Genetic and Psychosocial Risk Factors Associated with Suicide Among Community Veterans: Implications for Screening, Treatment and Precision Medicine.

INTRODUCTION: Since veteran suicide is a concern and our knowledge of predictive factors is still limited, our objective was to assess risk factors for suicide, including genetic factors, among deployed veterans. METHODS: For this study, we surveyed 1730 veterans who were outpatients in a multi-hospital system in Pennsylvania. Altogether, 1041 veterans (60%) provided a DNA sample. The genetic risk variants investigated were within loci previously associated with PTSD and substance misuse, including CRHR1, CHRNA5, RORA, and FKBP5 genetic variations, which were used to calculate a polygenic risk score (range=0-8, mean=3.6, SD=1.4). RESULTS: Most veterans (56.2%) were deployed to Vietnam while significant numbers were deployed to Iraq, Afghanistan, and other post-Vietnam conflicts. Overall, 95.1% of the veterans were male, their mean age was 56.2 (SD=12), and 95.6% were Caucasian. Among the veterans, 24% had high combat exposure. The prevalence of lifetime suicidal thoughts was 11.3%. Additionally, 5.7% ever developed a suicide plan or attempted suicide in their lifetimes. Among those with a history of a lifetime suicide attempt or suicide plan, the PTSD genetic risk score was significantly higher (OR=3.96 vs 3.55, p=0.033), but for suicidal thoughts, this association was not significant (p=0.717). In multivariable analysis (MVA) logistic regression, significant predictors of attempting suicide or having a suicide plan were history of depression (OR=5.04, p<0.001), PTSD genetic risk score (OR=1.25, p=0.036), history of childhood abuse/neglect (OR=2.24, p=0.009), and lifetime marijuana use (OR= 1.56, p=0.020). Conversely, rural residence was protective for suicide risk (OR=0.49; p=0.031). For suicidal thoughts, in the MVA genetic risk score was not significant (p=0.697), but history of child abuse/neglect (p<0.001), history of depression (p>0.001), low psychological resilience (p=0.004), and lifetime marijuana use (p=0.022) were significant. DISCUSSION: In this study, we identified genetic risk variants and other predictors for suicide among veterans that may have implications for future screening and clinical care. Further research is advised.

Evidence for Subcortical Plasticity after Paired Stimulation from a Wearable Device.

Existing non-invasive stimulation protocols can generate plasticity in the motor cortex and its corticospinal projections; techniques for inducing plasticity in subcortical circuits and alternative descending pathways such as the reticulospinal tract (RST) are less well developed. One possible approach developed by this laboratory pairs electrical muscle stimulation with auditory clicks, using a wearable device to deliver stimuli during normal daily activities. In this study, we applied a variety of electrophysiological assessments to male and female healthy human volunteers during a morning and evening laboratory visit. In the intervening time (∼6 h), subjects wore the stimulation device, receiving three different protocols, in which clicks and stimulation of the biceps muscle were paired at either low or high rate, or delivered at random. Paired stimulation: (1) increased the extent of reaction time shortening by a loud sound (the StartReact effect); (2) decreased the suppression of responses to transcranial magnetic brain stimulation (TMS) following a loud sound; (3) enhanced muscle responses elicited by a TMS coil oriented to induce anterior-posterior (AP) current, but not posterior-anterior (PA) current, in the brain. These measurements have all been suggested to be sensitive to subcortical, possibly reticulospinal, activity. Changes were similar for either of the two paired stimulus rates tested, but absent after unpaired (control) stimulation. Taken together, these results suggest that pairing clicks and muscle stimulation for long periods does indeed induce plasticity in subcortical systems such as the RST.SIGNIFICANCE STATEMENT Subcortical systems such as the reticulospinal tract (RST) are important motor pathways, which can make a significant contribution to functional recovery after cortical damage such as stroke. Here, we measure changes produced after a novel non-invasive stimulation protocol, which uses a wearable device to stimulate for extended periods. We observed changes in electrophysiological measurements consistent with the induction of subcortical plasticity. This protocol may prove an important tool for enhancing motor rehabilitation, in situations where insufficient cortical tissue survives to be a plausible substrate for recovery of function.

A Novel Wearable Device for Motor Recovery of Hand Function in Chronic Stroke Survivors.

Background. In monkey, reticulospinal connections to hand and forearm muscles are spontaneously strengthened following corticospinal lesions, likely contributing to recovery of function. In healthy humans, pairing auditory clicks with electrical stimulation of a muscle induces plastic changes in motor pathways (probably including the reticulospinal tract), with features reminiscent of spike-timing dependent plasticity. In this study, we tested whether pairing clicks with muscle stimulation could improve hand function in chronic stroke survivors. Methods. Clicks were delivered via a miniature earpiece; transcutaneous electrical stimuli at motor threshold targeted forearm extensor muscles. A wearable electronic device (WD) allowed patients to receive stimulation at home while performing normal daily activities. A total of 95 patients >6 months poststroke were randomized to 3 groups: WD with shock paired 12 ms before click; WD with clicks and shocks delivered independently; standard care. Those allocated to the device used it for at least 4 h/d, every day for 4 weeks. Upper-limb function was assessed at baseline and weeks 2, 4, and 8 using the Action Research Arm Test (ARAT), which has 4 subdomains (Grasp, Grip, Pinch, and Gross). Results. Severity across the 3 groups was comparable at baseline. Only the paired stimulation group showed significant improvement in total ARAT (median baseline: 7.5; week 8: 11.5; P = .019) and the Grasp subscore (median baseline: 1; week 8: 4; P = .004). Conclusion. A wearable device delivering paired clicks and shocks over 4 weeks can produce a small but significant improvement in upper-limb function in stroke survivors.

Multimodal stimuli modulate rapid visual responses during reaching.

The reticulospinal tract plays an important role in primate upper limb function, but methods for assessing its activity are limited. One promising approach is to measure rapid visual responses (RVRs) in arm muscle activity during a visually cued reaching task; these may arise from a tecto-reticulospinal pathway. We investigated whether changes in reticulospinal excitability can be assessed noninvasively using RVRs, by pairing the visual stimuli of the reaching task with electrical stimulation of the median nerve, galvanic vestibular stimulation, or loud sounds, all of which are known to activate the reticular formation. Surface electromyogram (EMG) recordings were made from the right deltoid of healthy human subjects as they performed fast reaching movements toward visual targets. Stimuli were delivered up to 200 ms before target appearance, and RVR was quantified as the EMG amplitude in a window 75-125 ms after visual target onset. Median nerve, vestibular, and auditory stimuli all consistently facilitated the RVRs, as well as reducing the latency of responses. We propose that this facilitation reflects modulation of tecto-reticulospinal excitability, which is consistent with the idea that the amplitude of RVRs can be used to assess changes in brain stem excitability noninvasively in humans.NEW & NOTEWORTHY Short-latency responses in arm muscles evoked during a visually driven reaching task have previously been proposed to be tecto-reticulospinal in origin. We demonstrate that these responses can be facilitated by pairing the appearance of a visual target with stimuli that activate the reticular formation: median nerve, vestibular, and auditory stimuli. We propose that this reflects noninvasive measurement and modulation of reticulospinal excitability.

Filtration of Short-Wavelength Light Provides Therapeutic Benefit in Retinitis Pigmentosa Caused by a Common Rhodopsin Mutation.

Purpose: The role of light exposure in accelerating retinitis pigmentosa (RP) remains controversial. Faster degeneration has however been observed in the inferior than superior retina in several forms ("sector" RP), including those caused by the rhodopsin P23H mutation, suggesting a modifying role of incident light exposure in such cases. Rearing of equivalent animal models in complete darkness has been shown to slow the degeneration. Here we investigate the use of red filters as a potential treatment strategy, with the hypothesis that minimizing retinal exposure to light <600 nm to which rods are maximally sensitive may provide therapeutic benefit. Methods: Knockin mice heterozygous for the P23H dominant rhodopsin mutation (RhoP23H/+) housed in red-tinted plastic cages were divided at weaning into either untinted or red-tinted cages. Subsequently, photoreceptor layer (PRL) thickness was measured by spectral-domain ocular coherence tomography, retinal function quantified by ERG, and cone morphology determined by immunohistochemical analysis (IHC) of retinal flatmounts. Results: Mice remaining in red-tinted cages had a significantly greater PRL thickness than those housed in untinted cages at all time points. Red housing also led to a highly significant rescue of retinal function as determined by both dark- and light-adapted ERG responses. IHC further revealed a dramatic benefit on cone morphology and number in the red- as compared with the clear-housed group. Conclusions: Limitation of short-wavelength light exposure significantly slows degeneration in the RhoP23H/+ mouse model. Red filters may represent a cost-effective and low-risk treatment for patients with rod-cone dystrophy in whom a sectoral phenotype is noted.

Fractionation of muscle activity in rapid responses to startling cues.

Movements in response to acoustically startling cues have shorter reaction times than those following less intense sounds; this is known as the StartReact effect. The neural underpinnings for StartReact are unclear. One possibility is that startling cues preferentially invoke the reticulospinal tract to convey motor commands to spinal motoneurons. Reticulospinal outputs are highly divergent, controlling large groups of muscles in synergistic patterns. By contrast the dominant pathway in primate voluntary movement is the corticospinal tract, which can access small groups of muscles selectively. We therefore hypothesized that StartReact responses would be less fractionated than standard voluntary reactions. Electromyogram recordings were made from 15 muscles in 10 healthy human subjects as they carried out 32 varied movements with the right forelimb in response to startling and nonstartling auditory cues. Movements were chosen to elicit a wide range of muscle activations. Multidimensional muscle activity patterns were calculated at delays from 0 to 100 ms after the onset of muscle activity and subjected to principal component analysis to assess fractionation. In all cases, a similar proportion of the total variance could be explained by a reduced number of principal components for the startling and the nonstartling cue. Muscle activity patterns for a given task were very similar in response to startling and nonstartling cues. This suggests that movements produced in the StartReact paradigm rely on similar contributions from different descending pathways as those following voluntary responses to nonstartling cues.NEW & NOTEWORTHY We demonstrate that the ability to activate muscles selectively is preserved during the very rapid reactions produced following a startling cue. This suggests that the contributions from different descending pathways are comparable between these rapid reactions and more typical voluntary movements.

Attenuated pupillary light responses and downregulation of opsin expression parallel decline in circadian disruption in two different mouse models of Huntington's disease.

Circadian deficits in Huntington's disease (HD) are recapitulated in both fragment (R6/2) and full-length (Q175) mouse models of HD. Circadian rhythms are regulated by the suprachiasmatic nuclei (SCN) in the hypothalamus, which are primarily entrained by light detected by the retina. The SCN receives input from intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the photopigment melanopsin, but also receive input from rods and cones. In turn, ipRGCs mediate a range of non-image forming responses to light including circadian entrainment and the pupillary light response (PLR). Retinal degeneration/dysfunction has been described previously in R6/2 mice. We investigated, therefore, whether or not circadian disruption in HD mice is due to abnormalities in retinal photoreception. We measured the expression of melanopsin, rhodopsin and cone opsin, as well as other retinal markers (tyrosine hydroxylase, calbindin, PKCα and Brna3), in R6/2 and Q175 mice at different stages of disease. We also measured the PLR as a 'readout' for ipRGC function and a marker of light reception by the retina. We found that the PLR was attenuated in both lines of HD mice. This was accompanied by a progressive downregulation of cone opsin and melanopsin expression. We suggest that disease-related changes in photoreception by the retina contribute to the progressive dysregulation of circadian rhythmicity and entrainment seen in HD mice. Colour vision is abnormal in HD patients. Therefore, if retinal deficits similar to those seen in HD mice are confirmed in patients, specifically designed light therapy may be an effective strategy to improve circadian dysfunction.

Spike Timing-Dependent Plasticity in the Long-Latency Stretch Reflex Following Paired Stimulation from a Wearable Electronic Device.

The long-latency stretch reflex (LLSR) in human elbow muscles probably depends on multiple pathways; one possible contributor is the reticulospinal tract. Here we attempted to induce plastic changes in the LLSR by pairing noninvasive stimuli that are known to activate reticulospinal pathways, at timings predicted to cause spike timing-dependent plasticity in the brainstem. In healthy human subjects, reflex responses in flexor muscles were recorded following extension perturbations at the elbow. Subjects were then fitted with a portable device that delivered auditory click stimuli through an earpiece, and electrical stimuli around motor threshold to the biceps muscle via surface electrodes. We tested the following four paradigms: biceps stimulus 10 ms before click (Bi-10ms-C); click 25 ms before biceps (C-25ms-Bi); click alone (C only); and biceps alone (Bi only). The average stimulus rate was 0.67 Hz. Subjects left the laboratory wearing the device and performed normal daily activities. Approximately 7 h later, they returned, and stretch reflexes were remeasured. The LLSR was significantly enhanced in the biceps muscle (on average by 49%) after the Bi-10ms-C paradigm, but was suppressed for C-25ms-Bi (by 31%); it was unchanged for Bi only and C only. No paradigm induced LLSR changes in the unstimulated brachioradialis muscle. Although we cannot exclude contributions from spinal or cortical pathways, our results are consistent with spike timing-dependent plasticity in reticulospinal circuits, specific to the stimulated muscle. This is the first demonstration that the LLSR can be modified via paired-pulse methods, and may open up new possibilities in motor systems neuroscience and rehabilitation. SIGNIFICANCE STATEMENT: This report is the first demonstration that the long-latency stretch reflex can be modified by repeated, precisely timed pairing of stimuli known to activate brainstem pathways. Furthermore, pairing was achieved with a portable electronic device capable of delivering many more stimulus repetitions than conventional laboratory studies. Our findings open up new possibilities for basic research into these underinvestigated pathways, which are important for motor control in healthy individuals. They may also lead to paradigms capable of enhancing rehabilitation in patients recovering from damage, such as after stroke or spinal cord injury.

Chronic Activation of γ2 AMPK Induces Obesity and Reduces ß Cell Function.

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.

Identification of benzopyrone as a common structural feature in compounds with anti-inflammatory activity in a zebrafish phenotypic screen.

Neutrophils are essential for host defence and are recruited to sites of inflammation in response to tissue injury or infection. For inflammation to resolve, these cells must be cleared efficiently and in a controlled manner, either by apoptosis or reverse migration. If the inflammatory response is not well-regulated, persistent neutrophils can cause damage to host tissues and contribute to the pathogenesis of chronic inflammatory diseases, which respond poorly to current treatments. It is therefore important to develop drug discovery strategies that can identify new therapeutics specifically targeting neutrophils, either by promoting their clearance or by preventing their recruitment. Our recent in vivo chemical genetic screen for accelerators of inflammation resolution identified a subset of compounds sharing a common chemical signature, the bicyclic benzopyrone rings. Here, we further investigate the mechanisms of action of the most active of this chemical series, isopimpinellin, in our zebrafish model of neutrophilic inflammation. We found that this compound targets both the recruitment and resolution phases of the inflammatory response. Neutrophil migration towards a site of injury is reduced by isopimpinellin and this occurs as a result of PI3K inhibition. We also show that isopimpinellin induces neutrophil apoptosis to drive inflammation resolution in vivo using a new zebrafish reporter line detecting in vivo neutrophil caspase-3 activity and allowing quantification of flux through the apoptotic pathway in real time. Finally, our studies reveal that clinically available 'cromones' are structurally related to isopimpinellin and have previously undescribed pro-resolution activity in vivo These findings could have implications for the therapeutic use of benzopyrones in inflammatory disease.

The hypothalamic photoreceptors regulating seasonal reproduction in birds: a prime role for VA opsin.

Extraretinal photoreceptors located within the medio-basal hypothalamus regulate the photoperiodic control of seasonal reproduction in birds. An action spectrum for this response describes an opsin photopigment with a λmax of ∼ 492 nm. Beyond this however, the specific identity of the photopigment remains unresolved. Several candidates have emerged including rod-opsin; melanopsin (OPN4); neuropsin (OPN5); and vertebrate ancient (VA) opsin. These contenders are evaluated against key criteria used routinely in photobiology to link orphan photopigments to specific biological responses. To date, only VA opsin can easily satisfy all criteria and we propose that this photopigment represents the prime candidate for encoding daylength and driving seasonal breeding in birds. We also show that VA opsin is co-expressed with both gonadotropin-releasing hormone (GnRH) and arginine-vasotocin (AVT) neurons. These new data suggest that GnRH and AVT neurosecretory pathways are endogenously photosensitive and that our current understanding of how these systems are regulated will require substantial revision.

A zebrafish compound screen reveals modulation of neutrophil reverse migration as an anti-inflammatory mechanism.

Diseases of failed inflammation resolution are common and largely incurable. Therapeutic induction of inflammation resolution is an attractive strategy to bring about healing without increasing susceptibility to infection. However, therapeutic targeting of inflammation resolution has been hampered by a lack of understanding of the underlying molecular controls. To address this drug development challenge, we developed an in vivo screen for proresolution therapeutics in a transgenic zebrafish model. Inflammation induced by sterile tissue injury was assessed for accelerated resolution in the presence of a library of known compounds. Of the molecules with proresolution activity, tanshinone IIA, derived from a Chinese medicinal herb, potently induced inflammation resolution in vivo both by induction of neutrophil apoptosis and by promoting reverse migration of neutrophils. Tanshinone IIA blocked proinflammatory signals in vivo, and its effects are conserved in human neutrophils, supporting a potential role in treating human inflammation and providing compelling evidence of the translational potential of this screening strategy.

The circadian clock and asthma.

It is characteristic of asthma that symptoms worsen overnight, particularly in the early hours of the morning. Nocturnal symptoms in asthma are common and are an important indicator for escalation of treatment. An extensive body of research has demonstrated that nocturnal symptoms of cough and dyspnea are accompanied by circadian variations in airway inflammation and physiologic variables, including airflow limitation and airways hyper-responsiveness. The molecular apparatus that underpins circadian variations, controlled by so called 'clock' genes, has recently been characterised. Clock genes control circadian rhythms both centrally, in the suprachiasmatic nucleus of the brain and peripherally, within every organ of the body. Here, we will discuss how clock genes regulate circadian rhythms. We will focus particularly on the peripheral lung clock and the peripheral immune clock and discuss how these might relate to both the pathogenesis and treatment of asthma.

Measuring and using light in the melanopsin age.

Light is a potent stimulus for regulating circadian, hormonal, and behavioral systems. In addition, light therapy is effective for certain affective disorders, sleep problems, and circadian rhythm disruption. These biological and behavioral effects of light are influenced by a distinct photoreceptor in the eye, melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to conventional rods and cones. We summarize the neurophysiology of this newly described sensory pathway and consider implications for the measurement, production, and application of light. A new light-measurement strategy taking account of the complex photoreceptive inputs to these non-visual responses is proposed for use by researchers, and simple suggestions for artificial/architectural lighting are provided for regulatory authorities, lighting manufacturers, designers, and engineers.

The importance of chronobiology to drug discovery.

Drug discovery scientists, faced with the myriad challenges involved in developing novel therapeutics as medicines, have tended to overlook the question of the most beneficial time to administer the drug. Recent developments in our understanding of circadian biology and the availability of tools to characterise the molecular clock indicate that time and duration of dosing may have profound consequences for the efficacy and safety of new and existing therapeutic agents. Progress in the field also suggests that many key physiological mechanisms are remarkably dependent on the circadian clock. It has also become clear that a number of diseases with important unmet medical need display marked circadian variation in their symptoms and severity. These discoveries now reveal opportunities for new therapeutic strategies to be developed that act by modulation of biological rhythms. These novel therapeutic approaches are likely to be facilitated by the continuing development of chemical probes and synthetic ligands targeted to an increasing number of the key proteins that regulate the molecular clock.

Corticomuscular coherence during bilateral isometric arm voluntary activity in healthy humans.

Bilateral voluntary contractions involve functional changes in both primary motor cortices. We investigated whether a voluntary contraction controlled by one hemisphere can influence oscillatory processes contralaterally. Corticomuscular coherence was calculated between EEG recorded over the motor cortex hand representation and electromyogram from the first dorsal interosseous muscle when the nondominant hand performed a precision grip task. The dominant arm remained at rest or performed a finger abduction or an elbow flexion task at 10, 40, and 70% of maximal isometric voluntary contraction (MVC). Mean coherence in the 15- to 30-Hz range in the hand performing a precision grip increased during 40% (by 72%) and 70% (by 73%) but not during 10% of MVC in the finger abduction task. Similarly, in the elbow flexion task, mean coherence increased during 40% (by 40%) and 70% (by 48%) but not during 10% of MVC. No differences were observed between the increments in coherence between the finger abduction and elbow flexion tasks at a given force level. We speculate that these results reflect the increased complexity of controlling a fine motor task with one hand while performing a strong contraction with the contralateral hand and suggest that increased oscillatory corticomuscular coupling may contribute to successful task performance.

Vertebrate ancient opsin photopigment spectra and the avian photoperiodic response.

In mammals, photoreception is restricted to cones, rods and a subset of retinal ganglion cells. By contrast, non-mammalian vertebrates possess many extraocular photoreceptors but in many cases the role of these photoreceptors and their underlying photopigments is unknown. In birds, deep brain photoreceptors have been shown to sense photic changes in daylength (photoperiod) and mediate seasonal reproduction. Nonetheless, the specific identity of the opsin photopigment 'sensor' involved has remained elusive. Previously, we showed that vertebrate ancient (VA) opsin is expressed in avian hypothalamic neurons and forms a photosensitive molecule. However, a direct functional link between VA opsin and the regulation of seasonal biology was absent. Here, we report the in vivo and in vitro absorption spectra (λ(max) = ~490 nm) for chicken VA photopigments. Furthermore, the spectral sensitivity of these photopigments match the peak absorbance of the avian photoperiodic response (λ(max) = 492 nm) and permits maximum photon capture within the restricted light environment of the hypothalamus. Such a correspondence argues strongly that VA opsin plays a key role in regulating seasonal reproduction in birds.

A new age for child protection--General Comment 13: why it is important, how it was constructed, and what it intends?

Children continue to be subjected to high levels of violence (i.e., physical, psychological and sexual maltreatment) throughout the world. International concern about violence against children has increased significantly during the last decade. A Study on Violence Against Children, encouraged by the UN Committee on the Rights of the Child, conducted under the auspices of the United Nations Secretary General and reported in 2006, has become a rallying call to improve child protection. Child protection practices and systems have been judged to be generally inadequate and, in some cases, destructive. It is widely recognized that business as usual-more of the same-will not do. A General Comment (guide to fulfilling obligations) for Article 19, the central conceptualization of child protection of the UN Convention on the Rights of the Child, has the potential to promote a worldwide reformulation of child protection priorities, policies, and practices by virtue of the infusion of a child rights approach. It can be a mechanism for framing and promoting the transformational change needed - for a genuine paradigm shift. Here, explication is given for the historical context, rationale, centrality of child rights, process of development, holistic nature, and primary elements of General Comment 13 (GC13): The child's right to freedom from all forms of violence. GC13 embodies and champions a child rights approach to child protection entailing strong support for proactive primary prevention, promotion of good child care, and a commitment to secure the rights and well-being of all children. A child rights-based, comprehensive coordinating framework is recommended for the implementation of GC13.

Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system.

AIMS: Our study sought to assess the prevalence of and risk factors for opioid drug dependence among out-patients on long-term opioid therapy in a large health-care system. METHODS: Using electronic health records, we identified out-patients receiving 4+ physician orders for opioid therapy in the past 12 months for non-cancer pain within a large US health-care system. We completed diagnostic interviews with 705 of these patients to identify opioid use disorders and assess risk factors. RESULTS: Preliminary analyses suggested that current opioid dependence might be as high as 26% [95% confidence interval (CI) = 22.0-29.9] among the patients studied. Logistic regressions indicated that current dependence was associated with variables often in the medical record, including age <65 [odds ratio (OR) = 2.33, P = 0.001], opioid abuse history (OR = 3.81, P < 0.001), high dependence severity (OR = 1.85, P = 0.001), major depression (OR = 1.29, P = 0.022) and psychotropic medication use (OR = 1.73, P = 0.006). Four variables combined (age, depression, psychotropic medications and pain impairment) predicted increased risk for current dependence, compared to those without these factors (OR = 8.01, P < 0.001). Knowing that the patient also had a history of severe dependence and opioid abuse increased this risk substantially (OR = 56.36, P < 0.001). CONCLUSION: Opioid misuse and dependence among prescription opioid patients in the United States may be higher than expected. A small number of factors, many documented in the medical record, predicted opioid dependence among the out-patients studied. These preliminary findings should be useful in future research efforts.

VA opsin-based photoreceptors in the hypothalamus of birds.

Studies in the 1930s demonstrated that birds possess photoreceptors that are located within the hypothalamus and regulate photoperiodic responses to day length. Most recently, photoperiod has been shown to alter the activity of the pars tuberalis to release thyrotrophin, which ultimately drives a reproductive response. Despite these significant findings, the cellular and molecular identity of the hypothalamic photoreceptors has remained a mystery. Action spectra implicated an opsin-based photopigment system, but further identification based on rod- or cone-opsin probes failed, suggesting the utilization of a novel opsin. The vertebrate ancient (VA) opsin photopigments were isolated in 1997 but were thought to have a restricted taxonomic distribution, confined to the agnatha and teleost fish. Here, we report the isolation of VA opsin from chicken and show that the two isoforms spliced from this gene (cVAL and cVA) are capable of forming functional photopigments. Further, we show that VA opsin is expressed within a population of hypothalamic neurons with extensive projections to the median eminence. These results provide the most complete cellular and molecular description of a deep brain photoreceptor in any vertebrate and strongly implicate VA opsin in mediating the avian photoperiodic response.