Effects of food on the pharmacokinetics of ponatinib in healthy subjects.

WHAT IS KNOWN AND OBJECTIVE: Ponatinib is a potent oral tyrosine kinase inhibitor with activity against BCR-ABL, the primary driver of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. This single-centre, single-dose, randomized, open-label, three-period crossover study evaluated the pharmacokinetics and bioavailability of a single oral dose of ponatinib (45-mg tablet) under fasting conditions and following consumption of high- and low-fat meals by healthy subjects. METHODS: Subjects were randomly assigned to one of the six possible treatment sequences, each evaluating three ponatinib 45-mg treatments: administered under fasting conditions; administered after a high-fat meal; or administered after a standardized low-fat meal. The high-fat meal derived approximately 50% of its total caloric content from fat, with approximately 150, 250 and 500-600 calories derived from protein, carbohydrates and fat, respectively (total of approximately 900-1000 calories). The standardized low-fat meal derived no more than 20% of total caloric content from fat, with approximately 56, 428 and 63 calories derived from protein, carbohydrates and fat, respectively (total of approximately 547 calories). During each of the three treatment periods, blood samples were collected predose and at 13 time points over the 96-h post-dose interval. Plasma concentrations of ponatinib were measured by liquid chromatography/tandem mass spectrometry. Mixed-model analyses of variance (anova) were performed on natural log-transformed PK parameters Cmax and AUC0-∞. RESULTS AND DISCUSSION: Geometric mean maximum plasma concentration (Cmax) values for the fasted, low-fat and high-fat regimens were 54·7, 51·6 and 51·5 ng/mL, respectively. Geometric mean area under the concentration-time curve from time zero to infinity (AUC0-∞) values for the fasted, low-fat and high-fat regimens were 1273, 1244 and 1392 h × ng/mL, respectively. All limits of the 90% CIs of the estimated geometric mean ratios for Cmax and all AUC comparisons fell within the 80%-125% margins. These results indicate that consumption of a high- or low-fat meal within 30 min prior to administration of ponatinib had no effect on the single-dose pharmacokinetics of ponatinib. WHAT IS NEW AND CONCLUSION: Food does not affect the single-dose pharmacokinetics of ponatinib. These data demonstrate that ponatinib may be administered with or without food.

Kondo-like transport and magnetic field effect of charge carrier fluctuations in granular aluminum oxide thin films.

Granular aluminum oxide is an attractive material for superconducting quantum electronics. However, its low-temperature normal state transport properties are still not fully understood, while they could be related to the unconventional phenomenon of the superconductivity in this material. In order to obtain useful information on this aspect, a detailed study of charge carrier fluctuations has been performed in granular aluminum oxide films. The results of electric noise measurements indicate the presence of a Kondo-type spin-flip scattering mechanism for the conducting electrons in the normal state, at low temperatures. Moreover, the magnetic field dependence of the noise amplitude suggests that interface magnetic moments are the main source of fluctuations. The identification of the nature of fluctuation processes is a mandatory requirement for the improvement of quality and performance of quantum devices.

Author Correction: Kondo-like transport and magnetic field effect of charge carrier fluctuations in granular aluminum oxide thin films.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

The unusual spectrum of mutations induced by hybrid dysgenesis at the Triplo-lethal locus of Drosophila melanogaster.

The Triplo-lethal locus (Tpl) is unique in its dosage sensitivity; no other locus in Drosophila has been identified that is lethal when present in three doses. Tpl is also haplo-lethal, and its function is still a mystery. Previous workers have found it nearly impossible to mutationally inactive Tpl other than by completely deleting the chromosomal region in which Tpl resides (83DE). We have utilized P-M hybrid dysgenesis in an effort to obtain new mutations of Tpl. We recovered 19 new duplications of Tpl, 15 hypomorphic mutations of Tpl (a previously rare class of mutation), and no null mutations. Surprisingly, 14 of the 15 hypomorphic alleles have no detectable P element sequences at the locus. The difficulty in recovering null mutations in Tpl suggests that it may be a complex locus, perhaps consisting of several genes with redundant functions. The relative ease with which we recovered hypomorphic alleles is in sharp contrast to previous attempts by others to mutagenize Tpl. A higher mutation rate with hybrid dysgenesis than with radiation or chemicals also suggests a peculiar genetic organization for the locus.

A recombinational hotspot at the triplo-lethal locus of Drosophila melanogaster.

In the genome of Drosophila melanogaster there is only one locus, Tpl, that is triplo-lethal; it is also haplo-lethal. Previous work has identified 3 hypomorphic alleles of Tpl which rescue animals carrying a duplication of Tpl, but which are not dominant lethals as null mutations or deficiencies would be. We have found that all three hypomorphic alleles act as site-specific hotspots for recombination when heterozygous with a wild-type homolog. Recombination between the flanking markers ri and Ki is increased 6.5-10.5-fold in the presence of Tpl hypomorphic alleles. The increased recombination was found to occur between Tpl and Ki, while recombination in other adjacent regions is unchanged. The use of isogenic Tpl+ controls, and the use of flanking intervals in the mutant chromosomes allows us to rule out the interchromosomal effect as a cause. We have also observed premeiotic recombination occurring at the Tpl hypomorphic alleles in male heterozygotes. We hypothesize that transposons are responsible for both the hypomorphic phenotype and the high frequency of recombination.

Transgene repeat arrays interact with distant heterochromatin and cause silencing in cis and trans.

Tandem repeats of Drosophila transgenes can cause heterochromatic variegation for transgene expression in a copy-number and orientation-dependent manner. Here, we demonstrate different ways in which these transgene repeat arrays interact with other sequences at a distance, displaying properties identical to those of a naturally occurring block of interstitial heterochromatin. Arrays consisting of tandemly repeated white transgenes are strongly affected by proximity to constitutive heterochromatin. Moving an array closer to heterochromatin enhanced variegation, and enhancement was reverted by recombination of the array onto a normal sequence chromosome. Rearrangements that lack the array enhanced variegation of white on a homologue bearing the array. Therefore, silencing of white genes within a repeat array depends on its distance from heterochromatin of the same chromosome or of its paired homologue. In addition, white transgene arrays cause variegation of a nearby gene in cis, a hallmark of classical position-effect variegation. Such spreading of heterochromatic silencing correlates with array size. Finally, white transgene arrays cause pairing-dependent silencing of a non-variegating white insertion at the homologous position.

The Triplo-lethal locus of Drosophila: reexamination of mutants and discovery of a second-site suppressor.

In the genome of Drosophila melanogaster there is a single locus, Triplo-lethal (Tpl), that causes lethality when present in either one or three copies in an otherwise diploid animal. Previous attempts to mutagenize Tpl produced alleles that were viable over a chromosome bearing a duplication of Tpl, but were not lethal in combination with a wild-type chromosome, as deficiencies for Tpl are. These mutations were interpreted as hypomorphic alleles of Tpl. In this work, we show that these alleles are not mutations at Tpl; rather, they are dominant mutations in a tightly linked, but cytologically distant, locus that we have named Suppressor-of-Tpl (Sul(Tpl)). Su(Tpl) mutations suppress the lethality associated with three copies of the Triplo-lethal locus and are recessive lethal. We have mapped Su(Tpl) to the approximate map position 3-46.5, within the cytological region 76B-76D.

Heterochromatic trans-inactivation of Drosophila white transgenes.

Position effect variegation of most Drosophila melanogaster genes, including the white eye pigment gene is recessive. We find that this is not always the case for white transgenes. Three examples are described in which a lesion causing variegation is capable of silencing the white transgene on the paired homologue (trans-inactivation). These examples include two different transgene constructs inserted at three distinct genomic locations. The lesions that cause variegation of white minimally disrupt the linear order of genes on the chromosomes, permitting close homologous pairing. At one of these sites, trans-inactivation has also been extended to include a vital gene in the vicinity of the white transgene insertion. These findings suggest that many Drosophila genes, in many positions in the genome, can sense the heterochromatic state of a paired homologue.

Suppression of a lethal trisomic phenotype in Drosophila melanogaster by increased dosage of an unlinked locus.

One of the most extreme examples of gene dosage sensitivity is the Triplo-lethal locus (Tpl) on the third chromosome of Drosophila melanogaster, which is lethal when present in either one or three copies. Increased dosage of an unlinked locus, Isis, suppresses the triplo-lethal phenotype of Tpl, but not the haplo-lethal phenotype. We have mapped Isis to the X chromosome region 7E3-8A5, and shown that the suppression is a gene dosage effect. Altered dosage of Isis in the presence of two copies of Tpl has no obvious effects. By examining the interactions between Isis dosage and Tpl we suggest that Isis does not directly repress Tpl expression, but acts downstream on the triplo-lethal phenotype of Tpl.

Impact of severity and chronicity of parental affective illness on adaptive functioning and psychopathology in children.

We report on the impact of specific indexes of the severity and chronicity of parental depression, measures of familial discord, and demographic variables as predictors of impaired adaptive functioning and psychopathology in children. Seventy-two children and their mothers from 37 families were interviewed in person. At least one biological parent in each family had a depressive disorder but neither parent had a history of mania, schizophrenia, or schizoaffective disorder. Almost every measure of severity and chronicity of depression in the biological parents has a statistically significant association with currently impaired adaptation and the presence of a DSM-III-diagnosed disorder in the children, as do the measures of increased discord among married or separated parents. Depression in the mother is more strongly associated with increased psychopathology in the children than is depression in the father.

Evaluation of the 11CO2 positron emission tomographic method for measuring brain pH. II. Quantitative pH mapping in patients with ischemic cerebrovascular diseases.

A practical method has been developed that, using 11CO2 and positron emission tomography (PET), computes and maps (a) "effective pH" (pHt), a weighted average of intra- and extracellular pH, and (b) "clearance" (K1), product of blood flow and 11CO2 extraction. This method, together with measurements of cerebral blood flow (CBF) and oxygen extraction fraction (OEF), was applied to 12 patients with cerebral ischemia or stroke. The regional K1 was positively correlated with CBF (n = +0.78). The k1/CBF ratio, representing the extraction fraction ratio of 11CO2 to H2 15O, was negatively correlated with CBF (r = -0.54), suggesting that 11CO2 extraction decreases as flow increases. In five acute stroke patients within 2 days of onset, the injured cortex had lower CBF (20.6 ml/min/100 g), higher OEF (78.1%), and lower pHt (6.96) than the contralateral cortex (CBF = 41.4 ml/min/100 g, OEF = 53.3%, pHt = 7.00), suggesting intracellular acidosis with intact cell membranes. In three stroke patients 5-8 days after onset, the injured cortex had higher CBF (60.9 ml/min/100 g), lower OEF (32.0%), and higher pHt (7.12) than the contralateral cortex (CBF = 45.3 ml/min/100 g, OEF = 58.0%, pHt = 7.06), which suggested an increase in extracellular volume compartment reflecting loss of cell membrane integrity. This method provides information on the regional tissue acid-base status and cell membrane integrity, which may be prognostic of tissue viability.

A crossover study of lecithin treatment of tardive dyskinesia.

The authors enrolled 21 patients in a random-order, crossover, double-blind trial of phosphatidylcholine (lecithin) 20 g/day and placebo. Fourteen patients completed at least 6 weeks of the second 8-week trial and were used for efficacy analyses. Side effects were minimal. The lecithin treatment effect--about one half of an Abnormal Involuntary Movement Scale point--was seen as a statistical effect of treatment order, based on differences between patients who took the active compound before or after they took the placebo. Clinically, however, the lecithin effect was negligible.

Maternal expressed emotion and parental affective disorder: risk for childhood depressive disorder, substance abuse, or conduct disorder.

Expressed emotion (EE) refers to a set of emotional aspects of speech for which ratings have been derived. Seven independent studies have established that higher EE ratings in the relatives of patients with schizophrenia predict higher rates of relapse in these patients and two studies have established an association of higher EE in spouses with relapse of depression in their mate. There are no previous studies of parental EE as a predictor of childhood affective disorder or other disorders not in the schizophrenia spectrum. In this study we investigated the relationship between the level of maternal EE and the incidence of DSM-III affective disorder (major depression or mania or dysthymia), substance abuse, or conduct disorder in 273 children. We found that a higher degree of maternal expressed emotion was associated with a three-fold increase in a child's risk (odds multiplier) for having at least one of the following diagnoses: depressive disorder (major depression or dysthymia), substance abuse, or conduct disorder. This increased risk acts in addition to the increased risk of child diagnosis associated with parental affective illness. Research and clinical implications are discussed.

Recovery and relapse in anorexia and bulimia nervosa: a 7.5-year follow-up study.

OBJECTIVE: To assess the course and outcome of anorexia nervosa (AN) and bulimia nervosa (BN) at a median of 90 months of follow-up in a large cohort of women with eating disorders. METHOD: A prospective, naturalistic, longitudinal design was used to map the course of AN and BN in 246 women. Follow-up data are presented in terms of full and partial recovery, predictors of time to recovery, and rates and predictors of relapse. RESULTS: The full recovery rate of women with BN was significantly higher than that of women with AN, with 74% of those with BN and 33% of those with AN achieving full recovery by a median of 90 months of follow-up. Intake diagnosis of AN was the strongest predictor of worse outcome. No predictors of recovery emerged among bulimic subjects. Eighty-three percent of women with AN and 99% of those with BN achieved partial recovery. Approximately one third of both women with AN and women with BN relapsed after full recovery. No predictors of relapse emerged. CONCLUSIONS: The findings suggest that the course of AN is characterized by high rates of partial recovery and low rates of full recovery, while the course of BN is characterized by higher rates of both partial and full recovery.

Affective disorder in childhood: separating the familial component of risk from individual characteristics of children.

In studying the risk of affective disorder in children, the investigator must deal with the problem that there are two possible units of analysis: the child and the family. An analysis based on children must take account of the intercorrelation within a sibship to produce correct results, while a family-based analysis makes it difficult to investigate individual characteristics of children that help determine the net risk. A two-stage iterative approach to this problem is proposed, yielding estimates of the effect of family-based factors (parental illness, family social class, marital status of parents) and individual factors (age and sex of child, previous non-affective illness). This technique is applied to a sample of 275 children from 143 families representing a wide range of familial risk for affective disorder. The final family-based model (predicting at least one child with affective disorder in the sibship) indicates a six-fold increase in risk to the child associated with maternal affective disorder (P less than 0.001), a three-fold increase in risk associated with paternal affective disorder (P less than 0.05) and divorce or separation of the biological parents, and a suggestion of increased risk in the highest social class (P = 0.06). The excess sibship risk, due to child factors age, prior anxiety disorder, and prior childhood diagnosis, contributed significantly to the family prediction (P less than 0.001).

Psychiatric disorder in adolescent offspring of parents with affective disorder in a non-referred sample.

The relationship between parental psychopathology and psychiatric disturbance in 153 offspring aged 6-19 was assessed in 81 families randomly selected from a prepaid health plan. Offspring of parents with a history of affective disorders and of parents with non-affective psychiatric disorders had higher rates of psychiatric diagnoses and poorer adaptive functioning than children of parents who had never experienced a psychiatric illness. Offspring whose parents had affective disorder had a rate of affective disorder of 30% compared to a rate of 2% in the rest of the sample. This relationship between parental affective disorder and poor child outcome was observed when the separated and divorced families were removed from the analyses.

31P Nuclear magnetic resonance spectroscopy findings in bipolar illness: a meta-analysis.

Published literature comparing 31P MR brain spectra of bipolar patients to healthy controls was evaluated, focusing on phosphomonoester (PME)/phosphodiester (PDE) resonance areas because these metabolites are related to membrane phospholipids and membrane defects in bipolar disorder have been suggested. Studies comparing PME and/or PDE values of bipolar subjects to values observed in healthy controls were reviewed. Data from the studies meeting our inclusion criteria (8 reports involving 139 bipolar and 189 comparison subjects) were grouped according to the mood state of the subjects. Meta-analyses of data were performed to compare PME and PDE levels of euthymic bipolar patients to healthy controls, as well as comparing PME levels during euthymia in bipolar subjects to values observed during manic and depressed states. The PME values of euthymic bipolar patients were found to be significantly lower than PME values of healthy controls. Depressed bipolar patients had significantly higher PME values in comparison to euthymic bipolar patients. No significant difference could be detected between the PDE values of bipolars and controls. This meta-analysis found support for trait- and possibly state-dependent abnormalities of membrane phospholipid metabolism, which may reflect a dysregulation in brain-signal transduction systems of relevance in bipolar illness.

SSRI and statin use increases the risk for vasospasm after subarachnoid hemorrhage.

BACKGROUND: Use of medications with vasoconstrictive or vasodilatory effects can potentially affect the risk for vasospasm after aneurysmal subarachnoid hemorrhage (SAH). METHODS: Using International Classification of Diseases-9 diagnostic codes followed by medical record review, the authors identified 514 patients with SAH admitted between 1995 and 2003 who were evaluated for vasospasm between days 4 and 14. The authors determined risks for vasospasm, symptomatic vasospasm, and poor clinical outcomes in patients with documented pre-hemorrhagic use of calcium channel blockers, beta-receptor blockers, ACE inhibitors, aspirin, selective serotonin reuptake inhibitors (SSRIs), non-SSRI vasoactive antidepressants, or statins. RESULTS: Vasospasm developed in 62%, and symptomatic vasospasm in 29% of the cohort. On univariate analysis, the risk for all vasospasm tended to increase in patients taking SSRIs (p = 0.09) and statins (p = 0.05); SSRI use increased the risk for symptomatic vasospasm (p = 0.028). The Cochran-Armitage trend test showed that the proportion of patients taking SSRIs and statins increased significantly across three worsening categories (none, asymptomatic, symptomatic) of vasospasm. Logistic regression analysis showed that SSRI use tended to predict all vasospasm (O.R. 2.01 [0.91 to 4.45]), and predicted symptomatic vasospasm (O.R. 1.42 [1.06 to 4.33]). Statin exposure increased the risk for vasospasm (O.R. 2.75 [1.16 to 6.50]), perhaps from abrupt statin withdrawal (O.R. 2.54 [0.78 to 8.28]). Age < 50 years, Hunt-Hess grade 4 or 5, and Fisher Group 3 independently predicted all vasospasm, symptomatic vasospasm, poor discharge clinical status, and death. CONCLUSION: Selective serotonin reuptake inhibitor and statin users have a higher risk for subarachnoid hemorrhage-related vasospasm. Whether the underlying disease indication, direct actions, or rebound effects from abrupt drug withdrawal account for the associated risk warrants further investigation.

Expansions of transgene repeats cause heterochromatin formation and gene silencing in Drosophila.

Closely linked repeats of a Drosophila P transposon carrying a white transgene were found to cause white variegation. Arrays of three or more transgenes produced phenotypes similar to classical heterochromatin-induced position-effect variegation (PEV), and these phenotypes were modified by known modifiers of PEV. This effect on the repeated transgenes was much stronger for a site near centric heterochromatin than it was for a medial site, and it strengthened with increasing copy number. Differences between variegated phenotypes could be accounted for if different topological structures were generated by pairing between closely linked repeat sequences. We propose that pairing of repeats underlies heterochromatin formation and is responsible for diverse gene silencing phenomena in animals and plants.

A novel RNA helicase gene tightly linked to the Triplo-lethal locus of Drosophila.

The Triplo-lethal (Tpl) locus of Drosophila is the only known locus which is lethal when present in three copies rather than the normal two. After recovering a hybrid-dysgenesis-induced mutation of Tpl we used a rapid combination of transposon tagging, chromosome microdissection and PCR to clone the P element that had transposed into the Tpl region. That P element is located within the gene for a new and unique member of the RNA helicase family. This new helicase differs from all others known by having glycine-rich repeats at both the amino and carboxyl termini. Curiously, genetic analysis shows that the P element inserted into this gene is not responsible for the Tpl mutant phenotype. We present possible explanations for these findings.