In advanced retinal degeneration loss of rods and cones leaves melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) as the only source of visual information. ipRGCs ...drive non-image-forming responses (e.g., circadian photoentrainment) under such conditions but, despite projecting to the primary visual thalamus dorsal lateral geniculate nucleus (dLGN), do not support form vision. We wished to determine what precludes ipRGCs supporting spatial discrimination after photoreceptor loss, using a mouse model (rd/rd cl) lacking rods and cones. Using multielectrode arrays, we found that both RGCs and neurons in the dLGN of this animal have clearly delineated spatial receptive fields. In the retina, they are typically symmetrical, lack inhibitory surrounds, and have diameters in the range of 10-30° of visual space. Receptive fields in the dLGN were larger (diameters typically 30-70°) but matched the retinotopic map of the mouse dLGN. Injections of a neuroanatomical tracer (cholera toxin β-subunit) into the dLGN confirmed that retinotopic order of ganglion cell projections to the dLGN and thalamic projections to the cortex is at least superficially intact in rd/rd cl mice. However, as previously reported for deafferented ipRGCs, onset and offset of light responses have long latencies in the rd/rd cl retina and dLGN. Accordingly, dLGN neurons failed to track dynamic changes in light intensity in this animal. Our data reveal that ipRGCs can convey spatial information in advanced retinal degeneration and identify their poor temporal fidelity as the major limitation in their ability to provide information about spatial patterns under natural viewing conditions.
Light is an influential regulator of behavioural and physiological state in mammals. Features of cognitive performance such as memory, vigilance and alertness can be altered by bright light exposure ...under laboratory and field conditions. However, the importance of light as a regulator of performance in everyday life is hard to assess and has so far remained largely unclear. We set out to address this uncertainty by developing a tool to capture measures of cognitive performance and light exposure, at scale, and during everyday life. To this end, we generated an app (Brighter Time) which incorporated a psychomotor vigilance (PVT), an N-back and a visual search task with questionnaire-based assessments of demographic characteristics, general health, chronotype and sleep. The app also measured illuminance during task completion using the smartphone’s intrinsic light meter. We undertook a pilot feasibility study of Brighter Time based on 91-week-long acquisition phases within a convenience sample (recruited by local advertisements and word of mouth) running Brighter Time on their own smartphones over two study phases in winter and summer. Study compliance was suitable (median = 20/21 requested task completions per subject). Statistically significant associations were observed between subjective sleepiness and performance in all tasks. Significant daily variations in PVT and visual search performance were also observed. Higher illuminance was associated with reduced reaction time and lower inverse efficiency score in the visual search. Brighter Time thus represents a viable option for large-scale collection of cognitive task data in everyday life, and is able to reveal associations between task performance and sleepiness, time of day and current illuminance. Brighter Time’s utility could be extended to exploring associations with longer-term patterns of light exposure and/or other light metrics by integrating with wearable light meters.
Preclinical studies have demonstrated that repeated methamphetamine (METH) injections (referred to herein as a "binge" treatment) cause persistent dopaminergic deficits. A few studies have also ...examined the persistent neurochemical impact of METH self-administration in rats, but with variable results. These latter studies are important because: 1) they have relevance to the study of METH abuse; and 2) the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure. Accordingly, the present study investigated the impact of METH self-administration on dopaminergic neuronal function. Results revealed that self-administration of METH, given according to a regimen that produces brain METH levels comparable with those reported postmortem in human METH abusers (0.06 mg/infusion; 8-h sessions for 7 days), decreased striatal dopamine transporter (DAT) uptake and/or immunoreactivity as assessed 8 or 30 days after the last self-administration session. Increasing the METH dose per infusion did not exacerbate these deficits. These deficits were similar in magnitude to decreases in DAT densities reported in imaging studies of abstinent METH abusers. It is noteworthy that METH self-administration mitigated the persistent deficits in dopaminergic neuronal function, as well as the increases in glial fibrillary acidic protein immunoreactivity, caused by a subsequent binge METH exposure. This protection was independent of alterations in METH pharmacokinetics, but may have been attributable (at least in part) to a pretreatment-induced attenuation of binge-induced hyperthermia. Taken together, these results may provide insight into the neurochemical deficits reported in human METH abusers.
A subpopulation of olivary pretectal nucleus (OPN) neurons discharges action potentials in an oscillatory manner, with a period of approximately two minutes. This ‘infra‐slow’ oscillatory activity ...depends on synaptic excitation originating in the retina. Signals from rod‐cone photoreceptors reach the OPN via the axons of either classic retinal ganglion cells or intrinsically photosensitive retinal ganglion cells (ipRGCs), which use melanopsin for photon capturing. Although both cell types convey light information, their physiological functions differ considerably. The aim of the present study was to disentangle how rod‐cone and melanopsin photoresponses contribute to generation of oscillatory activity. Pharmacological manipulations of specific phototransduction cascades were used whilst recording extracellular single‐unit activity in the OPN of anaesthetized rats. The results show that under photopic conditions (bright light), ipRGCs play a major role in driving infra‐slow oscillations, as blocking melanopsin phototransmission abolishes or transiently disturbs oscillatory firing of the OPN neurons. On the other hand, blocking rod‐cone phototransmission does not change firing patterns in photopic conditions. However, under mesopic conditions (moderate light), when melanopsin phototransmission is absent, blocking rod‐cone signalling causes disturbances or even the disappearance of oscillations implying that classic photoreceptors are of greater importance under moderate light. Evidence is provided that all photoreceptors are required for the generation of oscillations in the OPN, although their roles in driving the rhythm are determined by the lighting conditions, consistent with their relative sensitivities. The results further suggest that maintained retinal activity is crucial to observe infra‐slow oscillatory activity in the OPN.
A subpopulation of olivary pretectal nucleus (OPN) neurons discharges action potentials in an oscillatory manner, with a period of approximately two minutes. This ‘infra‐slow’ oscillatory activity depends on synaptic excitation originating in the retina. The aim of the present study was to disentangle how rod‐cone and melanopsin photoresponses contribute to generation of oscillatory activity. Our results show that under photopic conditions (bright light) ipRGCs play a major role in driving infra‐slow oscillations, since blocking melanopsin phototransmission abolishes or transiently disturbs oscillatory firing of the OPN neurons. Under mesopic conditions (moderate light), when melanopsin phototransmission is absent, blocking rod‐cone signalling causes disturbances or even the disappearance of oscillations implying that classic photoreceptors are of greater importance under moderate light. We provide evidence that all photoreceptors are required for the generation of oscillations in the OPN, although their roles in driving the rhythm are determined by the lighting conditions.
Colorectal cancer (CRC) is the second leading cause of cancer death among cancers affecting both men and women in the United States. The Centers for Disease Control and Prevention's Colorectal Cancer ...Control Program (CRCCP) supports both direct clinical screening services (screening provision) and activities to promote screening at the population level (screening promotion).
The purpose of this study was to characterize patient navigation (PN) programs for screening provision and promotion for the first 1 to 2 years of program funding.
We conducted a cross-sectional survey of the 29 CRCCP grantees (25 states and 4 tribal organizations) and 14 in-depth interviews to assess program implementation.
The survey and interview guide collected information on CRC screening provision and promotion activities and PN, including the structure of the PN program, characteristics of the navigators, funding mechanism, and navigators' activities.
Twenty-four of 28 CRCCP grantees of the survey used PN for screening provision whereas 18 grantees used navigation for screening promotion. Navigators were often trained in nursing or public health. Navigation activities were similar for both screening provision and promotion, and common tasks included assessing and responding to patient barriers to screening, providing patient education, and scheduling appointments. For screening provision, activities centered on making reminder calls, educating patients on bowel preparation for colonoscopies, and tracking patients for completion of the tests. Navigation may influence screening quality by improving patients' bowel preparation for colonoscopies.
Our study provides insights into PN across a federally funded CRC program. Results suggest that PN activities may be instrumental in recruiting people into cancer screening and ensuring completed screening and follow-up.
Background This paper identifies and describes measures of constructs relevant to the adoption or implementation of innovations (i.e., new policies, programs or practices) at the ...organizational-level. This work is intended to advance the field of dissemination and implementation research by aiding scientists in the identification of existing measures and highlighting methodological issues that require additional attention. Methods We searched for published studies (1973-2013) in 11 bibliographic databases for quantitative, empirical studies that presented outcome data related to adoption and/or implementation of an innovation. Included studies had to assess latent constructs related to the "inner setting" of the organization, as defined by the Consolidated Framework for Implementation Research. Results Of the 76 studies included, most (86%) were cross sectional and nearly half (49%) were conducted in health care settings. Nearly half (46%) involved implementation of evidence-based or "best practice" strategies; roughly a quarter (26%) examined use of new technologies. Primary outcomes most often assessed were innovation implementation (57%) and adoption (34%); while 4% of included studies assessed both outcomes. There was wide variability in conceptual and operational definitions of organizational constructs. The two most frequently assessed constructs included "organizational climate" and "readiness for implementation." More than half (55%) of the studies did not articulate an organizational theory or conceptual framework guiding the inquiry; about a third (34%) referenced Diffusion of Innovations theory. Overall, only 46% of articles reported psychometric properties of measures assessing latent organizational characteristics. Of these, 94% (33/35) described reliability and 71% (25/35) reported on validity. Conclusions The lack of clarity associated with construct definitions, inconsistent use of theory, absence of standardized reporting criteria for implementation research, and the fact that few measures have demonstrated reliability or validity were among the limitations highlighted in our review. Given these findings, we recommend that increased attention be devoted toward the development or refinement of measures using common psychometric standards. In addition, there is a need for measure development and testing across diverse settings, among diverse population samples, and for a variety of types of innovations. Keywords: Systematic review, Organizational characteristics, Measures, Innovation, Adoption and implementation, Innovations, Consolidated framework for implementation research
► Light drives sustained and transient responses throughout the LGN of mice with disrupted cone phototransduction and lacking Cx36 ► Both On and Off responses are retained in this animal ► ...Cx36-independent rod pathways can support diverse visual responses in the mouse thalamus.
Emerging evidence indicates rods can communicate with retinal ganglion cells (RGCs) via pathways that do not involve gap-junctions. Here we investigated the significance of such pathways for central visual responses, using mice lacking a key gap junction protein (
Cx36
−/−) and carrying a mutation that disrupts cone phototransduction (
Gnat2
cpfl3
). Electrophysiological recordings spanning the lateral geniculate revealed rod-mediated ON and OFF visual responses in virtually every cell from all major anatomical sub-compartments of this nucleus. Hence, we demonstrate that one or more classes of RGC receive input from Cx36-independent rod pathways and drive extensive ON and OFF responses across the visual thalamus.
In the failing human heart myofibrillar calcium sensitivity of tension development is greater and maximal myofibrillar ATPase activity is less than in the normal heart. Phosphorylation of the cardiac ...troponin I (cTnI)-specific NH2-terminus decreases myofilament sensitivity to calcium, while phosphorylation of other cTnI sites decreases maximal myofibrillar ATPase activity.
We examined cTnI phosphorylation in left ventricular myocardium collected from failing hearts at the time of transplant (n=20) and normal hearts from trauma victims (n=24). The relative amounts of actin, tropomyosin, and TnI did not differ between failing and normal myocardium. Using Western blot analysis with a monoclonal antibody (MAb) that recognizes the striated muscle TnI isoforms, we confirmed that the adult human heart expresses only cTnI. A cTnI-specific MAb recognized two bands of cTnI, designated cTnI1 and cTnI2, while a MAb whose epitope is located in the cTnI-specific NH2-terminus recognized only cTnI1. Alkaline phosphatase decreased the relative amount of cTnl1, while protein kinase A and protein kinase C increased cTnI1. The percentage of cTnI made up of cTnI1, the phosphorylated form of TnI, is greater in the normal than the failing human heart (P<.00).
This phosphorylation difference could underlie the reported greater myofibrillar calcium sensitivity of failing myocardium. The functional consequence of this difference may be an adaptive or maladaptive response to the lower and longer calcium concentration transient of the failing heart, eg, enhancing force development or producing ventricular diastolic dysfunction.
Abstract Background Pre-clinical studies indicate that high-dose, non-contingent methamphetamine (METH) administration both rapidly and persistently decreases serotonergic neuronal function. Despite ...research indicating the hippocampus plays an important role in METH abuse and is affected by METH use, effects of METH self-administration on hippocampal serotonergic neurons are not well understood, and were thus an important focus of the current study. Because humans often administer METH in a binge-like pattern, effects of prior METH self-administration on a subsequent “binge-like” METH treatment were also examined. Methods Rats were treated as described above, and sacrificed 1 or 8 d after self-administration or 1 h or 7 d after the final binge METH or saline exposure. Hippocampal serotonin (5-hydroxytryptamine; 5HT) content and transporter (SERT) function were assessed. Results METH self-administration per se had no persistent effect on hippocampal 5HT content or SERT function. However, this treatment attenuated the persistent, but not acute, hippocampal serotonergic deficits caused by a subsequent repeated, high-dose, non-continent METH treatment administered 1 d the last self-administration session. No attenuation in persistent deficits were seen when the high-dose administration of METH occurred 15 d after the last self-administration session. Conclusions The present findings demonstrate that METH self-administration alters serotonergic neurons so as to engender “tolerance” to the persistent serotonergic deficits caused by a subsequent METH exposure. However, this “tolerance” does not persist. These data provide a foundation to investigate complex questions including how the response of serotonergic neurons to METH may contribute to contingent-related disorders such as dependence and relapse.
PDF
