Polysialic acid as a drug carrier: evaluation of a new polysialic acid–epirubicin conjugate and its comparison against established drug carriers

This paper explores the potential of polysialic acid (PSA) as a carrier for low molecular weight anticancer drugs. A PSA–epirubicin (Epi) conjugate was synthesized and compared against Epi conjugates containing established carriers, namely: N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers, poly(ethylene glycol) (PEG) and polyglutamic acid (PGA). Biological assessments in the breast cancer cell line MCF-7 and in the anthracycline resistant MCF-7/DX showed that the PSA–Epi conjugate had the highest activity (40% and 30% cell death in the two cell lines at 1 mM Epi equiv., respectively). FACS studies confirmed internalization of all conjugates by cholesterol-dependent endocytosis. PSA–Epi showed release of Epi (40% at 5 h) when incubated with lysosome extracts. In vivo evaluation showed that all conjugates had a significantly longer half-life compared to free Epi. This study also allowed an investigation on the effect of the polymeric carrier on the biological activity of a conjugate, with the biodegradability of the carrier emerging as an important feature.

Cyclic prefixed OQAM-OFDM and its application to single-carrier FDMA

Single-carrier frequency division multiple access (SC-FDMA) has appeared to be a promising technique for high data rate uplink communications. Aimed at SC-FDMA applications, a cyclic prefixed version of the offset quadrature amplitude modulation based OFDM (OQAM-OFDM) is first proposed in this paper. We show that cyclic prefixed OQAMOFDM CP-OQAM-OFDM) can be realized within the framework of the standard OFDM system, and perfect recovery condition in the ideal channel is derived. We then apply CP-OQAMOFDM to SC-FDMA transmission in frequency selective fading channels. Signal model and joint widely linear minimum mean square error (WLMMSE) equalization using a prior information with low complexity are developed. Compared with the existing DFTS-OFDM based SC-FDMA, the proposed SC-FDMA can significantly reduce envelope fluctuation (EF) of the transmitted signal while maintaining the bandwidth efficiency. The inherent structure of CP-OQAM-OFDM enables low-complexity joint equalization in the frequency domain to combat both the multiple access interference and the intersymbol interference. The joint WLMMSE equalization using a prior information guarantees optimal MMSE performance and supports Turbo receiver for improved bit error rate (BER) performance. Simulation resultsconfirm the effectiveness of the proposed SC-FDMA in termsof EF (including peak-to-average power ratio, instantaneous-toaverage power ratio and cubic metric) and BER performances.

Socially anxious mothers’ narratives to their children, and their relation to child representations and adjustment

Anxious mothers’ parenting, particularly transfer of threat information, has been considered important in their children’s risk for social anxiety disorder (SAnxD), and maternal narratives concerning potential social threat could elucidate this contribution. Maternal narratives to their pre-school 4-5 year-old children, via a picture book about starting school, were assessed in socially anxious (N=73), and non-anxious (N=63) mothers. Child representations of school were assessed via Doll Play (DP). After one school term, mothers (CBCL) and teachers (TRF) reported on child internalizing problems, and child SAnxD was assessed via maternal interview. Relations between these variables, infant behavioral inhibition, and attachment, were examined. Socially anxious mothers showed more negative (higher threat attribution), and less supportive (lower encouragement) narratives, than controls, and their children’s DP representations, SAnxD and CBCL scores were more adverse. High narrative threat predicted child SAnxD; lower encouragement predicted negative child CBCL scores and, particularly for behaviorally inhibited children, TRF scores and DP representations. In securely attached children, CBCL scores and risk for SAnxD were affected by maternal anxiety and threat attributions, respectively. Low encouragement mediated the effects of maternal anxiety on child DP representations, and CBCL scores. Maternal narratives are affected by social anxiety, and contribute to adverse child outcome.

Single-carrier frequency domain equalisation for hammerstein communication systems using complex-valued neural networks

Single-carrier (SC) block transmission with frequency-domain equalisation (FDE) offers a viable transmission technology for combating the adverse effects of long dispersive channels encountered in high-rate broadband wireless communication systems. However, for high bandwidthefficiency and high power-efficiency systems, the channel can generally be modelled by the Hammerstein system that includes the nonlinear distortion effects of the high power amplifier (HPA) at transmitter. For such nonlinear Hammerstein channels, the standard SC-FDE scheme no longer works. This paper advocates a complex-valued (CV) B-spline neural network based nonlinear SC-FDE scheme for Hammerstein channels. Specifically, We model the nonlinear HPA, which represents the CV static nonlinearity of the Hammerstein channel, by a CV B-spline neural network, and we develop two efficient alternating least squares schemes for estimating the parameters of the Hammerstein channel, including both the channel impulse response coefficients and the parameters of the CV B-spline model. We also use another CV B-spline neural network to model the inversion of the nonlinear HPA, and the parameters of this inverting B-spline model can easily be estimated using the standard least squares algorithm based on the pseudo training data obtained as a natural byproduct of the Hammerstein channel identification. Equalisation of the SC Hammerstein channel can then be accomplished by the usual one-tap linear equalisation in frequency domain as well as the inverse B-spline neural network model obtained in time domain. Extensive simulation results are included to demonstrate the effectiveness of our nonlinear SC-FDE scheme for Hammerstein channels.

The expression of ferritin, lactoferrin, transferrin receptor and solute carrier family 11A1 in the host response to BCG-vaccination and Mycobacterium tuberculosis challenge

Iron is an essential cofactor for both mycobacterial growth during infection and for a successful protective immune response by the host. The immune response partly depends on the regulation of iron by the host, including the tight control of expression of the iron-storage protein, ferritin. BCG vaccination can protect against disease following Mycobacterium tuberculosis infection, but the mechanisms of protection remain unclear. To further explore these mechanisms, splenocytes from BCG-vaccinated guinea pigs were stimulated ex vivo with purified protein derivative from M. tuberculosis and a significant down-regulation of ferritin light- and heavy-chain was measured by reverse-transcription quantitative-PCR (P ≤0.05 and ≤0.01, respectively). The mechanisms of this down-regulation were shown to involve TNFα and nitric oxide. A more in depth analysis of the mRNA expression profiles, including genes involved in iron metabolism, was performed using a guinea pig specific immunological microarray following ex vivo infection with M. tuberculosis of splenocytes from BCG-vaccinated and naïve guinea pigs. M. tuberculosis infection induced a pro-inflammatory response in splenocytes from both groups, resulting in down-regulation of ferritin (P ≤0.05). In addition, lactoferrin (P ≤0.002), transferrin receptor (P ≤0.05) and solute carrier family 11A1 (P ≤0.05), were only significantly down-regulated after infection of the splenocytes from BCG-vaccinated animals. The results show that expression of iron-metabolism genes is tightly regulated as part of the host response to M. tuberculosis infection and that BCG-vaccination enhances the ability of the host to mount an iron-restriction response which may in turn help to combat invasion by mycobacteria.

Interpretation and expectations among mothers of children with anxiety disorders: associations with maternal anxiety disorder

Background Models of the development and maintenance of childhood anxiety suggest an important role for parent cognitions: that is, negative expectations of children's coping abilities lead to parenting behaviors that maintain child anxiety. The primary aims of the current study were to (1) compare expectations of child vulnerability and coping among mothers of children with anxiety disorders on the basis of whether or not mothers also had a current anxiety disorder, and (2) examine the degree to which the association between maternal anxiety disorder status and child coping expectations was mediated by how mothers interpreted ambiguous material that referred to their own experience. Methods The association between interpretations of threat, negative emotion, and control was assessed using hypothetical ambiguous scenarios in a sample of 271 anxious and nonanxious mothers of 7- to 12-year-old children with an anxiety disorder. Mothers also rated their expectations when presented with real life challenge tasks. Results There was a significant association between maternal anxiety disorder status and negative expectations of child coping behaviors. Mothers’ self-referent interpretations were found to mediate this relationship. Responses to ambiguous hypothetical scenarios correlated significantly with responses to real life challenge tasks. Conclusions Treatments for childhood anxiety disorders in the context of parental anxiety disorders may benefit from the inclusion of a component to directly address parental cognitions. Some inconsistencies were found when comparing maternal expectations in response to hypothetical scenarios with real life challenges. This should be addressed in future research.

B-spline neural network based single-carrier frequency domain equalisation for Hammerstein channels

A practical single-carrier (SC) block transmission with frequency domain equalisation (FDE) system can generally be modelled by the Hammerstein system that includes the nonlinear distortion effects of the high power amplifier (HPA) at transmitter. For such Hammerstein channels, the standard SC-FDE scheme no longer works. We propose a novel Bspline neural network based nonlinear SC-FDE scheme for Hammerstein channels. In particular, we model the nonlinear HPA, which represents the complex-valued static nonlinearity of the Hammerstein channel, by two real-valued B-spline neural networks, one for modelling the nonlinear amplitude response of the HPA and the other for the nonlinear phase response of the HPA. We then develop an efficient alternating least squares algorithm for estimating the parameters of the Hammerstein channel, including the channel impulse response coefficients and the parameters of the two B-spline models. Moreover, we also use another real-valued B-spline neural network to model the inversion of the HPA’s nonlinear amplitude response, and the parameters of this inverting B-spline model can be estimated using the standard least squares algorithm based on the pseudo training data obtained as a byproduct of the Hammerstein channel identification. Equalisation of the SC Hammerstein channel can then be accomplished by the usual one-tap linear equalisation in frequency domain as well as the inverse Bspline neural network model obtained in time domain. The effectiveness of our nonlinear SC-FDE scheme for Hammerstein channels is demonstrated in a simulation study.

Frequency of infant stroking reported by mothers moderates the effect of prenatal depression on infant behavioural and physiological outcomes

Animal studies find that prenatal stress is associated with increased physiological and emotional reactivity later in life, mediated via fetal programming of the HPA axis through decreased glucocorticoid receptor (GR) gene expression. Post-natal behaviours, notably licking and grooming in rats, cause decreased behavioural indices of fear and reduced HPA axis reactivity mediated via increased GR gene expression. Post-natal maternal behaviours may therefore be expected to modify prenatal effects, but this has not previously been examined in humans. We examined whether, according to self-report, maternal stroking over the first weeks of life modified associations between prenatal depression and physiological and behavioral outcomes in infancy, hence mimicking effects of rodent licking and grooming. From a general population sample of 1233 first time mothers recruited at 20 weeks gestation we drew a stratified random sample of 316 for assessment at 32 weeks based on reported inter-partner psychological abuse, a risk to child development. Of these 271 provided data at 5, 9 and 29 weeks post delivery. Mothers reported how often they stroked their babies at 5 and 9 weeks. At 29 weeks vagal withdrawal to a stressor, a measure of physiological adaptability, and maternal reported negative emotionality were assessed. There was a significant interaction between prenatal depression and maternal stroking in the prediction of vagal reactivity to a stressor (p = .01), and maternal reports of infant anger proneness (p = .007) and fear (p = .043). Increasing maternal depression was associated with decreasing physiological adaptability, and with increasing negative emotionality, only in the presence of low maternal stroking. These initial findings in humans indicate that maternal stroking in infancy, as reported by mothers, has effects strongly resembling the effects of observed maternal behaviours in animals, pointing to future studies of the epigenetic, physiological and behavioral effects of maternal stroking.

Threat interpretation bias in anxious children and their mothers

The role of parents in the development of anxiety disorders in children is of increasing research and clinical interest. This study investigated interpretation biases of anxious children and their mothers using the ambiguous stimuli task developed by Hadwin, Frost, French, and Richards (1997). Three groups of children (aged 7 to 12 years) and their mothers were recruited; 23 non-clinical controls, 18 children with an anxiety disorder and 15 children with an externalising disorder. Following diagnostic assessments of the children, children and their mothers independently completed the homophone task and self-report measures of anxiety. Mothers of anxious children had significantly higher self-reported anxiety than mothers of non-clinical children. As hypothesised, children in the anxious group had higher threat interpretation scores than the non-clinical group. The hypothesis that mothers of anxious children would make more threat interpretations was not supported. Paired correlations showed no significant association between threat interpretations made by children and their mothers. There was a significant positive correlation between maternal threat interpretation and child anxiety. The results suggest that there is a complex association between mother's anxiety and cognitions and those of their children, which requires further examination in controlled observational and experimental studies, including treatment trials.

Characterisation of dystrophin in carriers of Duchenne muscular dystrophy.

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, was studied in needle biopsy samples taken from the quadriceps muscle of 15 asymptomatic carriers of DMD (13 adults and 2 young girls) and one symptomatic adult carrier. Antibodies to N- and C-terminal regions of dystrophin were used for both Western blot analysis and immunocytochemistry and a monoclonal antibody to beta-spectrin used to assess membrane integrity. All asymptomatic adult carriers showed some abnormality in dystrophin immunostaining but very few negative fibres were present. A clear mosaic of dystrophin positive and negative fibres was seen only in the adult symptomatic carrier and the two young girls. On a Western blot, all carriers studied had dystrophin of normal molecular weight, but most had reduced abundance. In adult carriers, the amount of dystrophin relative to normal controls varied, but it was unrelated to age, serum creatine kinase (CK) levels or to the degree of pathology. Carriers with normal CK showed abnormalities in dystrophin expression. The dystrophin immunoblotting profile of the 2 young girls was very similar to that of their mothers, but the mosaic pattern of immunostaining was not apparent in the older carriers. In conclusion, dystrophin immunostaining and Western blot analysis of biopsy samples from asymptomatic carriers is often abnormal and they may be useful additional aids for establishing carrier status, particularly in younger girls.

Concord Grape Juice, cognitive function and driving performance: a 12 week, placebo controlled, randomised, crossover trial in mothers of pre-teen children

Background: Daily consumption of Concord grape juice (CGJ) over three to four months has been shown to improve memory function in adults with mild cognitive impairment, and reduce blood pressure in hypertensive adults. These benefits are likely due to the high concentration of polyphenols in CGJ. Increased stress can impair cognitive function and elevate blood pressure. Thus we examined the potential beneficial effect of CGJ in individuals experiencing somewhat stressful demanding lifestyles. Objective: To examine the effects of twelve weeks’ daily consumption of CGJ on cognitive function, driving performance, and blood pressure in healthy, middle-aged working mothers. Design: Twenty five healthy mothers of pre-teen children, aged 40-50 years, who were employed for > 30 hours/week consumed 12oz (355ml) CGJ (containing 777mg total polyphenols) or an energy, taste and appearance matched placebo daily for twelve weeks according to a randomised, crossover design with a four week washout. Verbal and spatial memory, executive function, attention, blood pressure and mood were assessed at baseline, six weeks and twelve weeks. Immediately following the cognitive battery, a subsample of seventeen females completed a driving performance assessment in the University of Leeds Driving Simulator. The twenty five minute driving task required participants to match the speed and direction of a lead vehicle. Results: Significant improvements in immediate spatial memory and driving performance were observed following CGJ relative to placebo. There was evidence of an enduring effect of CGJ such that participants who received CGJ in arm 1 maintained better performance in the placebo arm. Conclusions: Cognitive benefits associated with chronic consumption of flavonoid-rich grape juice are not exclusive to adults with mild cognitive impairment. Moreover, these cognitive benefits are apparent in complex everyday tasks such as driving. Effects may persist beyond cessation of flavonoid consumption and future studies should carefully consider the length of washout within crossover designs.