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.

Active by nature: exploring cancer survivors' exercise barriers, facilitators, preferences, and psychosocial benefits of engaging in outdoor physical activity.

INTRODUCTION: Large numbers of cancer survivors struggle with mental health after cancer diagnosis. Cancer survivors are encouraged to engage in physical activity in order to improve physical and mental health. Additional benefits to physical activity engagement in natural environments have been reported but this has not been explored in cancer survivors. METHODS: Study participants had to be over the age of 19, a Canadian resident, and have had a cancer diagnosis. Recruitment to complete an online survey occurred through social media and snowball sampling. The data collected included physical activity participation, preferences and location, barriers and facilitators of engagement in outdoor physical activity, nature-related questions, and measures of psychosocial health. The sample was split by the number of outdoor physical activity minutes (> 150 min per week). Correlations were computed to examine the role of outdoor physical activity minutes on measured psychosocial health outcomes. RESULTS: One hundred and fourteen (N = 114) cancer survivors completed the online questionnaire. More than half of the respondents indicated that an outdoor environment was central to their physical activity of choice with walking identified as the most common outdoor physical activity. Group support was the main expected facilitator of success in an outdoor walking program. Outdoor active participants were significantly more motivated and confident to be physically active and reported significantly more benefit and enjoyment in being physically active than outdoor inactive participants. Minutes of outdoor physical activity was significantly correlated with subjective happiness, nature relatedness, and higher quality of life. No significant correlations were found between minutes of outdoor physical activity and generalized anxiety. CONCLUSION: While future research is needed to further explore the role of nature in cancer survivor psychosocial health, we believe that our data suggests preference and benefit for outdoor physical activity in cancer survivors.

A mixed-methods evaluation of a group based trail walking program to reduce anxiety in cancer survivors

Background: Cancer survivorship results in an increased number of physical and psychosocial health issues. Engaging in physical activity in natural environments is often thought of as restorative. Despite the potential benefits of engaging in physical activity in natural environments there are no sustainable community-based programs for cancer survivors that employ this form of physical activity. This study aims to evaluate the impact of an 8-week trail-walking (TW) program on anxiety in a population of adult cancer survivors. Methods: The TW program consisted of two trail walks per week for 8 weeks led by a hiking guide. Individuals were eligible to participate if they were 19 years or older, were a cancer survivor, were not on active immunotherapy, and had medical clearance from their physician for physical activity. While 12 participants signed up for the program, 9 participants (N = 9, 8 F, 1 M) completed the program. A mixed methodology included preand-post quantitative program surveys and post-program interviews. Questionnaires measured generalized anxiety, sleep disturbances, self-efficacy, self-esteem, psychological well-being and depression as well as pre-and-post hike state anxiety. Data was analysed using paired t-tests. Interviews were transcribed verbatim and an inductive thematic analysis was conducted to consolidate meaning and identify themes using NVivo 11 software. Results: Average attendance was 74% of the 16 hikes. There was no significant reduction in the primary outcome of generalized anxiety (p = .38). There was a significant reduction in perceived stress after 8-weeks (p = .03) and a significant reduction in state anxiety after TW (p < .001). None of the other secondary outcomes were statistically significant (p > .05). Four overarching themes, or benefits, emerged from qualitative data analysis: (a) benefits of program design (b) physical benefits, (c) psychological benefits, and (d) social benefits. Conclusions: These findings demonstrate the utility of a TW program for cancer survivors in order to promote physical, psychological and social health. Feasibility of a TW program would be contingent on access to natural areas for TW and an instructor-led program with other cancer survivors.

Efficacy of a single oral dose of a live bivalent E. coli vaccine against post-weaning diarrhea due to F4 and F18-positive enterotoxigenic E. coli.

F4- and F18-positive enterotoxigenic E. coli strains (F4-ETEC and F18-ETEC) are important causes of post-weaning diarrhea (PWD) in pigs. F4 (antigenic variant ac) and F18 (ab and ac) fimbriae are major antigens that play an important role in the early stages of infection. Herein, the efficacy of a live oral vaccine consisting of two non-pathogenic E. coli strains, one F4ac- and one F18ac-positive, was evaluated using F4ac-ETEC and F18ab-ETEC challenge models. A randomized, masked, placebo-controlled, block design, parallel-group confirmatory study with two different vaccination-challenge intervals (7 and 21 days) was conducted for each challenge model. The vaccine was administered in one dose, to ≥18-day-old piglets via drinking water. Efficacy was assessed by evaluating diarrhea, clinical observations, weight gain and fecal shedding of F4-ETEC or F18-ETEC. Anti-F4 and anti-F18 immunoglobulins in blood were measured. The vaccination resulted in significant reductions in clinical PWD and fecal shedding of F4-ETEC and F18-ETEC after the 7- and 21-day-post-vaccination heterologous challenges, except for after the 21-day-post-vaccination F4-ETEC challenge, when the clinical PWD was too mild to demonstrate efficacy. A significant reduction of mortality and weight loss by vaccination were observed following the F18-ETEC challenge. The 7-day protection was associated with induction of anti-F4 and anti-F18 IgM, whereas the 21-day protection was mainly associated with anti-F4 and anti-F18 IgA. The 7-day onset and 21-day duration of protection induced by this vaccine administered once in drinking water to pigs of at least 18days of age were confirmed by protection against F4-ETEC and F18-ETEC, and induction of F4 and F18-specific immunity. Cross protection of the vaccine against F18ab-E. coli was demonstrated for both the 7- and 21-day F18-ETEC challenges.

The differential effects of norepinephrine and dopamine on cerebrospinal fluid pressure and spinal cord perfusion pressure after acute human spinal cord injury.

STUDY DESIGN: Prospective vasopressor cross-over interventional studyObjectives:To examine how two vasopressors used in acute traumatic spinal cord injury (SCI) affect intrathecal cerebrospinal fluid pressure and the corresponding spinal cord perfusion pressure (SCPP). SETTING: Vancouver, British Columbia, Canada. METHODS: Acute SCI patients over the age of 17 with cervical or thoracic ASIA Impairment Scale (AIS). A, B or C injuries were enrolled in this study. Two vasopressors, norepinephrine and dopamine, were evaluated in a 'crossover procedure' to directly compare their effect on the intrathecal pressure (ITP). The vasopressor cross-over procedures were performed in the intensive care unit where ITP, mean arterial pressure (MAP) and heart rate were being continuously measured. The SCPP was calculated as the difference between MAP and ITP. RESULTS: A total of 11 patients were enrolled and included in our analysis. There were 6 patients with AIS A, 3 with AIS B and 2 with AIS C injuries at baseline. We performed 24 cross-over interventions in these 11 patients. There was no difference in MAP with the use of norepinephrine versus dopamine (84±1 mm Hg for both; P=0.33). Conversely, ITP was significantly lower with the use of norepinephrine than with dopamine (17±1 mm Hg vs 20±1 mm Hg, respectively, P<0.001). This decrease in ITP with norepinephrine resulted in an increased SCPP during the norepinephrine infusion when compared with dopamine (67±1 mm Hg vs 65±1 mm Hg respectively, P=0.0049). CONCLUSION: Norepinephrine was able to maintain MAP with a lower ITP and a correspondingly higher SCPP as compared with dopamine in this study. These results suggest that norepinephrine may be preferable to dopamine if vasopressor support is required post SCI to maintain elevated MAPs in accordance with published guidelines.

Quality and accuracy of publicly accessible cancer-related physical activity information on the Internet: a cross-sectional assessment.

In this study, we assessed the quality of publicly available cancer-related physical activity (PA) information appearing on reputable sites from Canada and other English-speaking countries. A cross-sectional Internet search was conducted on select countries (Canada, USA, Australia, New Zealand, UK) using Google to generate top 50 results per country for the keywords "'physical activity' AND 'cancer'". Top results were assessed for quality of PA information based on a coding frame. Additional searches were performed for Canadian-based sites to produce an exhaustive list. Results found that many sites offered cancer-related PA information (94.5%), but rarely defined PA (25.2%). Top 50 results from each country did not differ on any indicator examined. The exhaustive list of Canadian sites found that many sites gave information about PA for survivorship (78.3%) and prevention (70.0%), but rarely defined (6.7%) or referenced PA guidelines (28.3%). Cancer-related PA information is plentiful on the Internet but the quality needs improvement. Sites should do more than mention PA; they should provide definitions, examples and guidelines. With improvements, these websites would enable healthcare providers to effectively educate their patients about PA, and serve as a valuable resource to the general public who may be seeking cancer-related PA information.

Development and validation of a computerized algorithm for International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI).

STUDY DESIGN: Validation study. OBJECTIVES: To describe the development and validation of a computerized application of the international standards for neurological classification of spinal cord injury (ISNCSCI). SETTING: Data from acute and rehabilitation care. METHODS: The Rick Hansen Institute-ISNCSCI Algorithm (RHI-ISNCSCI Algorithm) was developed based on the 2011 version of the ISNCSCI and the 2013 version of the worksheet. International experts developed the design and logic with a focus on usability and features to standardize the correct classification of challenging cases. A five-phased process was used to develop and validate the algorithm. Discrepancies between the clinician-derived and algorithm-calculated results were reconciled. RESULTS: Phase one of the validation used 48 cases to develop the logic. Phase three used these and 15 additional cases for further logic development to classify cases with 'Not testable' values. For logic testing in phases two and four, 351 and 1998 cases from the Rick Hansen SCI Registry (RHSCIR), respectively, were used. Of 23 and 286 discrepant cases identified in phases two and four, 2 and 6 cases resulted in changes to the algorithm. Cross-validation of the algorithm in phase five using 108 new RHSCIR cases did not identify the need for any further changes, as all discrepancies were due to clinician errors. The web-based application and the algorithm code are freely available at www.isncscialgorithm.com. CONCLUSION: The RHI-ISNCSCI Algorithm provides a standardized method to accurately derive the level and severity of SCI from the raw data of the ISNCSCI examination. The web interface assists in maximizing usability while minimizing the impact of human error in classifying SCI. SPONSORSHIP: This study is sponsored by the Rick Hansen Institute and supported by funding from Health Canada and Western Economic Diversification Canada.

Evaluation of a pilot Pressure Ulcer Prevention Initiative (PUPI) for patients with traumatic spinal cord injury.

OBJECTIVE: The purpose of this study was to determine whether implementation of a Pressure Ulcer Prevention Initiative (PUPI) changed the assessment and treatment of patients with a traumatic spinal cord injury (SCI) in an acute care setting, and improved patient outcomes. METHOD: The success of implementation was evaluated by examining the percentage of patients with completed occupational therapist (OT) skin care assessments and prescriptions for therapeutic support surfaces (TSS; i.e., mattresses) before implementation (historical, cohort 1) and after implementation (experimental, cohort 2). Patient outcomes were evaluated by examining changes in PU incidence, severity, timing and recurrence, as well as PU prevalence and satisfaction with life in the community. RESULTS: Final analysis included 70 patients in cohort 1 and 73 in cohort 2. OT skin care assessment documentation (31% to 60%; p<0.001) and TSS prescriptions (31% to 60%; p=0.02) significantly increased following the implementation. The PU incidence based on patient charts (both nursing and OT assessments) did not increase significantly (26% to 36%; p=0.2). However, documented PU incidence according to OT assessments showed a substantial increase (14% to 33%; p=0.002). No effect of the PUPI was seen on immediate or long-term patient outcomes during the study period. CONCLUSION: PUPI was successful in changing clinical practice in PU prevention but no statistically significant improvements in PU-related patient outcomes were demonstrated. Results from this study identified facilitators and barriers to implementation and highlighted the complexity and difficulty of instituting effective preventative or therapeutic interventions for this population in an acute care setting. This information will assist with refinements of the PUPI and inform similar future initiatives.

Monthly fluctuations of insomnia symptoms in a population-based sample.

STUDY OBJECTIVES: To document the monthly changes in sleep/insomnia status over a 12-month period; to determine the optimal time intervals to reliably capture new incident cases and recurrent episodes of insomnia and the likelihood of its persistence over time. DESIGN: Participants were 100 adults (mean age = 49.9 years; 66% women) randomly selected from a larger population-based sample enrolled in a longitudinal study of the natural history of insomnia. They completed 12 monthly telephone interviews assessing insomnia, use of sleep aids, stressful life events, and physical and mental health problems in the previous month. A total of 1,125 interviews of a potential 1,200 were completed. Based on data collected at each assessment, participants were classified into one of three subgroups: good sleepers, insomnia symptoms, and insomnia syndrome. RESULTS: At baseline, 42 participants were classified as good sleepers, 34 met criteria for insomnia symptoms, and 24 for an insomnia syndrome. There were significant fluctuations of insomnia over time, with 66% of the participants changing sleep status at least once over the 12 monthly assessments (51.5% for good sleepers, 59.5% for insomnia syndrome, and 93.4% for insomnia symptoms). Changes of status were more frequent among individuals with insomnia symptoms at baseline (mean = 3.46, SD = 2.36) than among those initially classified as good sleepers (mean = 2.12, SD = 2.70). Among the subgroup with insomnia symptoms at baseline, 88.3% reported improved sleep (i.e., became good sleepers) at least once over the 12 monthly assessments compared to 27.7% whose sleep worsened (i.e., met criteria for an insomnia syndrome) during the same period. Among individuals classified as good sleepers at baseline, risks of developing insomnia symptoms and syndrome over the subsequent months were, respectively, 48.6% and 14.5%. Monthly assessment over an interval of 6 months was found most reliable to estimate incidence rates, while an interval of 3 months proved the most reliable for defining chronic insomnia. CONCLUSIONS: Monthly assessment of insomnia and sleep patterns revealed significant variability over the course of a 12-month period. These findings highlight the importance for future epidemiological studies of conducting repeated assessment at shorter than the typical yearly interval in order to reliably capture the natural course of insomnia over time.

A prospective evaluation of hemodynamic management in acute spinal cord injury patients.

STUDY DESIGN: Prospective observational study of acute spinal cord-injured (SCI) patients. OBJECTIVES: To determine how effectively mean arterial blood pressure (MAP) and spinal cord perfusion pressure (SCPP) are maintained at target levels in acute SCI patients. SETTING: Single-institution study at a Canadian level-one trauma center. METHODS: Twenty-one individuals with cervical or thoracic SCI were enrolled within 48 h of injury. A lumbar intrathecal drain was inserted for monitoring intrathecal cerebrospinal fluid pressure (ITP). The MAP was monitored concurrently with ITP, and the SCPP was calculated. Data was recorded hourly from the time of first assessment until at least the end of the 5th day post injury. RESULTS: All subjects had at least one recorded episode with a MAP below 80 mm Hg, and 81% had at least one episode with a MAP below 70 mm Hg. On average, subjects with cervical injuries had 18.4% of their pressure recordings below 80 mm Hg. Subjects with thoracic cord injuries had on average 35.9% of their MAP recordings <80 mm Hg. CONCLUSION: It is common practice to establish MAP targets for optimizing cord perfusion in acute SCI. This study suggests that even in an acute SCI referral center, when prospectively scrutinized, the actual MAP may frequently fall below the intended targets. Such results raise awareness of the vigilance that must be kept in the hemodynamic management of these patients, and the potential discrepancy between routinely setting target MAP according to 'practice guidelines' and actually achieving them.

Medical, demographic and social cognitive correlates of physical activity in a population-based sample of colorectal cancer survivors.

Physical activity (PA) improves quality of life in colorectal cancer survivors (CRC) and may reduce the risk of disease recurrence and early death. Few studies, however, have examined the correlates of PA in CRC survivors. Using the Alberta Cancer Registry, 2000 randomly selected CRC survivors were mailed a self-reported questionnaire assessing medical, demographic, behavioural and social cognitive variables from the theory of planned behaviour (TPB). Of the 600 survivors who responded, 33% were meeting public health PA guidelines and almost half were completely sedentary. Higher PA was reported by survivors who were younger, unmarried, better educated, wealthier, employed, non-smokers, social drinkers, not treated with radiation therapy, disease-free, in better health and less comorbidity. In multivariate path analysis, these variables were not directly associated with PA after controlling for the TPB variables. The TPB explained 34% (P < 0.001) of the variance in PA behaviour with direct associations for intention (ß= 0.22; P= 0.015) and planning (ß= 0.18; P= 0.001). Intention, in turn, had 62% (P < 0.001) of its variance explained by perceived behavioural control (ß= 0.43; P < 0.001), affective attitude (ß= 0.25; P < 0.001) and instrumental attitude (ß= 0.15; P < 0.001). The TPB may be a useful framework for developing population-based interventions to increase PA in CRC survivors.

[Sensitivity and specificity of the worry and anxiety questionnaire (WAQ) in a sample of health-care users in the province of Quebec]. / Sensibilité et spécificité du questionnaire sur les inquiétudes et l'anxiété (QIA) dans un échantillon d'utilisateurs de soins de santé au Québec.

INTRODUCTION: Generalized anxiety disorder (GAD) is a prevalent anxiety disorder characterized by persistent, excessive worrying. Even if GAD's ill consequences on health and quality of life are well documented, this disorder is still difficult to identify in primary care. The worry and anxiety questionnaire (WAQ) is a questionnaire assessing specific GAD symptoms, as defined by the Diagnostic and Statistical Manual of Mental Disorders-4th Edition (DSM-IV). OBJECTIVES: This study aimed at assessing the capacity of the French version of the WAQ's to identify individuals with GAD in a sample of individuals reporting a certain level of anxiety. A second objective was to identify which of its items better distinguish individuals with GAD from those without. According to these results, different scoring algorithms have been developed and their effect on the WAQ's sensitivity and specificity indicators has been explored. DESIGN OF THE STUDY: The sample was drawn from a mother study in which 1110 health-care users completed questionnaires while waiting for a medical consultation with a family physician. Of those, a subsample of 219 individuals reported anxiety symptoms typical of GAD, as assessed by the WAQ. Among those who agreed to participate in the study's second phase (n=176), 100 were randomly selected and invited within one to three months to a clinical interview assessing their anxiety symptoms more thoroughly. Thirty-three individuals accepted and thus formed the present sample. The clinical interview was the anxiety disorders interview schedule (ADIS). The ADIS is a semi-structured diagnostic interview following the DSM-IV criteria. It assesses all anxiety disorders and includes screening questions on mood, substance use and psychotic disorders. Participants also completed the WAQ for a second time at the time of the interview. RESULTS: Nineteen individuals received a diagnosis of GAD after completing the ADIS while 13 did not. Sixteen of the 19 individuals with GAD were correctly identified with the WAQ, compared to eight out of 13 for individuals without GAD. Sensitivity of the WAQ's actual scoring algorithm is thus of 84.2% and its specificity of 61.5%. The number of false negatives produced by the WAQ in this sample (3/19, 15.8%) was lower than the number of false positives (5/13, 38.5%). Positive and negative predictive power is thus of 76.2% and 72.7%, respectively. Receiver-operating characteristic (ROC) curves analyses indicated that the most useful items to identify individuals with GAD were those assessing the presence of excessive worrying, the number of days disturbed by worries, the degree with which worries interfere with daily functioning and the degree of control over worries. Knowing an individual's outcome on the WAQ increases the probability of correctly identifying an individual with or without GAD by 8.5 times compared to mere chance. A new scoring algorithm, where the cut-off score on the excessive worrying item was increased by one unit, considerably improves the WAQ's specificity (84.6%), without altering its sensitivity by much (78.9%). This new scoring algorithm thus increases the probability of correctly identifying individuals with and without GAD to 20.6 times (again compared to chance). CONCLUSION: The WAQ is thus a useful instrument in screening GAD, even in a sample of anxious individuals. Its original scoring algorithm shows excellent sensitivity, a valued quality in an instrument used for screening. On the other hand, it is possible to increase the specificity of the WAQ by raising the cut-off point on the excessive worrying item, making the instrument useful as a diagnostic aid or as a screening questionnaire for GAD, in particular among a sample displaying anxiety. This questionnaire is thus an easy-to-complete and adaptable instrument that can be used by family physicians to help them identifying individuals with GAD.

Production of heterologous protein by Methylobacterium extorquens in high cell density fermentation.

The green fluorescent protein (GFP) was used as a model protein to study the recombinant protein production by the strain Methylobacterium extorquens ATCC 55366. Scale-up from shake flasks to 20 l fed-batch fermentation was achieved using methanol as a sole carbon and energy source and a completely minimal culture medium. Two different expression vectors were used to express GFP. Clone PCM-GFP containing the vector pCM110 with native promoter of the methanol dehydrogenase PmxaF produced approximately 100-fold more GFP than the clone PRK-GFP containing the vector pRK310 with the heterogeneous promoter Plac. Several fed-batch fermentations with and without selective pressure (tetracycline) were run in a 20 l stirred tank fermenter using the two different clones of M. extorquens. The methanol concentration was monitored with an on-line semiconductor gas sensor in the culture broth. It was maintained at a non-toxic level of 1.4 g l(-1) with an adaptative control which regulates the methanol feed rate. The same growth profile was achieved in all fermentations. The maximum growth rate (micro(max)) was 0.18 h(-1) with an overall yield (Y(X/S)) of 0.3 g g(-1) methanol. With this high cell density fermentation process, we obtained high levels (up to 4 g l(-1)) of GFP with the clone PCM-GFP. The maximum specific GFP production (Y(GFP/X)) with this clone was 80 mg g(-1) representing approximately 16% of the total cell protein. Additional feeding of pure oxygen to the fermenter permitted a longer phase of exponential growth but had no effect on the total yields of biomass and GFP. The specific GFP production of clone PCM-GFP remained unaffected in the presence or absence of selective pressure (tetracycline), within the initial 50 h of the fermentation culture. These results suggest that M. extorquens ATCC 55366 could be an interesting candidate for overexpression of recombinant proteins.

Histopathologic and bacteriologic evaluations of cellulitis detected in legs and caudal abdominal regions of turkeys.

The objective of this study was to identify the causative agent of cellulitis in turkeys. Eighteen flocks from nine producers were sampled at the local processing plant, and 37 birds with cellulitis on legs or caudal thoracic area were obtained. None of the 37 birds with cellulitis had lesions in other organs. On gross examination, lesions were categorized into two groups: cellulitis with unopened skin lesions (type a) and cellulitis with opened skin lesions (type b). Histopathologically, cellulitis with unopened skin lesions had dermal necrosis with underlying fibrin and inflammatory exudate but cellulitis with open skin lesions had chronic granulomatous/granulation tissue-type reaction associated with foreign material. A complete bacteriologic study was conducted on 25 of 37 birds. Bacteria were isolated from 12 of the 25 birds with cellulitis lesions. No aerobic, microaerophilic, or anaerobic bacteria were isolated from the remaining 13 birds with cellulitis lesions. Escherichia coli was isolated in low numbers in mixed cultures with Proteus mirabilis, Lactobacillus spp., Klebsiella spp., and Staphylococcus spp. in 9 of 12 lesions. The remaining few cases yielded P. mirabilis in pure culture or in mixed culture with Pseudomonas aeruginosa. Types a and b cellulitis lesions in turkeys could be associated with primary contact dermatitis and skin abrasions, respectively. Their occurrence is likely associated with different management practices.

The mouse fetoprotein transcription factor (FTF) gene promoter is regulated by three GATA elements with tandem E box and Nkx motifs, and FTF in turn activates the Hnf3beta, Hnf4alpha, and Hnf1alpha gene promoters.

Fetoprotein transcription factor (FTF) is an orphan nuclear receptor that activates the alpha(1)-fetoprotein gene during early liver developmental growth. Here we sought to define better the position of FTF in transcriptional cascades leading to hepatic differentiation. The mouse FTF gene was isolated and assigned to chromosome 1 band E4 (one mFTF pseudogene was also found). Exon/intron mapping shows an mFTF gene structure similar to that of its close homologue SF1, with two more N-terminal exons in the mFTF gene; exon mapping also delimits several FTF mRNA 5'- and 3'-splice variants. The mFTF transcription initiation site was located in adult liver at 238 nucleotides from the first translation initiator codon, with six canonical GATA, E box, and Nkx motifs clustered between -50/-140 base pairs (bp) from the cap site; DNA/protein binding assays also pinpointed an HNF4-binding element at +36 bp and an FTF-binding element at -257 bp. Transfection assays and point mutations showed that the mFTF promoter is activated by GATA, HNF4alpha, FTF, Nkx, and basic helix-loop-helix factors, with marked cooperativity between GATA and HNF4alpha. A tandem GATA/E box activatory motif in the proximal mFTF promoter is strikingly similar to a composite motif coactivated by differentiation inducers in the hematopoietic lineage; a tandem GATA-Nkx motif in the distal mFTF promoter is also similar to a composite motif transducing differentiation signals from transforming growth factor-beta-like receptors in the cardiogenic lineage. Three genes encoding transcription factors critical to early hepatic differentiation, Hnf3beta, Hnf4alpha, and Hnf1alpha, each contain dual FTF-binding elements in their proximal promoters, and all three promoters are activated by FTF in transfection assays. Direct DNA binding action and cooperativity was demonstrated between FTF and HNF3beta on the Hnf3beta promoter and between FTF and HNF4alpha on the Hnf1alpha promoter. These combined results suggest that FTF is an early intermediary between endodermal specification signals and downstream genes that establish and amplify the hepatic phenotype.

Quantitative three-dimensional analysis of chondrocytic kinetic responses to short-term stapling of the rat proximal tibial growth plate.

Although it has been demonstrated clinically that controlled compression across a growth plate will slow the rate of endochondral ossification and thus can be used to correct angular limb deformities, the cellular-based mechanism by which altered growth is achieved is poorly understood. This study used short-term uniaxial stapling of the rat proximal tibial growth plate as an experimental system to study chondrocytic responses in the growth plate that account quantitatively for the decreased rate of growth. Growth plates were labeled with oxytetracycline to measure bone growth, and with bromodeoxyuridine to analyze proliferative cell kinetics. Multiple indicators of chondrocytic activity, measured by stereological parameters, were analyzed using growth rate as the primary dependent variable. The unique feature of this analysis was the creation of three-dimensional reconstructions that allowed analysis of data in all directions with distance from the staple. A significant observation was that for the entire operated limb after both 3 and 6 days, all chondrocytic kinetic parameters were affected, indicating that proliferative and hypertrophic responses both act to decrease growth rate in response to stapling. This contradicted our hypothesis that proliferative and hypertrophic responses could occur independently, and that small changes in rate would be attributed primarily to the former and large changes to the latter. The data from this study also demonstrate that volume regulation during hypertrophy can be affected by a primarily mechanical perturbation. Because changes in hypertrophic cell number and volume throughout the growth plate that occur by day 3 remain similar at day 6, the initial modulation of chondrocytic volume and shape may represent the limit of the response while maintaining a growth plate capable of continued growth.

The hepatitis B virus core promoter is strongly activated by the liver nuclear receptor fetoprotein transcription factor or by ectopically expressed steroidogenic factor 1.

Orphan nuclear receptor fetoprotein transcription factor (FTF) was previously identified as a specific regulator of the alpha(1)-fetoprotein gene during early liver development and in response to hormonal signals (L. Galarneau, J.-F. Paré, D. Allard, D. Hamel, L. Lévesque, J. D. Tugwood, S. Green, and L. Bélanger, Mol. Cell. Biol. 16:3853-3865, 1996). Here we report a functional analysis of FTF interactions with the hepatitis B virus (HBV) nucleocapsid promoter. DNA-protein-binding assays show that the HBV core promoter contains two high-affinity FTF-binding sites and a third, lower-affinity site shared with other receptors. Transfections in HepG2, Hep3B, and PLC/PRF/5 hepatoma cells using chloramphenicol acetyltransferase reporter genes with the nucleocapsid promoter linked or not linked to enhancer I indicate that FTF is a potent activator of the HBV core promoter, more efficient than HNF4alpha, HNF3alpha, HNF3beta, or C/EBPalpha. Steroidogenic factor 1, a close FTF homolog which binds to the same DNA motif and is expressed ectopically in HepG2 cells, seems to be an even stronger inducer than FTF. Point mutations of the FTF-binding sites indicate direct FTF activatory effects on the core promoter and the use of both high-affinity sites for productive interaction between the core promoter and enhancer I. Coexpression assays further indicate that FTF and HNF4alpha are the most efficient partners for coactivation of the pregenomic core promoter, which may largely account for the hepatic tropism and the early amplification of HBV infection. Carboxy terminus-truncated FTF behaves as a dominant negative mutant to compete all three FTF sites and strongly deactivate core promoter interactions with enhancer I; this suggests possible new ways to interfere with HBV infection.

The nuclear receptor fetoprotein transcription factor is coexpressed with its target gene HNF-3beta in the developing murine liver, intestine and pancreas.

During organogenesis, the winged helix hepatocyte nuclear factor 3beta (HNF-3beta) protein participates in regulating gene transcription in the developing esophagus, trachea, liver, lung, pancreas, and intestine. Hepatoma cell transfection studies identified a critical HNF-3beta promoter factor, named UF2-H3beta, and here, we demonstrate that UF2-H3beta is identical to the fetoprotein transcription factor (FTF). In situ hybridization studies of mouse embryos demonstrate that FTF expression initiates in the foregut endoderm during liver and pancreatic morphogenesis (day 9) and that earlier expression of FTF is observed in the yolk sac endoderm, branchial arch and neural crest cells (day 8). Abundant FTF hybridization signals are observed throughout morphogenesis of the liver, pancreas, and intestine and its expression continues in the epithelial cells of these adult organs. In day 17 mouse embryos and adult pancreas, however, expression of FTF becomes restricted to the exocrine acinar and ductal epithelial cells.

Effectiveness of nifedipine GITS in combination with atenolol in chronic stable angina.

Nifedipine gastrointestinal therapeutic system (GITS) is a once-daily formulation of nifedipine that provides stable plasma concentrations over the entire 24 h dosing interval. Two-hundred and one patients with Canadian Cardiovascular Society class II to III angina who were on 50 mg of atenolol yet still experiencing angina symptoms were randomized to receive either placebo or nifedipine GITS 30, 60 or 90 mg/day. After four weeks of treatment, the changes in time from baseline to onset of 1 mm ST segment depression in the 183 eligible patients were 26.7+/-10.2 s, 40.9+/-11.3 s, 63.2+/-12.9 s and 70.3+/-12.6 for the placebo, and 30, 60 and 90 mg/day groups, respectively. These differences were significant (P<0.05) for the 60 and 90 mg/day groups compared with placebo and for the 60 mg/day group compared with the 30 mg/day group. The times to onset of pain and termination of exercise showed similar prolongation but did not achieve statistical significance. During the one-year open label phase of the study, patients exhibited statistically significant improvements in the time to onset of ST segment depression, time to anginal pain and time to termination of exercise at a mean dose of 52.3 mg/day of nifedipine GITS. Adverse events were primarily vasodilatory in nature. This study supports the use of nifedipine GITS in patients with chronic stable angina inadequately controlled on beta-blocker alone.