NIH electronic cigarette workshop: developing a research agenda.

BACKGROUND: Electronic cigarettes (e-cigarettes) represent an emerging public health issue. These devices deliver nicotine along with other constituents, including flavorants, via an inhalable aerosol. Their uptake is rapidly increasing in both adults and youths, primarily among current smokers. Public debate is increasing on how these devices should be regulated and used, yet only limited peer-reviewed research exists. To develop a informed policy for e-cigarettes, their effects on human behavior, physiology, and health need to be understood. PURPOSE: This paper describes proceedings from a National Institutes of Health-sponsored workshop, which was held in November 2013, to identify research needs related to the effects of e-cigarettes. Discussion topics included e-cigarette risks and abuse potential; the potential role for e-cigarettes in harm reduction and smoking cessation; unintended consequences of e-cigarette use, such as becoming a gateway to conventional cigarettes; and dual use of both e-cigarettes and conventional cigarettes. RESULTS AND CONCLUSIONS: The research needs identified by the workshop participants included the following: standards to measure the contents and emissions of e-cigarettes; biomarkers of exposure; physiological effects of e-cigarettes on tissues and organ systems, including pulmonary and cardiovascular; information on e-cigarette users, how the devices are used, and identification of the best tools to assess these measures; factors that drive use and influence patterns of use; and appropriate methods for evaluating a potential role for e-cigarettes in smoking or nicotine cessation. To understand fully the challenges and the opportunities that e-cigarettes represent, expertise will be needed in basic, behavioral, translational, and clinical sciences.

2011 investigation of internal contamination with radioactive strontium following rubidium Rb 82 cardiac PET scan.

During routine screening in 2011, US Customs and Border Protection (CBP) identified 2 persons with elevated radioactivity. CBP, in collaboration with Los Alamos National Laboratory, informed the Food and Drug Administration (FDA) that these people could have increased radiation exposure as a result of undergoing cardiac Positron Emission Tomography (PET) scans several months earlier with rubidium Rb 82 chloride injection from CardioGen-82. We conducted a multistate investigation to assess the potential extent and magnitude of radioactive strontium overexposure among patients who had undergone Rb 82 PET scans. We selected a convenience sample of clinical sites in 4 states and reviewed records to identify eligible study participants, defined as people who had had an Rb 82 PET scan between February and July 2011. All participants received direct radiation screening using a radioisotope identifier able to detect the gamma energy specific for strontium-85 (514 keV) and urine bioassay for excreted radioactive strontium. We referred a subset of participants with direct radiation screening counts above background readings for whole body counting (WBC) using a rank ordering of direct radiation screening. The rank order list, from highest to lowest, was used to contact and offer voluntary enrollment for WBC. Of 308 participants, 292 (95%) had direct radiation screening results indistinguishable from background radiation measurements; 261 of 265 (98%) participants with sufficient urine for analysis had radioactive strontium results below minimum detectable activity. None of the 23 participants who underwent WBC demonstrated elevated strontium activity above levels associated with routine use of the rubidium Rb 82 generator. Among investigation participants, we did not identify evidence of strontium internal contamination above permissible levels. This investigation might serve as a model for future investigations of radioactive internal contamination incidents.

A population model of chaparral vegetation response to frequent wildfires.

The recent increase in wildfire frequency in the Santa Monica Mountains (SMM) may substantially impact plant community structure. Species of Chaparral shrubs represent the dominant vegetation type in the SMM. These species can be divided into three life history types according to their response to wildfires. Nonsprouting species are completely killed by fire and reproduce by seeds that germinate in response to a fire cue, obligate sprouting species survive by resprouting from dormant buds in a root crown because their seeds are destroyed by fire, and facultative sprouting species recover after fire both by seeds and resprouts. Based on these assumptions, we developed a set of nonlinear difference equations to model each life history type. These models can be used to predict species survivorship under varying fire return intervals. For example, frequent fires can lead to localized extinction of nonsprouting species such as Ceanothus megacarpus while several facultative sprouting species such as Ceanothus spinosus and Malosma (Rhus) laurina will persist as documented by a longitudinal study in a biological preserve in the SMM. We estimated appropriate parameter values for several chaparral species using 25 years of data and explored parameter relationships that lead to equilibrium populations. We conclude by looking at the survival strategies of these three species of chaparral shrubs under varying fire return intervals and predict changes in plant community structure under fire intervals of short return. In particular, our model predicts that an average fire return interval of greater than 12 years is required for 50 % of the initial Ceanothus megacarpus population and 25 % of the initial Ceanothus spinosus population to survive. In contrast, we predict that the Malosma laurina population will have 90 % survivorship for an average fire return interval of at least 6 years.

Operant self-stimulation of dopamine neurons in the substantia nigra.

We examined the contribution of the nigrostriatal DA system to instrumental learning and behavior using optogenetics in awake, behaving mice. Using Cre-inducible channelrhodopsin-2 (ChR2) in mice expressing Cre recombinase driven by the tyrosine hydroxylase promoter (Th-Cre), we tested whether selective stimulation of DA neurons in the substantia nigra pars compacta (SNC), in the absence of any natural rewards, was sufficient to promote instrumental learning in naive mice. Mice expressing ChR2 in SNC DA neurons readily learned to press a lever to receive laser stimulation, but unlike natural food rewards the lever pressing did not decline with satiation. When the number of presses required to receive a stimulation was altered, mice adjusted their rate of pressing accordingly, suggesting that the rate of stimulation was a controlled variable. Moreover, extinction, i.e. the cessation of action-contingent stimulation, and the complete reversal of the relationship between action and outcome by the imposition of an omission contingency, rapidly abolished lever pressing. Together these results suggest that selective activation of SNC DA neurons can be sufficient for acquisition and maintenance of a new instrumental action.

Efficacy considerations for U.S. Food and Drug Administration approval of diagnostic radiopharmaceuticals.

The safety and efficacy expectations for U.S. Food and Drug Administration (FDA) approval of diagnostic radiopharmaceuticals (DRs) are described in laws that broadly apply to all prescription drugs and biologic products. These laws also outline efficacy expectations that are unique for DRs. The FDA regulations and guidance documents elaborate on DR efficacy expectations for clinical uses of the drugs, such as the delineation of anatomy, the characterization of a physiologic process, or the diagnosis of disease. As described in the FDA regulations, the approval of a DR necessitates that the imaging drug has the ability to provide clinically useful information. Here we cite approved DRs to illustrate how the imaging performance of the drugs was characterized in clinical studies and the clinical usefulness of the imaging information described in drug labels.

Nephrogenic systemic fibrosis and class labeling of gadolinium-based contrast agents by the Food and Drug Administration.

In 2007, the Food and Drug Administration requested that manufacturers of all approved gadolinium-based contrast agents (GBCAs), drugs widely used in magnetic resonance imaging, use nearly identical text in their product labeling to describe the risk of nephrogenic systemic fibrosis (NSF). Accumulating information about NSF risks led to revision of the labeling text for all of these drugs in 2010. The present report summarizes the basis and purpose of this class-labeling approach and describes some of the related challenges, given the evolutionary nature of the NSF risk evidence. The class-labeling approach for presentation of product risk is designed to decrease the occurrence of NSF and to enhance the safe use of GBCAs in radiologic practice.

A fast, effective filtering method for improving clinical pulsed arterial spin labeling MRI.

PURPOSE: To evaluate the effectiveness of a fully automated postprocessing filter algorithm in pulsed arterial spin labeling (PASL) MRI perfusion images in a large clinical population. MATERIALS AND METHODS: A mean and standard deviation-based filter was implemented to remove outliers in the set of perfusion-weighted images (control - label) before being averaged and scaled to quantitative cerebral blood flow (CBF) maps. Filtered and unfiltered CBF maps from 200 randomly selected clinical cases were assessed by four blinded raters to evaluate the effectiveness of the filter. RESULTS: The filter salvaged many studies deemed uninterpretable as a result of motion artifacts, transient gradient, and/or radiofrequency instabilities, and unexpected disruption of data acquisition by the technologist to communicate with the patient. The filtered CBF maps contained significantly (P < 0.05) fewer artifacts and were more interpretable than unfiltered CBF maps as determined by one-tail paired t-test. CONCLUSION: Variations in MR perfusion signal related to patient motion, system instability, or disruption of the steady state can introduce artifacts in the CBF maps that can be significantly reduced by postprocessing filtering. Diagnostic quality of the clinical perfusion images can be improved by performing selective averaging without a significant loss in perfusion signal-to-noise ratio.

The effect of daily caffeine use on cerebral blood flow: How much caffeine can we tolerate?

Caffeine is a commonly used neurostimulant that also produces cerebral vasoconstriction by antagonizing adenosine receptors. Chronic caffeine use results in an adaptation of the vascular adenosine receptor system presumably to compensate for the vasoconstrictive effects of caffeine. We investigated the effects of caffeine on cerebral blood flow (CBF) in increasing levels of chronic caffeine use. Low (mean = 45 mg/day), moderate (mean = 405 mg/day), and high (mean = 950 mg/day) caffeine users underwent quantitative perfusion magnetic resonance imaging on four separate occasions: twice in a caffeine abstinent state (abstained state) and twice in a caffeinated state following their normal caffeine use (native state). In each state, there were two drug conditions: participants received either caffeine (250 mg) or placebo. Gray matter CBF was tested with repeated-measures analysis of variance using caffeine use as a between-subjects factor, and correlational analyses were conducted between CBF and caffeine use. Caffeine reduced CBF by an average of 27% across both caffeine states. In the abstained placebo condition, moderate and high users had similarly greater CBF than low users; but in the native placebo condition, the high users had a trend towards less CBF than the low and moderate users. Our results suggest a limited ability of the cerebrovascular adenosine system to compensate for high amounts of daily caffeine use.

Methodological considerations for the quantification of self-reported caffeine use.

RATIONALE: The field of research regarding the effects of habitual caffeine use is immense and frequently utilizes self-report measures of caffeine use. However, various self-report measures have different methodologies, and the accuracy of these different methods has not been compared. MATERIALS AND METHODS: Self-reported caffeine use was estimated from two methods (a retrospective interview of weekly caffeine use and a 7-day prospective diary; n = 79). These estimates were then tested against salivary caffeine concentrations in a subset of participants (n = 55). RESULTS: The estimates of caffeine use (mg/day) from the interview- and diary-based methods correlated with one another (r = 0.77) and with salivary caffeine concentrations (r = 0.61 and 0.68, respectively). However, almost half of the subjects who reported more than 600 mg/day in the interview reported significantly less caffeine use in the diary. CONCLUSIONS: Self-report measures of caffeine use are a valid method of predicting actual caffeine levels. Estimates of high caffeine use levels may need to be corroborated by more than one method.

The impact of temporal regularization on estimates of the BOLD hemodynamic response function: a comparative analysis.

In fMRI data analysis it has been shown that for a wide range of situations the hemodynamic response function (HRF) can be reasonably characterized as the impulse response function of a linear and time invariant system. An accurate and robust extraction of the HRF is essential to infer quantitative information about the relative timing of the neuronal events in different brain regions. When no assumptions are made about the HRF shape, it is most commonly estimated using time windowed averaging or a least squares estimated general linear model based on either Fourier or delta basis functions. Recently, regularization methods have been employed to increase the estimation efficiency of the HRF; typically these methods produce more accurate HRF estimates than the least squares approach [Goutte, C., Nielsen, F.A., Hansen, L.K., 2000. Modeling the Haemodynamic Response in fMRI Using Smooth FIR Filters. IEEE Trans. Med. Imag. 19(12), 1188-1201.]. Here, we use simulations to clarify the relative merit of temporal regularization based methods compared to the least squares methods with respect to the accuracy of estimating certain characteristics of the HRF such as time to peak (TTP), height (HR) and width (W) of the response. We implemented a Bayesian approach proposed by Marrelec et al. [Marrelec, G., Benali, H., Ciuciu, P., Pelegrini-Issac, M., Poline, J.-B., 2003. Robust Estimation of the Hemodynamic Response Function in Event-Related BOLD fMRI Using Basic Physiological Information. Hum. Brain Mapp. 19, 1-17., Marrelec, G., Benali, H., Ciuciu, P., Poline, J.B. Bayesian estimation of the hemodynamic of the hemodynamic response function in functional MRI. In: R. F, editor; 2001; Melville. p 229-247.] and its deterministic counterpart based on a combination of Tikhonov regularization [Tikhonov, A.N., Arsenin, V.Y., 1977. Solution of ill-posed problems. Washington DC: W.H. Winston.] and generalized cross-validation (GCV) [Wahba, G., 1990. Spline Models for Observational Data. Philadelphia: SIAM.] for selecting the regularization parameter. The performance of both methods is compared with least square estimates as a function of temporal resolution, color and strength of the noise, and the type of stimulus sequences used. In almost all situations, under the considered assumptions (e.g. linearity, time invariance and smooth HRF), the regularization-based techniques more accurately characterize the HRF compared to the least-squares method. Our results clarify the effects of temporal resolution, noise color, and experimental design on the accuracy of HRF estimation.

Hemosuccus Pancreaticus as a Rare Complication of Bariatric Surgery.

Hemosuccus pancreaticus is a rare cause of gastrointestinal bleeding from the duct of Wirsung into the duodenum via the ampulla of Vater. Hemosuccus pancreaticus is difficult to diagnose because the bleeding is usually intermittent, and the clinical findings are often discordant. Patients present with pain, either left upper quadrant or epigastric, and bleeding, which may present as melena, bright red blood per rectum, or even shock, if the hemorrhage is severe. Hemosuccus pancreaticus is usually caused by rupture of a pseudoaneurysm of a peri-pancreatic artery, often the splenic artery, in the setting of pancreatitis; other causes are very rare. In this report, for the first time to our knowledge, we present a case of hemosuccus pancreaticus that occurred as a complication of bariatric surgery.

The roles of two C. elegans HOX co-factor orthologs in cell migration and vulva development.

Anteroposterior cell migration and patterning in C. elegans are governed by multiple, interacting signaling pathways and transcription factors. In this study, we have investigated the role of ceh-20, the C. elegans ortholog of the HOX co-factor Extradenticle (Exd/Pbx), and unc-62, the C. elegans ortholog of Homothorax (Hth/Meis/Prep), in two processes that are regulated by Hox gene lin-39: cell migration and vulva formation. As in lin-39 mutants, the anterior migrations of neuroblasts in the Q lineage are truncated in Hox co-factor mutants. Surprisingly, though, our findings suggested that the roles of ceh-20 and unc-62 are different from that of lin-39; specifically, ceh-20 and unc-62 but not lin-39 are required for the transmembrane protein MIG-13 to promote anterior migration. To our knowledge, ceh-20 and unc-62 are the only genes that have been implicated in the mig-13 pathway. We find that ceh-20 and unc-62 are also required for several steps in vulva development. Surprisingly, ceh-20 and unc-62 mutants have phenotypes that are starkly different from those of lin-39 mutants. Thus, in this process, too, ceh-20 and unc-62 are likely to have functions that are independent of lin-39.