PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes and is largely driven by the NOTCH/MYC pathway. Yet, additional oncogenic drivers are required for transformation. Here, we identify protein tyrosine phosphatase type 4 A3 (PRL3) as a collaborating oncogenic driver in T-ALL. PRL3 is expressed in a large fraction of primary human T-ALLs and is commonly co-amplified with MYC. PRL3 also synergized with MYC to initiate early-onset ALL in transgenic zebrafish and was required for human T-ALL growth and maintenance. Mass-spectrometry phosphoproteomic analysis and mechanistic studies uncovered that PRL3 suppresses downstream T-cell phosphorylation signaling pathways, including those modulated by VAV1, and subsequently suppresses apoptosis in leukemia cells. Taken together, our studies have identified new roles for PRL3 as a collaborating oncogenic driver in human T-ALL and suggest that therapeutic targeting of the PRL3 phosphatase will likely be a useful treatment strategy for T-ALL.

Recovery of an urbanised estuary: Clean-up, de-industrialisation and restoration of redundant dock-basins in the Mersey.

For much of the 20th century, the Mersey in North West England was one of the worst polluted estuaries in Europe. Water from a range of polluting industries plus domestic sewage was discharged into the Mersey Catchment and Estuary. Recovery came through a concerted clean-up campaign and tightening environmental regulations, partly driven by European Commission Directives, coupled with de-industrialisation from the 1970s onward. Recovery of oxygen levels in the Estuary led to the return of a productive ecosystem. This led to conservation designations, but also concerns about transfer of pollutants to higher trophic levels in fish, birds and humans. As part of urban renewal, ecosystems in disused dock basins were restored using mussel biofiltration and artificial de-stratification, facilitating commercial redevelopment and creation of a tourist destination. The degradation and recovery of the Mersey from peak-pollution in the mid-20th century is put in the context of wider environmental change and briefly compared to other systems to develop a hysteresis model of degradation and recovery, often to novel ecosystems.

Communication: Fragment-based Hamiltonian model of electronic charge-excitation gaps and gap closure.

Capturing key electronic properties such as charge excitation gaps within models at or above the atomic scale presents an ongoing challenge to understanding molecular, nanoscale, and condensed phase systems. One strategy is to describe the system in terms of properties of interacting material fragments, but it is unclear how to accomplish this for charge-excitation and charge-transfer phenomena. Hamiltonian models such as the Hubbard model provide formal frameworks for analyzing gap properties but are couched purely in terms of states of electrons, rather than the states of the fragments at the scale of interest. The recently introduced Fragment Hamiltonian (FH) model uses fragments in different charge states as its building blocks, enabling a uniform, quantum-mechanical treatment that captures the charge-excitation gap. These gaps are preserved in terms of inter-fragment charge-transfer hopping integrals T and on-fragment parameters U((FH)). The FH model generalizes the standard Hubbard model (a single intra-band hopping integral t and on-site repulsion U) from quantum states for electrons to quantum states for fragments. We demonstrate that even for simple two-fragment and multi-fragment systems, gap closure is enabled once T exceeds the threshold set by U((FH)), thus providing new insight into the nature of metal-insulator transitions. This result is in contrast to the standard Hubbard model for 1d rings, for which Lieb and Wu proved that gap closure was impossible, regardless of the choices for t and U.

Low urinary iodine postpartum is associated with hypothyroid postpartum thyroid dysfunction and predicts long-term hypothyroidism.

BACKGROUND: Postpartum thyroid dysfunction (PPTD) is characterized by an early hyperthyroid phase followed, with peak prevalence at 6 months, by a hypothyroid phase which carries a risk of long-term hypothyroidism. Iodine has a major effect on thyroid function. Western Australia has previously been shown to be iodine replete. OBJECTIVE: To examine the iodine status of women with and without PPTD and the relationship of iodine status postpartum with long-term hypothyroidism. DESIGN: Case-control with follow-up. PATIENTS: A total of 149 women at 6 months postpartum (74 PPTD, 75 controls) with 98 (46 PPTD, 52 controls) followed up at 12 years. MEASUREMENTS: Urinary iodine concentration (UIC) and thyroid function at 6 months postpartum; thyroid function at 12-year follow-up. RESULTS: At 6 months postpartum, median UIC (quartiles) for observed TSH ranges were: for TSH < 0·4 mU/l 130·0 µg/l (82·0, 170·0); for TSH 0·4-4·0 mU/l 123·0 µg/l (80·5, 168·0); for TSH > 4·0 mU/l 85·0 µg/l (40·0, 141·5), P = 0·018. The odds ratio (OR) of hypothyroid PPTD with each unit of decreasing log iodine was 2·54, (95%CI: 1·47, 4·35), and with UIC < 50 µg/l, OR 4·22, (95%CI: 1·54, 11·55). In the long term, decreased log UIC significantly predicted hypothyroidism at 12-year follow-up (P = 0·002); as did UIC < 100 µg/l (P = 0·03) and UIC < 50 µg/l (P = 0·02). The association was independent of antibody status. CONCLUSION: Low UIC measured at 6 months postpartum is associated with hypothyroid PPTD and independently predicts long-term hypothyroidism. We believe that it results from more severe preceding destructive thyroiditis, with discharge of thyroidal iodine, and thereby predicts a greater risk of long-term hypothyroidism.

Many-body dipole-dipole interactions between excited Rb atoms probed by wave packets and parametric four-wave mixing.

Dipole-dipole interactions between excited Rb atoms at long range (approximately 300a0-2150a0) have been observed with molecular wave packets and a coherent nonlinear optical process. Fourier analysis of the parametric four-wave mixing (PFWM) signal wave intensity produced in femtosecond pump-probe experiments demonstrates the appearance of sidebands associated with the Rb 7s-5d(5/2) quantum beating frequency of approximately 18.3 THz. Calculations show that the observed sideband splittings and Fourier domain profiles result from multiple atom, dipole-dipole interactions, and ensembles comprising five or fewer Rb (7s, 6p) atoms account for virtually all of the data.

Resting energy expenditure in females with cystic fibrosis: is it affected by puberty?

OBJECTIVE: The aims of this study were to determine the effect of puberty and the menstrual cycle on resting energy expenditure (REE) in females with cystic fibrosis (CF). DESIGN: Cross-sectional study. All participants had measurements of REE, anthropometry and pubertal staging. The measurements in the postmenarche group were carried out both in the follicular and luteal phases of their menstrual cycle. SETTING: CF outpatient clinic at the Children's Hospital at Westmead. SUBJECTS: Fifty-six females with CF and pancreatic insufficiency (13 postmenarche) were recruited from the hospital clinic and 63 controls (21 postmenarche) were recruited through families and friends of hospital staff. RESULTS: Females with CF had a higher REE than controls (111.6+/-12.8% of predicted from controls P<0.001). There was a significant effect of menarche on REE with a decrease in the postmenarche -470 kJ/24 h compared with premenarche after adjustment for fat-free mass, fat mass and group (control or CF). There was no difference in REE between the follicular and luteal phases for either CF or controls. CONCLUSIONS: Females with CF had raised REE that appeared to be independent of menarche. This study implies all females with CF and pancreatic insufficiency may need more intensive dietary management, owing to raised REE, to maintain growth and nutritional status, and possibly improve survival.

Iron status of young Vietnamese children in Australia.

OBJECTIVE: The aim of this study was to estimate the prevalence of iron deficiency in Vietnamese children living in Australia and to identify risk factors associated with iron deficiency. METHODS: A cohort of healthy term Vietnamese infants, were followed from birth (n = 210) to 18 months (n = 174) with anthropometry, dietary intake and feeding practices measured at seven time points. Socio-demographic data were collected from the parents at the first home visit. At 18 months iron status was examined by full blood count and plasma ferritin concentration in 129/152 (85%) of the eligible children. Iron depletion was defined as a plasma ferritin level < 10 microg/L. Iron deficiency without anaemia was defined as iron depletion plus MCV < 70fl and iron deficiency anaemia was defined as iron deficiency anaemia plus Hb < 110 g/L. RESULTS: The prevalence of iron deficiency was iron depletion 19.4% (95% CI: 13.0%, 27.3%), iron deficiency without anaemia 3.1% (95% CI: 0.9%, 7.8%) and iron deficiency anaemia 3.9% (95% CI: 1.3%, 8.8%). Multiple regression analysis showed three significant predictors of iron deficiency: cows milk intake (negative effect), meat, fish or poultry intake (positive effect) and weight gain (negative effect). A cows milk intake > or = 650 mL/day was a risk factor for iron deficiency. CONCLUSION: Prevalence of iron deficiency at 18 months was high despite appropriate infant feeding practices during the first year. Modification of the diet in the second year of life may decrease the risk of iron deficiency in Vietnamese children.

Outcomes of a nutrition audit in a tertiary paediatric hospital: implications for service improvement.

OBJECTIVE: To examine the process of anthropometric assessment of nutritional status in a tertiary paediatric hospital, to identify the barriers and to make recommendations for service improvement. METHODS: The accuracy of height and weight scales in wards was checked. Dietitians measured height and weight of a representative sample of 245 inpatients and checked whether these measurements had been recorded on bed charts. Patients were classified as overweight, obese or under-nourished. Diagnoses and procedures were obtained for each patient. Funding implications were modelled for inappropriate coding of nutritional status. RESULTS: The barriers to nutritional assessment and management of nutritional comorbidities were: (i) inaccurate height scales in seven out of 12 wards; (ii) under-recording of height and weight on patient bed charts (73% height missing, 12% both height and weight missing); (iii) under-reporting of obesity and under-nutrition in medical notes (one of eight obese patients, and none of 28 undernourished patients, reported); and (iv) low referral rate of obese or under-nourished children to dietetic services (two of 42 overweight/obese patients referred, five of 28 undernourished patients referred). Funding simulation showed that if under-nourished patients were correctly diagnosed then the potential facility reimbursement would have increased by $A52 326. CONCLUSIONS: Barriers to nutritional assessment can lead to failure to diagnose and treat both over- and under-nutrition, thereby affecting quality of patient care, and may have financial implications for hospitals. Suggestions for service improvement include provision of accurate equipment, adequate training of staff undertaking nutritional assessments and clear definitions of staff responsibilities in all aspects of the process.

Obesity and under-nutrition in a tertiary paediatric hospital.

OBJECTIVE: (i) To determine the prevalence of over- and under-nutrition in both inpatients and outpatients in a tertiary paediatric hospital; (ii) to compare the prevalence of over-nutrition with that in the Australian community and (iii) to determine whether nutritional status has an impact on length of stay in hospital. METHODS: Patients aged over 12 months were proportionately sampled from medical and surgical wards and outpatient clinics. Data were collected for 245 inpatients (54% male) and 272 outpatients (55% male). Children's height, weight and body mass index (kg/m2) were measured. Overweight, obesity and under-nutrition were defined according to international criteria. Prevalence of overweight and obesity was compared with that in the 1995 Australian National Nutrition Survey (NNS). RESULTS: Similar proportions of inpatients and outpatients were underweight (6%) and wasted (4%). The prevalence of overweight and obesity in inpatients (22%) was similar to the NNS but was significantly higher in outpatients (32%, P < 0.0001). In a regression model to predict inpatient length of stay, nutritional status (P = 0.004) and the interaction between age and nutritional status (P = 0.009) were significant predictors. For over-nourished inpatients, length of stay increased significantly with age. For normally nourished and under-nourished inpatients, length of stay was relatively constant, regardless of age. CONCLUSIONS: There is a high prevalence of over-nutrition in paediatric patients, and increased length of stay for older over-nourished inpatients. These issues need to be addressed in terms of opportunities for intervention and impact on hospital resources.

Growth and feeding practices of Vietnamese infants in Australia.

OBJECTIVE: To investigate the growth and feeding practices in first-generation Vietnamese infants living in Australia. DESIGN: Cohort study. SETTING: The study was conducted between 1999 and 2002 in Sydney. SUBJECTS: A total of 239 Vietnamese women were recruited randomly from antenatal clinics, and of these 210 were initially seen. During the first year, 20 cases (9.5%) were lost to follow-up. Data were collected at 0.5, 2, 4, 6, 9 and 12 months. RESULTS: Vietnamese infants were significantly longer and heavier than reference data (both P<0.0001). The Vietnamese infants had a significant decline in weight growth with age compared with reference data (P<0.001). The Vietnamese infants had marginally higher s.d. score for ideal weight for length than reference data (P=0.044). There was a significant decline in ideal weight for length with age compared with reference data (P=0.0065). Both parents were significantly shorter (mean s.d. height scores: -1.5+/-0.8 (mother) and -1.8+/-0.8 (father)) than reference data (P<0.001). The incidence of breast feeding was 79%, but half of the breast feeding women had stopped breast feeding by 3 months. A total of 162 (79.8%) infants were given infant formula within the first week, of whom 131 (80.1%) were fed infant formula within the first 24 h after birth. CONCLUSIONS: Vietnamese infants in this study had growth comparable with reference data despite their parents being shorter than reference data. Breast feeding duration was short with infant formula being introduced early.

Variations in the measurement of resting energy expenditure in children with cystic fibrosis.

OBJECTIVE: To investigate in children with cystic fibrosis (CF) and children without CF: (1) the test-retest reproducibility of a 20 min resting energy expenditure (REE) measurement; and (2) the long-term reproducibility of REE measurements in children with CF using longitudinal data. DESIGN: Cross-sectional study and longitudinal cohort. SETTING: A tertiary referral paediatric hospital. SUBJECTS: A total of 31 (11 male, 20 female) children (aged 12.8+/-3.6 y) with CF and 32 (14 male, 18 female) healthy children without CF (aged 12.2+/-2.3 y) were enrolled in the short-term reproducibility study. Long-term REE measurement reproducibility was assessed in another 14 children (5 male, 9 female) with CF, comparing their initial REE measurement with a subsequent measurement 1-2 y later. METHODS: All children had measurements of height, weight, skinfold thickness and indirect calorimetry. RESULTS: There was no statistically significant difference in REE between repeated measurements in children with CF (mean+/-s.d., 6240+/-1280 and 6220+/-1315 kJ/24 h) and in the children without CF (6040+/-956 and 6015+/-943 kJ/24 h). For the children with CF, the intraclass correlation coefficient was 0.99 and for children without CF the intraclass correlation coefficient was 0.97. The measurement errors were 119 and 177 kJ, respectively. Approximately 80% of the variation in REE in the CF group and 70% in the group without CF was explained by fat-free mass (FFM). Analysis of the longitudinal CF data show there was no difference in REE between a child's first measurement (5140+/-1140 kJ) and their subsequent measurement (5460+/-1190 kJ), after adjustment for changes in body size between the measurements. CONCLUSION: This study has demonstrated that a short-term 20 min REE measurement is reproducible and therefore valid in children with CF and children without CF. These results also indicate that in children with CF, long-term REE measurements are reproducible.

In vivo proton (H1) magnetic resonance spectroscopy for cervical carcinoma.

Proton magnetic resonance spectroscopy (MRS) may be a useful tool in both the initial diagnosis of cervical carcinoma and the subsequent surveillance after radiation therapy, particularly when other standard diagnostic methods are inconclusive. Single voxel magnetic resonance (MR) spectral data were acquired from 8 normal volunteers, 16 patients with cervical cancer before radiation therapy, and 18 patients with cervical cancer after radiation therapy using an external pelvic coil at a 1.5-T on a Signa system. The presence or absence of various resonances within each spectrum was evaluated for similarities within each patient group and for spectral differences between groups. Resonances corresponding to lipid and creatine dominated the spectrum for the eight normal volunteers without detection of a choline resonance. Spectra from 16 pretreatment patients with biopsy-proven cervical cancer revealed strong resonances at a chemical shift of 3.25 ppm corresponding to choline. Data acquired from the 18 posttreatment setting studies was variable, but often correlated well with the clinical findings. Biopsy confirmation was obtained in seven patients. H1 MRS of the cervix using a noninvasive pelvic coil consistently demonstrates reproducible spectral differences between normal and neoplastic cervical tissue in vivo. However, signal is still poor for minimal disease recurrence. Further study is needed at intervals before, during, and after definitive irradiation with biopsy confirmation to validate the accuracy of MRS in distinguishing persistence or recurrence of disease from necrosis and fibrosis.

Pursuit of optimal carbohydrate-based anticancer vaccines: preparation of a multiantigenic unimolecular glycopeptide containing the Tn, MBr1, and Lewis(y) antigens.

A novel preparation of nonnatural glycoamino acids starting from n-pentenyl glycosides is described. The approach involves a Horner-Emmons olefination with a suitably protected glycine-derived phosphonate, followed by catalytic asymmetric hydrogenation, which proceeds with excellent diastereomeric selectivity. The synthetic methodology was useful for the preparation of glycoamino acids containing the Tn antigen, the MBr1 antigen (Globo-H), the Le(y) antigen, and lactose. These glycoamino acids can also serve as units for peptide synthesis. The synthesis of polyvalent glycopeptides containing three different antitumor antigens is described (28 and 29), and these have been prepared for conjugation to carrier protein in order to access the immunogenicity for tumor immunotherapy applications.

Isolation of the components of a complex mixture by means of column switching for their enhanced detection by mass spectrometry.

Mass spectral characterization of low-level impurities in drug substances and formulations may be challenging when using a validated HPLC method developed for optimal chromatographic performance. In many cases, either the mobile phase contains non-volatile additives that are deleterious to the operation of the mass spectrometer, or some of the related substances fail to ionize effectively under electrospray ionization or atmospheric pressure chemical ionization conditions. This paper describes a way to capture these low-level compounds from an analytical HPLC column using a small trapping column. Mixture components are retained on the trapping column by means of reducing the solvent strength of the eluent. Subsequent elution of trapped compounds using mobile phases more amenable to mass spectral analysis yields improved detection and characterization of low-level compounds of interest. Possible applications of peak trapping and elution include: (1) analysis of compounds separated using a mobile phase containing high concentrations of non-volatile additives, (2) analysis of organic acids separated using a low-pH mobile phase (containing trifluoroacetic acid), and (3) improving the detection limit of a low-level compound of interest through multiple collections. The peak trapping apparatus and optimization experiments are described.

The biochemical and clinical course of postpartum thyroid dysfunction: the treatment decision.

OBJECTIVE: To follow the clinical and biochemical course of a cohort of women who had postpartum thyroid dysfunction (PPTD) at 6 months postpartum and to examine the treatment practices of general practitioners and endocrinologists in the setting of PPTD. DESIGN: Prospective longitudinal study. SETTING: Metropolitan, Perth, Australia. PARTICIPANTS: Eighty-six Caucasian women who were identified to have PPTD at 6 months postpartum in a cross-sectional study of 748 women. MAIN OUTCOME MEASURES: Characteristics of the clinical and biochemical course of PPTD and documentation of the treatment practices and factors influencing treatment of PPTD by general practitioners and endocrinologists. RESULTS: Sixteen of 86 women (19%) were receiving treatment at 9 months postpartum and by 30 months postpartum 27% of women had received treatment for PPTD. Fifty-one percent of those not treated were biochemically euthyroid at 9 months, although, for those with hypothyroid biochemistry at 6 months, the median TSH at 18 months was at the upper limit of the reference range. Thyroid peroxidase antibody titre fell over the 2 years of follow-up. There was no significant change in clinical parameters over the study. Forty-nine percent of endocrinologists and 73% of general practitioners reported that they required clinical signs or symptoms before initiating treatment for hypothyroid PPTD. CONCLUSIONS: In a cohort of women with postpartum thyroid dysfunction, a quarter received treatment. Elevated TSH in untreated women does not completely return to the normal median. The role of clinical assessment in treatment decision-making differs between primary care physicians and endocrinologists. A case is made for the early Institution of permanent thyroxine replacement in women with postpartum thyroid dysfunction, elevated TSH and positive thyroid antibodies.

A disturbed child's use of a public event: Cotard's syndrome in a ten-year-old.

Public events can be incorporated into the mental life and life narratives of children with psychiatric illnesses. A 10-year-old boy who was not in Oklahoma City at the time of the 1995 bombing of the Murrah Federal Building and who knew no one directly impacted, claimed that he himself was dead, then that his grandfather, and finally that a peer and the peer's family had been killed in the blast. This is the first known reported case of Cotard's syndrome, the delusion of being dead, in a prepubescent child. The article also explores the relationships between this boy's symptoms, transference phenomena, real life events, themes of loss, abandonment, neglect, and death, and his fabricated stories.

A second generation synthesis of the MBr1 (globo-H) breast tumor antigen: new application of the n-pentenyl glycoside method for achieving complex carbohydrate protein linkages.

A new synthesis of the hexasaccharide MBr1 antigen (globo-H) is reported. A revised construction with improved efficiency was necessary because an anti-cancer vaccine containing this antigen is entering phase II and phase III clinical trials for prostate cancer. The key feature of this second generation synthesis is the preparation of globo-H as its n-pentenyl glycoside. This group serves as an anomeric protecting group and as a linker for bioconjugation to carrier protein. The resultant synthesis allows for the production of suitable quantities of globo-H for clinical trials.