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[Optimizing epilepsy therapy in children and adolescents with lamotrigine].

Lamotrigine is a broadly effective antiepileptic drug in mono- and add-on therapy for children and adolescents with focal and generalized epilepsies. Some epileptologists consider lamotrigine as the drug of primary choice in older school children and adolescents because of its good tolerability (no increase of body weight, no impairment of cognitive functions, due to new data probably no teratogenic properties). Lamotrigine can be used with good efficacy in numerable epilepsy diseases, such as tuberous sclerosis, juvenile neuronal lipofuscinosis and Rett syndrome. The first studies show that lamotrigine is also effective in children under 2 years of age. For therapy of difficult-to-treat epilepsies the combination of lamotrigine with valproate has proved as especially useful. This clinical observation is supported by new results of animal experiments. The dose-dependant and typical CNS side effects vertigo, ataxia, nausea, tremor and diplopia are found most frequently. The rate of allergic skin rashes which was very high before 1998 has decreased markedly by new dosage guidelines and is now as low as in older antiepileptic drugs. Lamotrigine does not impair cognitive functions, especially not memory and language. It has mood-stabilizing features and may improve quality of life. In animal experiments lamotrigine shows antiepileptogenic and neuroprotective effects.

Adolescent↗

PubMed2002

Bright compact breathers.

In this communication we will consider the potential of some general classes of nonlinear lattice models to support bright discrete compact breather solutions (compactlets). We analyze the conditions for which such solutions are possible and classify the models as belonging in three general categories: a class with no compact breather solutions, one with one-parameter families of solutions, and a class with "isolated" solutions (i.e., no free parameters). In the latter two cases we construct the solutions and analyze their linear stability. The drastically different stability features of these solutions in comparison with their smoothly decaying counterparts are discussed. Stable breather solutions with compact support are identified in the one-parameter families of solutions, while the corresponding solutions found in the zero-parameter families are always found to be unstable.

Journal Article↗

PubMed1987

Formulations of self and family systems.

The observations of systemic family therapy and self psychology fit together conceptually because both rest upon systems theory. Underlying assumptions common to both fields of inquiry are reviewed. The concept of the self and its parts is examined, with discussion of its systems properties featuring stability and change. Parallels are noted between healthy self-functioning and healthy family functioning; self-formation processes and family developmental processes; and sense of self and family paradigm. It is suggested that there are isomorphic patterns in these formulations that allow us to switch back and forth easily between the individual and the family. Two clinical case examples are also included.

Adolescent↗

PubMed2004

Cardiac neuronal hierarchy in health and disease.

The cardiac neuronal hierarchy can be represented as a redundant control system made up of spatially distributed cell stations comprising afferent, efferent, and interconnecting neurons. Its peripheral and central neurons are in constant communication with one another such that, for the most part, it behaves as a stochastic control system. Neurons distributed throughout this hierarchy interconnect via specific linkages such that each neuronal cell station is involved in temporally dependent cardio-cardiac reflexes that control overlapping, spatially organized cardiac regions. Its function depends primarily, but not exclusively, on inputs arising from afferent neurons transducing the cardiovascular milieu to directly or indirectly (via interconnecting neurons) modify cardiac motor neurons coordinating regional cardiac behavior. As the function of the whole is greater than that of its individual parts, stable cardiac control occurs most of the time in the absence of direct cause and effect. During altered cardiac status, its redundancy normally represents a stabilizing feature. However, in the presence of regional myocardial ischemia, components within the intrinsic cardiac nervous system undergo pathological change. That, along with any consequent remodeling of the cardiac neuronal hierarchy, alters its spatially and temporally organized reflexes such that populations of neurons, acting in isolation, may destabilize efferent neuronal control of regional cardiac electrical and/or mechanical events.

Animals↗

PubMed2006

Molecular characterization of a DNA fragment harboring the replicon of pBMB165 from Bacillus thuringiensis subsp. tenebrionis.

BACKGROUND: Bacillus thuringiensis belongs to the Bacillus cereus sensu lato group of Gram-positive and spore-forming bacteria. Most isolates of B. thuringiensis can bear many endogenous plasmids, and the number and size of these plasmids can vary widely among strains or subspecies. As far as we know, the replicon of the plasmid pBMB165 is the first instance of a plasmid replicon being isolated from subsp. tenebrionis and characterized. RESULTS: A 20 kb DNA fragment containing a plasmid replicon was isolated from B. thuringiensis subsp. tenebrionis YBT-1765 and characterized. By Southern blot analysis, this replicon region was determined to be located on pBMB165, the largest detected plasmid (about 82 kb) of strain YBT-1765. Deletion analysis revealed that a replication initiation protein (Rep165), an origin of replication (ori165) and an iteron region were required for replication. In addition, two overlapping ORFs (orf6 and orf10) were found to be involved in stability control of plasmid. Sequence comparison showed that the replicon of pBMB165 was homologous to the pAMbeta1 family replicons, indicating that the pBMB165 replicon belongs to this family. The presence of five transposable elements or remnants thereof in close proximity to and within the replicon control region led us to speculate that genetic exchange and recombination are potentially responsible for the divergence among the replicons of this plasmid family. CONCLUSION: The replication and stability features of the pBMB165 from B. thuringiensis subsp. tenebrionis YBT-1765 were identified. Of particular interest is the homology and divergence shared between the pBMB165 replicon and other pAMbeta1 family replicons.

Bacillus thuringiensis↗

PubMed2003

A comparison of the decontamination efficacy of foam-making blends based on cationic and nonionic tensides against organophosphorus compounds determined in vitro and in vivo.

The ability of foam-making blends to decontaminate the skin exposed to organophosphorus compounds was tested. The appropriate composition and rheological features (stability, grade of foaming) of tested blends were evaluated by in vitro methods and their ability to remove the contaminants from hard surface and to transform the contaminants into nontoxic compounds was evaluated by in vivo methods. The blends containing cationic and nonionic tensides as well as alkalized hydrogen peroxide seem to be the most efficacious to decontaminate the skin exposed to organophosphorus compounds according to the literature data. The composition of tested blends was optimized because particular components often have antagonistic effects. Cationic tensides support the reactivity of the blend and control the grade of foaming. Nonionic tensides control the stability of the foams but also react as retardants of the reactivity of the foams. Hydrogen peroxide is a real reacting component when it is transformed into hydrogen peroxide anion. It also acts as buffer if pH is higher than 11. Our in vivo results confirm that Desam OX (34 and 68%) and the foam-making blend containing benzalkonium chloride--Althosan MB (8%), Slovasol 2510 (2%) and hydrogen peroxide (3%) alkalized at pH 12 seem to be the most efficacious to remove contaminants (soman, VX) from the skin and transform them into nontoxic compounds. Therefore they could be used for primary decontamination of chemical casualties contaminated with nerve agents in the field condition.

Administration, Cutaneous↗

PubMed2003

[The chemistry of pericyclic reactions and their application to syntheses of heterocyclic compounds].

Diels-Alder reactions of benzylidenecyanomethyl-1,3-benzothiazoles 17 and -1,3-benzoxazoles 18 as 1-aza-1,3-butadienes are described. The dienes 17 and 18 featuring stabilized imine moieties in the form of heteroaromatic rings react with both electron-deficient and electron-rich dienophiles to give corresponding cycloadducts regioselectively. The cycloadditions of the intramolecular systems 34c,d and 35c,d proceeded smoothly via the exo-transition state, stereoselectively affording polycyclic compounds 36c,d and 37c,d in good to excellent yields. The diene systems of 17 and 18 were extended to dienes 19a-c with ester groups at diene-4-positions. Dienes 19a-c exhibited high Diels-Alder reactivities with electron-rich alkenes. Dienes 19a-c also reacted with allyl alcohols 55-58 in the presence of stanoxane catalyst 53 to give cycloadducts 59-62 via transesterification and intramolecular cycloaddition. Although alpha-alkoxycarbonylnitrones 64 have been very attractive nitrones for the syntheses of amino acids, the nitrones 64 exist as equilibrating mixtures of (E)-64 and (Z)-64. To solve this problem, three methods were explored: 1) sequential transesterification and intermolecular cycloaddition of nitrones 64 with allyl alcohols; 2) use of chiral and geometry-fixed nitrone 84; and 3) selective activation of (Z)-64 by Eu(fod)3. These methods were applied to syntheses of nikkomycins, clavalanine, and beta-substituted alpha-amino acids. The reactions of photoinduced carbonyl ylides from alpha,beta-unsaturated gamma,delta-epoxy nitriles were studied. Direct irradiation (lambda = 254 nm) of (E)-129 led selectively to products arising from the carbonyl ylide XXV or the carbene intermediate XXVI. The carbonyl ylides generated from (E)-129, (E)-139, and (Z)-143 were trapped with MeOH in the presence of amine, affording the corresponding acetals in moderate yields (Schemes 42 and 43). Photocyclization reactions of delta-hydroxyalkyl epoxy nitriles 148a-e led to spiro acetals arising from the carbonyl ylides (Scheme 45). The photoinduced carbonyl ylides from the epoxy dinitriles 158 and 160-163 underwent 1,3-dipolar cycloaddition with enol ethers, leading to a tetrahydrofuran system (Schemes 49 and 50, Table 14). Electrocyclization of 3-butadienylindoles 184 to intermediary dihydrocarbazoles XXXII followed by elimination of MeOH gave 3-oxyganated carbazoles 185, which were transformed to carbazole alkaloids hyellazole 168, 4-demethoxycarbazomycin B 170 and carazostatin 171, respectively. Claisen rearrangement of 3-(1-amino-1-vinyloxy) indolines derived from 3-hydroxyindolines 192 and amide acetal 193 gave indol-4-ylacetamides 194, which was reduced to afford 4-(2-aminoethyl) indoles 198, which has a framework of biologically active 4-substituted indole compounds. Claisen rearrangement of 3-allyloxyindoles produced in situ by condensation of indolin-3-ones 202 with allyl alcohols 203 and 206-211 gave 2-allylindolin-3-ones 204, 205 and 212-220. The domino reactions, Horner-Wadsworth-Emmons olefination of 2-allyloxyindole 233, isomerization, and Claisen rearrangement produced 3-allylindolin-2-one 234, which was derivatized to 3a-allylpyrrolo [2,3-b] indole alkaloid, flustramine C 221. Reverse aromatic Cope rearrangement of 2-allyl-3-indolidene acetonitriles 241-243, formed by Horner-Wadsworth-Emmons reaction of 2-allylindolin-3-ones 238-240, afforded indoles 244-246.

Aza Compounds↗

PubMed2004

Folding Trp-cage to NMR resolution native structure using a coarse-grained protein model.

We develop a coarse-grained protein model with a simplified amino acid interaction potential. Using this model, we perform discrete molecular dynamics folding simulations of a small 20-residue protein--Trp-cage--from a fully extended conformation. We demonstrate the ability of the Trp-cage model to consistently reach conformations within 2-angstroms backbone root-mean-square distance from the corresponding NMR structures. The minimum root-mean-square distance of Trp-cage conformations in simulations can be <1 angstroms. Our findings suggest that, at least in the case of Trp-cage, a detailed all-atom protein model with a molecular mechanics force field is not necessary to reach the native state of a protein. Our results also suggest that the success of folding Trp-cage in our simulations and in the reported all-atom molecular mechanics simulation studies may be mainly due to the special stabilizing features specific to this miniprotein.

Algorithms↗

PubMed1995

Automated chromosome classification limitations due to image processing.

Automated chromosome classification from metaphase spreads has been a difficult research problem over the past 30 years. Numerous techniques have been implemented to address the research problem. Image processing techniques support many methods utilized for automated and/or semiautomated karyotyping. Some current systems correctly classify individual chromosomes at high rates but lack the capability to properly classify chromosomes for entire cells consistently. Most systems attain high classification rates ignoring overlapping metaphase chromosomes for testing purposes. Chromosome classification depends on identifying features common to each chromosome class or number. Some of the common features incorporated into various chromosome classification systems include length, centromere location, banding pattern, and width. To complicate classification, chromosome features tend to vary not only between people but from cell to cell for the same person. Additionally, chromosomes found in metaphase spreads may have any orientation and virtually any degree of overlap with other chromosomes present. Besides the inherent barriers impeding chromosome classification, many systems perform image processing operations to the chromosomes for feature determination. Image processing operations, such as image rotation, that manipulate the chromosome grey-level information may distort the feature calculations utilized in karyotyping. Consequently, feature stability becomes an important issue for improving karyotyping capability.

Chromosomes, Human↗

PubMed2003

Early-onset schizophrenia in children with mental retardation: diagnostic reliability and stability of clinical features.

OBJECTIVES: To investigate the presentation of early-onset schizophrenia in children with mental retardation (MR) and the stability of clinical features over time. METHOD: A purpose-designed assessment protocol was developed based on best-practice recommendations in the research literature. Diagnostic reliability, investigated in a group of 20 children with MR, was found to be very good (kappa = 0.87). Using this protocol, the clinical service identified 10 children with an initial diagnosis of schizophrenia. This group was then reassessed 2 years later. RESULTS: At the end of 2 years, 8 of the 10 children with schizophrenia still warranted this diagnosis. However, there was considerable instability in relation to certain diagnostic criteria, notably delusions and visual hallucinations. In all cases some improvements in severity were seen at follow-up. However, the eight whose schizophrenia was confirmed at follow-up showed major deterioration in cognitive level. CONCLUSIONS: It is possible to make reliable diagnoses of early-onset schizophrenia in people with MR, provided the assessment system is carefully structured and pays attention to all the important sources of information. However, symptoms should be reviewed frequently, particularly those that cannot be substantiated by patient interview.

Adolescent↗

PubMed1994

Unique structural features important for stabilization versus polarization of the alpha 2A-adrenergic receptor on the basolateral membrane of Madin-Darby canine kidney cells.

The alpha 2A-adrenergic receptor (alpha 2AAR) is polarized to the basolateral membrane of Madin-Darby canine kidney cells via direct targeting. Examination of mutant alpha 2AAR reveals that direct delivery is independent of NH2-terminal glycosylation, COOH-terminal acylation, or protein sequences within the large third cytoplasmic loop or COOH-terminal tail. Combined mutation of these structural features also does not perturb alpha 2AAR delivery, suggesting that a three-dimensional structure imparted by non-contiguous endofacial sequences does not confer alpha 2AAR targeting and that motifs in or near the bilayer must be involved in targeting of the alpha 2AAR. Mutation of a conserved Asp residue in transmembrane two that alters receptor-G-protein interactions also does not impair alpha 2AAR targeting. Finally, modification of sequences in transmembrane seven that resemble tyrosine-containing endocytosis motifs utilized for targeting by some proteins does not perturb alpha 2AAR sorting. Interestingly, deletion of the large third cytoplasmic loop of the alpha 2AAR decreases receptor half-life on the basolateral surface from approximately 11 to 4.5 h without altering the ability of the alpha 2AAR to couple to G-proteins. These data suggest that although targeting of the alpha 2AAR likely involves bilayer sequences, the third cytoplasmic loop may contain structural features that promote stabilization of the alpha 2AAR on the basolateral surface of Madin-Darby canine kidney cells.

Amino Acid Sequence↗

PubMed2001

Comparison between CUUG and UUCG tetraloops: thermodynamic stability and structural features analyzed by UV absorption and vibrational spectroscopy.

CUUG loop is one of the most frequently occurring tetraloops in bacterial 16S rRNA. This tetraloop has a high thermodynamic stability as proved by previous UV absorption and NMR experiments. Here, we present our results concerning the thermodynamic and structural features of the 10mer 5'-r(GCG-CUUG-CGC)-3', forming a highly stable CUUG tetraloop hairpin in aqueous solution, by means of several optical techniques (UV and FT-IR absorption, Raman scattering). UV melting profile of this decamer provides a high melting temperature (60.7 degrees C). A set of Raman spectra recorded at different temperatures allowed us to analyze the order-to-disorder (hairpin-to-random coil) transition. Assignment of vibrational markers led us to confirm the particular nucleoside conformation, and to get information on the base stacking and base pairing in the hairpin structure. Moreover, comparison of the data obtained from two highly stable CUUG and UUCG tetraloops containing the same nucleotides but in a different order permitted an overall discussion of their structural features on the basis of Raman marker evidences.

Nucleic Acid Conformation↗

PubMed2004

Co-morbidity and stability of melancholic features in DSM-IV major depressive disorder.

BACKGROUND: The descriptive validity of the melancholic features specifier of the DSM-IV major depressive disorder (MDD) is uncertain. Little is known about its relationship to psychiatric co-morbidity, stability across episodes, or strength in predicting course of illness. METHOD: The Vantaa Depression Study (VDS) is a prospective, naturalistic cohort study of 269 patients with a new episode of DSM-IV MDD who were interviewed with SCAN and SCID-II between 1 February 1997 and 31 May 1998, and again at 6 and 18 months. Ninety-seven (36%) MDD patients met DSM-IV criteria for the melancholic features specifier, and were contrasted with 172 (64 %) subjects with a non-melancholic MDD. The duration of the index episode was examined using a life chart. RESULTS: We found no difference in rates of any current co-morbid Axis I or II disorders between melancholic and non-melancholic depressed patients. Of those who had melancholic features at the index episode and subsequent episodes during the 18-month follow-up, only 22 % (5/23) presented melancholic features during the latter. The non-melancholic subtype switched to melancholic in 25 % (8/32) of cases. Differences in the course of melancholic and non-melancholic depression were very minor. CONCLUSIONS: The descriptive validity of the DSM-IV melancholic features specifier may be questionable in MDD. There appear to be no major differences in current co-morbidity, or course of depression between melancholic and non-melancholic patients. The consistency of DSM-IV melancholic features across episodes appears weak.

Adult↗

PubMed2026

Using the DNA language model, GROVER, to parse effects of sequence, chromatin and regulatory features on genome stability.

MOTIVATION: Genome stability is shaped by DNA sequence and chromatin context, but their relative contributions to double-strand break (DSB) sensitivity remain unclear. RESULTS: We show that the DNA language model, GROVER, can infer DSB location based on sequence. DSB hotspots tend to contain GC-rich sequences that belong to promoters, genes and short interspersed nuclear elements (SINEs). Additionally, we identified several specific short sequences (tokens) that are associated with modulating DSB sensitivity. Another model using chromatin and genome regulatory features outperforms the sequence-only model, highlighting complementary and cell-type specific information. Integrating sequence and genome biological features yields the best performance, demonstrating their synergy. Analyzing this model revealed that, dependent on the sample, genome stability information encoded in H3K36me3 and DNase-seq can be learned from the sequence, but not H3K27ac or H3K9me3. Embedding chromatin data directly into the GROVER architecture enabled cell-type specific modeling with performance matching the full chromatin feature model. Our results suggest that while chromatin and regulatory context provides important information, such as cell-type specificity, much of the information shaping DSB patterns is already encoded in the DNA sequence itself. Our integrative modeling approach not only reveals DSB patterns but also provides a generalizable strategy for tracing predictions in genomic data. AVAILABILITY: Data, models, and a tutorial are available on Zenodo.

Chromatin↗

PubMed2002

Propofol-sufentanil anesthesia for thyroid surgery: optimal concentrations for hemodynamic and electroencephalogram stability, and recovery features.

UNLABELLED: Hypnotics and opioids interact synergistically to block responses to surgery and different dose combinations may be used to provide adequate anesthesia. In this study, we sought to determine the optimal concentrations of propofol and sufentanil, given by target-controlled infusions, to ensure hemodynamic stability, adequate hypnosis (assessed by electroencephalogram bispectral index), and fast recovery for a moderately painful operation. Forty-five patients, ASA physical status I or II, undergoing thyroidectomy, were randomly assigned to a sufentanil target concentration (STC) that was maintained throughout surgery (0.1, 0.2, or 0.3 ng/mL). The propofol target concentration was adjusted to keep mean arterial blood pressure within 30% of a reference value, and bispectral index between 40 and 60. Adequate anesthesia was obtained in all groups. Hypertension and clinically dangerous movements were more frequent with the small STC, and hypotension requiring treatment was more frequent with the large STC. Propofol target concentration during surgery decreased significantly with increasing STC (median at thyroid removal 5.0, 4.0, and 2.5 microg/mL, respectively) as well as the propofol consumption (740, 668, 474 mg/h). The 0.3 ng/mL STC significantly delayed the return of spontaneous breathing. IMPLICATIONS: Given as a target-controlled infusion for thyroid surgery, sufentanil 0.3 ng/mL for intubation and 0.2 ng/mL during surgery, combined with propofol 4 microg/mL (corresponding to a maintenance infusion rate of approximately 7-10 mg. kg(-1). h(-1)), is recommended to ensure both optimal intraoperative stability and fast recovery.

Adolescent↗

PubMed1996

A correlation between thermal stability and structural features of staphylokinase and selected mutants: a Fourier-transform infrared study.

Variants of recombinant staphylokinase (Sak) were investigated by Fourier-transform infrared spectroscopy: Sak (wild type), Sak-M26A, Sak-M26L, and Sak-G34S/R36G/R43H (Sak-B). Estimation of the secondary structure and hydrogen-deuterium exchange experiments revealed the existence of fast-exchanging and strongly solvent-exposed fractions of the helical structures in the two samples Sak and Sak-M26L. These two samples are also thermally less stable with unfolding transition temperatures of 43.7 degrees C (Sak) and 43.5 degrees C (Sak-M26L), respectively. On contrast, Sak-M26A and Sak-G34S/R36G/R43H have a slower hydrogen-deuterium exchange, have a smaller solvent-exposed portion of the helical part, and are more resistant against thermal unfolding; the transition temperatures are 51.7 degrees C and 59.3 degrees C, respectively. The secondary structure analysis was performed by two different approaches, by curve-fitting after band narrowing and by pattern recognition (factor analysis) based upon reference spectra of proteins with known crystal structure. Within the limits of the used methods, we are unable to detect significant differences in the secondary structure of the four variants of Sak. According to the results of the factor analysis, the portions of secondary structure elements were obtained to 16-20% alpha-helix, 28-30% beta-sheet, 23-27% turns, 28-30% irregular (random) and other structure. The sharp differences in the specific plasminogen-activating capacity (Sak, Sak-G34S/R36G/R43H and Sak-M26L are fully active, but Sak-M26A does not form a stable complex with plasminogen) are not reflected in the structural features revealed by the infrared spectra of this study.

Deuterium↗

PubMed2003

Thermodynamic stability and structural features of the J4/5 loop in a Pneumocystis carinii group I intron.

The J4/5 loop of the group I intron in the mouse-derived fungal pathogen Pneumocystis carinii is the docking site for the first step of the RNA-catalyzed self-splicing reaction and thus is a model of a potential drug target. This purine-rich asymmetric internal loop, 5'GGAAG/3'UAGU, is also thermodynamically more stable than other internal loops with two GU closing pairs and three nucleotides opposite two nucleotides. The results from optical melting, nuclear magnetic resonance spectroscopy, and functional group substitution experiments suggest that the GU closing pairs form and that sheared GA pairs form in the internal loop. The NMR spectra show evidence of conformational dynamics, and several GA pairings are possible. Thus, this dynamic loop presents several possible structures for potential binding of drugs that target group I self-splicing introns. The results also contribute to understanding the structural and dynamic basis for the function and thermodynamic stability of this loop.

Adenine↗

PubMed2006

Retinol and retinoic acid bind human serum albumin: stability and structural features.

Vitamin A components, retinol and retinoic acid, are fat-soluble micronutrients and critical for many biological processes, including vision, reproduction, growth, and regulation of cell proliferation and differentiation. The cellular uptake of Vitamin A is through specific interaction of a plasma membrane receptor with serum retinol-binding protein. Human serum albumin (HSA), as a transport protein, is the major target of several micronutrients in vivo. The aim of present study was to examine the interaction of retinol and retinoic acid with human serum albumin in aqueous solution at physiological conditions using constant protein concentration and various retinoid contents. FTIR, UV-vis, CD and fluorescence spectroscopic methods were used to determine retinoid binding mode, the binding constant and the effects of complexation on protein secondary structure. Structural analysis showed that retinol and retinoic acid bind non-specifically (H-bonding) via protein polar groups with binding constants of K(ret)=1.32 (+/-0.30)x10(5)M(-1) and K(retac)=3.33 (+/-0.35)x10(5)M(-1). The protein secondary structure showed no alterations at low retinoid concentrations (0.125 mM), whereas at high retinoid content (1mM), an increase of alpha-helix from 55% (free HSA) to 60% and a decrease of beta-sheet from 22% (free HSA) to 18% occurred in the retinoid-HSA complexes. The results point to a partial stabilization of protein secondary structure at high retinoid content.

Humans↗