Engineering CREB-activated promoters for adenosine-induced gene expression.

Accumulation of the ribonucleoside, adenosine (ADO), triggers a cAMP response element binding protein (CREB)-mediated signaling pathway to suppress the function of immune cells in tumors. Here, we describe a collection of CREB-activated promoters that allow for strong and tunable ADO-induced gene expression in human cells. By optimizing number of CREB transcription factor binding sites and altering the core promoter region of CREB-based hybrid promoters, we created synthetic constructs that drive gene expression to higher levels than strong, endogenous mammalian promoters in the presence of ADO. These synthetic promoters are induced up to 47-fold by ADO, with minimal expression in their "off" state. We further determine that our CREB-based promoters are activated by other compounds that act as signaling analogs, and that combinatorial addition of ADO and these compounds has a synergistic impact on gene expression. Surprisingly, we also detail how background ADO degradation caused by the common cell culture media additive, fetal bovine serum (FBS), confounds experiments designed to determine ADO dose-responsiveness. We show that only after long-term heat deactivation of FBS can our synthetic promoters enable gene expression induction at physiologically relevant levels of ADO. Finally, we demonstrate that the strength of a CREB-based promoter is enhanced by incorporating other transcription factor binding sites.

Effectiveness of a Promotores Network to Improve Health in an Emerging Latino Community.

BACKGROUND: Latinos living in emerging communities (i.e., nontraditional destinations with a small but growing population) face obstacles to their mental and physical health. This study evaluated the effectiveness of a 6-month, promotor-led intervention on access to care, physical activity, dietary practices, and perceived social support among Latino adults living in an emerging community, compared with a nonrandomly assigned control group. METHOD: Participants (n = 81 intervention; n = 86 control) were drawn from Allegheny county, Pennsylvania. Promotores used an intervention tool offering nondirective social support to assist participants in developing SMART goals to address their life concerns in eight domains (e.g., social, diet, and exercise/recreation); the control group received printed materials. Participants completed a survey in Spanish at baseline and follow-up to assess outcomes and had their height and weight measured. Adjusted linear mixed effects models compared change in outcomes over time. RESULTS: There was a marginally significant improvement in dietary practices in the intervention group at follow-up, and no change in access to care. Both groups experienced an improvement in social support. There was a significant intervention-by-time interaction such that the intervention group increased physical activity by 259 minutes/week compared with the control group. CONCLUSION: This study demonstrates the potential effectiveness of a promotores network in assisting individuals living in an emerging Latino community to address their life concerns and improve health behaviors. Future studies should include objective and more rigorous measures with a larger sample to replicate these results.

A Male Promotores Network for Latinos: Process Evaluation From a Community-Based Participatory Project.

Background Lay health advisor (LHA) interventions with Latino men are rare, especially in emerging Latino communities. We present a process evaluation of a male LHA network aiming at connecting Latino men to various kinds of services and to the Latino community. It assesses the feasibility of (1) maintaining a steering coalition; (2) hiring, training, and retaining male LHA; and (3) recruiting and assisting underserved participants. Methods Project management data and LHA debriefings were analyzed qualitatively and compared to a logic model and evaluation table prepared before the project started. Results The community coalition steered the project during its implementation. Eleven men attended the initial LHA training. Two thirds of them reflected the community in educational level. One third did not and required extra mentoring from the other LHA to recruit participants. LHA requested topics for monthly trainings according to their needs in the field, including housing, sexual health, and immigration. LHA enrolled 182 participants. Participants' needs went beyond health issues. Therefore, LHA needed to forge new collaborations with local social service organizations. Conclusions Recruiting male LHA is feasible. LHA and the community coalition can suggest adaptations to fit the local context.

Participatory assessment of the health of Latino immigrant men in a community with a growing Latino population.

Latino immigrant men are an understudied population in the US, especially in areas with small yet growing Latino populations. For this community-based participatory health assessment we conducted four focus groups and 66 structured surveys with Latino immigrant men, and 10 openended interviews with service providers. We analyzed transcripts using content analysis and survey data using Pearson Chi-square tests. Overall, 53% of participating men had not completed high school. Our findings suggest that their social circumstances precluded men from behaving in a way they believe would protect their health. Loneliness, fear and lack of connections prompted stress among men, who had difficulty locating healthcare services. Newly immigrated men were significantly more likely to experience depression symptoms. Latino immigrant men face social isolation resulting in negative health consequences, which are amplified by the new growth community context. Men can benefit from interventions aimed at building their social connections.

Enhancing collaborative pharmaceutical care for patients with chronic kidney disease: survey of community pharmacists.

BACKGROUND: The Kidney Care Clinic at Sunnybrook Health Sciences Centre provides multidisciplinary care for patients with stage 4 or 5 chronic kidney disease. These patients are at high risk of drug therapy problems. Clinic pharmacists review medications and provide recommendations at each visit, but potential gaps in care exist between clinic visits. Community pharmacists are ideally situated to identify and resolve drug therapy problems between visits. OBJECTIVES: To determine community pharmacists' confidence in managing care for patients with chronic kidney disease; to identify opportunities for improving collaboration between clinic and community pharmacists; and to determine the key clinical information that community pharmacists would use when caring for these patients. METHODS: An anonymous survey was sent by mail and electronically to community pharmacies that were providing prescription medications for clinic patients. A total of 318 surveys were sent to 96 pharmacies. Data analysis was based on descriptive statistics, including frequencies, ranges, and measures of central tendency. RESULTS: Fifty-one completed surveys were returned (response rate 16%). Thirty-five (69%) of the responding pharmacists were not aware or were unsure that a patient from the Kidney Care Clinic was a client of their pharmacy. Forty-six (90%) were confident in providing counselling about medications used to manage chronic kidney disease, and 32 (63%) indicated confidence in recommending drug dosing changes based on kidney function. Forty-five (88%) of the pharmacists indicated a willingness to play a greater role in reviewing medications for patients with chronic kidney disease, and all agreed that they would benefit from education about the complications of this disease and their management. Clinical information ranked most useful included an updated medication list with indications and details regarding recent medication changes. CONCLUSIONS: Community pharmacists indicated willingness to have greater involvement in the care of patients with chronic kidney disease. The survey results revealed a need to increase awareness of clinic patients among community providers. Participants were receptive to continuing education, and initial efforts should focus on dosing adjustments of renal drugs and the complications of chronic kidney disease. Tools for transferring clinical information must be developed.

CONTEXTE: La clinique de santé rénale du Sunnybrook Health Sciences Centre fournit des soins multidisciplinaires aux patients atteints d'une insuffisance rénale chronique de stade 4 ou 5. Ces patients sont exposés à un risque élevé de problèmes pharmacothérapeutiques. Les pharmaciens de la clinique effectuent une évaluation de la médication et formulent des recommandations à chaque visite, mais certaines lacunes potentielles dans les soins entre chaque visite à la clinique ne sont pas à exclure. Les pharmaciens communautaires sont les mieux placés pour déceler et résoudre les problèmes pharmacothérapeutiques entre les visites. OBJECTIFS: Déterminer à quel point les pharmaciens communautaires se sentent à l'aise à l'idée de prendre en charge les soins de patients atteints d'une insuffisance rénale chronique; identifier les occasions qui permettraient d'améliorer la collaboration entre les pharmaciens communautaires et ceux de la clinique; et préciser les informations cliniques clés que les pharmaciens communautaires pourraient utiliser lorsqu'ils s'occupent de ces patients. MÉTHODES: Un sondage anonyme a été envoyé par la poste et par courriel aux pharmacies communautaires qui fournissent des médicaments d'ordonnance à des patients qui fréquentent la clinique. Un total de 318 sondages ont été envoyés à 96 pharmacies. L'analyse des données reposait sur des statistiques descriptives, notamment les fréquences, les étendues et les mesures de la tendance centrale. RÉSULTATS: Cinquante et un sondages remplis ont été retournés (taux de réponse de 16 %). Trente-cinq (69 %) des pharmaciens ayant répondu au sondage ignoraient ou étaient incertains si un patient de la clinique de santé rénale était un client de leur pharmacie. Quarante-six (90 %) se sentaient à l'aise à l'idée de fournir des conseils sur les médicaments utilisés pour traiter l'insuffisance rénale chronique et 32 (63 %) ont reconnu qu'ils se sentaient à l'aise à l'idée de recommander des posologies adaptées à la fonction rénale. Quarante-cinq pharmaciens (88 %) ont manifesté leur volonté de jouer un rôle plus important dans l'évaluation de la médication des patients atteints d'une insuffisance rénale chronique et tous s'entendaient pour dire qu'ils tireraient profit d'une formation sur les complications de cette maladie et leur prise en charge. Parmi les informations cliniques jugées les plus utiles se trouvait une liste à jour des médicaments accompagnée de leurs indications et de précisions quant aux récents changements à la pharmacothérapie. CONCLUSIONS: Les pharmaciens communautaires ont manifesté leur volonté de jouer un rôle plus important dans la prise en charge des patients atteints d'une insuffisance rénale chronique. Les résultats du sondage ont mis en relief la nécessité de mieux signaler les patients de la clinique aux pharmaciens communautaires. Les participants étaient ouverts à la formation continue et les mesures en ce sens devraient d'abord être axées sur l'ajustement posologique de médicaments éliminés par voie rénale et sur les complications liées à l'insuffisance rénale chronique. De plus, des outils visant à transmettre les informations cliniques doivent être développés. [Traduction par l'éditeur].

Chronic fondaparinux use in a hemodialysis patient with heparin-induced thrombocytopenia type II and extracorporeal circuit thrombosis-a case report and review of the literature.

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening condition that can develop after exposure to unfractionated or low-molecular-weight heparins. Treatment options appear to be limited in patients on concurrent intermittent hemodialysis. We report the case of an 88-year-old man newly initiated on high-flux hemodialysis who developed HIT and extracorporeal circuit thrombosis after 3 weeks of exposure to unfractionated heparin. Our patient was successfully treated with fondaparinux 2.5 mg subcutaneously three times per week and citrate during dialysis sessions. Antifactor Xa levels were measured on several occasions while receiving fondaparinux.

Using Audio Computer-Assisted Self-Interviewing and Interactive Voice Response to Measure Elder Mistreatment in Older Adults: Feasibility and Effects on Prevalence Estimates.

Demographic trends indicate an aging population, highlighting the importance of collecting valid survey data from older adults. One potential issue when surveying older adults is use of technology to collect data on sensitive topics. Survey technologies like A-CASI and IVR have not been used with older adults to measure elder mistreatment. We surveyed 903 adults age 60 and older in Allegheny County, Pennsylvania (U.S.) with random assignment to one of four survey modes: (1) CAPI, (2) A-CASI, (3) CATI; and (4) IVR. We assessed financial, psychological, and physical mistreatment, and examined feasibility of A-CASI and IVR, and effects on prevalence estimates relative to CAPI and CATI. Approximately 83% of elders randomized to A-CASI/IVR used each technology, although 28% of respondents in the A-CASI condition refused to use headphones and read the questions instead. A-CASI produced higher six month prevalence rates of financial and psychological mistreatment than CAPI. IVR produced higher six month prevalence rates of psychological mistreatment than CATI. We conclude that, while IVR may be useful, A-CASI offers a more promising approach to the measurement of elder mistreatment.

African American veterans' experiences with mobile geriatric care.

To explore perspectives concerning use of a mobile geriatrics unit (MGU) by underserved populations in low-income urban neighborhoods, we recruited 18 elderly African American patients and engaged them in in-depth semistructured interviews. Using grounded theory techniques of constant comparative analysis, we found that most patients learned about the MGU from community members and initially visited it to determine whether it would be worth using in the future. In describing their MGU experiences, patients tended to focus on three main factors: quality of care, accessibility of services, and ambience of the care setting. They reported that the MGU allowed them to have their health conditions and medications monitored regularly and functioned as a central link to the larger Veterans Affairs health care system. The findings suggest that using MGUs is an acceptable and effective way to help medically underserved populations receive primary medical care and referrals to specialty care.

Analysis of the human cytomegalovirus genomic region from UL146 through UL147A reveals sequence hypervariability, genotypic stability, and overlapping transcripts.

BACKGROUND: Although the sequence of the human cytomegalovirus (HCMV) genome is generally conserved among unrelated clinical strains, some open reading frames (ORFs) are highly variable. UL146 and UL147, which encode CXC chemokine homologues are among these variable ORFs. RESULTS: The region of the HCMV genome from UL146 through UL147A was analyzed in clinical strains for sequence variability, genotypic stability, and transcriptional expression. The UL146 sequences in clinical strains from two geographically distant sites were assigned to 12 sequence groups that differ by over 60% at the amino acid level. The same groups were generated by sequences from the UL146-UL147 intergenic region and the UL147 ORF. In contrast to the high level of sequence variability among unrelated clinical strains, the sequences of UL146 through UL147A from isolates of the same strain were highly stable after repeated passage both in vitro and in vivo. Riboprobes homologous to these ORFs detected multiple overlapping transcripts differing in temporal expression. UL146 sequences are present only on the largest transcript, which also contains all of the downstream ORFs including UL148 and UL132. The sizes and hybridization patterns of the transcripts are consistent with a common 3'-terminus downstream of the UL132 ORF. Early-late expression of the transcripts associated with UL146 and UL147 is compatible with the potential role of CXC chemokines in pathogenesis associated with viral replication. CONCLUSION: Clinical isolates from two different geographic sites cluster in the same groups based on the hypervariability of the UL146, UL147, or the intergenic sequences, which provides strong evidence for linkage and no evidence for interstrain recombination within this region. The sequence of individual strains was absolutely stable in vitro and in vivo, which indicates that sequence drift is not a mechanism for the observed sequence hypervariability. There is also no evidence of transcriptional splicing, although multiple overlapping transcripts extending into the adjacent UL148 and UL132 open reading frames were detected using gene-specific probes.

Concordance of four methods of disability assessment using performance in the home as the criterion method.

OBJECTIVE: To determine the concordance of 4 methods of disability assessment with the criterion method. Performance testing in the home was selected as the criterion. METHODS: The task performance of 57 community-dwelling older women (>/=70 years) with knee osteoarthritis was examined through self report, proxy report, clinical judgment based on impairment measures, performance testing in an occupational therapy clinic, and performance testing in participants' homes. The 26 tasks represented 4 domains of daily living activities: 5 functional mobility, 3 personal care, 14 cognitively oriented instrumental activities of daily living (IADL), and 4 physically oriented IADL. RESULTS: In general, self reports and proxy reports had the highest concordance with in-home performance test results. Nonetheless, even for these methods, depending on task domain, the rate of discordance ranged from 31% to 54%, being least in personal care and greatest in the physically oriented IADL. CONCLUSION: Disability estimates based on self reports, proxy reports, clinical judgments, and hospital performance-based assessments are not interchangeable with in-home task performance.

The determinants of attitudinal change among medical students participating in home care training: a multi-center study.

PURPOSE: To report attitudinal changes of medical students from five medical schools rotating through a home care program, and to determine which of the program characteristics influenced attitudes the most. METHOD: A survey instrument covering four home care domains (general attitudes, home-based therapies, home care training, and time and reimbursement) was designed and validated by the five schools involved. Using pre- and post-rotation scores, analyses were done to evaluate for attitudinal changes within and among schools. The programs had similar basic characteristics (home visits, attending physicians' involvement, didactics), but had differing degrees of these components. RESULTS: Significant improvements in attitude scores were found in three domains: general attitudes, homebased therapies, and home care training. For time and reimbursement, only three schools improved significantly between pre- and post-rotation scores. Among the five schools, there were significant differences in the homebased therapies and home care training domains (p <.05), and in the time and reimbursement domain the difference approached significance (p =.06). None of the students' characteristics but all of the programs' characteristics significantly correlated with changes in total scores. In the first multiple regression model, educational level (third year instead of fourth) was the only independent predictor of change in score, (adjusted r(2) =.14). In Model 2, the strongest predictor was "contact with physician-program director," followed by "number of visits" and "physician-precepted visits" (r(2) =.23). CONCLUSION: Educational home care programs of varying intensities can positively affect medical students' attitudes towards home care. At least three program characteristics, (the physician-program director, number of visits, and physician-precepted home visits), are important parts of a successful program.