Publications

BACKGROUND

The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis.

METHODS

An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142-3p on phenotype and function of proinflammatory M1 and immunosuppressive M2 macrophages were determined. The therapeutic effect of miR-142-3p was ascertained in immune-competent C57BL/6J mice harboring intracerebral GL261 gliomas and in genetically engineered Ntv-a mice bearing high-grade gliomas. Student t test was used to evaluate the differences between ex vivo datasets. Survival was analyzed with the log-rank test and tumor sizes with linear mixed models and F test. All statistical tests were two-sided.

RESULTS

miR-142-3p was the most downregulated miRNA (approximately 4.95-fold) in glioblastoma-infiltrating macrophages. M2 macrophages had lower miR-142-3p expression relative to M1 macrophages (P = .03). Overexpression of miR-142-3p in M2 macrophages induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset (P = .01). In vivo miR-142-3p administration resulted in glioma growth inhibition (P = .03, n = 5) and extended median survival (miR-142-3p-treated C57BL/6J mice vs scramble control: 31 days vs 23.5 days, P = .03, n = 10; miR-142-3p treated Ntv-a mice vs scramble control: 32 days vs 24 days, P = .03, n = 9), with an associated decrease in infiltrating macrophages (R (2) = .303).

CONCLUSIONS

These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway.

BACKGROUND

Cerebrospinal fluid (CSF) is commonly acquired in dogs with intervertebral disk herniation (IVDH) and is a common method to assess inflammatory responses following spinal cord injury (SCI).

OBJECTIVES

The purpose of the study was to describe relationships between cisternal CSF characteristics, behavioral measures of SCI, T2- weighted (T2W) hyperintensity on magnetic resonance imaging (MRI), and long-term outcome in dogs with IVDH. Diagnostic accuracy of CSF for differentiating IVDH from other myelopathies was also assessed.

METHODS

The retrospective case series included 727 dogs, 443 with thoracolumbar IVDH, 103 with cervical IVDH, and 181 with other spinal cord diseases. Signalment, initial neurologic function, ambulatory function at long-term follow-up, T2W MRI, and CSF variables were recorded for dogs with IVDH. Signalment, etiology, and CSF data were retrieved for dogs with other myelopathies. Associations between CSF predictors, diagnosis, and outcomes were assessed.

RESULTS

CSF total nucleated cell count (TNCC) increased with SCI severity (rho -0.256, P < .001) in dogs with IVDH, TNCC was significantly higher in the presence of T2W hyperintensity (P = .001) in dogs with thoracolumbar IVDH, but TNCC, RBC count, microprotein, and percent neutrophils decreased with increasing injury duration (rho -0.253, P < .001; rho -0.269, P < .001; rho -0.141, P = .004, and rho -0.356, P < .001, respectively). CSF characteristics were not accurate for differentiating IVDH from other spinal cord diseases.

CONCLUSIONS

In dogs with IVDH, CSF TNCC, RBC count, microprotein, and percent neutrophils are correlated with clinical aspects of SCI such as injury severity and duration, but cannot differentiate IVDH from other etiologies.

BACKGROUND

Fixed-dose combination of isosorbide dinitrate and hydralazine (FDC-I/H) reduced mortality by 43% and death or first hospitalization for heart failure (HF) by 37% in the African-American Heart Failure Trial (A-HeFT). Reduction in mortality makes it difficult to determine the effect on hospitalizations unless the analysis adjusts for death as a competing risk.

METHODS AND RESULTS

In A-HeFT, 1050 self-identified black patients with moderate to severe HF were randomized to FDC-I/H or placebo. The effects of FDC-I/H on first and all hospitalizations and 30-day readmission rates were analyzed. Deaths as competing risks were adjusted using Fine-Gray regression and joint models of hospitalizations and mortality. There were 558 all-cause and 251 HF hospitalizations in placebo compared with 435 and 173 hospitalizations in the FDC-I/H group. Adjusting for deaths as a competing risk, the effect of FDC-I/H on the first hospitalization for HF, expressed in hazard ratio (95% confidence interval), was 0.61 (0.47-0.80; P<0.001) and 0.88 (0.72-1.06; P=0.18) on the first all-cause hospitalization. The effect of FDC-I/H on all recurrent hospitalizations for HF was 0.66 (0.52-0.83; P=0.0005), similar to the effect on the first hospitalizations for HF, whereas the effect on all hospitalizations for any cause was 0.75 (0.63-0.91; P=0.003). The 30-day all-cause readmission rate after the first hospitalization for HF was 23.6% (29 of 123) in placebo versus 14.8% (12 of 81) in the FDC-I/H group, but the effect (0.59; 0.30-1.16; P=0.12) in this small subgroup was not significant.

CONCLUSIONS

Treatment with FDC-I/H was associated with a substantial reduction in the first and recurrent HF hospitalizations, and in total all-cause hospitalizations, reducing the total burden of costly and distressing hospitalizations.

CLINICAL TRIAL REGISTRATION URL

http://www.clinicaltrials.gov. Unique identifier: NCT00047775.

We evaluated motorcycle taxi ('boda-boda') drivers in Kampala for the prevalence of HIV/sexually transmitted infections. We used respondent-driven sampling to recruit a cross-sectional sample of boda-boda drivers. We collected data through audio computer-assisted self-administered interviews. Men were tested for HIV, syphilis serology using Rapid Plasma Reagin and enzyme immunoassay, and Chlamydia and gonorrhoea using urine polymerase chain reaction. We recruited 683 men. Median age was 26 years; 59.4% were single. The prevalence of HIV was 7.5% (95% CI 5.2-10.0), of positive syphilis serology was 6.1% (95% CI 4.3-8.1), of Chlamydia was 1.1% (95% CI 0.4-2.0), and of gonorrhoea was 1.2% (95% CI 0.1-1.2). Many men (67.8%) had both casual and regular partners, sex with other men (8.7%), and commercial sex (33.1%). Factors associated with having HIV included reporting a genital ulcer (odds ratio [OR] =2.4, 95% CI 1.4-4.4), drinking alcohol during last sex (OR 2.0, 95% CI 1.1-3.7), having 4-6 lifetime partners (OR 2.2, 95% CI 1.0-4.8), and having one's last female partner be >24 years of age (OR 2.8, 95% CI 1.2-6.6). Independent predictors of HIV included age ≥31 (adjusted OR (aOR) 5.8, 95% CI 1.5-48.5), having 4-6 partners (aOR 2.2, 95%CI 1.0-5.1), and self-report of a genital ulcer (OR 2.3, 95% CI 1.2-4.1). Only 39.2% of men were circumcised, and 36.9% had been HIV tested in the past. Male boda-boda drivers have a higher prevalence of HIV than the general population, and low frequency of preventive behaviours, such as circumcision and HIV testing. Targeted and intensified interventions for this group are warranted.

The National Institute of Diabetes and Digestive and Kidney Diseases-supported Kidney Research National Dialogue asked the scientific community to formulate and prioritize research objectives that would enhance understanding of kidney function and disease and improve clinical outcomes. An engaged and growing group of investigators working in type 2 translation (from clinical evidence to implementation in the community) identified barriers to improving patient care in CKD and suggested research priorities to test translational strategies that have been effective for other chronic diseases.