unfolding of the secondary structure as evidenced also by a sharp increase in absorbance at 280 nm and inactivation of the enzyme. The process of heat activation of GDH from 40 to 80 degrees C is accompanied by a much smaller increase in absorbance at 280 nm and a reversible increase in heat capacity with delta(cal) = 187 Kcal [mol GDH]-1 and Tm = 57 degrees C. This absorbance change as well as the moderate increase in heat capacity suggest that thermal activation leads to some exposure of hydrophobic groups to solvent water as the GDH structure is opened slightly. The increase in absorbance at 280 nm during activation is only 12% of that for denaturation. Overall, GDH appears to be well adapted to correspond with the growth response of P. furiosus to temperature.

Charge effect in the interaction of doxorubicin and derivatives with polydeoxynucleotides.

The equilibrium interaction of doxorubicin and its N-acetyl derivative with a series of purine-pyrimidine alternating polydeoxynucleotides has been studied through spectrofluorometry to assess the relevance of the electrostatic contribution to DNA intercalation. The results have shown that: (a) the suppression of the positive charge on the aminosugar has: (I) a profound negative effect on the free energy of intercalation, as expected, and (II) a negligible influence on the base specificity, which supports the notion of an essentially electrostatic effect of N-acetylation on intercalation; (b) a reasonably good accord with the demands of a polyelectrolytic model, due to Friedman and Manning, is found.

Microbial manganese reduction mediated by bacterial strains isolated from aquifer sediments.

One hundred and five strains isolated from aquifer sediments andEscherichia coli ML30S were tested for their ability to reduce manganese oxides. Eighty-two strains, includingE. coli, reduced manganese. In most cases the bacterial activity decreased the pH and Eh below 6.75 and 350 mV, respectively, enhancing a spontaneous and nonspecific reduction of manganese. However, for 12 strains the reduction was specifically catalyzed by bacteria; the high pH and Eh values would not permit a spontaneous reduction of manganese. Some of the most active strains were identified as genera common in soils and waters, i.e.,Pseudomonas, Bacillus, Corynebacterium, andAcinetobacter. Two strains were studied in detail. One of the strains, identified asPseudomonas fluorescens, required contact between the cells and the manganese oxides for reduction to occur. The reduction was inhibited by 15 mM of sodium azide. The other strain, identified asAcinetobacter johnsonii, catalyzed manganese reduction by an inductive and dialyzable substance which was excreted by the bacteria. The mechanism involved has not been previously demonstrated.

Cancer of the piriform sinus: treatment by radiation therapy alone and with surgery.

To ascertain the optimal treatment for carcinoma of the piriform sinus, the authors determined survival rates and local and regional tumor growth for two groups of patients: those treated by radiation therapy alone (n = 209) and those treated by radiation therapy combined with surgery (n = 154). The two groups were similar with respect to the characteristics of primary tumor stage and degree of nodal involvement. The overall 3-year and 5-year actuarial survival rates were 19.2% and 15.5%, respectively. For 5-year actuarial survival, there was no significant difference between patients with T1 and T2 tumors, but there was a significant difference between patients with T1 + T2 tumors versus those with T3 tumor. There was no significant difference in 3- and 5-year survival between patients with N0 and N1 nodal involvement and those with N1 and N2 involvement, but there was a significant difference between patients with N0 versus those with N3 involvement. The 5-year actuarial survival rate is significantly better for patients who underwent surgery followed by radiation therapy than for those who received only radiation therapy. However, for patients with early-stage (T1 and T2) tumors, radiation therapy alone controls local tumor growth as well as the combination of surgery and radiation therapy does. For each treatment group, the causes of death and patterns of failure were studied and compared with investigations to date.

On the interaction of small molecules with hemoglobin: orientational effects of hydration layers in protein crystal.

The spin label TEMPO does not show a binding to hemoglobin molecule in solution. In the crystal however the spin label is bound and a considerable anisotropy in the ESR spectra is observed similar to that with covalent spin labeling. Since TEMPO is a small spherical molecule the anisotropy should be a consequence of the ordering in the crystal packing observed for the hydration layers. Besides the anisotropic sites (one per asymmetric unit) an isotropic signal is apparent. The population of these sites is sensitive to the temperature and above around 30 degrees C a transition is observed of the label from the anisotropic site to the isotropic one. This is consistent with a change in the hydration structure above this temperature so that the spin label is sensitive to the reorganization of water or crystallization. Results of simulations based on the relaxation theory in liquids are compared for different hemoglobin physical states: crystal, powder and solution. It is shown that the ESR parameters obtained in the crystal are very different from those used for spectral stimulation at low temperature.