Feasibility study of a parent-driven intervention for youth with Down syndrome.

BACKGROUND: Children with Down syndrome present with behavioural and emotional difficulties, including noncompliance, rule-breaking, emotion dysregulation and delays in executive functioning. Few behavioural interventions have been designed specifically for children with Down syndrome. The Research Units in Behavioral Intervention (RUBI) Parent Training for Disruptive Behaviors is a structured empirically supported parent training programme developed for caregivers of children with autism. This feasibility trial explored the feasibility and acceptability of an abbreviated RUBI intervention with caregivers of children with Down syndrome and identified promising outcome measures to target in future larger clinical trials. METHOD: A double-blind randomised feasibility pilot clinical trial allocated participants to a behavioural intervention (BEH) or educational (EDU) group. BEH and EDU consisted of five individual sessions over the course of 5 to 8 weeks. Measures were administered to 20 caregivers and their youth with Down syndrome at three time points. RESULTS: Both BEH and EDU were rated as feasible with high parental adherence and acceptable with high treatment satisfaction. Both BEH and EDU demonstrated decreased externalising behaviours, irritability and hyperactivity and improved behavioural regulation in executive functioning over time. No impact was noted on caregiver functioning. CONCLUSION: The feasibility trial has strong findings regarding feasibility and satisfaction and has promising findings regarding the selection of measures for future trials testing an adapted RUBI programme and an education programme to reduce behavioural challenges in children with Down syndrome. Larger scale clinical trials are needed to confirm promising findings of these feasible treatments.

Direct measurement of the PSF for Coulomb delocalization - a reconsideration.

An interpretation of Coulomb delocalization, which limits the spatial resolution of inelastic TEM or STEM images, is given. We conclude that the corresponding point spread function cannot be measured as a broadening of a STEM probe.

Anatomic accuracy of airway training manikins compared with humans.

Airway simulators, or training manikins, are frequently used in research studies for device development and training purposes. This study was designed to determine the anatomic accuracy of the most frequently used low-fidelity airway training manikins. Computerised tomography scans and ruler measurements were taken of the SynDaver® , Laerdal® and AirSim® manikins. These measurements were compared with human computerised tomography (CT) scans (n = 33) from patients at the University of Michigan Medical Center or previously published values. Manikin measurements were scored as a percentile among the distribution of the same measurements in the human population and 10 out of 27 manikin measurements (nine measurements each in three manikins) were outside of two standard deviations from the mean in the participants. All three manikins were visually identifiable as outliers when plotting the first two dimensions from multidimensional scaling. In particular, the airway space between the epiglottis and posterior pharyngeal wall, through which airway devices must pass, was too large in all three manikins. SynDaver, Laerdal and AirSim manikins do not have anatomically correct static dimensions in relation to humans and these inaccuracies may lead to imprecise airway device development, negatively affect training and cause over-confidence in users.

Exogenous ghrelin administration increases alcohol self-administration and modulates brain functional activity in heavy-drinking alcohol-dependent individuals.

Preclinical evidence suggests that ghrelin, a peptide synthesized by endocrine cells of the stomach and a key component of the gut-brain axis, is involved in alcohol seeking as it modulates both central reward and stress pathways. However, whether and how ghrelin administration may impact alcohol intake in humans is not clear. For, we believe, the first time, this was investigated in the present randomized, crossover, double-blind, placebo-controlled, human laboratory study. Participants were non-treatment-seeking alcohol-dependent heavy-drinking individuals. A 10-min loading dose of intravenous ghrelin/placebo (3 mcg kg-1) followed by a continuous ghrelin/placebo infusion (16.9 ng/kg/min) was administered. During a progressive-ratio alcohol self-administration experiment, participants could press a button to receive intravenous alcohol using the Computerized Alcohol Infusion System. In another experiment, brain functional magnetic resonance imaging was conducted while participants performed a task to gain points for alcohol, food or no reward. Results showed that intravenous ghrelin, compared to placebo, significantly increased the number of alcohol infusions self-administered (percent change: 24.97±10.65, P=0.04, Cohen's d=0.74). Participants were also significantly faster to initiate alcohol self-administration when they received ghrelin, compared to placebo (P=0.03). The relationships between breath alcohol concentration and subjective effects of alcohol were also moderated by ghrelin administration. Neuroimaging data showed that ghrelin increased the alcohol-related signal in the amygdala (P=0.01) and modulated the food-related signal in the medial orbitofrontal cortex (P=0.01) and nucleus accumbens (P=0.08). These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder.

Activation of LINE-1 Retrotransposon Increases the Risk of Epithelial-Mesenchymal Transition and Metastasis in Epithelial Cancer.

Epithelial cancers comprise 80-90% of human cancers. During the process of cancer progression, cells lose their epithelial characteristics and acquire stem-like mesenchymal features that are resistant to chemotherapy. This process, termed the epithelial-mesenchymal transition (EMT), plays a critical role in the development of metastases. Because of the unique migratory and invasive properties of cells undergoing the EMT, therapeutic control of the EMT offers great hope and new opportunities for treating cancer. In recent years, a plethora of genes and noncoding RNAs, including miRNAs, have been linked to the EMT and the acquisition of stem cell-like properties. Despite these advances, questions remain unanswered about the molecular processes underlying such a cellular transition. In this article, we discuss how expression of the normally repressed LINE-1 (or L1) retrotransposons activates the process of EMT and the development of metastases. L1 is rarely expressed in differentiated stem cells or adult somatic tissues. However, its expression is widespread in almost all epithelial cancers and in stem cells in their undifferentiated state, suggesting a link between L1 activity and the proliferative and metastatic behaviour of cancer cells. We present an overview of L1 activity in cancer cells including how genes involved in proliferation, invasive and metastasis are modulated by L1 expression. The role of L1 in the differential expression of the let-7 family of miRNAs (that regulate genes involved in the EMT and metastasis) is also discussed. We also summarize recent novel insights into the role of the L1-encoded reverse transcriptase enzyme in epithelial cell plasticity that suggest it might be a potential therapeutic target that could reverse the EMT and the metastasis-associated stem cell-like properties of cancer cells.

The medial sural artery perforator flap and its application in electrical injury to the hand.

We describe the use of a free medial sural artery perforator flap to reconstruct a complex composite defect to the dorsum of the right index finger following a low voltage electrical injury. The resulting defect was a 3.5 × 5 cm full thickness wound, with segmental tendon loss and loss of underlying periosteum. Due to both size and local vascular injury related to the mechanism, free tissue transfer was felt to be the most reliable option to resurface the composite defect in a single stage. The medial sural artery perforator flap, for reasons outlined below, was felt to be the best option: 1. Thin profile. 2. Vascularised fascia can be taken as a tongue, adjacent to the skin paddle: a gliding surface to prevent the tendon graft sticking to exposed bone. 3. Long pedicle: micro-anastomosis away from zone of injury. 4. Little donor site morbidity: can be closed directly (if <6 cm wide) and does not require sacrifice of any major blood vessel. 5. Can be harvested with nerve and tendon from the same wound. 6. Can include as little or as much tissue required and compared to other fasciocutaneous flaps matches the texture and thickness of the hand most closely. We describe the reconstruction of the composite defect on day 42 post-injury, following one prior debridement. This case highlights the versatility and suitability of the medial sural artery flap in the reconstruction of complex hand burns with resulting composite defects.

Vortex beam production and contrast enhancement from a magnetic spiral phase plate.

Electron vortex beam probes offer the possibility of mapping magnetic moments with atomic resolution. In this work we consider using the stray magnetic field produced from a narrow ferromagnetic rod magnetised along its long axis to produce a vortex beam probe, as an alternative to the currently used holographic apertures or gratings. We show through numerical modelling, electron holography observations and direct imaging of the electron probe, that a long narrow ferromagnetic rod induces a phase shift in the wave-function of passing electrons that approximately describes a helix in the regions near its ends. Directing this rod towards the optical axis of a charged-particle beam probe forming system at a limiting aperture position, with the free-end sufficiently close to the axis, is shown to offer a point spread function composed of vortex modes, with evidence of this appearing in observations of the electron probe formed from inserting a micro-fabricated CoFe rod into the beam path of a 300 keV transmission electron microscope (TEM). If the rod is arranged to contain the magnetic flux of h/e, thus producing a maximum phase shift of 2π, it produces a simple spiral-like phase contrast transfer function for weak phase objects. In this arrangement the ferromagnetic rod can be used as a phase plate, positioned at the objective aperture position of a TEM, yielding enhanced image contrast which is simulated to be intermediate between comparable Zernike and Hilbert phase plates. Though this aspect of the phase plate performance is not demonstrated here, agreement between our observations and models for the probe formed from an example rod containing a magnetic flux of ~2.35h/e, indicate this phase plate arrangement could be a simple means of enhancing contrast and gaining additional information from TEM imaged weak phase samples, while also offering the capability to produce vortex beam probes. However, steps still need to be taken to either remove or improve the support membrane for the rod in our experiments to reduce any effects from charging in the phase plate.

Characterisation of ferromagnetic rings for Zernike phase plates using the Aharonov-Bohm effect.

Holographic measurements on magnetised thin-film cobalt rings have demonstrated both onion and vortex states of magnetisation. For a ring in the vortex state, the difference between phases of electron paths that pass through the ring and those that travel outside it was found to agree very well with Aharonov-Bohm theory within measurement error. Thus the magnetic flux in thin-film rings of ferromagnetic material can provide the phase shift required for phase plates in transmission electron microscopy. When a ring of this type is used as a phase plate, scattered electrons will be intercepted over a radial range similar to the ring width. A cobalt ring of thickness 20 nm can produce a phase difference of π/2 from a width of just under 30 nm, suggesting that the range of radial interception for this type of phase plate can be correspondingly small.

The impact of glutathione transferase kappa deficiency on adiponectin multimerisation in vivo.

Glutathione transferase Kappa (GSTK1-1) also termed disulfide bond-forming oxidoreductase A-like protein (DsbA-L) has been implicated in the post-translational multimerization of adiponectin and has been negatively correlated with obesity in mice and humans. We investigated adiponectin in Gstk1(-/-) mice and surprisingly found no difference in the levels of total serum adiponectin or the level of high molecular weight (HMW) multimers when compared with normal controls. Non-reducing SDS-polyacrylamide gel electrophoresis and western blotting also showed a similar distribution of low, middle and HMW multimers in normal and Gstk1(-/-) mice. Variation in adiponectin has been correlated with glucose tolerance and with the levels of phosphorylated AMP-kinase but we found similar glucose tolerance and similar levels of phospho 5-AMP-activated protein kinase in normal and Gstk1(-/-) mice. Consequently, our findings suggest that GSTK1-1 is not absolutely required for adiponectin multimerization in vivo and alternate pathways may be activated in GSTK1-1 deficiency.

Sarcomas in the groin and inguinal canal--often missed and difficult to manage.

INTRODUCTION: This is a 7-year retrospective review summarising the North of England Bone and Soft Tissue Tumour Service's experience of managing 13 cases of groin sarcoma requiring soft tissue flap reconstruction. This study was performed to try to identify where national referral guidelines in sarcoma management had been followed and reasons for any delays. The study also includes outcome data relating to these patients. PATIENTS AND METHODS: A retrospective, case-note review was undertaken using the local sarcoma database to identify appropriate patients. RESULTS: In nine patients, national referral guidelines were not followed. This resulted in a mean delay of presentation to the multidisciplinary team of 4.4 months. Ten patients had unplanned excision or exploration of tumours before referral. There were no lower limb amputations. All patients with narrow margins or high grade tumours were referred for radiotherapy. Four patients died; three as a result of distant metastases and one as a result of local recurrence. CONCLUSIONS: Despite delays in referral, treatment by wide excision and plastic surgical reconstruction allowed for local control of these tumours with functional limb salvage. Implementation of National Institute for Health and Clinical Excellence (NICE) guidelines and local strategies could improve the expedient management of these patients.

Taking a history in aesthetic surgery: SAGA--the surgeon's tool for patient selection.

Most patient dissatisfaction in Aesthetic surgery is based on failures of communication and patient selection criteria, and not on technical faults [Ward CM. Consenting and consulting for cosmetic surgery. Br J Plast Surg 1998;51:547-50; Gorney M. (2004) Essentials of malpractice claims prevention for the plastic surgeon. eMedicine; Jan 5, 2004]. Litigation leaves the surgeon perplexed when the operation has been performed to his or her satisfaction. Taking a history of Aesthetic Distress is critical in understanding the patient's complaint and postoperative expectation. It is often overlooked. This valuable information influences patient selection for surgery and shapes the operation to be performed. If a carefully selected patient has a surgical result that addresses their complaint and meets their expectation, the rate of dissatisfaction is reduced and litigation is avoided or more easily defended. An historical literature review of patient selection for aesthetic surgery is offered. It confirms that the need for establishing a rapport with the patient has been recognised and, indeed, stressed for many years. However, while we have found negative lists of the types of patient to avoid, and aspersions of psychiatric conditions in dissatisfied patients, we have been unable to find any structure or template for eliciting the required history, which is all important in determining patient selection. SAGA is a simple template for questioning, during consultation. It provides the surgeon with a systematic tool for recording the history of the complaint of appearance, whilst establishing rapport with the patient. It gives insight into the patient's personality and complaint, thus aiding patient selection for surgery and shaping the operation performed. Finally it provides a record for "rebuttal" in the postoperative period, should this be necessary. It has served the senior author well for twenty-five years.

One-solvent polymorph screen of carbamazepine.

To emphasize the fact that solvents can be either critical or immaterial in crystallizing specific polymorphs, a method for obtaining multiple polymorphs of a compound using only one solvent is demonstrated. By varying the crystallization temperature and level of supersaturation, three of the four polymorphs of carbamazepine (CBZ; 5H-dibenz [b,f]azepine-5-carboxamide) were crystallized from cumene (isopropyl benzene). Form III, also referred to as the primitive monoclinic form, was produced at temperatures below 60 degrees C from supersaturated solutions concentrated at less than twice the solubility of that form. When the supersaturation was increased to twice the solubility of form III at temperatures below 60 degrees C, form II, also referred to as the trigonal form, was produced. Form I, also referred to as the triclinic form, was produced regardless of the level of supersaturation at temperatures above 80 degrees C. Between 60 degrees C and 80 degrees C, mixtures of forms were produced. Competition slurries were employed to establish the transition temperature to be between 79 degrees C and 82 degrees C for the enantiotropically related forms III and I. These results indicate that crystallization of CBZ from cumene can either be under thermodynamic control or affected by the kinetics of crystallization of metastable forms. This raises the question about the importance of solvent diversity when looking for polymorphs, suggesting that a rational experimental design can be used to greatly reduce the number of solvents and crystallization conditions. The results of this one-solvent polymorph screen correlate somewhat with a phase-solubility diagram for CBZ.

Perinuclear localisation of cellular retinoic acid binding protein I mRNA.

Retinoids are important metabolic and developmental regulators that act through nuclear receptors. The cellular retinoic acid binding protein CRABPI has been suggested to play a role in trafficking of retinoic acid but its exact functions and subcellular localisation remain unclear. Here we show that in CHO cells both exogenous CRABPI transcripts and tagged CRABPI protein have a perinuclear distribution that depends upon the 3'UTR of the mRNA. The CRABPI 3'UTR conferred perinuclear localisation on globin reporter transcripts. Deletion analysis indicated that the first 123nt of CRABPI 3'UTR are necessary for localisation of both CRABPI mRNA and protein. We propose that CRABPI mRNA is localised by a signal within its 3'UTR and that this partly determines the distribution of CRABPI protein.

Trends over time in the management of subarachnoid haemorrhage in newcastle: review of 1609 patients.

This article reviews trends in the management of subarachnoid haemorrhage (SAH) at the Regional Neurosurgery Unit in Newcastle over 9 years. This is a comprehensive analysis of prospectively collected data on patients with SAH. We review the changes in clinical therapy and outcome with regards to conservative (non-surgical), surgical and endovascular therapy. Since 1990, the demographic and management/outcome details of patients with SAH have been recorded systematically. This study involves patients admitted over the 9 years, from January 1990 to December 1998. The data were computerized using Microsoft Access (Microsoft Inc. USA), and analysed using SPSS statistical package. A total of 1609 had aneurysmal SAH confirmed with CT, lumbar puncture and/or angiography. Sixty-seven per cent (1,073 patients) were female with a female to male ratio of 2:1. This ratio was maintained from 1990 to date. The mean age has slowly increased from 49 years in 1990 to 55 years of age in 1998, (range 18-91). Overall, 53.9% (from 66.3% in 1990 to 35.3% in 1998) were surgically treated, 8.1% had embolization (range 0.6-18.4%) and 38% (range 28.2-46.4%) were managed without surgical intervention for the aneurysm. The proportion of patients undergoing surgery has decreased since 1994 with improvements in endovascular therapy, participation in the ISAT trial and increased admission of poor grade patients (WFNS grades 4 and 5, from 17% in 1990 to 31% in 1998). The mortality rate has doubled over the years under review (18-32%). The percentage of severely disabled patients has remained constant at about 7% with none in a vegetative state. Only 54% had a favourable outcome in 1998 compared with 78% in 1990. Total morbidity and mortality has increased particularly during the last 3 years. This has been associated with double the number of admissions in grade 5. Favourable outcome occurred in 90% of good grade patients (WFNS 1 and 2) with 6.2% mortality in surgical candidates and 5.5% in patients treated endovascularly. The mortality for poor grade (WFNS 4 and 5) patients was 64%.

GSTZ1d: a new allele of glutathione transferase zeta and maleylacetoacetate isomerase.

The zeta class glutathione transferases (GSTs) are known to catalyse the isomerization of maleylacetoacetate (MAA) to fumarylacetoacetate (FAA), and the biotransformation of dichloroacetic acid to glyoxylate. A new allele of human GSTZ1, characterized by a Thr82Met substitution and termed GSTZ1d, has been identified by analysis of the expressed sequence tag (EST) database. In European Australians, GSTZ1d occurs with a frequency of 0.16. Like GSTZ1b-1b and GSTZ1c-1c, the new isoform has low activity with dichloroacetic acid compared with GSTZ1a-1a. The low activity appears to be due to a high sensitivity to substrate inhibition. The maleylacetoacetate isomerase (MAAI) activity of all known variants was compared using maleylacetone as a substrate. Significant differences in activity were noted, with GSTZ1a-1a having a notably lower catalytic efficiency. The unusual catalytic properties of GSTZ1a-1a in both reactions suggest that its characteristic arginine at position 42 plays a significant role in the regulation of substrate access and/or product release. The different amino acid substitutions have been mapped on to the recently determined crystal structure of GSTZ1-1 to evaluate and explain their influence on function.

Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity.

Although genetically engineered adenoviruses hold promise for the treatment of cancer, clinical trial reports have utilized intratumoral injection to date. To determine the feasibility of intravenous delivery of ONYX-015, an E1B-55kD gene-deleted replication selective adenovirus with demonstrated clinical safety and antitumoral activity following intratumoral injection, we performed a clinical trial in patients with metastatic solid tumors. ONYX-015 was infused intravenously at escalating doses of 2 x 10(10) to 2 x 10(13) particles via weekly infusion within 21-day cycles in 10 patients with advanced carcinoma metastatic to the lung. No dose-limiting toxicity was identified. Mild to moderate fever, rigors and a dose-dependent transient transaminitis were the most common adverse events. Neutralizing antibody titers significantly increased within 3 weeks in all patients. IL-6, gamma-IFN, TNF-alpha and IL-10 increased within 24 h following treatment. Evidence of viral replication was detectable in three of four patients receiving ONYX-015 at doses > or = 2 x 10(12) particles and intratumoral replication was confirmed in one patient. In conclusion, intravenous infusion of ONYX-015 was well tolerated at doses up to 2 x 10(13) particles and infection of metastatic pulmonary sites with subsequent intratumoral viral replication was seen. The intravenous administration of genetically altered adenovirus is a feasible approach.

Crystal structure of maleylacetoacetate isomerase/glutathione transferase zeta reveals the molecular basis for its remarkable catalytic promiscuity.

Maleylacetoacetate isomerase (MAAI), a key enzyme in the metabolic degradation of phenylalanine and tyrosine, catalyzes the glutathione-dependent isomerization of maleylacetoacetate to fumarylacetoacetate. Deficiencies in enzymes along the degradation pathway lead to serious diseases including phenylketonuria, alkaptonuria, and the fatal disease, hereditary tyrosinemia type I. The structure of MAAI might prove useful in the design of inhibitors that could be used in the clinical management of the latter disease. Here we report the crystal structure of human MAAI at 1.9 A resolution in complex with glutathione and a sulfate ion which mimics substrate binding. The enzyme has previously been shown to belong to the zeta class of the glutathione S-transferase (GST) superfamily based on limited sequence similarity. The structure of MAAI shows that it does adopt the GST canonical fold but with a number of functionally important differences. The structure provides insights into the molecular bases of the remarkable array of different reactions the enzyme is capable of performing including isomerization, oxygenation, dehalogenation, peroxidation, and transferase activity.

Identification of novel glutathione transferases and polymorphic variants by expressed sequence tag database analysis.

The human expressed sequence tag (EST) database can be searched by different sequence alignment strategies to identify new members of gene families and allelic variants. To illustrate the value of database analysis for gene discovery, we have focused on the glutathione S-transferase (GST) super family, an approach that has led to the identification of the Zeta class. The Zeta class GSTs catalyze the glutathione-dependent biotransformation of alpha-haloacids and the isomerization of maleylacetoacetic acid to fumarylacetoacetic acid, an essential step in the catabolism of tyrosine. Allelic variants of the GST Z1 and GST A2 genes have also been identified by EST database analysis. One GST Z1 variant (GST Z1A) has significantly higher activity with dichloroacetic acid as a substrate than other GST Z1 isoforms. This variant may be important in the clinical treatment of lactic acidosis where dichloroacetic acid is prescribed. Our experience with the application of EST database searching methods suggests that it may be productively applied to other gene families of pharmacogenetic interest.