Faculty Bibliography

PURPOSE/OBJECTIVES: To assess the effects of high blood sugar at the levels of diabetic or prediabetic states during cancer treatment because patients undergoing chemotherapy (CTX) experience multiple symptoms that vary among individuals and may be affected by glucose levels. DESIGN: Descriptive, cross-sectional. SETTING: Two comprehensive cancer centers, one Veterans Affairs hospital, and four community-based oncology programs. SAMPLE: 244 outpatients with breast, gastrointestinal, gynecologic, and lung cancers. METHODS: Patients completed demographic and symptom questionnaires. Glycosylated hemoglobin A1c (HbA1c) was evaluated to determine diabetic state. Descriptive statistics and one-way analyses of variance were used in the analyses. MAIN RESEARCH VARIABLES: HbA1c, symptom severity scores, patient and clinical characteristics (e.g., age, gender, comorbidities, sociodemographic information, body mass index [BMI], lifestyle factors). FINDINGS: HbA1c results showed 9% of the sample in the diabetic and 26% in the prediabetic state. Patients in the diabetic state reported a higher number of comorbid conditions and were more likely to be African American. Patients in the prediabetic state were older aged. Patients in the diabetic and prediabetic states had a higher BMI compared to nondiabetic patients. No differences in symptom severity or quality-of-life (QOL) scores were found among the three diabetic states. CONCLUSIONS: This study is the first to evaluate for associations between diabetic states and symptom severity and QOL scores in patients receiving CTX. This study confirmed that older age, as well as having higher BMI and having multiple comorbidities, were associated with increased mean glycemic levels. IMPLICATIONS FOR NURSING: Clinicians should assess and identify patients with diabetes or prediabetes undergoing treatment for cancer. Patients who are older aged, those with a high BMI, and those with multiple comorbid conditions may be at increased risk for higher glycemic states.

RATIONALE: The touchscreen continuous trial-unique non-matching-to-location task (cTUNL) has been developed to optimise a battery of tasks under NEWMEDS (Novel Methods leading to New Medication in Depression and Schizophrenia, http://www.newmeds-europe.com ). It offers novel task features of both a practical and a theoretical nature compared to existing touchscreen tasks for spatial working memory. OBJECTIVES: The objective of this study was to determine whether the cTUNL task is sufficiently sensitive to differentiate between dentate gyrus (DG) and CA3 hippocampal subregion contributions to performance. METHODS: The effect of DG and CA3 dysfunction on memory for locations in the cTUNL task was tested. Rats were assessed on versions of the task-two-choice and three-choice-that differed in memory load. Performance was challenged using manipulations of delay and the spatial separation between target and sample locations. RESULTS: Dysfunction of the DG disrupts performance across both delay and spatial separations in two-choice cTUNL when the delay is variable and unpredictable. Increasing the working memory load (three stimuli) increases sensitivity to DG dysfunction, with deficits apparent at fixed, short delays. In contrast, CA3 dysfunction did not disrupt performance. CONCLUSION: Acquisition of cTUNL was rapid, and the task was sensitive to manipulations of delays and separations. A three-choice version of the task was found to be viable. Finally, both the two- and three-choice versions of the task were able to differentiate between limited dysfunction to different areas within the hippocampus. DG dysfunction affected performance when using unpredictable task parameters. CA3 dysfunction did not result in impairment, even at the longest delays tested.

RATIONALE: The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com ) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. OBJECTIVES: This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. METHODS: The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. RESULTS: The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. CONCLUSION: This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.

Objective: To assess group-differences in movement measures in published studies contrasting Attention-Deficit/Hyperactivity Disorder (ADHD) vs. controls. Background: ADHD diagnoses continue to be completely based on clinical history, which is subjective and subject to recall bias. In response, investigators have proposed incorporating objective measures such as locomotor activity which can be measured with actigraphy or with a high spatial and temporal resolution infrared camera. In May 2014, the United States Food and Drug Administration cleared an example of the latter, the Qb-Test, as a device to be used in supporting the diagnosis of ADHD. A review of the literature did not reveal any prior meta-analyses of such data. Methods: We performed a systematic review and meta-analysis of published studies on motion measures contrasting individuals diagnosed with ADHD and healthy controls. Two authors reviewed a total of 89 abstracts culled from an initial search of 356. After applying inclusion and exclusion criteria, 13 papers were included in our analyses of actigraphy and five papers in analyses of motion tracking systems. Results: The combined sample sizes were 406 patients with ADHD versus 359 controls with actigraphy data and 164 patients with ADHD versus 156 controls with motion tracking system data. Meta-analyses revealed medium effect sizes for actigraphy (standardized mean difference [SMD]: 0.64, 95 % CI: 0.43, 0.85) and large effects for motion tracking systems (SMD: 0.92, 95 % CI: 0.65, 1.20) in differentiating individuals with ADHD from controls. Conclusions: When measured objectively, locomotor hyperactivity robustly differentiates groups of patients with ADHD from healthy controls. Inclusion of objective locomotion measures is likely to be useful in circumstances in which ancillary information is not available, such as when evaluating adults with possible ADHD. However, even the relatively large effect sizes reported to date are unlikely to yield clinically actionable information for individual patients on their own. How to best incorporate such objective data in the diagnostic process remains unclear

BACKGROUND AND PURPOSE: The pituitary gland is located outside of the blood-brain barrier. Dynamic T1 weighted contrast enhanced sequence is considered to be the gold standard to evaluate this region. However, it does not allow assessment of intrinsic permeability properties of the gland. Our aim was to demonstrate the utility of radial volumetric interpolated brain examination with the golden-angle radial sparse parallel technique to evaluate permeability characteristics of the individual components (anterior and posterior gland and the median eminence) of the pituitary gland and areas of differential enhancement and to optimize the study acquisition time. MATERIALS AND METHODS: A retrospective study was performed in 52 patients (group 1, 25 patients with normal pituitary glands; and group 2, 27 patients with a known diagnosis of microadenoma). Radial volumetric interpolated brain examination sequences with golden-angle radial sparse parallel technique were evaluated with an ROI-based method to obtain signal-time curves and permeability measures of individual normal structures within the pituitary gland and areas of differential enhancement. Statistical analyses were performed to assess differences in the permeability parameters of these individual regions and optimize the study acquisition time. RESULTS: Signal-time curves from the posterior pituitary gland and median eminence demonstrated a faster wash-in and time of maximum enhancement with a lower peak of enhancement compared with the anterior pituitary gland (P < .005). Time-optimization analysis demonstrated that 120 seconds is ideal for dynamic pituitary gland evaluation. In the absence of a clinical history, differences in the signal-time curves allow easy distinction between a simple cyst and a microadenoma. CONCLUSIONS: This retrospective study confirms the ability of the golden-angle radial sparse parallel technique to evaluate the permeability characteristics of the pituitary gland and establishes 120 seconds as the ideal acquisition time for dynamic pituitary gland imaging.

Familial dysautonomia (FD) is a rare genetic disease with extremely labile blood pressure due to baroreflex deafferentation. Patients have marked surges in sympathetic activity, frequently surrounding meals. We conducted an observational study to document the autonomic responses to eating in patients with FD, and to determine whether sympathetic activation was caused by chewing, swallowing or stomach distension. Blood pressure and RR intervals were measured continuously while chewing gum (n = 15), eating (n = 20) and distending the stomach with a percutaneous endoscopic gastrostomy (PEG) tube feeding (n = 9). Responses were compared to those of normal controls (n = 10) and of patients with autonomic failure (n = 10) who have chronically impaired sympathetic outflow. In patients with FD, eating was associated with a marked, but transient pressor response (p<0.0001) and additional signs of sympathetic activation including tachycardia, diaphoresis and flushing of the skin. Chewing gum evoked a similar increase in blood pressure that was higher in patients with FD than in controls (p = 0.0001), but was absent in patients with autonomic failure. In patients with FD distending the stomach with a PEG tube feeding failed to elicit a pressor response. The results provide indirect evidence that chewing triggers sympathetic activation. The increase in blood pressure that is exaggerated in patients with FD due to blunted afferent baroreceptor signalling. The chewing pressor response may be useful as a counter-manoeuvre to raise blood pressure and prevent symptomatic orthostatic hypotension in patients with FD

The mediodorsal thalamic nucleus (MDT) is a higher order thalamic nucleus and its role in cognition is increasingly well established. Interestingly, components of the MDT also have a somewhat unique sensory function as they link primary olfactory cortex to orbitofrontal associative cortex. In fact, anatomical evidence firmly demonstrates that the MDT receives direct input from primary olfactory areas including the piriform cortex and has dense reciprocal connections with the orbitofrontal cortex. The functions of this olfactory pathway have been poorly explored but lesion, imaging, and electrophysiological studies suggest that these connections may be involved in olfactory processing including odor perception, discrimination, learning, and attention. However, many important questions regarding the MDT and olfaction remain unanswered. Our goal here is not only to briefly review the existing literature but also to highlight some of the remaining questions that need to be answered to better define the role(s) of the MDT in olfactory processing.

Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders. In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells. Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders.

Control of movement is a fundamental and complex task of the vertebrate nervous system, which relies on communication between circuits distributed throughout the brain and spinal cord. Many of the networks essential for the execution of basic locomotor behaviors are composed of discrete neuronal populations residing within the spinal cord. The organization and connectivity of these circuits is established through programs that generate functionally diverse neuronal subtypes, each contributing to a specific facet of motor output. Significant progress has been made in deciphering how neuronal subtypes are specified and in delineating the guidance and synaptic specificity determinants at the core of motor circuit assembly. Recent studies have shed light on the basic principles linking locomotor circuit connectivity with function, and they are beginning to reveal how more sophisticated motor behaviors are encoded. In this review, we discuss the impact of developmental programs in specifying motor behaviors governed by spinal circuits. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 31 is October 06, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.