Recent Publications by CFE Educators

Neuromyelitis optica (NMO) is an aggressive demyelinating disease that typically affects the optic nerves and spinal cord. While it is increasingly recognized that cerebral lesions are common in NMO, there have been no reported cases of NMO presenting with psychiatric symptoms and polydipsia. We describe a patient with classic signs and symptoms of NMO who also demonstrated prominent psychiatric symptoms and polydipsia that were tied to his flares and resolved with treatment of his NMO. This case expands our understanding of possible presentations of NMO.

RATIONALE

Despite ongoing ethical debate concerning who should control decisions to discontinue life support for incapacitated, critically ill patients, the perspectives of surrogate decision makers are poorly understood.

OBJECTIVES

To determine (1) what degree of decisional authority surrogates prefer for value-sensitive life support decisions compared with more technical biomedical decisions, and (2) what predicts surrogates' preferences for more control over life support decisions.

METHODS

This was a prospective study of 230 surrogate decision makers for incapacitated, mechanically ventilated patients at high risk of death. Surrogates reported their preferred degree of decisional authority using the Degner Control Preferences Scale for two types of decisions: a value-sensitive decision about whether to discontinue life support and a decision regarding which antibiotic to prescribe for an infection.

MEASUREMENTS AND MAIN RESULTS

The majority of surrogates (55%, 127/230; 95% confidence interval, 49-62%) preferred to have final control over the value-sensitive life support decision; 40% (91/230) wished to share control equally with the physician; 5% (12/230) of surrogates wanted the physician to make the decision. Surrogates preferred significantly more control over the value-sensitive life support decision compared with the technical decision about choice of antibiotics (P 0.0001). Factors independently associated with surrogates' preference for more control over the life support decision were: less trust in the intensive care unit physician, male sex, and non-Catholic religious affiliation.

CONCLUSIONS

Surrogates vary in their desire for decisional authority for value-sensitive life support decisions, but prefer substantially more authority for this type of decision compared with technical, medical judgments. Low trust in physicians is associated with surrogates preferring more control of life support decisions.

In vivo iron load must be monitored to prevent complications from iron overload diseases such as hemochromatosis or transfusion-dependent anemias. While liver biopsy is the gold standard for determining in vivo iron load, MRI offers a noninvasive approach. MR phantoms have been reported that estimate iron concentration in the liver and mimic relaxation characteristics of in vivo deposits of hemosiderin. None of these phantoms take into account the size distribution of hemosiderin, which varies from patient to patient based on iron load. We synthesized stable and reproducible microsphere-ferritin conjugates (ferribeads) of different sizes that are easily characterized for several parameters that are necessary for modeling such as iron content and bead fraction. T(1) s and T(2) s were measured on a 1.41-T low-resolution NMR spectrometer and followed a size-dependent trend. Ferribeads imaged at 4.7 and 14.1 T showed that signal intensities are dependent on the distribution of ferritin around the bead rather than the iron concentration alone. These particles can be used to study the effects of particle size, ferritin distribution, and bead fraction on proton relaxation and may be of use in mimicking hemosiderin in a phantom for estimating iron concentration.

BACKGROUND

Hepatitis C (HCV) knowledge is limited in injection drug users (IDU). Vulnerable populations including IDUs are disproportionally affected by HCV. Effective HCV education can potentially reduce disparity in HCV prevalence and its outcome in this population.

AIM

This study aimed to assess the impact of formal HCV education and factors associated with improved HCV knowledge in the vulnerable population.

METHODS

Over 18 months, 201 HCV-infected patients underwent a 2-h standardized education and completed demographic and pre- and post-education questionnaires.

RESULTS

Patient characteristics were: 69% male, mean age 49±10, 49% White (26% AA, 10% Latino), 75% unemployed, 83% high school education and above, 64% were IDU, and 7% were HIV co-infected. On multivariate analysis, baseline knowledge scores were higher in patients with at least a high school education (coef 7.1, p=0.045). Baseline knowledge scores were lower in African Americans (coef -12.3, p=0.004) and older patients (coef -0.7, p=0.03). Following HCV education, the overall test scores improved significantly by 14% (p=0.0001) specifically in the areas of HCV transmission (p=0.003), general knowledge (p=0.02), and health care maintenance (p=0.004). There was a high compliance with liver specialty clinic attendance following education.

CONCLUSIONS

Formal HCV education is effective in improving HCV knowledge. Although White race, younger age, and higher education were predictors of having more HCV knowledge prior to education, all patients independent of racial background had a significant improvement in their knowledge after education. Therefore, promoting effective HCV education among vulnerable populations may be an important factor in reducing the disparities in HCV disease.

OBJECTIVE

To determine whether raltegravir-containing antiretroviral therapy (ART) intensification reduces HIV levels in the gut.

DESIGN

Open-label study in HIV-positive adults on ART with plasma HIV RNA below 40 copies/ml.

METHODS

Seven HIV-positive adults received 12 weeks of ART intensification with raltegravir alone or in combination with efavirenz or darunavir. Gut cells were obtained by upper and lower endoscopy with biopsies from duodenum, ileum, colon, and rectum at baseline and 12 weeks. Study outcomes included plasma HIV RNA, HIV DNA and RNA from peripheral blood mononuclear cells (PBMC) and four gut sites, T-cell subsets, and activation markers.

RESULTS

Intensification produced no consistent decrease in HIV RNA in the plasma, PBMC, duodenum, colon, or rectum. However, five of seven participants had a decrease in unspliced HIV RNA per 10 CD4(+) T cells in the ileum. There was a trend towards decreased T-cell activation in all sites, which was greatest for CD8(+) T cells in the ileum and PBMC, and a trend towards increased CD4(+) T cells in the ileum.

CONCLUSION

Most HIV RNA and DNA in the blood and gut is not the result of ongoing replication that can be impacted by short-term intensification with raltegravir. However, the ileum may support ongoing productive infection in some patients on ART, even if the contribution to plasma RNA is not discernible.

Human cytomegalovirus (HCMV) has a relatively large and complex genome, a protracted lytic replication cycle, and employs a strategy of replicational latency as part of its lifelong persistence in the infected host. An important form of gene regulation in plants and animals revolves around a type of small RNA known as microRNA (miRNA). miRNAs can serve as major regulators of key developmental pathways, as well as provide subtle forms of regulatory control. The human genome encodes over 900 miRNAs, and miRNAs are also encoded by some viruses, including HCMV, which encodes at least 14 miRNAs. Some of the HCMV miRNAs are known to target both viral and cellular genes, including important immunomodulators. In addition to expressing their own miRNAs, infections with some viruses, including HCMV, can result in changes in the expression of cellular miRNAs that benefit virus replication. In this review, we summarize the connections between miRNAs and HCMV biology. We describe the nature of miRNA genes, miRNA biogenesis and modes of action, methods for studying miRNAs, HCMV-encoded miRNAs, effects of HCMV infection on cellular miRNA expression, roles of miRNAs in HCMV biology, and possible HCMV-related diagnostic and therapeutic applications of miRNAs.

Point mutations at m.8993T>C and m.8993T>G of the mtDNA ATPase 6 gene cause the neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome, a mitochondrial disorder characterized by retinal, central and peripheral neurodegeneration. We performed detailed neurological, neuropsychological and ophthalmological phenotyping of a mother and four daughters with NARP syndrome from the mtDNA m.8993T>C ATPase 6 mutation, including 3-T brain MRI, spectral domain optical coherence tomography (SD-OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), electromyography and nerve conduction studies (EMG-NCS) and formal neuropsychological testing. The degree of mutant heteroplasmy for the m.8993T>C mutation was evaluated by real-time allele refractory mutation system quantitative PCR of mtDNA from hair bulbs (ectoderm) and blood leukocytes (mesoderm). There were marked phenotypic differences between family members, even between individuals with the greatest degrees of ectodermal and mesodermal heteroplasmy. 3-T MRI revealed cerebellar atrophy and cystic and cavitary T2 hyperintensities in the basal ganglia. SD-OCT demonstrated similarly heterogeneous areas of neuronal and axonal loss in inner and outer retinal layers. AOSLO showed increased cone spacing due to photoreceptor loss. EMG-NCS revealed varying degrees of length-dependent sensorimotor axonal polyneuropathy. On formal neuropsychological testing, there were varying deficits in processing speed, visual-spatial functioning and verbal fluency and high rates of severe depression. Many of these cognitive deficits likely localize to cerebellar and/or basal ganglia dysfunction. High-resolution retinal and brain imaging in NARP syndrome revealed analogous patterns of tissue injury characterized by heterogeneous areas of neuronal loss.

Fatty acid-binding proteins (FABPs) 4 and 5 play coordinated roles in rodent models of inflammation, insulin resistance, and atherosclerosis, but little is known of their role in human disease. The aim of this study was to examine the hypothesis that plasma adipocyte and macrophage FABP4 and FABP5 levels would provide additive value in the association with metabolic and inflammatory risk factors for cardiovascular disease as well as subclinical atherosclerosis. Using the Penn Diabetes Heart Study (PDHS; n = 806), cross-sectional analysis of FABP4 and FABP5 levels with metabolic and inflammatory parameters and with coronary artery calcium, a measure of subclinical coronary atherosclerosis, was performed. FABP4 and FABP5 levels had strong independent associations with the metabolic syndrome (for a 1-SD change in FABP levels, odds ratio [OR] 1.85, 95% confidence interval [CI] 1.43 to 2.23, and OR 1.66, 95% CI 1.41 to 1.95, respectively) but had differential associations with metabolic syndrome components. FABP4 and FABP5 were also independently associated with C-reactive protein and interleukin-6 levels. FABP4 (OR 1.26, 95% CI 1.05 to 1.52) but not FABP5 (OR 1.13, 95% CI 0.97 to 1.32) was associated with the presence of coronary artery calcium. An integrated score combining FABP4 and FABP5 quartile data had even stronger associations with the metabolic syndrome, C-reactive protein, interleukin-6, and coronary artery calcium compared to either FABP alone. In conclusion, this study provides evidence for an additive relation of FABP4 and FABP5 with the metabolic syndrome, inflammatory cardiovascular disease risk factors, and coronary atherosclerosis in type 2 diabetes mellitus. These findings suggest that FABP4 and FABP5 may represent mediators of and biomarkers for metabolic and cardiovascular disease in type 2 diabetes mellitus.

BACKGROUND

The gut is a major reservoir for human immunodeficiency virus (HIV) in patients receiving antiretroviral therapy (ART). We hypothesized that distinct immune environments within the gut may support varying levels of HIV.

METHODS

In 8 HIV-1-positive adults who were receiving ART and had CD4(+) T cell counts of >200 cells/μL and plasma viral loads of 40 copies/mL, levels of HIV and T cell activation were measured in blood samples and endoscopic biopsy specimens from the duodenum, ileum, ascending colon, and rectum.

RESULTS

HIV DNA and RNA levels per CD4(+) T cell were higher in all 4 gut sites compared with those in the blood. HIV DNA levels increased from the duodenum to the rectum, whereas the median HIV RNA level peaked in the ileum. HIV DNA levels correlated positively with T cell activation markers in peripheral blood mononuclear cells (PBMCs) but negatively with T cell activation markers in the gut. Multiply spliced RNA was infrequently detected in gut, and ratios of unspliced RNA to DNA were lower in the colon and rectum than in PBMCs, which reflects paradoxically low HIV transcription, given the higher level of T cell activation in the gut.

CONCLUSIONS

HIV DNA and RNA are both concentrated in the gut, but the inverse relationship between HIV DNA levels and T cell activation in the gut and the paradoxically low levels of HIV expression in the large bowel suggest that different processes drive HIV persistence in the blood and gut.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT00884793 (PLUS1).