A skin-selective homing mechanism for human immune surveillance T cells

Effective immune surveillance is essential for maintaining protection and homeostasis of peripheral tissues. However, mechanisms controlling memory T cell migration to peripheral tissues such as the skin are poorly understood. Here, we show that the majority of human T cells in healthy skin express the chemokine receptor CCR8 and respond to its selective ligand I-309/CCL1. These CCR8(+) T cells are absent in small intestine and colon tissue, and are extremely rare in peripheral blood, suggesting healthy skin as their physiological target site. Cutaneous CCR8(+) T cells are preactivated and secrete proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma, but lack markers of cytolytic T cells. Secretion of interleukin (IL)-4, IL-10, and transforming growth factor-beta was low to undetectable, arguing against a strict association of CCR8 expression with either T helper cell 2 or regulatory T cell subsets. Potential precursors of skin surveillance T cells in peripheral blood may correspond to the minor subset of CCR8(+)CD25(-) T cells. Importantly, CCL1 is constitutively expressed at strategic cutaneous locations, including dermal microvessels and epidermal antigen-presenting cells. For the first time, these findings define a chemokine system for homeostatic T cell traffic in normal human skin.     

Identifying hepatic nuclear factor 1alpha mutations in children and young adults with a clinical diagnosis of type 1 diabetes

OBJECTIVE: HNF-1alpha gene mutations (MODY3) present with marked hyperglycemia in lean young adults and may, therefore, be mistaken for type 1 diabetes, with implications for individual treatment and risk of diabetes in other family members. We examined the prevalence of HNF-1alpha mutations in families with three generations of diabetes identified in a population-based study of childhood diabetes, representing a subpopulation in which misclassification was likely. RESEARCH DESIGN AND METHODS: In a study population of 1,470 families, 36 families (2.4%) with three affected generations were identified. In the 18 families in whom DNA samples were available, islet autoantibody testing, HLA class II genotyping, and HNF-1alpha sequencing were performed. RESULTS: At least one islet autoantibody was found in 13 of 14 probands, and diabetes-associated HLA class II haplotypes were found in 17 of 18. One proband, who had no islet autoantibodies and was homozygous for the protective HLA haplotype DRB1*02-DQB1*0602, had a novel HNF-1alpha heterozygous nonsense mutation (R54X). This mutation cosegregated with diabetes in the family. The proband, his brother, mother, and maternal grandmother were diagnosed with type 1 diabetes aged 14-18 years and treated with insulin (0.39-0.74 units/kg) from diagnosis. The mother has since been successfully transferred to sulfonylurea treatment. CONCLUSIONS: Family history alone is of limited value in identification of individuals with HNF-1alpha mutations, and we propose a stepwise approach that restricts sequencing of the HNF-1alpha gene to those with a family history of diabetes who also test negative for islet autoantibodies.     

The challenge of using evidence-based practice

Establishing evidence-based practice is a difficult process. The authors describe an innovative collaborative project for establishing evidence-based practice in managing pain in pediatric oncology patients. Using the project as an example, they address the theoretical foundation to support evidence-based practice, barriers to adopting evidence, and strategies for overcoming barriers.     

Mental health differences among middle-aged sawmill workers in rural compared to urban British Columbia

The study sought to determine whether differences in mental health outcomes were observable in a cohort of workers living in rural compared to urban places in the Canadian province of British Columbia. The study was based on a cohort of male sawmill workers. The cohort was probabilistically linked to the BC Linked Health Database in order to yield objective mental health outcomes. A nested case control design was used. Univariate and multivariate models were constructed using conditional logistic regression. While results differed according to the particular mental health outcome, after controlling for socio-economic confounders it was found that workers who remained in or migrated to rural places tended to have better mental health outcomes than workers who remained in or migrated to urban places.     

Relationship Styles and Mortality in Patients With Diabetes

OBJECTIVE

Prior research has shown that less social support is associated with increased mortality in individuals with chronic illnesses. We set out to determine whether lower propensity to seek support as indicated by relationship style, based on attachment theory, is associated with mortality in patients with diabetes.

RESEARCH DESIGN AND METHODS

A total of 3,535 nondepressed adult patients with type 1 and type 2 diabetes enrolled in a health maintenance organization in Washington State were surveyed at baseline and followed for 5 years. Relationship style was assessed at baseline. Patients with a greater propensity to seek support were classified as having an interactive relationship style and those less inclined to seek support as having an independent relationship style. We collected Washington State mortality data and used Cox proportional hazards models to estimate relative risk (RR) of death for relationship style groups.

RESULTS

The rate of death in the independent and interactive relationship style groups was 39 and 29 per 1,000 individuals, respectively. Unadjusted RR of death was 1.33 (95% CI 1.12–1.58), indicating an increased risk of death among individuals with an independent relationship style. After adjustment for demographic and clinical covariates, those with an independent relationship style still had a greater risk of death compared with those with an interactive relationship style (hazard ratio 1.20 [95% CI 1.01–1.43]).

CONCLUSIONS

In a large sample of adult patients with diabetes, a lower propensity to reach out to others is associated with higher mortality over 5 years. Further research is needed to examine possible mechanisms for this relationship and to develop appropriate interventions.The presence of a supportive social network positively affects health by increasing access to instrumental, informational, and emotional support (1). In patients with diabetes, a higher level of social support is associated with improved treatment adherence, better glycemic control, and greater diabetes knowledge (2). Conversely, lower social support has been associated with higher mortality in patients with various chronic conditions (3,4), including patients with diabetes (5).Clinicians treating patients with chronic conditions generally understand these associations and attempt to encourage patients to seek and receive greater support from patients'' family, friends, peers, and social agencies. Clinicians may also encourage greater collaboration in the patient-provider relationship. Although many patients are receptive to such suggestions and efforts, a significant proportion is less receptive or not receptive at all. For example, regardless of the ready availability of a social network, many patients do not benefit from their support at times of need. Among patients who do not collaborate well with others, many have long-term patterns of not doing so, suggesting the influence of stable characteristics. If there are measurable patient characteristics that predict an individual''s capacity to use supports over time, such information may be useful for shaping approaches and recommendations that providers make in clinical settings.Attachment theory provides a theoretical, evidence-based model for understanding the propensity and ability of individuals to reach out to others for support. This theory posits that all individuals develop a cognitive map based on prior experiences that determines one''s comfort and ability to interact with or reach out to others, particularly at times of distress (6). On the basis of empirical research in infants, children, and adults over the past 30 years, distinct relationship styles arising from these cognitive maps have been identified (7) and demonstrate high levels of stability and continuity between early childhood and adulthood (8). Two of the styles, “dismissing” and “fearful” attachment style, are characterized by difficulty reaching out for support or trusting others, and patients with these styles and characteristics have been described as having an independent relationship style (9). Among clinical populations with diabetes, 48% of patients are typically found to have an independent relationship style (10). The remainder have an interactive relationship style, comprising those with “secure” and “preoccupied” attachment styles. Patients with an interactive relationship style have greater comfort reaching out to others, although individuals with a preoccupied style are often characterized as being highly dependent on others (11).In a large sample of primary care patients with diabetes (9,12), an independent relationship style has been associated with more missed primary care visits, lower satisfaction with care, higher A1C levels, and decreased adherence to exercise, quitting smoking, foot care, diet, and oral hypoglycemic medications. Another study showed that having a relationship style characterized by difficulty trusting or reaching out to others is associated with decreased adherence to glucose monitoring and insulin injections among patients with diabetes (13).In a recent article, we demonstrated that patients with major depression in this epidemiological sample were more likely to die over a 5-year period (hazard ratio [HR] 1.53) (14). In the current study, we set out to determine whether relationship styles are associated with mortality in patients with diabetes. Because depression status is associated with poorer collaboration as measured by relationship style (15), we conducted our analyses in nondepressed patients. In the current study, we hypothesized that among nondepressed patients with diabetes, those with an independent relationship style would have higher mortality over a 5-year period than patients with an interactive relationship style.     

Comparison of Cox and Gray's survival models in severe sepsis

BACKGROUND: Although survival is traditionally modeled using Cox proportional hazards modeling, this approach may be inappropriate in sepsis, in which the proportional hazards assumption does not hold. Newer, more flexible models, such as Gray's model, may be more appropriate. OBJECTIVES: To construct and compare Gray's model and two different Cox models in a large sepsis cohort. To determine whether hazards for death after sepsis were nonproportional. To explore how well the different survival modeling approaches describe these data. DESIGN: Analysis of combined data from the treatment and placebo arms of a large, negative, sepsis trial. SETTING: Intensive care units at 136 U.S. medical centers. SUBJECTS: A total of 1090 adults aged 18 yrs or older with signs and symptoms of severe sepsis and documented or probable Gram-negative infection. MEASUREMENTS: We considered 27 potential baseline risk factors and modeled survival over the 28 days after the onset of sepsis. We tested proportionality in single-variable Cox analysis using Schoenfeld residuals and log-log plots. We constructed a traditional multivariable Cox model, a multivariable Cox model with time-varying covariates, and a multivariable Gray's model. RESULTS: In single-variable analyses, 20 of the 27 potential factors were significantly associated with mortality, and 10 of 20 had nonproportional hazards. In multivariate analysis, all three models retained a very similar set of significant covariates (two models retained the identical set of nine variables, and the third differed only in that it retained the same nine plus a tenth variable). Four of the nine common covariates had nonproportional hazards. Of the three models, Gray's model best captured these changing hazard ratios over time. CONCLUSION: We confirm that many of the important predictors of mortality in severe sepsis are nonproportional and find that Gray's model seems best suited for modeling survival in this condition.     

Impact of the Combination of Daptomycin and Trimethoprim-Sulfamethoxazole on Clinical Outcomes in Methicillin-Resistant Staphylococcus aureus Infections

Complicated Staphylococcus aureus infections, including bacteremia, are often associated with treatment failures, prolonged hospital stays, and the emergence of resistance to primary and even secondary therapies. Daptomycin is commonly used as salvage therapy after vancomycin failure for the treatment of methicillin-resistant S. aureus (MRSA) infections. Unfortunately, the emergence of daptomycin resistance, especially in deep-seated infections, has been reported, prompting the need for alternative or combination therapy. Numerous antibiotic combinations with daptomycin have been investigated clinically and in vitro. Of interest, the combination of daptomycin and trimethoprim-sulfamethoxazole (TMP-SMX) has proved to be rapidly bactericidal in vitro to strains that are both susceptible and nonsusceptible to daptomycin. However, to date, there is limited clinical evidence supporting the use of this combination. This was a multicenter, retrospective case series of patients treated with the combination of daptomycin and TMP-SMX for at least 72 h. The objective of this study was to describe the safety and effectiveness of this regimen in clinical practice. The most commonly stated reason that TMP-SMX was added to daptomycin was persistent bacteremia and/or progressive signs and symptoms of infection. After the initiation of combination therapy, the median time to clearance of bacteremia was 2.5 days. Microbiological eradication was demonstrated in 24 out of 28 patients, and in vitro synergy was demonstrated in 17 of the 17 recovered isolates. Further research with this combination is necessary to describe the optimal role and its impact on patient outcomes.