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1.  IL-4 Suppresses the Responses to TLR7 and TLR9 Stimulation and Increases the Permissiveness to Retroviral Infection of Murine Conventional Dendritic Cells 
PLoS ONE  2014;9(1):e87668.
Th2-inducing pathological conditions such as parasitic diseases increase susceptibility to viral infections through yet unclear mechanisms. We have previously reported that IL-4, a pivotal Th2 cytokine, suppresses the response of murine bone-marrow-derived conventional dendritic cells (cDCs) and splenic DCs to Type I interferons (IFNs). Here, we analyzed cDC responses to TLR7 and TLR9 ligands, R848 and CpGs, respectively. We found that IL-4 suppressed the gene expression of IFNβ and IFN-responsive genes (IRGs) upon TLR7 and TLR9 stimulation. IL-4 also inhibited IFN-dependent MHC Class I expression and amplification of IFN signaling pathways triggered upon TLR stimulation, as indicated by the suppression of IRF7 and STAT2. Moreover, IL-4 suppressed TLR7- and TLR9-induced cDC production of pro-inflammatory cytokines such as TNFα, IL-12p70 and IL-6 by inhibiting IFN-dependent and NFκB-dependent responses. IL-4 similarly suppressed TLR responses in splenic DCs. IL-4 inhibition of IRGs and pro-inflammatory cytokine production upon TLR7 and TLR9 stimulation was STAT6-dependent, since DCs from STAT6-KO mice were resistant to the IL-4 suppression. Analysis of SOCS molecules (SOCS1, −2 and −3) showed that IL-4 induces SOCS1 and SOCS2 in a STAT6 dependent manner and suggest that IL-4 suppression could be mediated by SOCS molecules, in particular SOCS2. IL-4 also decreased the IFN response and increased permissiveness to viral infection of cDCs exposed to a HIV-based lentivirus. Our results indicate that IL-4 modulates and counteracts pro-inflammatory stimulation induced by TLR7 and TLR9 and it may negatively affect responses against viruses and intracellular parasites.
doi:10.1371/journal.pone.0087668
PMCID: PMC3906189  PMID: 24489947
2.  Myeloid Dendritic Cells from B6.NZM Sle1/Sle2/Sle3 Lupus-prone Mice express an Interferon Signature that Precedes Disease Onset 
Patients with systemic lupus erythematosus (SLE) show an over-expression of Type I Interferon (IFN) responsive genes called “Interferon Signature”. We found that the B6.NZMSle1/Sle2/Sle3 (Sle1,2,3) lupus-prone mice also express an Interferon Signature compared to non autoimmune C57BL/6 mice. In vitro, myeloid dendritic cells (mDCs)(GM-CSF bone marrow-derived BMDCs) from Sle1,2,3 mice constitutively over-expressed IFN responsive genes such as IFNb, Oas-3, Mx-1, ISG-15 and CXCL10, and the members of IFN signaling pathway STAT1, STAT2, and IRF7. The Interferon Signature was similar in Sle1,2,3 BMDCs from young, pre-autoimmune mice and from mice with high titers of autoantibodies, suggesting that the Interferon Signature in mDCs precedes disease onset and it is independent from the autoantibodies. Sle1,2,3 BMDCs hyper-responded to stimulation with IFNa and the TLR7 and TLR9 agonists R848 and CpGs. We propose that this hyper-response is induced by the Interferon Signature and only partially contributes to the Signature, since oligonucleotides inhibitory for TLR7 and TLR9 only partially suppressed the constitutive Interferon Signature and pre-exposure to IFNa induced the same hyper-response in wild type BMDCs than in Sle1,2,3 BMDCs. In vivo, mDCs and with lesser extent T and B cells from young pre-diseased Sle1,2,3 mice also expressed the Interferon Signature, although they lacked the strength that BMDCs showed in vitro. Sle1,2,3 plasmacytoid DCs expressed the Interferon Signature in vitro but not in vivo, suggesting that mDCs may be more relevant before disease onset. We propose that Sle1,2,3 mice are useful tools to study the role of the Interferon Signature in lupus pathogenesis.
doi:10.4049/jimmunol.1101686
PMCID: PMC3381850  PMID: 22661089
Myeloid Dendritic cells; Type I Interferon; systemic lupus erythematosus; TLR; gene expression
3.  COMMUNICATION PATTERNS FOR THE MOST SERIOUS POISON CENTER CALLS 
Context
The communication demands faced by specialists in poison information (SPI) are challenging in the health care context.
Objectives
1: Describe SPI communication patterns for the highest risk poison exposure calls using cluster analysis, and 2: describe variation in communication patterns or clusters.
Methods
A sample of 1 year of poison exposure calls to a regional PCC with SPIs’ perceived severity rating of major/moderate perceived was collected. Digital voice recordings were linked with medical records and were coded using the Roter Interaction Analysis System (RIAS). Descriptive analyses were applied and cluster-analytic techniques were used to assess variation in call communication and factors associated with that variation.
Results
Cases were described and 4 communication styles were identified. The Informational cluster represents 24% of calls and represent a pattern of relatively high levels of SPI clinical information and caller questions. The Facilitative cluster represents 35% of calls with a pattern of relatively high SPI questions and caller information provision. The Planning cluster represents 33.5% of calls representing a pattern of relatively high levels of SPI relationship talk. The Emotional cluster represents 7.5% of calls representing a pattern of relatively high caller and SPI emotion. Multinomial logistic regression using call/case characteristics as stepwise predictors of cluster membership revealed relationships between cluster membership and number of substances, type of exposure (intentional vs. unintentional), caller relationship to patient, length of call (χ2s > 21.59, df =3, ps < .01)and SPI identity (χ2 = 88.34, df =33, p < .01).
Conclusion
This study provides a beginning step to understanding SPI communication behaviors. Our results suggest that SPIs are able to use a range of communication strategies that often involve not only information but also emotional responsiveness and rapport building. Findings also point to the opportunity for future communication training for SPIs to meet the needs of the heterogeneous caller population.
doi:10.3109/15563650.2011.569932
PMCID: PMC3167491  PMID: 21563908
communication; poison control; cluster analysis
4.  The effectiveness of health coaching, home blood pressure monitoring, and home-titration in controlling hypertension among low-income patients: protocol for a randomized controlled trial 
BMC Public Health  2009;9:456.
Background
Despite the many antihypertensive medications available, two-thirds of patients with hypertension do not achieve blood pressure control. This is thought to be due to a combination of poor patient education, poor medication adherence, and "clinical inertia." The present trial evaluates an intervention consisting of health coaching, home blood pressure monitoring, and home medication titration as a method to address these three causes of poor hypertension control.
Methods/Design
The randomized controlled trial will include 300 patients with poorly controlled hypertension. Participants will be recruited from a primary care clinic in a teaching hospital that primarily serves low-income populations.
An intervention group of 150 participants will receive health coaching, home blood pressure monitoring, and home-titration of antihypertensive medications during 6 months. The control group (n = 150) will receive health coaching plus home blood pressure monitoring for the same duration. A passive control group will receive usual care. Blood pressure measurements will take place at baseline, and after 6 and 12 months. The primary outcome will be change in systolic blood pressure after 6 and 12 months. Secondary outcomes measured will be change in diastolic blood pressure, adverse events, and patient and provider satisfaction.
Discussion
The present study is designed to assess whether the 3-pronged approach of health coaching, home blood pressure monitoring, and home medication titration can successfully improve blood pressure, and if so, whether this effect persists beyond the period of the intervention.
Trial Registration
ClinicalTrials.gov identifier: NCT01013857
doi:10.1186/1471-2458-9-456
PMCID: PMC2797520  PMID: 20003300
5.  Cost-effectiveness of insulin analogues for diabetes mellitus 
Background
Insulin analogues may be associated with fewer episodes of hypoglycemia than conventional insulins. However, they are costly alternatives. We compared the cost-effectiveness of insulin analogues and conventional insulins used to treat type 1 and type 2 diabetes mellitus in adults.
Methods
We conducted a cost-effectiveness evaluation of insulin analogues versus conventional insulins using the Center for Outcomes Research Diabetes Model. We compared rapid-acting analogues (insulin aspart and insulin lispro) with regular human insulin, and long-acting analogues (insulin glargine and insulin detemir) with neutral protamine Hagedorn insulin. We derived clinical information for the comparisons from meta-analyses of randomized controlled trials. We obtained cost and utility estimates from published sources. We performed sensitivity analyses to test the robustness of our results.
Results
For type 1 diabetes, insulin aspart was more effective and less costly than regular human insulin. Insulin lispro was associated with an incremental cost of Can$28 996 per quality-adjusted life-year. The incremental cost per quality-adjusted life-year was Can$87 932 for insulin glargine and Can$387 729 for insulin detemir, compared with neutral protamine Hagedorn insulin. For type 2 diabetes, insulin aspart was associated with an incremental cost of Can$22 488 per quality-adjusted life-year compared with regular human insulin. For insulin lispro, the incremental cost was Can$130 865. Compared with neutral protamine Hagedorn insulin, insulin detemir was less effective and more costly. Insulin glargine was associated with an incremental cost of Can$642 994 per quality-adjusted life-year. The model was sensitive to changes in the effect size of hemoglobin A1c and to decrements applied to utility scores when fear of hypoglycemia was included as a factor.
Interpretation
The cost-effectiveness of insulin analogues depends on the type of insulin analogue and whether the patient receiving the treatment has type 1 or type 2 diabetes. With the exception of rapid-acting insulin analogues in type 1 diabetes, routine use of insulin analogues, especially long-acting analogues in type 2 diabetes, is unlikely to represent an efficient use of finite health care resources.
doi:10.1503/cmaj.081180
PMCID: PMC2638053  PMID: 19221353
6.  Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis 
Background
Although insulin analogues are commonly prescribed for the management of diabetes mellitus, there is uncertainty regarding their optimal use. We conducted meta-analyses to compare the outcomes of insulin analogues with conventional insulins in the treatment of type 1, type 2 and gestational diabetes.
Methods
We updated 2 earlier systematic reviews of the efficacy and safety of rapid-and long-acting insulin analogues. We searched electronic databases, conference proceedings and “grey literature” up to April 2007 to identify randomized controlled trials that compared insulin analogues with conventional insulins. Study populations of interest were people with type 1 and type 2 diabetes (adult and pediatric) and women with gestational diabetes.
Results
We included 68 randomized controlled trials in the analysis of rapid-acting insulin analogues and 49 in the analysis of long-acting insulin analogues. Most of the studies were of short to medium duration and of low quality. In terms of hemoglobin A1c, we found minimal differences between rapid-acting insulin analogues and regular human insulin in adults with type 1 diabetes (weighted mean difference for insulin lispro: –0.09%, 95% confidence interval [CI] –0.16% to –0.02%; for insulin aspart: –0.13%, 95% CI –0.20% to –0.07%). We observed similar outcomes among patients with type 2 diabetes (weighted mean difference for insulin lispro: –0.03%, 95% CI –0.12% to –0.06%; for insulin aspart: –0.09%, 95% CI –0.21% to 0.04%). Differences between long-acting insulin analogues and neutral protamine Hagedorn insulin in terms of hemoglobin A1c were marginal among adults with type 1 diabetes (weighted mean difference for insulin glargine: –0.11%, 95% CI –0.21% to –0.02%; for insulin detemir: –0.06%, 95% CI –0.13% to 0.02%) and among adults with type 2 diabetes (weighted mean difference for insulin glargine: –0.05%, 95% CI –0.13% to 0.04%; for insulin detemir: 0.13%, 95% CI 0.03% to 0.22%). Benefits in terms of reduced hypoglycemia were inconsistent. There were insufficient data to determine whether insulin analogues are better than conventional insulins in reducing long-term diabetes-related complications or death.
Interpretation
Rapid-and long-acting insulin analogues offer little benefit relative to conventional insulins in terms of glycemic control or reduced hypoglycemia. Long-term, high-quality studies are needed to determine whether insulin analogues reduce the risk of long-term complications of diabetes.
doi:10.1503/cmaj.081041
PMCID: PMC2638025  PMID: 19221352
7.  Becoming the best mom that I can: women's experiences of managing depression during pregnancy – a qualitative study 
BMC Women's Health  2007;7:13.
Background
The purpose of this constructivist grounded theory study was to develop a theoretical model that explains women's processes of managing diagnosed depression when pregnant.
Methods
We explored the experiences of 19 women in Ontario who were diagnosed with depression during their pregnancy.
Results
The model that emerged from the analysis was becoming the best mom that I can. Becoming the best mom that I can explains the complex process of the women's journey as they travel from the depths of despair, where the depression is perceived to threaten their pregnancy and their ability to care for the coming baby, to arrive at knowing the self and being in a better place. In order to reground the self and regain control of their lives, the women had to recognize the problem, overcome shame and embarrassment, identify an understanding healthcare provider, and consider the consequences of the depression and its management. When confronting and confining the threat of depression, the women employed strategies of overcoming barriers, gaining knowledge, and taking control. As a result of counseling, medication, or a combination of both, women felt that they had arrived at a better place.
Conclusion
For many women, the idea that depression could occur during pregnancy was antithetical to their vision of the pregnant self. The challenge for a pregnant woman who is diagnosed with depression, is that effective care for her may jeopardize her baby's future health. This provides a dilemma for about-to-be parents and their healthcare providers. Improved awareness of depression during pregnancy on the part of healthcare professionals is needed to improve the women's understanding of this disorder and their ability to recognize and seek help with depression should it occur during the prenatal period. Further qualitative research is needed to determine the specific aspects that need to be addressed in such classes.
doi:10.1186/1472-6874-7-13
PMCID: PMC2048943  PMID: 17848199
8.  Transcriptional Analysis of Latent and Inducible Kaposi's Sarcoma-Associated Herpesvirus Transcripts in the K4 to K7 Region†  
Journal of Virology  2005;79(24):15099-15106.
Kaposi's sarcoma-associated herpesvirus (KSHV) is a gamma-2 herpesvirus with a genome containing a long unique coding region (LUR) flanked by GC-rich terminal repeat sequences. The LUR encodes approximately 90 annotated open reading frames (ORFs) with complex patterns of gene expression during viral latency, reactivation, and de novo infection. To identify unannotated KSHV genes, we examined the region between 21,500 and 30,000 bp of the KSHV LUR, representing approximately 8.5 kb of sequence. This region encodes seven known single-exon ORFs (K4, K4.1, K4.2, K5, K6, K7, and PAN), but previous computer analyses have failed to identify additional likely genes in the remaining 5.2 kb. We identified four novel transcripts using Northern blotting, phage library screening, and 5′ rapid amplification of cDNA ends analysis in the region between ORFs K4.2 and K7. In vitro analysis of KSHV-infected primary effusion lymphoma cell lines in the presence of 12-O-tetradecanoylphorbol-13-acetate and phosphonoformic acid suggests that one latent transcript is coterminal with the previously annotated K3 gene encoding an ubiquitin-ligase known to downregulate major histocompatibility complex class I expression. This alternatively spliced transcript may contribute to KSHV adaptive immune evasion during latent infection. Other transcripts are inducible, including a 6.1-kb transcript that is the largest transcript found in the KSHV genome to date.
doi:10.1128/JVI.79.24.15099-15106.2005
PMCID: PMC1315995  PMID: 16306581
9.  Risks of untreated depression during pregnancy. 
Canadian Family Physician  2004;50:37-39.
QUESTION: One of my patients who was taking an antidepressant for major depression is now pregnant and does not wish to take it any more. I believe she needs to continue her medication. She, however, is adamant about stopping it because she believes it would put her baby at risk. Is there evidence that not treating depression during pregnancy puts babies at risk? ANSWER: A growing body of literature investigating the effects of not treating depression on mother and developing fetus suggests that untreated depression is associated with adverse fetal outcomes and a higher risk of maternal morbidity, including suicide ideation and attempts, and postpartum depression.
PMCID: PMC2214485  PMID: 14761100
10.  Internet based consultations to transfer knowledge for patients requiring specialised care: retrospective case review 
BMJ : British Medical Journal  2003;326(7391):696-699.
Objective
To assess whether transferring knowledge from specialists at centres of excellence to referring doctors through online consultations can improve the management of patients requiring specialised care.
Design
Retrospective case review of the first year of internet based patient initiated consultations between referring doctors and consulting specialists.
Setting
US teaching hospitals affiliated with an organisation providing internet based consultations.
Participants
Doctors in various settings around the world engaging in internet based consultations with specialists.
Main outcome measures
New recommendations for treatment, change in diagnosis, and turnaround time for consultation compared with time to see a specialist.
Results
79 consultations took place. 90% (n=71) of consultations were for services related to oncology. 90% of consultations involved new recommendations for treatment. The most common recommendation was a new chemotherapeutic regimen (68%, n=54). Diagnosis changed in 5% (n=4) of cases. The average turnaround time was 6.8 working days compared with an average of 19 working days to see a comparable specialist.
Conclusions
Internet based consultations between specialists at centres of excellence and referring doctors contribute to patient care through recommendations for new treatment and timely access to specialist knowledge. Although change in diagnosis occurred in only a few cases, the prognostic and therapeutic implications for these patients may be profound.
What is already known on this topicTelemedicine could improve health care by transferring knowledge from centres of excellence to patients' doctorsFew studies have systematically assessed the value of such internet based specialty consultationsWhat this study addsPatients can benefit from internet based consultations between their doctor and consulting specialistsNew recommendations for treatment were discussed in 90% of cases, and change in diagnosis occurred in 5% of casesPatients can access a specialist's opinion more quickly than waiting to see a specialist
PMCID: PMC152369  PMID: 12663408

Results 1-10 (10)