Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity

Natural killer (NK) cells are innate lymphocytes that play an important role against viral infections and cancer. This effect is achieved through a complex mosaic of inhibitory and activating receptors expressed by NK cells that ultimately determine the magnitude of the NK-cell response. The T-cell immunoglobulin- and mucin domain-containing (Tim)-3 receptor was initially identified as a T-helper 1-specific type I membrane protein involved in regulating T-cell responses. Human NK cells transcribe the highest amounts of Tim-3 among lymphocytes. Tim-3 protein is expressed on essentially all mature CD56(dim)CD16(+) NK cells and is expressed heterogeneously in the immature CD56(bright)CD16(-) NK-cell subset in blood from healthy adults and in cord blood. Tim-3 expression was induced on CD56(bright)CD16(-) NK cells after stimulation with IL-15 or IL-12 and IL-18 in vitro, suggesting that Tim-3 is a maturation marker on NK cells. Whereas Tim-3 has been used to identify dysfunctional T cells, NK cells expressing high amounts of Tim-3 are fully responsive with respect to cytokine production and cytotoxicity. However, when Tim-3 was cross-linked with antibodies it suppressed NK cell-mediated cytotoxicity. These findings suggest that NK-cell responses may be negatively regulated when NK cells encounter target cells expressing cognate ligands of Tim-3.     

Patient‐reported convenience of once‐daily versus three‐times‐daily dosing during long‐term studies of pramipexole in early and advanced Parkinson’s disease

Background and purpose: In chronic diseases including Parkinson’s disease (PD), complex pharmacotherapy dosing schedules are reported to reduce adherence, perhaps leading to less‐effective symptom control and, in PD, more erratic stimulation of dopamine receptors. However, blinded clinical‐trial designs preclude direct comparisons of adherence to various schedules. Methods: In two double‐blind (DB) studies of early PD and one of advanced PD, subjects received three‐times‐daily (t.i.d.) pramipexole or placebo. In open‐label (OL) extensions, subjects took extended‐release, once‐daily (q.d.) pramipexole. At 24 or 32 OL weeks, q.d. versus t.i.d. dosing preference was surveyed by questionnaire. Results: Of 590 DB‐trial completers with early PD, 511 entered the OL extension. Of 374 survey respondents, 94.4% preferred q.d. dosing (72.2% of them found it ‘very much more convenient’ and 27.8%‘more convenient’), 2.7% preferred t.i.d., and 2.9% chose ‘no difference’. Of 465 DB‐trial completers with advanced PD, 391 entered its OL extension. Of 334 survey respondents, 88.9% preferred q.d. dosing (59.9% of them found it ‘very much more convenient’ and 40.1%‘more convenient’), 5.7% preferred t.i.d., and 5.4% chose ‘no difference’. Results excluding DB‐placebo recipients were highly similar. Conclusions: In this first direct comparison of patient preference for q.d. versus t.i.d. dopamine‐agonist dosing, patients with early or advanced PD had a strong preference for q.d. rather than t.i.d. pramipexole. The high proportion of advanced‐PD patients declaring this preference indicates that it does not depend on whether a patient is taking concomitant PD medications dosed more frequently than q.d.     

An update on diastolic dysfunction

Diastolic dysfunction refers to abnormal diastolic filling properties of the left ventricle regardless of whether systolic function is normal or the patient has symptoms. Diastolic heart failure (HF), or more accurately, HF with preserved systolic function, is a distinct clinical entity characterized by the presence of the triad of impaired diastolic function, normal systolic function (left ventricular ejection fraction > 50%), and symptoms of HF. Patients with HF with preserved systolic function are frequently symptomatic from both acute and chronic elevations in left ventricular end-diastolic pressure and/or left atrial pressure.     

The association of health literacy with illness perceptions,medication beliefs,and medication adherence among individuals with type 2 diabetes

Background

Beliefs in medications and illness perceptions is associated with medication adherence among individuals with diabetes and several adherence interventions focus on patients' beliefs in medicines and illnesses. Though health literacy is important in medication adherence, the relationship between health literacy and medication adherence remains inconclusive; thus raising the question as to whether health literacy has an amplifying or reducing effect on the relationship between beliefs and adherence.

Adverse Childhood Experiences and Child Health Outcomes: Comparing Cumulative Risk and Latent Class Approaches

Objectives This study seeks to further the work exploring adverse childhood experiences (ACEs) by proposing a novel approach to understanding the impact of ACEs through applying advanced analytical methods to examine whether combinations of ACEs differentially impact child health outcomes. Methods Using National Survey of Children’s Health data, we use latent class analysis to estimate associations between classes of ACEs and child health outcomes. Results Class membership predicts child poor health, with differences found for specific ACE combinations. A subgroup of children exposed to poverty and parental mental illness are at higher risk for special healthcare needs than all other groups, including children exposed to 3 or more ACEs. Conclusions Different combinations of ACEs carry different risk for child health. Interventions tailored to specific ACEs and ACE combinations are likely to have a greater effect on improving child health. Our findings suggest children who experience specific ACE combinations (e.g., poverty and parental mental illness) are at particularly high risk for poor health outcomes. Therefore, clinicians should routinely assess for ACEs to identify children exposed to the most problematic ACE combinations; once identified, these children should be given priority for supportive interventions tailored to their specific ACE exposure and needs.     

Correlation between high risk obesity groups and low socioeconomic status in school children

OBJECTIVE: Obesity is a major health problem among children and adolescents which is potentially affected by socioeconomic status (SES). The high risk group (HRG) comprises those youths with a body mass index (BMI) between the 85th and 95th percentile (at risk for overweight) and > or = 95th percentile (overweight). We sought a potential link between the HRG and SES. METHODS: Public schools in Chesterfield County, Virginia measured BMI among students in kindergarten and third, seventh, and tenth grades. We assessed SES based on eligibility for the National School Lunch Program and the percentage of the school-age population living in poverty based on per capita income from the 2000 Census. RESULTS: From 28 to 38% of children and adolescents were in the high risk group. Low SES had robust and highly significant correlations with HRG status with r-values ranging from 0.565 to 0.842, P < 0.0001. CONCLUSIONS: Low SES appears to be an important factor in childhood and adolescent obesity.     

Alpha/beta T-cell antigen receptor gene and protein expression occurs at early stages of thymocyte differentiation.

Alterations in gene expression that orchestrate eukaryotic cellular differentiation often require appropriate interactions between differentiating cells and a specialized microenvironment. During T-lymphocyte differentiation, immature thymocytes undergo a stringent intrathymic selection process that requires intimate contact with thymic stromal elements. Since this selection process generates T cells that are self-tolerant and recognize nominal antigen only within the context of self-major histocompatibility antigen complex molecules, it is possible that thymocyte/stromal cell interactions are mediated, in part, by antigen-specific receptors expressed on differentiating thymocytes. However, the developmental stage at which alpha/beta antigen-specific receptors are expressed during T-cell maturation has been a matter of debate. To address this issue, we have studied alpha/beta T-cell antigen receptor gene and protein expression on normal thymocyte subsets of AKR/J mice, as well as on a panel of AKR/J primary thymic lymphomas characterized for CD4 (L3T4) and CD8 (Lyt-2) differentiation antigen expression. The data unequivocally demonstrate that alpha/beta heterodimers are expressed not only on phenotypically mature thymocytes but also on the majority of CD4+8+ double-positive cells that comprise the predominant nonmature thymocyte subset. Furthermore, a fraction of thymocytes in the CD4-8- double-negative compartment, known to contain progenitor cells, also expresses readily detectable cell-surface alpha/beta receptors. Therefore, during the process of intrathymic selection, interactions between nonmature thymocytes and stromal cells via the antigen-receptor complex may play a pivotal role in T-cell differentiation and should be considered in formulating schemes for functional T-cell selection.