Placental determinants of fetal growth: identification of key factors in the insulin-like growth factor and cytokine systems using artificial neural networks

<p>Abstract</p> <p>Background</p> <p>Changes and relationships of components of the cytokine and IGF systems have been shown in placenta and cord serum of fetal growth restricted (FGR) compared with normal newborns (AGA). This study aimed to analyse a data set of clinical and biochemical data in FGR and AGA newborns to assess if a mathematical model existed and was capable of identifying these two different conditions in order to identify the variables which had a mathematically consistent biological relevance to fetal growth.</p> <p>Methods</p> <p>Whole villous tissue was collected at birth from FGR (N = 20) and AGA neonates (N = 28). Total RNA was extracted, reverse transcribed and then real-time quantitative (TaqMan) RT-PCR was performed to quantify cDNA for IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IL-6. The corresponding proteins with TNF-α in addition were assayed in placental lysates using specific kits. The data were analysed using Artificial Neural Networks (supervised networks), and principal component analysis and connectivity map.</p> <p>Results</p> <p>The IGF system and IL-6 allowed to predict FGR in approximately 92% of the cases and AGA in 85% of the cases with a low number of errors. IGF-II, IGFBP-2, and IL-6 content in the placental lysates were the most important factors connected with FGR. The condition of being FGR was connected mainly with the IGF-II placental content, and the latter with IL-6 and IGFBP-2 concentrations in placental lysates.</p> <p>Conclusion</p> <p>These results suggest that further research in humans should focus on these biochemical data. Furthermore, this study offered a critical revision of previous studies. The understanding of this system biology is relevant to the development of future therapeutical interventions possibly aiming at reducing IL-6 and IGFBP-2 concentrations preserving IGF bioactivity in both placenta and fetus.</p

Impaired GH Secretion in Patients with SHOX Deficiency and Efficacy of Recombinant Human GH Therapy.

Background/Aims: Mutations of the short stature homeobox-containing (SHOX) gene on the pseudoautosomal region of the sex chromosomes cause short stature. GH treatment has been recently proposed to improve height in short patients with SHOX deficiency. The aim of this study was to evaluate GH secretion and analyze growth and safety of recombinant human GH (rhGH) therapy in short children and adolescents with SHOX deficiency. Patients and Design: We studied 16 patients (10 females; 9.7 ± 2.9 years old; height -2.46 ± 0.82 standard deviation score, SDS) with SHOX deficiency. All subjects underwent auxological evaluations, biochemical investigations, and were treated with rhGH (0.273 ± 0.053 mg/kg/week). Results: Impaired GH secretion was present in 37.5% of the studied subjects. Comparing baseline data with those at the last visit, we found that rhGH treatment improved growth velocity SDS (from -1.03 ± 1.44 to 2.77 ± 1.95; p = 0.001), height SDS (from -2.41 ± 0.71 to -1.81 ± 0.87; p < 0.001), and IGF-1 values (from -0.57 ± 1.23 to 0.63 ± 1.63 SDS, p = 0.010) without affecting body mass index SDS. Height SDS measured at the last visit was significantly correlated with chronological age (r = -0.618, p = 0.032), bone age (r = -0.582, p = 0.047) and height SDS (r = 0.938, p < 0.001) at the beginning of treatment. No adverse events were reported on rhGH therapy which was never discontinued. Conclusion: These data showed that impaired GH secretion is not uncommon in SHOX deficiency subjects, and that rhGH therapy may be effective in increasing height in most of these patients independent of their GH secretory status, without causing any adverse events of concern

Evaluation of Two Models for Human Topoisomerase I Interaction with dsDNA and Camptothecin Derivatives

Human topoisomerase I (Top1) relaxes supercoiled DNA during cell division. Camptothecin stabilizes Top1/dsDNA covalent complexes which ultimately results in cell death, and this makes Top1 an anti-cancer target. There are two current models for how camptothecin and derivatives bind to Top1/dsDNA covalent complexes (Staker, et al., 2002, Proc Natl Acad Sci USA 99: 15387–15392; and Laco, et al., 2004, Bioorg Med Chem 12: 5225–5235). The interaction energies between bound camptothecin, and derivatives, and Top1/dsDNA in the two models were calculated. The published structure-activity-relationships for camptothecin and derivatives correlated with the interaction energies for camptothecin and derivatives in the Laco et al. model, however, this was not the case for several camptothecin derivatives in the Stacker et al. model. By defining the binding orientation of camptothecin and derivatives in the Top1/dsDNA active-site these results allow for the rational design of potentially more efficacious camptothecin derivatives

Including the public in pandemic planning: a deliberative approach

Background: Against a background of pandemic threat posed by SARS and avian H5N1 influenza, this study used deliberative forums to elucidate informed community perspectives on aspects of pandemic planning. Methods: Two deliberative forums were carried out with members of the South Australian community. The forums were supported by a qualitative study with adults and youths, systematic reviews of the literature and the involvement of an extended group of academic experts and policy makers. The forum discussions were recorded with simultaneous transcription and analysed thematically. Results: Participants allocated scarce resources of antiviral drugs and pandemic vaccine based on a desire to preserve society function in a time of crisis. Participants were divided on the acceptability of social distancing and quarantine measures. However, should such measures be adopted, they thought that reasonable financial, household and psychological support was essential. In addition, provided such support was present, the participants, in general, were willing to impose strict sanctions on those who violated quarantine and social distancing measures. Conclusions: The recommendations from the forums suggest that the implementation of pandemic plans in a severe pandemic will be challenging, but not impossible. Implementation may be more successful if the public is engaged in pandemic planning before a pandemic, effective communication of key points is practiced before and during a pandemic and if judicious use is made of supportive measures to assist those in quarantine or affected by social isolation measures.Annette J Braunack-Mayer, Jackie M Street, Wendy A Rogers, Rodney Givney, John R Moss, Janet E Hiller, Flu Views tea

Pollen, biomarker and stable isotope evidence of late Quaternary environmental change at Lake McKenzie, southeast Queensland

Unravelling links between climate change and vegetation response during the Quaternary is important if the climate–environment interactions of modern systems are to be fully understood. Using a sediment core from Lake McKenzie, Fraser Island, we reconstruct changes in the lake ecosystem and surrounding vegetation over the last ca. 36.9 cal kyr. Evidence is drawn from multiple sources, including pollen, micro-charcoal, biomarker and stable isotope (C and N) analyses, and is used to gain a better understanding of the nature and timing of past ecological changes that have occurred at the site. The glacial period of the record, from ca. 36.9 to 18.3 cal kyr BP, is characterised by an increased abundance of plants of the aquatic and littoral zone, indicating lower lake water levels. High abundance of biomarkers and microfossils of the colonial green alga Botryococcus occurred at this time and included large variation in individual botryococcene d13C values. A slowing or ceasing of sediment accumulation occurred during the time period from ca. 18.3 to 14.0 cal kyr BP. By around 14.0 cal kyr BP fire activity in the area was reduced, as was abundance of littoral plants and terrestrial herbs, suggesting wetter conditions from that time. The Lake McKenzie pollen record conforms to existing records from Fraser Island by containing evidence of a period of reduced effective precipitation that commenced in the mid-Holocene

Polymorphisms in folate-metabolizing genes, chromosome damage, and risk of Down syndrome in Italian women: identification of key factors using artificial neural networks

<p>Abstract</p> <p>Background</p> <p>Studies in mothers of Down syndrome individuals (MDS) point to a role for polymorphisms in folate metabolic genes in increasing chromosome damage and maternal risk for a Down syndrome (DS) pregnancy, suggesting complex gene-gene interactions. This study aimed to analyze a dataset of genetic and cytogenetic data in an Italian group of MDS and mothers of healthy children (control mothers) to assess the predictive capacity of artificial neural networks assembled in TWIST system in distinguish consistently these two different conditions and to identify the variables expressing the maximal amount of relevant information to the condition of being mother of a DS child.</p> <p>The dataset consisted of the following variables: the frequency of chromosome damage in peripheral lymphocytes (BNMN frequency) and the genotype for 7 common polymorphisms in folate metabolic genes (<it>MTHFR </it>677C>T and 1298A>C, <it>MTRR </it>66A>G, <it>MTR </it>2756A>G, <it>RFC1 </it>80G>A and <it>TYMS </it>28bp repeats and 1494 6bp deletion). Data were analysed using TWIST system in combination with supervised artificial neural networks, and a semantic connectivity map.</p> <p>Results</p> <p>TWIST system selected 6 variables (BNMN frequency, <it>MTHFR </it>677TT, <it>RFC1 </it>80AA, <it>TYMS </it>1494 6bp +/+, <it>TYMS </it>28bp 3R/3R and <it>MTR </it>2756AA genotypes) that were subsequently used to discriminate between MDS and control mothers with 90% accuracy. The semantic connectivity map provided important information on the complex biological connections between the studied variables and the two conditions (being MDS or control mother).</p> <p>Conclusions</p> <p>Overall, the study suggests a link between polymorphisms in folate metabolic genes and DS risk in Italian women.</p

Clone-specific expression, transcriptional regulation, and action of interleukin-6 in human colon carcinoma cells

<p>Abstract</p> <p>Background</p> <p>Many cancer cells produce interleukin-6 (IL-6), a cytokine that plays a role in growth stimulation, metastasis, and angiogenesis of secondary tumours in a variety of malignancies, including colorectal cancer. Effectiveness of IL-6 in this respect may depend on the quantity of basal and inducible IL-6 expressed as the tumour progresses through stages of malignancy. We therefore have evaluated the effect of <it>IL-6 </it>modulators, i.e. IL-1β, prostaglandin E₂, 17β-estradiol, and 1,25-dihydroxyvitamin D₃, on expression and synthesis of the cytokine at different stages of tumour progression.</p> <p>Methods</p> <p>We utilized cultures of the human colon carcinoma cell clones Caco-2/AQ, COGA-1A and COGA-13, all of which expressed differentiation and proliferation markers typical of distinct stages of tumour progression. IL-6 mRNA and protein levels were assayed by RT-PCR and ELISA, respectively. DNA sequencing was utilized to detect polymorphisms in the <it>IL-6 </it>gene promoter.</p> <p>Results</p> <p><it>IL-6 </it>mRNA and protein concentrations were low in well and moderately differentiated Caco-2/AQ and COGA-1A cells, but were high in poorly differentiated COGA-13 cells. Addition of IL-1β (5 ng/ml) to a COGA-13 culture raised IL-6 production approximately thousandfold via a prostaglandin-independent mechanism. Addition of 17β-estradiol (10^-7M) reduced basal IL-6 production by one-third, but IL-1β-inducible IL-6 was unaffected. Search for polymorphisms in the <it>IL-6 </it>promoter revealed the presence of a single haplotype, i.e., -597A/-572G/-174C, in COGA-13 cells, which is associated with a high degree of transcriptional activity of the <it>IL-6 </it>gene. IL-6 blocked differentiation only in Caco-2/AQ cells and stimulated mitosis through up-regulation of c-<it>myc </it>proto-oncogene expression. These effects were inhibited by 10^-8M 1,25-dihydroxyvitamin D₃.</p> <p>Conclusion</p> <p>In human colon carcinoma cells derived from well and moderately differentiated tumours, IL-6 expression is low and only marginally affected, if at all, by PGE₂, 1,25-dihydroxyvitamin D₃, and 17β-estradiol. However, IL-6 is highly abundant in undifferentiated tumour cells and is effectively stimulated by IL-1β. In case of overexpression of an <it>IL-6 </it>gene variant with extreme sensitivity to IL-1β, massive release of the cytokine from undifferentiated tumour cells may accelerate progression towards malignancy by paracrine action on more differentiated tumour cells with a still functioning proliferative IL-6 signalling pathway.</p

What effect does physician "profiling" have on inpatient physician satisfaction and hospital length of stay?

BACKGROUND: 2002 marked the first time that the rate of hospital spending in the United States outpaced the overall health care spending rate of growth since 1991. As hospital spending continues to grow and as reimbursement for hospital expenses has moved towards the prospective payment system, there is still increasing pressure to reduce costs. Hospitals have a major incentive to decrease resource utilization, including hospital length of stay. We evaluated whether physician profiling affects physician satisfaction and hospital length of stay, and assessed physicians' views concerning hospital cost containment and the quality of care they provide. METHODS: To determine if physician profiling affects hospital length of stay and/or physician satisfaction, we used quasi-experimental with before-versus-after and intervention-versus-control comparisons of length of stay data collected at an intervention and six control hospitals. Intervention hospital physicians were informed their length of stay would be compared to their peers and were given a questionnaire assessing their experience. RESULTS: Nearly half of attending pre-profiled physicians felt negative about the possibility of being profiled, while less than one-third of profiled physicians reported feeling negative about having been profiled. Nearly all physicians greatly enjoyed their ward month. Length of stay at the profiled site decreased by an additional 1/3 of a day in the profiling year, compared to the non-profiled sites (p < 0.001). CONCLUSION: A relatively non-instrusive profiling intervention modestly reduced length of stay without adversely affecting physician satisfaction

Transition from Child and Adolescent to Adult Mental Health Services in Young People with Depression: On What Do Clinicians Base their Recommendation?

BACKGROUND: Clinicians in Child and Adolescent Mental Healthcare Services (CAMHS) face the challenge to determine who is at risk of persistence of depressive problems into adulthood and requires continued treatment after reaching the CAMHS upper age limit of care-provision. We assessed whether risk factors for persistence were related to CAMHS clinicians’ transition recommendations. METHODS: Within the wider MILESTONE cohort study, 203 CAMHS users were classified with unipolar depressive disorder by their clinician, and 185 reported clinical levels of depressive problems on the DSM-oriented Depressive Problems scale of the Achenbach Youth Self Report. Logistic regression models were fitted to both subsamples to assess the relationship between clinicians’ transition recommendations and risk factors for persistent depression. RESULTS: Only clinicianrated severity of psychopathology was related to a recommendation to continue treatment for those classified with unipolar depressive disorder (N = 203; OR = 1 45, 95% CI (1.03–2.03), p = 044) and for those with self-reported depressive problems on the Achenbach DSM-oriented Depressive Problems scale (N = 185; OR = 1 62, 95% CI (1.12–2.34), p = 012). CONCLUSION: Transition recommendations and need for continued treatment are based on clinical expertise, rather than self-reported problems and needs