Publications

BACKGROUND

Patients presenting with ST-elevation myocardial infarction commonly have multi-vessel coronary artery disease. After the culprit artery is treated, the optimal treatment strategy for the residual disease is not yet defined. Large observational studies suggest that treatment of residual disease should be deferred but smaller randomised controlled trials (RCTs) suggest multi-vessel primary percutaneous coronary intervention (MV-PPCI) at the time of STEMI is safe. We examine if allocation bias of high-risk patients could explain the conflicting results between observational studies and RCTs and aim to resolve the paradox between the two.

METHODS

A meta-analysis of registries comparing culprit-only PPCI to MV-PPCI was performed. We then determined if high-risk patients were more likely to be allocated to MV-PPCI. A meta-regression was performed to determine if any allocation bias of high-risk patients could explain the difference in outcomes between therapies.

RESULTS

47,717 patients (19 studies) were eligible. MV-PPCI had higher mortality than culprit-only PPCI (OR 1.59, 95% CI 1.12 to 2.24, p=0.03). However, higher risk patients were more likely to be allocated to MV-PPCI (OR 1.45, 95% CI 1.18 to 1.78, p=0.0005). When this was accounted for, there was no difference in mortality between culprit-only PPCI and MV-PPCI (OR 0.99, 95% CI 0.69 to 1.41, p=0.94).

DISCUSSION

Clinicians preferentially allocate higher-risk patients to MV-PPCI at the time of STEMI, resulting in observational studies reporting higher mortality with this strategy. When this is accounted for, these large observational studies in 'real world' patients support the conclusion of the smaller RCTs in the field: MV-PPCI has equivalent mortality to a culprit-only approach.

The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.

Homeostasis of the gastrointestinal (GI) tract is controlled by complex interactions between epithelial and immune cells and the resident microbiota. Here, we studied the role of Wnt signaling in GI homeostasis using knockout () mice, which display an increase in whole gut transit time. This phenotype is associated with a reduction and mislocalization of Paneth cells and an increase in CD8 T cells in the lamina propria. Bone marrow chimera experiments demonstrated that GI dysfunction requires abnormalities in both epithelial and immune cells. mice exhibit a significantly distinct GI microbiota, and manipulation of the gut microbiota in mutant mice rescued the GI transit abnormality without correcting the Paneth and CD8 T cell abnormalities. Moreover, manipulation of the gut microbiota in wild-type mice induced a GI transit abnormality akin to that seen in mice. Together, these data indicate that microbiota manipulation can overcome host dysfunction to correct GI transit abnormalities. Our findings illustrate a mechanism by which the epithelium and immune system coregulate gut microbiota composition to promote normal GI function.

AIM

This study examined the career anchor characteristics that are possessed by Japanese occupational health nurses.

METHOD

Sixteen occupational health nurses participated in the semistructured interview. Data analyses were conducted using descriptive qualitative methods.

RESULTS

The data showed the following five categories: practices concerning relationships and positions; development of occupational health practices; management skills for effective work; practices that are approved inside and outside the organization; and work and private life considerations.

CONCLUSIONS

This study described the career anchors among occupational health nurses in Japan. The participants emphasized the following: the importance of maintaining good cooperative relationships with workers and supervisors; balancing professional and organized labor; and practicing effective occupational health services. Moreover, the occupational health nurses emphasized receiving approval from inside and outside of the organization. These results were consistent with the actual practices of occupational health nursing.

Early after HIV infection there is substantial depletion of CD4 T cells in the gastrointestinal (GI) tract lamina propria (LP), with associated epithelial barrier damage, leading to microbial translocation and systemic inflammation and immune activation. In this study, we analyzed these early events in the GI tract in a cohort of Thai acute HIV-infected patients and determined the effect of early combination antiretroviral treatment (cART). HIV-uninfected and chronically and acutely HIV-infected patients at different Fiebig stages (I-V) underwent colonic biopsies and then received cART. Immunohistochemistry and quantitative image analysis were performed on cross-sectional and longitudinal colon biopsy specimens (day 0 to week 96) to measure GI tract damage (infiltration of polymorphonuclear cells), inflammation (M×1, TNF-α), immune activation (Ki-67), and the CD4 T cell population in the LP. The magnitude of GI tract damage, immune activation, and inflammation was significantly increased, with significantly depleted CD4 T cells in the LP in all acutely infected groups prior to cART compared with HIV-uninfected control participants. While most patients treated during acute infection resolved GI tract inflammation and immune activation back to baseline levels after 24 weeks of cART, most acutely infected participants did not restore their CD4 T cells after 96 weeks of cART.