Oncofetal protein IGF2BP1 regulates IQGAP3 expression to maintain stem cell potential in cancer.

We reported earlier that IQGAP3 is an important stem cell factor in rapidly proliferating isthmus stem cells in the stomach and that IQGAP3 expression is robustly induced in terminally differentiated chief cells and de-differentiated cells following tissue damage. The elevated IQGAP3 expression in cancer and its association with metastasis suggest a fundamental role for IQGAP3 in proliferating cancer stem cells. What causes IQGAP3 upregulation in cancer is unclear. Here, we show that IGF2BP1 and IQGAP3 expression levels are highest in the blastocyst, with both decreasing during adulthood. This suggests that IQGAP3, like IGF2BP1, is an early developmental gene that is aberrantly upregulated upon re-expression of IGF2BP1 during carcinogenesis. IGF2BP1 binds and stabilizes m6A-modified IQGAP3 transcripts. Downstream targets of IGF2BP1, namely SRF and FOXM1, also upregulate IQGAP3 expression. These multiple layers of IQGAP3 regulation, which may safeguard against inappropriate stem cell proliferation, present additional drug targets to inhibit IQGAP3-driven malignant growth.

Why language survives as the dominant communication tool: A neurocognitive perspective.

By focusing on the contributions of subcortical structures, our commentary suggests that the functions of the hippocampus underlying "displacement," a feature enabling humans to communicate things and situations that are remote in space and time, make language more effective at social bonding. Based on the functions of the basal ganglia and hippocampus, evolutionary trajectory of the subcomponents of music and language in different species will also be discussed.

A domain-general perspective on the role of the basal ganglia in language and music: Benefits of music therapy for the treatment of aphasia.

In addition to cortical lesions, mounting evidence on the links between language and the subcortical regions suggests that subcortical lesions may also lead to the emergence of aphasic symptoms. In this paper, by emphasizing the domain-general function of the basal ganglia in both language and music, we highlight that rhythm processing, the function of temporal prediction, motor programming and execution, is an important shared mechanism underlying the treatment of non-fluent aphasia with music therapy. In support of this, we conduct a literature review on the music therapy treating aphasia. The results show that rhythm processing plays a key role in Melodic Intonation Therapy in the rehabilitation of non-fluent aphasia patients with lesions on the basal ganglia. This paper strengthens the correlation between the basal ganglia lesions and language deficits, and provides support to the direction of taking advantage of rhythm as an important point in music therapy in clinical studies.

Modulation of AMPA Receptor Gating by the Anticonvulsant Drug, Perampanel.

Postsynaptic AMPA/glutamate receptors, essential for neuronal excitability, are important targets for anticonvulsant therapy. This single channel study of the selective noncompetitive AMPA receptor antagonist, perampanel, was performed on homotetrameric GluA3 receptor-channels that open in a stepwise manner to four distinct conductance levels through independent subunit activation. Previous structural studies show that perampanel binds to four sites located within the extracellular/transmembrane boundary of closed AMPA receptor-channel subunits. We found that channels exposed to 1 or 2 µM perampanel opened mainly to the two lower conductance levels in a dose-dependent manner. Comparison of the single channel results in the structures of the full length AMPA receptor in the closed state bound to perampanel, and the open state provide insights into the mechanism of allosteric reduction of AMPA-receptor-mediated excitation in epilepsy.

Noncompetitive antagonists induce cooperative AMPA receptor channel gating.

Glutamate is released from presynaptic nerve terminals in the central nervous system (CNS) and spreads excitation by binding to and activating postsynaptic iGluRs. Of the potential glutamate targets, tetrameric AMPA receptors mediate fast, transient CNS signaling. Each of the four AMPA subunits in the receptor channel complex is capable of binding glutamate at its ligand-binding domains and transmitting the energy of activation to the pore domain. Homotetrameric AMPA receptor channels open in a stepwise manner, consistent with independent activation of individual subunits, and they exhibit complex kinetic behavior that manifests as temporal shifts between four different conductance levels. Here, we investigate how two AMPA receptor-selective noncompetitive antagonists, GYKI-52466 and GYKI-53655, disrupt the intrinsic step-like gating patterns of maximally activated homotetrameric GluA3 receptors using single-channel recordings from cell-attached patches. Interactions of these 2,3-benzodiazepines with residues in the boundary between the extracellular linkers and transmembrane helical domains reorganize the gating behavior of channels. Low concentrations of modulators stabilize open and closed states to different degrees and coordinate the activation of subunits so that channels open directly from closed to higher conductance levels. Using kinetic and structural models, we provide insight into how the altered gating patterns might arise from molecular contacts within the extracellular linker-channel boundary. Our results suggest that this region may be a tunable locus for AMPA receptor channel gating.

Early Posthepatoportoenterostomy Predictors of Native Liver Survival in Biliary Atresia.

OBJECTIVES: Most infants with biliary atresia (BA) require liver transplantation (LT) after hepatoportoenterostomy (HPE), including those who initially clear jaundice. The aim of the present study was to identify clinical and routine laboratory factors in infants with BA post-HPE that predict native liver survival at 2 years. METHODS: A retrospective cohort study was conducted in 217 patients with BA undergoing HPE in Sydney, Australia and Toronto, Canada between January 1986 and July 2009. Univariate and multivariate logistic regression using backwards-stepwise elimination identified variables at 3 months after HPE most associated with 2-year native liver survival. RESULTS: Significant variables (P < 0.05) on univariate analysis included serum total bilirubin (TB) and albumin at 3 months post-HPE, bridging fibrosis or cirrhosis on initial liver biopsy, ascites of <3 months post-HPE, type 3 BA anatomy, age at HPE of >45 days, change in length z scores within 3 months of HPE, and center. On multivariate analysis, TB (P < 0.0001) and albumin (P = 0.02) at 3 months post-HPE, and center (P = 0.0003) were independently associated with native liver survival. Receiver operating characteristic analysis revealed an optimal cut-off value of TB <74 µmol/L (4.3 mg/dL; area under the receiver operating characteristic curve 0.8990) and serum albumin level >35 g/L (3.5 mg/dL; area under the receiver operating characteristic curve 0.7633) to predict 2-year native liver survival. TB and albumin levels 3 months post-HPE defined 3 groups (1: TB ≤74 µmol/L, albumin >35 g/L; 2: TB ≤74 µmol/L, albumin ≤35 g/L; 3: TB >74 µmol/L) with distinct short- and long-term native liver survival rates (log-rank P < 0.001). Length z scores 3 months post-HPE were poorer for group 2 than group 1 (-0.91 vs -0.30, P = 0.0217) with similar rates of coagulopathy. CONCLUSIONS: Serum TB and albumin levels 3 months post-HPE independently predicted native liver survival in BA when controlling for center. Serum albumin level <35 g/L in infants with BA who were no longer jaundiced at 3 months post-HPE was a poor prognostic indicator. Poorer linear growth and absence of significant coagulopathy suggest a role for early aggressive nutritional therapy in this group.

Congenital diaphragmatic hernia in Northern Queensland.

AIMS: To investigate the survival of non-syndromic live born infants diagnosed in Northern Queensland with congenital diaphragmatic hernia (CDH). METHOD: Case note audit was completed of all live born newborns with a diagnosis of CDH admitted between February 1987 and December 2010. Demographic and clinical data were extracted. RESULTS: Overall survival to time of discharge for all infants was 67.3% (n = 35/52). For infants born before 2003 survival was 59.5% and for those born in 2003 and onwards was 86.7% (P = 0.10, OR 4.4, 95% confidence interval (CI) 0.87-22.55). Infants born prior to 2003, compared to those born from 2003 onwards, were less likely to survive with an isolated defect (P = 0.04, OR 8.0, 95% CI 0.93-68.62). Isolated congenital diaphragmatic hernia survival since 2003 was 92.3%. A significant difference was found in the time to surgery with those born in 2003 onwards having surgery significantly later, median 134 h, compared to the earlier cohorts median time to surgery of 83 h (P < 0.005, 95% CI 32.61-167.09). Premature infants had poorer survival (46.7%) compared to term infants (75.7%) (P < 0.0001 OR 3.6, 95% CI 1.99-6.68). Univariate analysis identified low birthweight was associated with poorer survival. CONCLUSIONS: Survival to discharge in our cohort equals other reported rates in Australia and around the world, including centres with tertiary paediatric services. The current management strategies used for these infants have seen a significant improvement in outcomes over time.

A population-based study of the outcome after small bowel atresia/stenosis in New South Wales and the Australian Capital Territory, Australia, 1992-2003.

PURPOSE: The purpose of the study was to describe the incidence, epidemiology, and survival of infants with small bowel atresia/stenosis in New South Wales (NSW) and the Australian Capital Territory (ACT), Australia. METHODS: A population-based cohort study was conducted of infants diagnosed with small bowel atresia/stenosis in NSW and the ACT from 1992 to 2003. Data were obtained from the prospectively collated NSW and ACT Neonatal Intensive Care Units' data collection. Individual risk factors for mortality were assessed using the chi(2) test. RESULTS: The incidence of small bowel atresia/stenosis in NSW and the ACT was 2.9 per 10,000 births. Of 299 infants identified with small bowel atresia, 13 were stillborn. Of the 286 live born infants, most (52%) were delivered preterm (<37 weeks' gestation) with an 87% survival, whereas 48% were term with a 98% survival. More than half the infants (54%) had an associated birth defect. The overall mortality was 8%. Prematurity and low birth weight were identified as independent risk factors for mortality (P < .001). CONCLUSIONS: This study of small bowel atresia/stenosis provides population-based outcomes for clinicians and families. It is important to investigate infants with small bowel atresia for associated birth defects. Although the mortality rate has decreased over the last 50 years, it remains substantial at 8% and is higher in premature and low birth weight infants.

A population-based study of congenital diaphragmatic hernia outcome in New South Wales and the Australian Capital Territory, Australia, 1992-2001.

PURPOSE: The aim of the study was to describe the incidence and survival of infants born with congenital diaphragmatic hernia (CDH) in the state of New South Wales (NSW) and the Australian Capital Territory (ACT), Australia. METHODS: A population-based cohort study of all infants inclusive up to 1 month of age diagnosed with CDH in NSW and the ACT between 1992 and 2001 was conducted. Data sources were the NSW and ACT Neonatal Intensive Care Data Collection (Neonatal Intensive Care Units Study), NSW Birth Defects Register, Population Health Research Centre of ACT Health, and NSW Midwives Data Collection. Individual risk factors for mortality were assessed using the chi(2) test with P < .05 being considered statistically significant. Multivariate analysis was performed using logistic regression to adjust for potential confounding variables. RESULTS: From the databases used, the incidence of CDH in NSW and the ACT was 1 per 3800 births. Of 242 infants identified with CDH, 8% underwent termination of pregnancy, 10% were stillborn after 20 weeks' gestation, and 82% were liveborn. Most liveborn infants (70%) were delivered at term with a 64% survival, whereas 30% were preterm with a 35% survival. For liveborn infants, the overall preoperative mortality was 35% with 56% surviving to discharge. Logistic regression identified a low 5-minute Apgar score, prematurity, and air leak as independent risk factors for mortality. CONCLUSIONS: This population-based study of CDH provides us with baseline data for our states. Mortality is high in preterm infants and in the preoperative period. Avoiding preterm delivery and improving preoperative stabilization are the measures most likely to improve survival.

Quantitative evaluation of regular morning meetings aimed at improving work practices associated with effective interdisciplinary communication.

In 2000, an interdisciplinary surgical morning meeting (SMM) was introduced into the infants' and toddlers' ward of a major paediatric hospital to help overcome a number of communication and work process problems among the health professionals providing care to children/families. The objective of this study was to evaluate the impact of the SMM on a range of work practices. Comparative design including pre- and postintervention data collection was used. Data were collected on 100 patient records. Twenty children, from each of the five diagnostic-related groups most commonly admitted to the ward, were included. Demographic, medical review, documentation, critical incidents and complaint variables were obtained from three sources: the hospital clinical information system, the children's medical records and the hospital reporting systems for complaints and critical incidents. Children in the postintervention group were significantly more likely to be reviewed regularly by medical staff, to be reviewed in the morning, to have plans for discharge documented regularly throughout their admission and to have admission summary sheets completed at the time of discharge. The findings of the quantitative evaluation add some weight to the arguments for the purposely structured introduction of interdisciplinary teams into acute-care environments.

Qualitative evaluation of regular morning meetings aimed at improving interdisciplinary communication and patient outcomes.

Effective interdisciplinary communication is at the heart of clinical decision-making in contemporary health-care environments. Efforts to enhance communication and work processes among nurses and doctors in an infants-and-toddler ward of a specialist paediatric hospital led to the establishment of Surgical Morning Meetings (SMMs). To evaluate the experiences of nursing and medical team members and their perceptions of the changes brought about by the SMM, qualitative evaluation of the SMM was undertaken through semistructured interviews. The analysis identified four major areas of impact: predictability: a nice way to start the day, which captured the ways in which the SMM led to better planning of the day's activities, knowledge and perspectives: learning from each other, which highlighted the way that ongoing discussions led to greater understanding and respect, relationships and support: getting to know you, which reflected the benefits derived from greater commitment, and desired outcomes: making a difference to staff, children and families. Overall, we believe that initiatives as simple as discussions among nurses and doctors can enhance personal and professional experience and lead to improved health outcomes for our patients.

Functional outcome and quality of life after ileal pouch-anal anastomosis in children and adults.

BACKGROUND: In the past, children with ulcerative colitis were treated with a total colectomy, ileostomy and mucous fistula; ileal pouch-anal anastomosis was postponed until adulthood. The aim of the present study was to assess the functional outcome and quality of life after ileal pouch-anal anastomosis and determine whether it is justified to perform the operation in children when surgery is indicated. METHODS: A retrospective review of 38 medical records was carried out, of which there were 19 paediatric patients and 19 adult patients (control). A questionnaire survey was conducted. Telephone interviews were carried out for the non-respondents. RESULTS: Sixteen patients in the paediatric group (nine boys, mean age: 12 years) and 16 patients in the adult group (10 men, mean age: 39 years) were available for analysis. There was no operative mortality. The mean bowel frequency per week was 37 and 42. Furthermore, bowel frequency during the day was slightly lower in the paediatric group. Children had marginally better continence than adults. In the quality of life assessment, the mean utilities in the paediatric group were 0.69 and 0.84 in the preoperative and postoperative status, respectively. These were similar to those in the adult group (0.62 and 0.82). Both groups achieved significantly favourable postoperative responses in terms of ability to perform social activity, recreation and enjoying food. CONCLUSIONS: Ileal pouch-anal anastomosis in children is safe, results in good functional outcome and improves the quality of life. Hence, it is justified to perform ileal pouch-anal anastomosis as soon as surgery is indicated rather than as a delayed procedure.

Gastroduodenal intussusception due to Peutz-Jeghers syndrome in infancy.

A case of Peutz-Jeghers Syndrome (PJS) presenting in infancy with gastric-outlet obstruction is described. PJS may become symptomatic at any age and should be suspected when there are obstructive symptoms or gastrointestinal blood loss in a baby with a positive family history. Contrast studies and endoscopy are useful in diagnosis and surveillance. Treatment requires a combination of endoscopy and laparotomy/laparoscopy. Because of the reported cancer risk, we recommend surveillance from the age of diagnosis.