Faculty Bibliography

Traumatic brain injury (TBI) remains one of the most prevalent forms of morbidity among Veterans and Service Members, particularly for those engaged in the conflicts in Iraq and Afghanistan. Neuroimaging has been considered a potentially useful diagnostic and prognostic tool across the spectrum of TBI generally, but may have particular importance in military populations where the diagnosis of mild TBI is particularly challenging, given the frequent lack of documentation on the nature of the injuries and mixed etiologies, and highly comorbid with other disorders such as post-traumatic stress disorder, depression, and substance misuse. Imaging has also been employed in attempts to understand better the potential late effects of trauma and to evaluate the effects of promising therapeutic interventions. This review surveys the use of structural and functional neuroimaging techniques utilized in military studies published to date, including the utilization of quantitative fluid attenuated inversion recovery (FLAIR), susceptibility weighted imaging (SWI), volumetric analysis, diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), positron emission tomography (PET), magnetoencephalography (MEG), task-based and resting state functional MRI (fMRI), arterial spin labeling (ASL), and magnetic resonance spectroscopy (MRS). The importance of quality assurance testing in current and future research is also highlighted. Current challenges and limitations of each technique are outlined, and future directions are discussed.

BACKGROUND: Patients undergoing cardiovascular procedures remain at increased risk for myocardial infarction, stroke, and cardiovascular death. Risk factor control in this patient population remains suboptimal and would likely benefit from strategies targeting education, lifestyle, and healthy behaviors. DESIGN: The IMPACT trial is a 400-subject prospective randomized trial designed to compare different cardiovascular prevention strategies in subjects following a cardiovascular intervention. The trial began enrollment in the Spring of 2012 and is randomizing subjects in a 1:1:1 manner to usual care, a one-time cardiovascular prevention consult, or a one-time cardiovascular prevention consult plus behavioral intervention program (telephone-based motivational interviewing and tailored text messages) over a 6-month period. The primary end point is non-high-density lipoprotein cholesterol. Secondary end points include other plasma lipid values, metabolic risk, smoking cessation, physical activity, dietary intake, medication use and adherence, and quality of life. CONCLUSIONS: The IMPACT trial provides data on different management strategies for risk factor optimization in subjects following cardiovascular procedures. The results will provide a platform for the continued development of novel multidisciplinary interventions in this high-risk population.

Children having cerebral palsy will incur life-long disabilities, which require high costs of medical and nursing care. This imposes a tremendous burden on the families of the affected children, whether financially or emotionally. It is understandable for the affected families to initiate court litigation in order to alleviate the financial burden and at the same time to overcome the emotional pain associated with the permanent and lifetime implications which cerebral palsy entails. However, suing for such injuries in court and identification of medical malpractice is not an easy task for the families. Further, court litigation tends to be tedious, lengthy and unpleasant. The hazards of litigation have prompted several countries to find an available alternative to court litigation, such as the implementation of a no-fault compensation system, to settle these types of claims. Thus, it is much applauded that the Japan Obstetric Compensation System for Cerebral Palsy was established in January 2009, with the aim of helping children with such disabilities to improve their quality of life and to provide monetary compensation in order to lessen the economic burden on the family. The system features two vital pillars; that is, compensation and causal analysis prevention. The system aims at improving the quality of maternity care and analyzing the causes of accidents in order to prevent similar cases from happening in the future. Overall, the system clearly depicts social solidarity in encouraging collective responsibility for the mishaps suffered by the community.

OBJECTIVES: Vitiligo commonly presents in children, with half of all cases developing before 20 years of age. Although studies have characterized differences between pediatric and adult vitiligo, little is known about vitiligo presenting in early childhood. The purpose of this study was to compare clinical features of early-onset (<3 years old) and later-onset (3-18 years old) childhood vitiligo. METHODS: This retrospective case series examined patients given a diagnosis of vitiligo in a pediatric dermatology practice at an academic medical center from 1990 to 2014. Characteristics of the early- and later-onset groups were compared by chi2 and t test for categorical and continuous variables, respectively. RESULTS: Of the 208 children in the study, 31 had early-onset and 177 had later-onset disease. Early-onset vitiligo was associated with higher percentages of body surface area involvement and increased rates of disease progression during an average 1.9 years of follow-up. There were no significant differences between the 2 groups in repigmentation, vitiligo type, halo nevi, gender ratio, or personal and family history of autoimmune diseases. LIMITATIONS: This was a retrospective, single-institution study. CONCLUSION: Patients given a diagnosis of vitiligo at younger ages tend to have more extensive and progressive disease.

BACKGROUND: Equilibrative nucleoside transporters (ENTs) facilitate the import of nucleosides and their analogs into cells in a bidirectional, non-concentrative manner. However, in contrast to their name, most characterized plant ENTs act in a concentrative manner. A direct characterization of any ENT protein has been hindered due to difficulties in overexpression and obtaining pure recombinant protein. METHODS: The equilibrative nucleoside transporter 7 from Arabidopsis thaliana (AtENT7) was expressed in Xenopus laevis oocytes to assess mechanism of substrate uptake. Recombinant protein fused to enhanced green fluorescent protein (eGFP) was expressed in Pichia pastoris to characterize its oligomeric state by gel filtration and substrate binding by microscale thermophoresis (MST). RESULTS: AtENT7 expressed in X. laevis oocytes works as a classic equilibrative transporter. The expression of AtENT7-eGFP in the P. pastoris system yielded milligram amounts of pure protein that exists as stable homodimers. The concentration dependent binding of purine and pyrimidine nucleosides to the purified recombinant protein, assessed by MST, confirmed that AtENT7-eGFP is properly folded. For the first time the binding of nucleobases was observed for AtENT7. SIGNIFICANCE: The availability of pure recombinant AtENT7 will permit detailed kinetic and structural studies of this unique member of the ENT family and, given the functional similarity to mammalian ENTs, will serve as a good model for understanding the structural basis of translocation mechanism for the family.

Sugars in the natural environment can be detected through taste-dependent and taste-independent modalities. Taste-dependent modalities consist mainly of peripheral chemosensory neurons such as sweet taste receptors, which primarily detect the orosensory value of sugar (i.e. sweetness). Evidence of a taste-independent modality - a post-ingestive sugar sensor - that detects the nutritional value of sugar has been shown in insects and mammals. However, the identity of the post-ingestive sugar sensor and the mechanism by which animals respond to the nutritional content of sugar independently of orosensory value is not currently understood. Here, we show that six neurosecretory cells in the Drosophila brain that produce Diuretic hormone 44 (Dh44), a homologue of the mammalian corticotropin- releasing hormone (CRH), were activated by nutritive sugars that are present in the hemolymph and not by nonnutritive sugars. Dh44 neuronal cell bodies are located primarily in the pars intercerebralis and extend their dendrites to the dorsal region of the subesophageal ganglion zone (SEZ), and project their axons along the esophagus to innervate the gut. Flies in which the activity of these neurons or the expression of the Dh44 gene was disrupted failed to select nutritive sugars over nonnutritive ones after periods of starvation. Manipulation of the function of Dh44 receptors had a similar effect. Notably, artificial activation of Dh44 receptor-1 neurons dramatically increased the rate of proboscis extension reflex (PER) responses, promoting food intake, and excretion. Conversely, reduced Dh44 activity led to decreased excretion. Together, we propose that the Dh44 system directs the detection, ingestion, and digestion of nutritive sugar through a positive feedback loop to continue consumption of nutritive sugar

Natural killer cells are regulated by killer cell immunoglobulin-like receptor (KIR) interactions with HLA class I ligands. Several models of natural killer cell reactivity have been associated with improved outcomes after myeloablative allogeneic hematopoietic cell transplantation (HCT), but this issue has not been rigorously addressed in reduced-intensity conditioning (RIC) unrelated donor (URD) HCT. We studied 909 patients undergoing RIC-URD HCT. Patients with acute myeloid leukemia (AML, n = 612) lacking ≥ 1 KIR ligands experienced higher grade III to IV acute graft-versus-host disease (GVHD) (HR, 1.6; 95% CI, 1.16 to 2.28; P = .005) compared to those with all ligands present. Absence of HLA-C2 for donor KIR2DL1 was associated with higher grade II to IV (HR, 1.4; P = .002) and III to IV acute GVHD (HR, 1.5; P = .01) compared with HLA-C2(+) patients. AML patients with KIR2DS1(+), HLA-C2 homozygous donors had greater treatment-related mortality compared with others (HR, 2.4; 95% CI, 1.4 to 4.2; P = .002) but did not experience lower relapse. There were no significant associations with outcomes for AML when assessing donor-activating KIRs or centromeric KIR content or for any donor-recipient KIR-HLA assessments in patients with myelodysplastic syndrome (n = 297). KIR-HLA combinations in RIC-URD HCT recapitulate some but not all KIR-HLA effects observed in myeloablative HCT.

BACKGROUND: We report a case with bilateral endogenous fungal subretinal abscesses. To our knowledge, this is the first report from Japan in which Scedosporium prolificans (S. prolificans) was cultured from intraocular tissue. CASE: A 74-year-old man, receiving chemotherapy for acute myeloid leukemia, complained of visual loss in both eyes. Best-corrected visual acuity was hand motion in the right and 2/200 in the left eye. His right eye showed exophthalmos, inflammation in the anterior chamber and iris neovascularization. Funduscopy revealed no details as there was vitreous opacity in the right eye, and irregular round yellowish-white subretinal lesions involving the macula in the left eye. Blood culture was negative, and C-reactive protein (CRP) and beta-D glucan titers were high. An antifungal drug and broad-spectrum antibiotics were initiated. Two days after the initial visit, right visual acuity had deteriorated to light perception. Enucleation of the right eye was performed for diagnosis and treatment. Fungi were cultured from the subretinal lesion, confirming a diagnosis of S. prolificans infection. After systemic administration and intravitreal injections of antifungal agents, the subretinal abscess in the left eye gradually diminished. At present, six months after the first visit, left visual acuity is 20/200. CONCLUSION: Although S. prolificans endophthalmitis can be intractable, this case suggests that repeated intravitreal antifungal agent injections can be effective.

Metabolomics is an emerging field that involves qualitative and quantitative measurements of small molecule metabolites in a biological system. These measurements can be useful for developing biomarkers for diagnosis, prognosis, or predicting response to therapy. Currently, a wide variety of metabolomics approaches, including nontargeted and targeted profiling, are used across laboratories on a routine basis. A diverse set of analytical platforms, such as NMR, gas chromatography-mass spectrometry, Orbitrap mass spectrometry, and time-of-flight-mass spectrometry, which use various chromatographic and ionization techniques, are used for resolution, detection, identification, and quantitation of metabolites from various biological matrices. However, few attempts have been made to standardize experimental methodologies or comparative analyses across different laboratories. The Metabolomics Research Group of the Association of Biomolecular Resource Facilities organized a "round-robin" experiment type of interlaboratory study, wherein human plasma samples were spiked with different amounts of metabolite standards in 2 groups of biologic samples (A and B). The goal was a study that resembles a typical metabolomics analysis. Here, we report our efforts and discuss challenges that create bottlenecks for the field. Finally, we discuss benchmarks that could be used by laboratories to compare their methodologies.