Identification and expansion of highly suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation

FoxP3(+) confers suppressive properties and is confined to regulatory T cells (T(reg)) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4(+) T(reg) are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8(+) population of FoxP3(+) T(reg) that convert from CD8(+) conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8(+) T(reg) undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4(+)FoxP3(+) population and is more potent in exerting class I-restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8(+)FoxP3(+) T(reg) are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8(+)FoxP3(+) T(reg) thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I-restricted T-cell responses after bone marrow transplantation.     

Advanced Glycation End Products and β(2)-Microglobulin as Predictors of Carpal Tunnel Syndrome in Hemodialysis Patients

Background/Aims: Carpal tunnel syndrome (CTS) is a common clinical presentation of dialysis-related amyloidosis. It was determined whether β(2)-microglobulin (β2M) and advanced glycation end products in serum are predictors of CTS in dialysis patients. Methods: A total of 385 hemodialysis patients were screened for CTS. β2M in serum was determined by a competitive enzyme-linked immunoassay, CML by a competitive enzyme-linked immunosorbent assay and total pentosidine by reverse-phase high-performance liquid chromatography. Results: 127 patients (33%) were treated with biocompatible membranes, 174 (45%) with high-flux dialysis. 122 patients (31.7%) had clinical signs of CTS. Significant predictors of CTS were: age, female gender, serum β2M, total protein, dialysis with non-biocompatible high-flux dialysis compared to non-biocompatible low-flux dialysis, Kt/V and serum concentration of CML (OR 2.47 for the 3rd vs. 1st quartile, 95% CI 1.229-4.961, p = 0.011). Conclusion: The prevalence of CTS as a possible manifestation of dialysis-related amyloidosis is still high. Serum concentration of CML may be a predictor of CTS besides β2M and malnutrition.     

From gene to brain to behavior: schizophrenia‐associated variation in AMBRA1 alters impulsivity‐related traits

Recently, genome‐wide association between schizophrenia and an intronic variant in AMBRA1 (rs11819869) was reported. Additionally, in a reverse genetic approach in adult healthy subjects, risk allele carriers showed a higher medial prefrontal cortex blood oxygen level‐dependent (BOLD) response during a flanker task examining motor inhibition as an aspect of impulsivity. To test whether this finding can be expanded to further aspects of impulsivity, we analysed the effects of the rs11819869 genotype on impulsivity‐related traits on a behavioral, temperament and neural level in a large sample of healthy adolescents. We consider this reverse genetic approach specifically suited for use in a healthy adolescent sample, as these individuals comprise those who will eventually develop mental disorders in which impulsivity is implicated. Healthy adolescents from the IMAGEN study were included in the neuropsychological analysis (n = 848) and a functional magnetic resonance imaging (fMRI) task (n = 512). Various aspects of impulsivity were assessed using the Temperament and Character Inventory‐Revised, the Substance Use Risk Profile Scale, the Cambridge Cognition Neuropsychological Test Automated Battery, and the Stop Signal Task (SST) in the fMRI paradigm. On a behavioral level, increased delay aversion was observed in risk allele carriers. Furthermore, risk allele carriers showed a higher BOLD response in an orbito‐frontal target region during the SST, which declined to trend status after Family Wise Error correction. Our findings support the hypothesis that the schizophrenia‐related risk variant of rs11819869 is involved in various aspects of impulsivity, and that this involvement occurs on a behavioral as well as an imaging genetics level.     

Religious Values and Healthcare Accommodations: Voices from the American Muslim Community

BACKGROUND

Minority populations receive a lower quality healthcare in part due to the inadequate assessment of, and cultural adaptations to meet, their culturally informed healthcare needs. The seven million American Muslims, while ethnically and racially diverse, share religiously informed healthcare values that influence their expectations of healthcare. There is limited empirical research on this community??s preferences for cultural modifications in healthcare delivery.

OBJECTIVE

Identify healthcare accommodations requested by American Muslims.

METHODS

Using community-based participatory research (CBPR) methods, we partnered with four community organizations in the Greater Detroit area to design and conduct thirteen focus groups at area mosques serving African American, Arab American, and South Asian American Muslims. Qualitative content analysis utilized a framework team-based approach.

KEY RESULTS

Participants reported stigmatization within the healthcare system and voiced the need for culturally competent healthcare providers. In addition, they identified three key healthcare accommodations to address Muslim sensitivities: the provision of (1) gender-concordant care, (2) halal food and (3) a neutral prayer space. Gender concordance was requested based on Islamic conceptions of modesty and privacy. Halal food was deemed to be health-promoting and therefore integral to the healing process. Lastly, a neutral prayer space was requested to ensure security and privacy during worship.

CONCLUSIONS

This study informs efforts to deliver high-quality healthcare to American Muslims in several ways. We note three specific healthcare accommodations requested by this community and the religious values underlying these requests. Healthcare systems can further cultural sensitivity, engender trust, and improve the healthcare experiences of American Muslims by understanding and then attempting to accommodate these values as much as possible.     

IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation

Aims/hypothesis

IL-6 was recently shown to control alpha cell expansion. As beta cells expand following partial pancreatic-duct ligation (PDL) in adult mice, we investigated whether PDL also causes alpha cells to expand and whether IL-6 signalling is involved. As alpha cells can reprogramme to beta cells in a number of beta cell (re)generation models, we examined whether this phenomenon also exists in PDL pancreas.

Methods

Total alpha cell volume, alpha cell size and total glucagon content were evaluated in equivalent portions of PDL- and sham-operated mouse pancreases. Proliferation of glucagon⁺ cells was assessed by expression of the proliferation marker Ki67. Inter-conversions between alpha and beta cells were monitored in transgenic mice with conditional cell-type-specific labelling. The role of IL-6 in regulating alpha cell proliferation was evaluated by in situ delivery of an IL-6-inactivating antibody.

Results

In response to PDL surgery, alpha cell volume in the ligated tissue was increased threefold, glucagon content fivefold and alpha cell size by 10%. Activation of alpha cell proliferation in PDL pancreas required IL-6 signalling. A minor fraction of alpha cells derived from beta cells, whereas no evidence for alpha to beta cell conversion was obtained.

Conclusions/interpretation

In PDL-injured adult mouse pancreas, new alpha cells are generated mainly by IL-6-dependent self-duplication and seldom by reprogramming of beta cells.     

Regional proton magnetic resonance spectroscopy patterns in dementia with Lewy bodies

Magnetic resonance spectroscopy (MRS) characteristics of dementia with Lewy bodies (DLB) Alzheimer's disease (AD) and cognitively normal controls were compared. DLB (n = 34), AD (n = 35), and cognitively normal controls (n = 148) participated in a MRS study from frontal, posterior cingulate, and occipital voxels. We investigated DLB patients with preserved hippocampal volumes to determine the MRS changes in DLB with low probability of overlapping AD pathology. DLB patients were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) in the occipital voxel. AD patients were characterized by lower NAA/Cr in the frontal and posterior cingulate voxels. Normal NAA/Cr levels in the frontal voxel differentiated DLB patients with preserved hippocampal volumes from AD patients. DLB and AD patients had elevated choline/creatine, and myo-Inositol/creatine in the posterior cingulate. MRS abnormalities associated with loss of neuronal integrity localized to the occipital lobes in DLB, and the posterior cingulate gyri and frontal lobes in AD. This pattern of MRS abnormalities may have a role in differential diagnosis of DLB and in distinguishing DLB patients with overlapping AD pathology.     

Dynamic changes in respiratory frequency/tidal volume may predict failures of ventilatory liberation in patients on prolonged mechanical ventilation and normal preliberation respiratory frequency/tidal volume values

Rapid shallow breathing index (RSBI, respiratory frequency [f] divided by tidal volume [Vt]) has been used to prognosticate liberation from mechanical ventilation (LMV). We hypothesize that dynamic changes in RSBI predict failed LMV better than isolated RSBI measurements. We conducted a retrospective study of patients who were mechanically ventilated (MV) for longer than 72 hours. Failed LMV was defined as need for reinstitution of MV within 48 hours post-LMV. Ventilatory frequency (f) and Vt (liters) were serially recorded. The instantaneous RSBI (i-RSBI) was defined as f/Vt. Dynamic f/Vt ratio (d-RSBI) was defined as the ratio between two consecutive i-RSBI (f/Vt) measurements ([f(2)/Vt(2)]/[f(1)/Vt(1)]). RSBI Product (RSB-P) was defined as (i-RSBI × d-RSBI). Data from 32 patients were analyzed (Acute Physiology and Chronic Health Evaluation II 13.4, male 69%, mean age 57 years). Mean length of stay was 19.5 days (11.5 ventilator; 14.1 intensive care unit days). For LMV failures, mean time to reinstitution of invasive MV was 20.8 hours. All patients had pre-LMV i-RSBI less than 100. Failed LMVs had higher i-RSBI values (68.9, n = 18) than successful LMVs (44.2, n = 23, P < 0.01). Failures had higher d-RSBI (1.48) than successful LMVs (1.05, P < 0.04). The RSB-P was higher for failed LMVs (118) than for successful LMVs (48.8, P < 0.01) with failures having larger proportion of pre-LMV d-RSBI values greater than 1.5 (39.0 vs 10.7%, P < 0.03). Pre-LMV RSB-P may offer early prediction of failed LMV in patients on MV for longer than 72 hours despite normal pre-LMV i-RSBI. Divergence between RSB-P for successful and failed LMVs occurred earlier than i-RSBI divergence with a greater proportion of pre-LMV d-RSBI greater than 1.5 among failures.     

Factors associated with physical activity in children attending family child care homes

Objective

To determine the relationship between family child care home (FCCH) practices and characteristics, and objectively measured physical activity (PA) among children attending FCCHs.

Methods

FCCH practices and characteristics were assessed in 45 FCCHs in Oregon (USA) in 2010-2011 using the Nutrition and Physical Activity Self-Assessment for Child Care Instrument. Within the 45 FCCHs, 136 children between ages 2 and 5 years wore an accelerometer during child care attendance over a one-week period. Time spent in light, moderate, and vigorous PA per hour was calculated using intensity-related cut-points (Pate et al., 2006).

Results

FCCH characteristics and practices associated with higher levels of PA (min/h; p < 0.05) included provision of sufficient outdoor active play [32.2 (1.0) vs. 28.6 (1.3)], active play using portable play equipment [31.7 (1.0) vs. 29.3 (1.4)], the presence of a variety of fixed play equipment [32.2 (1.0) vs. 28.9 (1.3)], and suitable indoor play space [32.2 (1.0) vs. 28.6 (1.3)], engaging in active play with children [32.1 (1.1) vs. 29.6 (1.2)], and receiving activity-related training [33.1 (1.2) vs. 30.3 (1.1)].

Conclusions

This is the first study to identify practices and characteristics of FCCHs that influence children's PA. These data should be considered when developing programs and policies to promote PA in FCCHs.