The patient advisor, an organizational resource as a lever for an enhanced oncology patient experience (PAROLE-onco): a longitudinal multiple case study protocol.

BACKGROUND: Quebec is one of the Canadian provinces with the highest rates of cancer incidence and prevalence. A study by the Rossy Cancer Network (RCN) of McGill university assessed six aspects of the patient experience among cancer patients and found that emotional support is the aspect most lacking. To improve this support, trained patient advisors (PAs) can be included as full-fledged members of the healthcare team, given that PA can rely on their knowledge with experiencing the disease and from using health and social care services to accompany cancer patients, they could help to round out the health and social care services offer in oncology. However, the feasibility of integrating PAs in clinical oncology teams has not been studied. In this multisite study, we will explore how to integrate PAs in clinical oncology teams and, under what conditions this can be successfully done. We aim to better understand effects of this PA intervention on patients, on the PAs themselves, the health and social care team, the administrators, and on the organization of services and to identify associated ethical and legal issues. METHODS/DESIGN: We will conduct six mixed methods longitudinal case studies. Qualitative data will be used to study the integration of the PAs into clinical oncology teams and to identify the factors that are facilitators and inhibitors of the process, the associated ethical and legal issues, and the challenges that the PAs experience. Quantitative data will be used to assess effects on patients, PAs and team members, if any, of the PA intervention. The results will be used to support oncology programs in the integration of PAs into their healthcare teams and to design a future randomized pragmatic trial to evaluate the impact of PAs as full-fledged members of clinical oncology teams on cancer patients' experience of emotional support throughout their care trajectory. DISCUSSION: This study will be the first to integrate PAs as full-fledged members of the clinical oncology team and to assess possible clinical and organizational level effects. Given the unique role of PAs, this study will complement the body of research on peer support and patient navigation. An additional innovative aspect of this study will be consideration of the ethical and legal issues at stake and how to address them in the health care organizations.

Preeclampsia: effect on newborn blood pressure in the 3 days following preterm birth: a cohort study.

Maternal hypertension and preeclampsia are associated with greater risk of hypertension in childhood, and cardiovascular events in adulthood. However, whether preeclampsia affects blood pressure (BP) in the newborn period is unclear. Previous neonatal studies were based on small sample sizes, very low birth weight or gestational age or limited duration (h). To delineate hemodynamic repercussions of maternal preeclampsia on preterm infants (gestational ages ⩾29 weeks) with/without intrauterine growth restriction (IUGR) in the first 3 postnatal days, we conducted a single-centre retrospective cohort study of singleton births at 29-35 weeks of gestation in Montreal, Canada, from 2008 to 2011. Data were obtained from medical charts. Exclusion criteria included congenital anomalies, infections, pre-pregnancy maternal hypertension and gestational diabetes. IUGR was defined as birth weight <10th percentile. Of the 338 eligible neonates, 230 were included: 75 preeclampsia-IUGR, 72 preeclampsia-only and 83 controls. The preeclampsia-IUGR group had longer gestations than the preeclampsia-only or control groups (32.4±1.8 vs. 31.3±1.6 vs. 31.7±1.6 weeks, respectively; P<0.001). Mean BPs increased over the first 3 days for all newborns (P<0.001). Infants with preeclampsia-associated IUGR had the highest systolic and diastolic BPs, even after adjustment for birth weight, and preeclampsia-only the next highest. Systolic BP progression showed significant differences between groups (P<0.05). We conclude that impact of preeclampsia on children blood pressure was manifest within days of birth, over and above coexisting IUGR. Long-term cardiovascular follow-up and targeted preventive strategies are advised for this underrecognized high-risk population.

Measuring the prevalence of chronic diseases using population surveys by pooling self-reported symptoms, diagnosis and treatments: results from the World Health Survey of 2003 for South Asia.

OBJECTIVES: Measuring disease prevalence poses challenges in countries where information systems are poorly developed. Population surveys soliciting information on self-reported diagnosis also have limited capacity since they are influenced by informational and recall biases. Our aim is to propose a method to assess the prevalence of chronic disease by combining information on self-reported diagnosis, self-reported treatment and highly suggestive symptoms. METHODS: An expanded measure of prevalence was developed using data from the World Health Survey for Bangladesh, India and Sri Lanka. Algorithms were constructed for six chronic diseases. RESULTS: The expanded measures of chronic disease increase the prevalence estimates. Prevalence varies across socio-demographic characteristics, such as age, education, socioeconomic status (SES), and country. Finally, the association, as also risk factor, between chronic disease status and poor self-rated health descriptions increases significantly when one takes into account highly suggestive symptoms of diseases. CONCLUSIONS: Our expanded measure of chronic disease could form a basis for surveillance of chronic diseases in countries where health information systems have been poorly developed. It represents an interesting trade-off between the bias associated with usual surveillance data and costs.

Blood pressures in newborns with twin-twin transfusion syndrome.

OBJECTIVE: In addition to unbalanced flow through placental anastomoses, evidence suggests that transfer of circulating vasoactive elements from the donor to the recipient contribute to the pathological process of twin-twin transfusion syndrome (TTTS). The objective of this study was to test the hypothesis that TTTS recipients have higher blood pressure (BP) at birth than donors. STUDY DESIGN: Chart review of all TTTS infants born from 1996 to 2007 with both twins alive 24 h (51 pairs; average gestational age 30±3 weeks). RESULTS: Both systolic and diastolic neonatal BPs were significantly higher in recipients. When expressed relative to predicted BP for birth weight (BW), BP were lower than expected in donors and higher in recipients. CONCLUSIONS: Data indicate that TTTS recipients have BP significantly higher than donors and than BP expected for BW. The long-term impact of these early hemodynamic perturbations remains to be determined.

Identification of six new HLA-G alleles with non-coding DNA base changes.

We identified six novel human leukocyte antigen-G alleles with synonymous mutations in Caucasian and/or African populations.

Effects of dihydrotestosterone on skeletal muscle transcriptome in mice measured by serial analysis of gene expression.

In order to characterize the action of androgen in skeletal muscle, we have investigated the effects of castration (GDX) and dihydrotestosterone (DHT) on global gene expression in mice. The serial analysis of gene expression method was performed in the muscle of male mice in six experimental groups: intact, GDX and GDX+DHT injection 1, 3, 6 or 24 h before they were killed. A total of 780 822 sequenced tags quantified the expression level of 80 142 tag species. Thirteen and seventy-nine transcripts were differentially expressed in GDX and DHT respectively (P < 0.05), including eight partially characterized and 21 potential novel transcripts. The induced transcripts within 3 h after DHT injection were involved in the following functions: transcription, protein synthesis, modification and degradation, muscle contraction and relaxation, cell signaling, polyamine biosynthesis, cell cycle progression and arrest, angiogenesis, energy metabolism and immunity. However, the inductions of transcripts related to cell cycle arrest and angiogenesis were no longer significant 24 h after DHT injection. The current study might suggest that DHT promotes protein synthesis, cell signaling, cell proliferation and ATP production, as well as muscle contraction and relaxation at the transcriptional level in skeletal muscle in vivo.

Reproducibility, bioinformatic analysis and power of the SAGE method to evaluate changes in transcriptome.

The serial analysis of gene expression (SAGE) method is used to study global gene expression in cells or tissues in various experimental conditions. However, its reproducibility has not yet been definitively assessed. In this study, we have evaluated the reproducibility of the SAGE method and identified the factors that affect it. The determination coefficient (R2 ) for the reproducibility of SAGE is 0.96. However, there are some factors that can affect the reproducibility of SAGE, such as the replication of concatemers and ditags, the number of sequenced tags and double PCR amplification of ditags. Thus, corrections for these factors must be made to ensure the reproducibility and accuracy of SAGE results. A bioinformatic analysis of SAGE data is also presented in order to eliminate these artifacts. Finally, the current study shows that increasing the number of sequenced tags improves the power of the method to detect transcripts and their regulation by experimental conditions.

P element-encoded regulatory products enhance Repeat-Induced Gene Silencing (RIGS) of P-lacZ-white clusters in Drosophila melanogaster.

In Drosophila melanogaster, some clusters of P transgenes ( P-lacZ-white) display a variegating phenotype for the white marker in the eye, a phenomenon termed "Repeat-Induced Gene Silencing" (RIGS). We have tested the influence of the P element repression state (P cytotype) on the eye phenotype of several P-lac-w clusters that differ in transgene copy number or genomic insertion site. P element-encoded regulatory products strongly enhance RIGS. The effect occurs in both sexes, is detectable with clusters having at least three copies and is observed at both genomic locations tested (cytogenetic regions 50C and 92E). Single variegating P-lac-w transgenes located in pericentromeric heterochromatin are not affected by P regulatory products. All P strain backgrounds tested enhance RIGS, including chromosomes bearing a single P element encoding a truncated P transposase or carrying a single internally deleted KP element. Therefore, clusters are highly sensitive to different types of P repressors. Finally, a chimeric gene in which the 5' portion of the P element is fused to the polyhomeotic coding sequence (ph(p1)) also strongly enhances silencing of P-lac-w clusters. These results have implications for the mechanism of action of the P repressors and show that P transgene clusters represent a new class of P-sensitive alleles, providing a simple assay for somatic P repression that can be completed in one generation.

Dominant modifiers of the polyhomeotic extra-sex-combs phenotype induced by marked P element insertional mutagenesis in Drosophila.

Members of the Polycomb group (Pc-G) and trithorax group (trx-G) of genes, as well as the enhancers of trx-G and Pc-G (ETP), function together to maintain segment identity during Drosophila development. In order to obtain new marked P mutations in these genes, we screened for dominant modifiers of the extra-sex-combs phenotype displayed by males mutant for the polyhomeotic (ph) gene, a member of the Pc-G group. Five P(lacW) insertions in four different genes were found to stably suppress ph: two are allelic to trithorax, one is the first allele specific to the Minute(2)21C gene, and the remaining two define new trx-G genes, toutatis (tou) in 48A and taranis (tara) in 89B10-13. tou is predicted to encode a 3109 amino acid sequence protein (TOU), which contains a TAM DNA-binding domain, a WAKZ motif, two PHD zinc fingers and a C-terminal bromodomain, and as such is likely to be involved in regulation of chromatin structure as a subunit of a novel chromatin remodelling complex. In a previous study, we found that insertion of a P(ph) transposable element containing ph regulatory sequences creates a high frequency of mutations modifying ph homeotic phenotypes. One such insertion enhanced the ph phenotype and we show that it is a new allele of UbcD1/eff, a gene encoding a ubiquitin-conjugating enzyme that is involved in telomere association and potentially in chromatin remodelling.

[Maintenance of cellular memory by Polycomb group genes]. / Le maintien de la mémoire cellulaire par les gènes du groupe Polycomb.

The Polycomb-group genes (PcG) encode a group of repressors well known for their function in stably maintaining the inactive expression patterns of key developmental regulators, including homeotic genes. PcG genes are structurally and functionally conserved in Drosophila and Mammalians, and some homologues have been found in worms, yeast and plants. Their products act through different complexes and at least one of these complexes seems to induce histone deacetylation. In Drosophila, building of PcG complexes depends on both protein-protein interactions and recognition near target genes of specific DNA sequences called Polycomb-group response element (PRE). Together with the counteracting trithorax-group proteins, PcG products establish a form of cellular memory by faithfully maintaining transcription states determined early in embryogenesis. Here, we discuss several aspects of PcG functions: the composition of the different complexes, the establishment and the transmission of silencing to subsequent cell generations as well as the subnuclear localisation of the PcG products.

P-Element repression in Drosophila melanogaster by variegating clusters of P-lacZ-white transgenes.

In Drosophila, clusters of P transgenes (P-lac-w) display a variegating phenotype for the w marker. In addition, X-ray-induced rearrangements of chromosomes bearing such clusters may lead to enhancement of the variegated phenotype. Since P-lacZ transgenes in subtelomeric heterochromatin have some P-element repression abilities, we tested whether P-lac-w clusters also have the capacity to repress P-element activity in the germline. One cluster (T-1), located on a rearranged chromosome (T2;3) and derived from a line bearing a variegating tandem array of seven P-lac-w elements, partially represses the dysgenic sterility (GD sterility) induced by P elements. This cluster also strongly represses in trans the expression of P-lacZ elements in the germline. This latter suppression shows a maternal effect. Finally, the combination of variegating P-lac-w clusters and a single P-lacZ reporter inserted in subtelomeric heterochromatic sequences at the X chromosome telomere (cytological site 1A) leads to strong repression of dysgenic sterility. These results show that repression of P-induced dysgenic sterility can be elicited in the absence of P elements encoding a polypeptide repressor and that a transgene cluster can repress the expression of a single homologous transgene at a nonallelic position. Implications for models of transposable element silencing are discussed.

Contribution of hyperinsulinemia to modulation of lipoprotein lipase activity in the obese Zucker rat.

This study was designed to assess the contribution of hyperinsulinemia to the maintenance of high adipose and low muscle lipoprotein lipase (LPL) activity in the obese Zucker fa/fa rat. Insulinemia in obese Zucker rats was reduced for 4 days with a single injection of low-dose streptozotocin (STZ). Saline-injected intact obese (obese-INT) and STZ-injected obese (obese-STZ) rats were compared with a lean Fa/? reference group. LPL activity was assessed after a 12-hour fast, with or without a 1-hour refeeding period. Fasting serum insulin levels were 17-fold higher in obese-INT versus lean rats and were reduced to 60% of obese-INT levels in obese-STZ animals. In the postprandial state, serum insulin levels remained low in obese-STZ rats and were similar to the values in lean animals, whereas insulinemia increased in the obese-INT group to 18-fold the levels in lean rats. Serum glucose, nonesterified fatty acid (NEFA), and triglyceride levels, which were higher in obese-INT versus lean rats, were further increased in the obese-STZ group. Tissue weights of obese rats were unaffected by STZ treatment. Fasting LPL specific activity was higher in white adipose tissue ([WAT] +87%) and brown adipose tissue ([BAT] +167%) of obese-INT versus lean rats. Reducing the insulinemia in obese-STZ rats reduced fasting enzyme activity to the levels in lean animals in both WAT and BAT. Insulinemia and adipose LPL activity were positively correlated in the fasted state. Acute food intake increased WAT LPL activity in lean animals, but not in obese animals. Soleus LPL activity was lower in obese-INT compared with lean rats and was further decreased in obese-STZ animals. Heart LPL was decreased only in obese-STZ rats compared with the lean group. LPL in muscle tissue was not correlated with insulinemia, but an inverse relationship was found between serum NEFA levels and enzyme activity. It is concluded that in the obese Zucker rat, hyperinsulinemia is responsible for the maintenance of elevated basal LPL activity in adipose tissue independently of fat mass, whereas muscle enzyme activity appears to be more strongly and inversely related to the availability or tissue utilization of lipid substrates.

One-to-one correspondence between the two genetic units and the tandemly duplicated transcriptional units of the polyhomeotic locus of Drosophila.

polyhomeotic (ph) is a complex locus in Drosophila defined by two genetic units. Two mutational events are necessary to obtain the null lethal phenotype. Molecular analysis has shown that the ph locus contains two transcriptional units coding for two very similar proteins. Although a strong argument in favor of a strict correlation between the genetic and molecular units can be constructed, there is no direct evidence for the hypothesis. Here, we show for all cases with detectable molecular defects that X-ray-induced generation of an amorphic allele from a pre-existing X-ray-induced hypomorphic allele with a lesion limited to one unit invariably involves a rearrangement in the other unit. This result proves that each genetic unit corresponds to one transcription unit.

In vivo chromatin accessibility correlates with gene silencing in Drosophila.

Gene silencing by heterochromatin is a well-known phenomenon that, in Drosophila, is called position effect variegation (PEV). The long-held hypothesis that this gene silencing is associated with an altered chromatin structure received direct support only recently. Another gene-silencing phenomenon in Drosophila, although similar in its phenotype of variegation, has been shown to be associated with euchromatic sequences and is dependent on developmental regulators of the Polycomb group (Pc-G) of gene products. One model proposes that the Pc-G products may cause a local heterochromatinization that maintains a repressed state of transcription of their target genes. Here, we test these models by measuring the accessibility of white or miniwhite sequences, in different contexts, to the Escherichia coli dam DNA methyltransferase in vivo. We present evidence that PEV and Pc-G-mediated repression mechanisms, although based on different protein factors, may indeed involve similar higher-order chromatin structure.

Dietary rat models in which the development of hypertriglyceridemia and that of insulin resistance are dissociated.

The consequences of chronic ingestion of a high-carbohydrate (starch + glucose [HCHO]) and high-fat (lard + corn oil [HFAT]) diet on triglyceride metabolism and insulin sensitivity were evaluated in fasted and fed rats. Compared with their HFAT counterparts, animals fed the HCHO diet displayed fasting and postprandial hypertriglyceridemia that was apparent after 3 weeks of feeding and persisted after 6 weeks. It was determined that hypertriglyceridemia was due to oversecretion of triglycerides into the circulation. During fasting triglyceride accumulation in plasma after administration of Triton WR1339 was indeed twofold higher in HCHO than in HFAT rats, whereas the global capacity for intravascular triglyceride hydrolysis, as assessed by an intravenous fat tolerance test and measurement of postheparin plasma lipoprotein and hepatic lipase activities, was comparable in both dietary cohorts. The postprandial increase in triglycerides after a high-carbohydrate meal was larger in HCHO than in HFAT rats. A fasting intravenous glucose tolerance test (IVGTT) showed that HFAT animals displayed insulin resistance after 3 weeks of feeding, which worsened after 6 weeks of treatment. Thus, the HCHO diet elicited fasting and postprandial hypertriglyceridemia without impairment of insulin sensitivity as compared with the HFAT diet, whereas the latter brought about deterioration of the sensitivity of glucose metabolism to insulin without affecting triglyceridemia. From these studies and other animal models, it is suggested that rapid delivery of fatty acids to tissues from chylomicron-derived triglycerides leads to insulin insensitivity, while fatty acids may not be available to increase endogenous production of triglycerides because they are mainly oxidized. In contrast, dietary starch/glucose increases hepatic synthesis and secretion of triglycerides that result in hypertriglyceridemia, but the deleterious effects of glucose-fatty acid competition on insulin sensitivity are prevented because endogenously derived triglycerides are catabolized more slowly and glucose is available for oxidation. The present results support the concept that coexistence of hypertriglyceridemia and resistance of glucose metabolism to insulin may be frequent but not obligatory.

Postprandial modulation of lipoprotein lipase in rats with insulin resistance.

The purpose of this study was to determine whether the postprandial modulation of lipoprotein lipase (LPL) activity was altered in rats with resistance of glucose metabolism to insulin action induced by a high-fat diet. Relationships between serum insulin and tissue LPL activity were established in rats chronically fed a high-carbohydrate or high-fat diet, and the effects of fasting and intake of meals of habitual and alternate composition were contrasted. The feeding paradigm did not result in the development of obesity. Global resistance of glucose metabolism to insulin brought about by chronic high-fat feeding was confirmed by an intravenous glucose tolerance test. Fasting serum glucose and insulin concentrations were similar in both cohorts, as was LPL activity in retroperitoneal and inguinal white adipose tissues (WAT), the heart, and soleus. A high-carbohydrate meal brought about higher postprandial insulinemia in the cohort chronically fed the high-fat diet. This was associated with larger changes in LPL activity, that is, an increase in inguinal WAT and in brown adipose tissue and a decrease in soleus, red vastus lateralis, and the heart. Thus the established postprandial modulation of LPL, presumably by insulin, was potentiated in the presence of hyperinsulinemia induced by chronic high-fat feeding despite the concomitant impairment of glucose metabolism.

Tissue- and gender-specific modulation of lipoprotein lipase in intact and gonadectomised rats treated with dl-fenfluramine.

This study evaluated the respective and interactive effects of chronic dl-fenfluramine treatment, an anorectic serotoninergic agonist, and gonadectomy on lipoprotein lipase activity in adipose tissue and skeletal muscle. Male and female Sprague-Dawley rats were gonadectomised. These as well as intact animals were treated with dl-fenfluramine or a placebo for 28 days. Gonadectomy brought about an increase in final body weight of females (16-18%, P < 0.0001), but a decrease in that of male animals (9-13%, P < 0.001). These changes were proportional to those of food intake. The increase in body weight of gonadectomised female rats was paralleled by that of retroperitoneal adipose tissue and vastus lateralis muscle weights, whereas in male rats, gonadectomy diminished muscle weight only. Lipoprotein lipase activity was doubled (P < 0.0001) by gonadectomy in adipose tissue of female rats, but remained unaltered by the surgery in male animals. Enzyme activity in muscle was unaffected by gonadectomy in both genders. Treatment with dl-fenfluramine reduced weight gain in males and females, whether they had been gonadectomised or not. A concomitant reduction was observed in adipose tissue mass and lipoprotein lipase activity, which was reduced to 50-65% of the activity measured in placebo-treated animals (P < 0.01). The drug remained without effect on muscle weight and lipoprotein lipase activity in either gender. Thus removal of gonadal steroids had divergent effects on LPL activity with regard to gender and tissue. In addition, dl-fenfluramine treatment was followed by decreased enzyme activity in adipose tissue, but not in muscle, this pattern being independent of the nature or presence of gonadal steroids.(ABSTRACT TRUNCATED AT 250 WORDS)