Search

Background: Patients with advanced heart failure (AHF) desire communication around values and goals prior to treatment decisions., Objectives: To evaluate the timing and content of the first serious illness communication (SI conversation) for patients with AHF after referral to a specialist palliative care (PC) team (HeartPal)., Methods: In this retrospective cohort study, we used electronic health records to identify patients referred to HeartPal and their first SI conversations at a tertiary care hospital between October 2018 and September 2021. We used natural language processing and predetermined codes to quantify prevalence of prior goals of care conversations by the cardiology team within six months preceding the HeartPal consultation and the prevalence of hopes, fears, and seven conversation content codes. Consecutive SI conversations and patient outcomes were followed until March 2022., Results: Of 468 patients (mean age: 64 years, 72 % male, 66 % referred for goals of care conversation), 25.2 % had prior documented goals of care conversations preceding the HeartPal consultation. During the study period, 206 (44.0 %) patients died (median time from initial SI conversation to death: 65 days, IQR 206) and 43.2 % engaged in multiple SI conversations before death. SI conversation analysis (n = 324) revealed that patients hoped to "be at home" (74.1 %, n = 240), "be independent" (65.7 %, n = 213) and "live as long as possible" (53.4 %, n = 173). Conversation content included goals of care (83.0 %), strengths (83.0 %), decision-making (79.3 %), spirituality (71.0 %), coping (52.2 %), and prognostic communication (43.5 %)., Conclusion: Specialist PC service provides documentation of goals and values and offers longitudinal follow-up for patients with AHF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

For older adults with serious, life-limiting illnesses near the end of life, clinicians frequently face difficult decisions about the medical care they provide because of clinical uncertainty. This difficulty is further complicated by unique challenges and medical advancements for patients with advanced heart diseases. In this article, we describe common mistakes encountered by clinicians when having goals-of-care conversations (e.g. conversations between clinicians and seriously ill patients/surrogates to discuss patient's values and goals for clinical care near the end of life.). Then, we delineate an evidence-based approach in goals-of-care conversations and highlight the unique challenges around decision-making in the cardiac intensive care unit., Competing Interests: Conflict of interest: K.O. has received advisory fees from Jolly Good, Inc (a virtual reality company). All other authors have nothing to report., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: To evaluate the safety, efficacy, and outcomes of outpatient intravenous diuresis in a rural setting and compare it to urban outcomes., Methods: A single-center study was conducted on 60 patients (131 visits) at the Dartmouth-Hitchcock Medical Center (DHMC) from 1/2021-12/2022. Demographics, visit data, and outcomes were collected and compared to urban outpatient IV centers, and inpatient HF hospitalizations from DHMC FY21 and national means. Descriptive statistics, T-tests and chi-squares were used., Results: The mean age was 70 ± 13 years, 58% were male, and 83% were NYHA III-IV. Post-diuresis, 5% had mild-moderate hypokalemia, 16% had mild worsening of renal function, and 3% had severe worsening of renal function. No hospitalizations occurred due to adverse events. The mean infusion-visit urine output was 761 ± 521 ml, and post-visit weight loss was -3.9 ± 5.0 kg. No significant differences were observed between HFpEF and HFrEF groups. 30-day readmissions were similar to urban outpatient IV centers, DHMC FY21, and the national mean (23.3% vs. 23.5% vs. 22.2% vs. 22.6%, respectively; p  = 0.949). 30-day mortality was similar to urban outpatient IV centers but lower than DHMC FY21 and the national means (1.7% vs. 2.5% vs. 12.3% vs. 10.7%, respectively; p  < 0.001). At 60 days, 42% of patients had ≥1 clinic revisit, 41% had ≥1 infusion revisit, 33% were readmitted to the hospital, and two deaths occurred. The clinic avoided 21 hospitalizations, resulting in estimated cost savings of $426,111., Conclusion: OP IV diuresis appears safe and effective for rural HF patients, potentially decreasing mortality rates and healthcare expenses while mitigating rural-urban disparities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Pathangey, D’Anna, Moudgal, Min, Manning, Taub and Gilstrap.)

Bacteriophage 80α is a representative of a class of temperate phages that infect Staphylococcus aureus and other Gram-positive bacteria. Many of these phages carry genes encoding toxins and other virulence factors. This phage, 80α, is also involved in high-frequency mobilization of S. aureus pathogenicity islands (SaPIs), mobile genetic elements that carry virulence factor genes. Bacteriophage 80α encodes a minor capsid protein, gp44, between the genes for the portal protein and major capsid protein. Gp44 is essential for a productive infection by 80α but not for transduction of SaPIs or plasmids. We previously demonstrated that gp44 is an ejection protein that acts to promote progression to the lytic cycle upon infection and suggested that the protein might act as an anti-repressor of CI in the lytic-lysogenic switch. However, an 80α Δ44 mutant also exhibited a reduced rate of lysogeny. Here, we show that gp44 is a non-specific DNA binding protein with affinity for the blunt ends of linear DNA. Our data suggest a model in which gp44 promotes circularization of the genome after injection into the host cell, a key initial step both for lytic growth and for the establishment of lysogeny.

Staphylococcus aureus is a common cause of infections in humans. The emergence of virulent, antibiotic-resistant strains of S. aureus is a significant public health concern. Most virulence and resistance factors in S. aureus are encoded by mobile genetic elements, and transduction by bacteriophages represents the main mechanism for horizontal gene transfer. The baseplate is a specialized structure at the tip of bacteriophage tails that plays key roles in host recognition, cell wall penetration, and DNA ejection. We have used high-resolution cryo-electron microscopy to determine the structure of the S. aureus bacteriophage 80α baseplate at 3.75 Å resolution, allowing atomic models to be built for most of the major tail and baseplate proteins, including two tail fibers, the receptor binding protein, and part of the tape measure protein. Our structure provides a structural basis for understanding host recognition, cell wall penetration and DNA ejection in viruses infecting Gram-positive bacteria. Comparison to other phages demonstrates the modular design of baseplate proteins, and the adaptations to the host that take place during the evolution of staphylococci and other pathogens., Competing Interests: The authors have declared that no competing interests exist.

The medial division of the medial geniculate (MGM) and the posterior intralaminar nucleus (PIN) are association nuclei of the auditory thalamus. We made tracer injections in these nuclei to evaluate/compare their presynaptic terminal and postsynaptic target features in auditory cortex, amygdala and striatum, at the light and electron microscopic levels. Cortical labeling was concentrated in Layer 1 but in other layers distribution was location-dependent. In cortical areas designated dorsal, primary and ventral (AuD, Au1, AuV) terminals deep to Layer 1 were concentrated in infragranular layers and sparser in the supragranular and middle layers. In ectorhinal cortex (Ect), distributions below Layer 1 changed with concentrations in supragranular and middle layers. In temporal association cortex (TeA) terminal distributions below Layer 1 was intermediate between AuV/1/D and Ect. In amygdala and striatum, terminal concentrations were higher in striatum but not as dense as in cortical Layer 1. Ultrastructurally, presynaptic terminal size was similar in amygdala, striatum or cortex and in all cortical layers. Postsynaptically MGM/PIN terminals everywhere synapsed on spines or small distal dendrites but as a population the postsynaptic structures in cortex were larger than those in the striatum. In addition, primary cortical targets of terminals were larger in primary cortex than in area Ect. Thus, although postsynaptic size may play some role in changes in synaptic influence between areas it appears that terminal size is not a variable used for that purpose. In auditory cortex, cortical subdivision-dependent changes in the terminal distribution between cortical layers may also play a role., (© 2019 Wiley Periodicals, Inc.)

Many staphylococcal bacteriophages encode a minor capsid protein between the genes for the portal and scaffolding proteins. In Staphylococcus aureus bacteriophage 80α, this protein, called gp44, is essential for the production of viable phage, but dispensable for the phage-mediated mobilization of S. aureus pathogenicity islands. We show here that gp44 is not required for capsid assembly, DNA packaging or ejection of the DNA, nor for generalized transduction of plasmids. An 80α Δ44 mutant could be complemented in trans by gp44 expressed from a plasmid, indicating that gp44 plays a post-injection role in the host. Our results show that gp44 is an ejection (pilot) protein that is involved in deciding the fate of the phage DNA after injection. Our data are consistent with a model in which gp44 acts as a regulatory protein that promotes progression to the lytic cycle., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Current concepts suggest that impaired representation of information in cortical networks contributes to loss of consciousness under anaesthesia. We tested this idea in rat auditory cortex using information theory analysis of multiunit responses recorded under three anaesthetic agents with different molecular targets: isoflurane, propofol, and dexmedetomidine. We reasoned that if changes in the representation of sensory stimuli are causal for loss of consciousness, they should occur regardless of the specific anaesthetic agent., Methods: Spiking responses were recorded with chronically implanted microwire arrays in response to acoustic stimuli incorporating varied temporal and spectral dynamics. Experiments consisted of four drug conditions: awake (pre-drug), sedation (i.e. intact righting reflex), loss of consciousness (a dose just sufficient to cause loss of righting reflex), and recovery. Measures of firing rate, spike timing, and mutual information were analysed as a function of drug condition., Results: All three drugs decreased spontaneous and evoked spiking activity and modulated spike timing. However, changes in mutual information were inconsistent with altered stimulus representation being causal for loss of consciousness. First, direction of change in mutual information was agent-specific, increasing under dexmedetomidine and decreasing under isoflurane and propofol. Second, mutual information did not decrease at the transition between sedation and LOC for any agent. Changes in mutual information under anaesthesia correlated strongly with changes in precision and reliability of spike timing, consistent with the importance of temporal stimulus features in driving auditory cortical activity., Conclusions: The primary sensory cortex is not the locus for changes in representation of information causal for loss of consciousness under anaesthesia., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

In the tailed bacteriophages, DNA is packaged into spherical procapsids, leading to expansion into angular, thin-walled mature capsids. In many cases, this maturation is accompanied by cleavage of the major capsid protein (CP) and other capsid-associated proteins, including the scaffolding protein (SP) that serves as a chaperone for the assembly process. Staphylococcus aureus bacteriophage 80α is capable of high frequency mobilization of mobile genetic elements called S. aureus pathogenicity islands (SaPIs), such as SaPI1. SaPI1 redirects the assembly pathway of 80α to form capsids that are smaller than those normally made by the phage alone. Both CP and SP of 80α are N-terminally processed by a host-encoded protease, Prp. We have analyzed phage mutants that express pre-cleaved or uncleavable versions of CP or SP, and show that the N-terminal sequence in SP is absolutely required for assembly, but does not need to be cleaved in order to produce viable capsids. Mutants with pre-cleaved or uncleavable CP display normal viability. We have used cryo-EM to solve the structures of mature capsids from an 80α mutant expressing uncleavable CP, and from wildtype SaPI1. Comparisons with structures of 80α and SaPI1 procapsids show that capsid maturation involves major conformational changes in CP, consistent with a release of the CP N-arm by SP. The hexamers reorganize during maturation to accommodate the different environments in the 80α and SaPI1 capsids., Competing Interests: The authors declare no conflict of interest.

Staphylococcus aureus pathogenicity islands (SaPIs), such as SaPI1, exploit specific helper bacteriophages, like 80α, for their high frequency mobilization, a process termed 'molecular piracy'. SaPI1 redirects the helper's assembly pathway to form small capsids that can only accommodate the smaller SaPI1 genome, but not a complete phage genome. SaPI1 encodes two proteins, CpmA and CpmB, that are responsible for this size redirection. We have determined the structures of the 80α and SaPI1 procapsids to near-atomic resolution by cryo-electron microscopy, and show that CpmB competes with the 80α scaffolding protein (SP) for a binding site on the capsid protein (CP), and works by altering the angle between capsomers. We probed these interactions genetically and identified second-site suppressors of lethal mutations in SP. Our structures show, for the first time, the detailed interactions between SP and CP in a bacteriophage, providing unique insights into macromolecular assembly processes.

Staphylococcus aureus pathogenicity islands (SaPIs) are phage satellites that exploit the life cycle of their helper phages for their own benefit. Most SaPIs are packaged by their helper phages using a headful (pac) packaging mechanism. These SaPIs interfere with pac phage reproduction through a variety of strategies, including the redirection of phage capsid assembly to form small capsids, a process that depends on the expression of the SaPI-encoded cpmA and cpmB genes. Another SaPI subfamily is induced and packaged by cos-type phages, and although these cos SaPIs also block the life cycle of their inducing phages, the basis for this mechanism of interference remains to be deciphered. Here we have identified and characterized one mechanism by which the SaPIs interfere with cos phage reproduction. This mechanism depends on a SaPI-encoded gene, ccm, which encodes a protein involved in the production of small isometric capsids, compared with the prolate helper phage capsids. As the Ccm and CpmAB proteins are completely unrelated in sequence, this strategy represents a fascinating example of convergent evolution. Moreover, this result also indicates that the production of SaPI-sized particles is a widespread strategy of phage interference conserved during SaPI evolution.This article is part of the themed issue 'The new bacteriology'., (© 2016 The Authors.)

Background: The International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of pulmonary adenocarcinomas identifies indolent lesions associated with low recurrence, superior survival, and the potential for sublobar resection. The distinction, however, is determined on the pathologic evaluation, limiting preoperative surgical planning. We sought to determine whether preoperative computed tomography (CT) characteristics could guide decisions about the extent of the pulmonary resection., Methods: We reviewed the preoperative CT scans for 136 patients identified to have adenocarcinomas with lepidic features on the final pathologic evaluation. The solid component on CT was substituted for the invasive component, and patients were radiologically classified as adenocarcinoma in situ, 3 cm or less with no solid component; minimally invasive adenocarcinoma, 3 cm or less with a solid component of 5 mm or less; or invasive adenocarcinoma, exceeding 3 cm or solid component exceeding 5 mm, or both. Analysis of variance, t test, χ(2) test, and Kaplan-Meier methods were used for analysis., Results: The radiologic classification identified 35 adenocarcinomas in situ (26%) and 12 minimally invasive (9%) and 89 invasive adenocarcinoma (65%) lesions. At a 32-month median follow-up, patient outcomes associated with the radiologic classification were similar to the pathologic-based classification: the radiologic classification identified 14 of 16 patients with recurrent disease and all 6 who died of lung cancer. In addition, patients with radiologic adenocarcinoma in situ and minimally invasive adenocarcinoma who underwent sublobar resections had no recurrence and 100% disease-free and overall survival at 5 years., Conclusions: The radiologic classification of patients with lepidic adenocarcinomas is associated with similar oncologic and survival outcomes compared with the pathologic classification and may guide decision making in the approach to surgical resection., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Ribosomal protein L27 is a component of the eubacterial large ribosomal subunit that has been shown to play a critical role in substrate stabilization during protein synthesis. This function is mediated by the L27 N-terminus, which protrudes into the peptidyl transferase center. In this report, we demonstrate that L27 in Staphylococcus aureus and other Firmicutes is encoded with an N-terminal extension that is not present in most Gram-negative organisms and is absent from mature ribosomes. We have identified a cysteine protease, conserved among bacteria containing the L27 N-terminal extension, which performs post-translational cleavage of L27. Ribosomal biology in eubacteria has largely been studied in the Gram-negative bacterium Escherichia coli; our findings indicate that there are aspects of the basic biology of the ribosome in S. aureus and other related bacteria that differ substantially from that of the E. coli ribosome. This research lays the foundation for the development of new therapeutic approaches that target this novel pathway., (© 2014 John Wiley & Sons Ltd.)

The non-mevalonate or 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway is responsible for generating isoprenoid precursors in plants, protozoa, and bacteria. Because this pathway is absent in humans, its enzymes represent potential targets for the development of herbicides and antibiotics. 1-Deoxy-d-xylulose (DXP) reductoisomerase (DXR) is a particularly attractive target that catalyzes the pathway's first committed step: the sequential isomerization and NADPH-dependent reduction of DXP to MEP. This article provides a comprehensive review of the mechanistic and structural investigations on DXR, including its discovery and validation as a drug target, elucidation of its chemical and kinetic mechanisms, characterization of inhibition by the natural antibiotic fosmidomycin, and identification of structural features that provide the molecular basis for inhibition of and catalysis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The mechanism of loss of consciousness (LOC) under anesthesia is unknown. Because consciousness depends on activity in the cortico-thalamic network, anesthetic actions on this network are likely critical for LOC. Competing theories stress the importance of anesthetic actions on bottom-up "core" thalamo-cortical (TC) vs. top-down cortico-cortical (CC) and matrix TC connections. We tested these models using laminar recordings in rat auditory cortex in vivo and murine brain slices. We selectively activated bottom-up vs. top-down afferent pathways using sensory stimuli in vivo and electrical stimulation in brain slices, and compared effects of isoflurane on responses evoked via the two pathways. Auditory stimuli in vivo and core TC afferent stimulation in brain slices evoked short latency current sinks in middle layers, consistent with activation of core TC afferents. By contrast, visual stimuli in vivo and stimulation of CC and matrix TC afferents in brain slices evoked responses mainly in superficial and deep layers, consistent with projection patterns of top-down afferents that carry visual information to auditory cortex. Responses to auditory stimuli in vivo and core TC afferents in brain slices were significantly less affected by isoflurane compared to responses triggered by visual stimuli in vivo and CC/matrix TC afferents in slices. At a just-hypnotic dose in vivo, auditory responses were enhanced by isoflurane, whereas visual responses were dramatically reduced. At a comparable concentration in slices, isoflurane suppressed both core TC and CC/matrix TC responses, but the effect on the latter responses was far greater than on core TC responses, indicating that at least part of the differential effects observed in vivo were due to local actions of isoflurane in auditory cortex. These data support a model in which disruption of top-down connectivity contributes to anesthesia-induced LOC, and have implications for understanding the neural basis of consciousness.

Solitary fibrous tumors of the pleura (SFTPs) are mesenchymal neoplasms that arise from the pleura. SFTPs can grow slowly and may become big masses with malignant behaviors and metastases. The ratio of benign to malignant is 7:1, and pathology is necessary to differentiate between benign and malignant. We present a case of a 37-year-old man with a presumptive diagnosis of benign SFTP by 18F-fluorodeoxyglucose positron emission tomography/computed tomography, which was confirmed by pathology., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A new method is presented for measuring kinetic isotope effects (KIEs) by (1)H-detected 2D [(13)C,(1)H]-heteronuclear single quantum coherence (HSQC) NMR spectroscopy. The high accuracy of this approach was exemplified for the reaction catalyzed by glucose-6-phosphate dehydrogenase by comparing the 1-(13)C KIE with the published value obtained using isotope ratio mass spectrometry. High precision was demonstrated for the reaction catalyzed by 1-deoxy-D-xylulose-5-phosphate reductoisomerase from Mycobacterium tuberculosis. 2-, 3-, and 4-(13)C KIEs were found to be 1.0031(4), 1.0303(12), and 1.0148(2), respectively. These KIEs provide evidence for a cleanly rate-limiting retroaldol step during isomerization. The high intrinsic sensitivity and signal dispersion of 2D [(13)C,(1)H]-HSQC offer new avenues to study challenging systems where low substrate concentration and/or signal overlap impedes 1D (13)C NMR data acquisition. Moreover, this approach can take advantage of highest-field spectrometers, which are commonly equipped for (1)H detection with cryogenic probes.

The ventral and dorsal medial geniculate (MGV and MGD) constitute the major auditory thalamic subdivisions providing thalamocortical inputs to layer IV and lower layer III of auditory cortex. No quantitative evaluation of this projection is available. Using biotinylated dextran amine (BDA)/biocytin injections, we describe the cortical projection patterns of MGV and MGD cells. In primary auditory cortex the bulk of MGV axon terminals are in layer IV/lower layer III with minor projections to supragranular layers and intermediate levels in infragranular layers. MGD axons project to cortical regions designated posterodorsal (PD) and ventral (VA) showing laminar terminal distributions that are quantitatively similar to the MGV-to-primary cortex terminal distribution. At the electron microscopic level MGV and MGD terminals are non-γ-aminobutyric acid (GABA)ergic with MGD terminals in PD and VA slightly but significantly larger than MGV terminals in primary cortex. MGV/MGD terminals synapse primarily onto non-GABAergic spines/dendrites. A small number synapse on GABAergic structures, contacting large dendrites or cell bodies primarily in the major thalamocortical recipient layers. For MGV projections to primary cortex or MGD projections to PD or VA, the non-GABAergic postsynaptic structures at each site were the same size regardless of whether they were in supragranular, granular, or infragranular layers. However, the population of MGD terminal-recipient structures in VA were significantly larger than the MGD terminal-recipient structures in PD or the MGV terminal-recipient structures in primary cortex. Thus, if terminal and postsynaptic structure size indicate strength of excitation then MGD to VA inputs are strongest, MGD to PD intermediate, and MGV to primary cortex the weakest., (Copyright © 2011 Wiley Periodicals, Inc.)

Primary sensory cortical responses are modulated by the presence or expectation of related sensory information in other modalities, but the sources of multimodal information and the cellular locus of this integration are unclear. We investigated the modulation of neural responses in the murine primary auditory cortical area Au1 by extrastriate visual cortex (V2). Projections from V2 to Au1 terminated in a classical descending/modulatory pattern, with highest density in layers 1, 2, 5, and 6. In brain slices, whole-cell recordings revealed long latency responses to stimulation in V2L that could modulate responses to subsequent white matter (WM) stimuli at latencies of 5-20 ms. Calcium responses imaged in Au1 cell populations showed that preceding WM with V2L stimulation modulated WM responses, with both summation and suppression observed. Modulation of WM responses was most evident for near-threshold WM stimuli. These data indicate that corticocortical projections from V2 contribute to multimodal integration in primary auditory cortex.

Evidence indicates that visual stimuli influence cells in the primary auditory cortex. To evaluate potential sources of this visual input and how they enter into the circuitry of the auditory cortex, we examined axonal terminations in the primary auditory cortex from nonprimary extrastriate visual cortex (V2M, V2L) and from the multimodal thalamic suprageniculate nucleus (SG). Gross biocytin/biotinylated dextran amine (BDA) injections into the SG or extrastriate cortex labeled inputs terminating primarily in superficial and deep layers. SG projects primarily to layers I, V, and VI while V2M and V2L project primarily to layers I and VI, with V2L also targeting layers II/III. Layer I inputs differ in that SG terminals are concentrated superficially, V2L are deeper, and V2M are equally distributed throughout. Individual axonal reconstructions document that single axons can 1) innervate multiple layers; 2) run considerable distances in layer I; and 3) run preferentially in the dorsoventral direction similar to isofrequency axes. At the electron microscopic level, SG and V2M terminals 1) are the same size regardless of layer; 2) are non-gamma-aminobutyric acid (GABA)ergic; 3) are smaller than ventral medial geniculate terminals synapsing in layer IV; 4) make asymmetric synapses onto dendrites/spines that 5) are non-GABAergic and 6) are slightly larger in layer I. Thus, both areas provide a substantial feedback-like input with differences that may indicate potentially different roles.

Exposure of normal adult rats of a variety of species to trains of light flashes leads to acquisition of an enduring high amplitude visual cortical response [Uhlrich DJ, Manning KA, O'Laughlin ML, Lytton WW (2005) Photic-induced sensitization: acquisition of an augmenting spike-wave response in the adult rat through repeated strobe exposure. J Neurophysiol 94:3925-3937]. The photically-induced sensitized response exhibits epileptiform characteristics, including spike-wave morphology, tendency to generalize across the brain, and sensitivity to the anti-epileptic drug ethosuximide. These findings and anecdotal clinical reports raise the possibility that certain sensory stimulation could induce neural plastic changes that affect seizures in some individuals. We hypothesize that photic-induced sensitization can prime seizure-related neural circuitry, resulting in exacerbation of seizures. To test this we compared seizure kindling rates using the pentylenetetrazol (PTZ) model of epileptogenesis in sensitized and unsensitized adult Sprague-Dawley rats. Experimental group rats were sensitized by exposure to repetitive stroboscopic stimulation over 4-6 days until the sensitized photic response fully developed and response magnitude stabilized at its highest plateau. Rats then received a sub-convulsive injection of PTZ (24 mg/kg i.p.) every other day until they attained class 5 seizures. Control rats were not strobed or sensitized, but were otherwise treated identically. Chronic electrodes overlying the dura in occipital cortex recorded the primary visual response. Similar electrodes near the border of somatosensory and motor cortex (SM) were used to record spread of the sensitized response to a patently non-visual region. Rat behavior was monitored by direct observation and digital audio/video recording. All control rats and seven of 14 photically sensitized rats kindled seizures at rates consistent with those reported previously. However, the seven other photically sensitized rats displayed markedly accelerated seizure kindling. Rats with accelerated kindling showed greater spread of the sensitized visual response to somato-motor cortex and, when tested in a post hoc experiment, exhibited a higher likelihood of photo-triggered seizures. These results indicate that photic-induced sensitization in susceptible individuals can prime neural circuitry involved in the generation of PTZ-kindled seizures.

We reported previously that exposure to repetitive visual stimulation in ordinary adult rats results in acquisition of an enduring increase in magnitude and change in character of visual cortical responses. This sensitization is consistent with experience-dependent neuroplastic changes, but could also reflect alterations in response with behavioral state during testing. The aim of this study was to distinguish the contributions of behavioral state and neural plasticity in this photic-induced sensitization. We used repetitive light-emitting diode flashes delivered monocularly and recorded electrocorticographically in the albino rat in which retino-geniculo-cortical projections are predominantly crossed. This enabled comparison of visual responses of sensitized visual circuitry associated with one eye to responses from effectively unsensitized circuitry associated with the second eye at similar time points in an animal, thus providing an internal control for behavioral state. Following sensitization, monocular stimulation of one eye produced the characteristic high amplitude driven spike-wave response in corresponding contralateral visual cortex, but not ipsilateral cortex. Expression of the sensitized driven response was optimal in the quiet awake state and suppressed during active exploration, drowsiness, or anesthesia. When the animal was in the quiet awake state, producing sensitized responses to stimulation of the first eye, no such response was observed on alternate trials upon stimulation of the second eye. Only after extended exposure of the second eye did the high amplitude driven spike-wave response in contralateral visual cortex develop. The data further suggest some degree of sensitization of ipsilateral pathways may accompany monocular stimulation and that effects of monocular sensitization could include suppression in pathways related to the unstimulated eye. Thus, while behavioral state influences expression of the sensitized driven visual response, the eye-specific nature of the effect provides strong evidence that response enhancement reflects neuroplasticity in visual pathways and not a more general change in behavioral state during testing.

It is well established that patterns of sensory input can affect neuroplastic changes during early development. The scope and consequences of experience-dependent plasticity in the adult are less well understood. We studied the possibility that repeated exposure to trains of stroboscopic stimuli could induce a sensitized and potentially aberrant response in ordinary individuals. Chronic electrocorticographic recording electrodes enabled measurement of responses in awake, freely moving animals. Normal adult rats, primarily Sprague-Dawley, were exposed to 20-40 strobe trains per day after a strobe-free adaptation period. The common response to strobe trains changed in 34/36 rats with development of a high-amplitude spike-wave response that emerged fully by the third day of photic exposure. Onset of this sensitized response was marked by short-term augmentation of response to successive strobe flashes. The waveform generalized across the brain, reflected characteristics of the visual stimulus, as well as an inherent 6- to 8-Hz pacing, and was suppressed with ethosuximide administration. Spike-wave episodes were self-limiting but could persist beyond the strobe period. Sensitization lasted 2-4 wk after last strobe exposure. The results indicate visual stimulation, by itself, can induce in adult rats an enduring sensitization of visual response with epileptiform characteristics. The results raise the question of the effects of such neuroplastic change on sensation and epileptiform events.

The visual sector of the thalamic reticular nucleus is the source of the primary inhibitory projection to the visual thalamic relay nucleus, the dorsal lateral geniculate nucleus. The purpose of this study was to investigate laminar and cellular targets of individual thalamic reticular nucleus axons in the highly laminated lateral geniculate nucleus of the prosimian primate Galago to better understand the nature and function of this projection. Thalamic reticular axons labeled anterogradely by means of biotinylated dextran amine were examined by using light microscopic serial reconstruction and electron microscopic analysis in combination with postembedding immunohistochemical labeling for the neurotransmitter gamma-aminobutyric acid (GABA). The synaptic targets of labeled reticular terminal profiles were primarily GABA-negative dendrites (79-84%) of thalamocortical cells, whereas up to 16% were GABA-positive dendritic shafts or F2 terminals of interneurons. Reconstructed thalamic reticular nucleus axons were narrowly aligned along a single axis perpendicular to the geniculate laminar plane, exhibiting a high degree of visuotopic precision. Individual reticular axons targeted multiple or all geniculate laminae, with little laminar selectivity in the distribution of swellings with regard to the eye of origin or to the parvocellular, koniocellular, or magnocellular type neurons contained in the separate layers of the Galago lateral geniculate nucleus. These results suggest that cells in the visual thalamic reticular nucleus influence the lateral geniculate nucleus retinotopically, with little regard to visual functional streams., (Copyright 2003 Wiley-Liss, Inc.)

We investigated the effects of the central histaminergic system on afferent sensory signals in the retinogeniculocortical pathway in the intact brain. Extracellular physiological recordings in vivo were obtained from neurons in the cat dorsal lateral geniculate nucleus (LGN) in conjunction with electrical activation of the histamine-containing cells in the tuberomammillary nucleus of the hypothalamus. Tuberomammillary activation resulted in a rapid and significant increase in the amplitude of baseline activity and visual responses in LGN neurons. Geniculate X- and Y-cells were affected similarly. LGN cells that exhibited a burst pattern of activity in the control condition switched to a tonic firing pattern during tuberomammillary activation. Effects on visual response properties were assessed using drifting sinusoidal gratings of varied spatial frequency. The resultant spatial tuning curves were elevated by tuberomammillary activation, but there was no change in tuning curve shape. Rather, the effect was proportionate to the control response, with the greatest tuberomammillary effects at spatial frequencies already optimal for the cell. Tuberomammillary activation caused a small phase lag in the visual response that was similar at all spatial frequencies, consistent with the induced shift from burst to tonic firing mode. These results indicate a significant histaminergic effect on LGN thalamocortical cells, with no clear effect on thalamic inhibitory neurons. The histaminergic system appears to strengthen central transmission of afferent information, intensifying but not transforming the retinally derived signals. Promoting sensory input may be one way in which the histaminergic system plays a role in arousal.

The cholinergic and histaminergic projections have important neuromodulatory functions in the ascending visual pathways, so we compared the pattern and mode of innervation of the two projections in the lateral geniculate complex (dorsal lateral geniculate nucleus and pregeniculate nucleus) of the macaque monkey. Brain tissue from macaques was immunoreacted by means of antibodies to choline acetyltransferase (ChAT) or to histamine and processed for light and electron microscopy. A dense plexus of thin, highly branched ChAT-immunoreactive axons laden with varicosities was found in all layers of the dLGN including the koniocellular laminae and in the pregeniculate nucleus. ChAT label was more dense in magnocellular layers 1 and 2 than in parvocellular layers 3-6 and relatively sparse in the interlaminar zones. Varicosities associated with the cholinergic axons had an average of three conventional asymmetric synapses per varicosity, and these appeared to contact dendrites of both thalamocortical cells and interneurons. Histamine-immunoreactive axons were distributed homogeneously throughout all laminar and interlaminar zones of the dLGN, but were denser in the pregeniculate nucleus than in the dLGN. Histaminergic axons branched infrequently and were typically larger in caliber than cholinergic axons. The overwhelming majority of varicosities were found en passant and rarely displayed conventional synapses, despite the abundance of synaptic vesicles, and were not associated preferentially with specific cellular structures. The innervation of the macaque dLGN complex by cholinergic and histaminergic systems is consistent with their proposed role in state dependent modulation of thalamic activity. The dense and highly synaptic innervation by cholinergic axons supports the proposal of additional involvement of these axons in functions related to eye movements.

Neural activity in the dorsal lateral geniculate nucleus of the thalamus (DLG) is modulated by an ascending cholinergic projection from the brainstem. The purpose of this study was to identify and localize specific muscarinic receptors for acetylcholine in the DLG. Receptors were identified in rat and cat tissue by means of antibodies to muscarinic receptor subtypes, ml-m4. Brain sections were processed immunohistochemically and examined with light and electron microscopy. Rat DLG stained positively with antibodies to the m1, m2,and m3 receptor subtypes but not with antibodies to the m4 receptor subtype. The m1 and m3 antibodies appeared to label somata and dendrites of thalamocortical cells. The m1 immunostaining was pale, whereas m3-positive neurons exhibited denser labeling with focal concentrations of staining. Strong immunoreactivity to the m2 antibody was widespread in dendrites and somata of cells resembling geniculate interneurons. Most m2-positive synaptic contacts were classified as F2-type terminals, which are the presynaptic dendrites of interneurons. The thalamic reticular nucleus also exhibited robust m2 immunostaining. Cat DLG exhibited immunoreactivity to the m2 and m3 antibodies. The entire DLG stained darkly for the m2 receptor subtype, except for patchy label in the medial interlaminar nucleus and the ventralmost C laminae. The staining for m3 was lighter and was distributed more homogeneously across the DLG. The perigeniculate nucleus also was immunoreactive to the m2 and m3 subtype-specific antibodies. Immunoreactivity in cat to the m1 or m4 receptor antibodies was undetectable. These data provide anatomical evidence for specific muscarinic-mediated actions of acetylcholine on DLG thalamocortical cells and thalamic interneurons.

The histaminergic system is involved in the control of arousal in the brain and may impact significantly on visual processing. However, little is known about the histaminergic innervation of visual areas, or the histamine system in the primate brain, in general. We examined in Macaca mulatta the location of histamine-immunoreactive neurons and the innervation of important cortical and subcortical visual areas by histamine-immunoreactive axons. Brain sections were treated with an antibody to histamine and processed with standard immunohistological procedures. Histamine-immunoreactive neurons (20-45 microns in diameter) were localized bilaterally in the hypothalamus, particularly in ventral, lateral, posterior, and perimammillary hypothalamic areas. These hypothalamic cells appear to provide the sole neural source of histamine in the macaque brain. A plexus of varicose histamine-immunoreactive axons was present throughout the superior colliculus, the dorsal and ventral lateral geniculate nuclei of the thalamus, the reticular nucleus of the thalamus, the lateral posterior/pulvinar complex, and the visual cortex, including areas 17, 18, and the nearby extrastriate cortex. The axons nearly homogeneously innervated every region and layer in these structures, except for an increase in density in layer 1 of the visual cortex and in the superficial-most layers of the superior colliculus. Histaminergic axons broadly innervated every visual region examined. In comparison with the other aminergic and the cholinergic projection systems, which show considerable projection specificity, the histaminergic projection exhibited great homogeneity. The breadth of the distribution of histaminergic axons ensures that virtually all levels of visual processing in the primate can be influenced, either directly or indirectly, by the neuromodulatory effects of histamine.

The dorsal lateral geniculate nucleus of the thalamus transmits visual signals from the retina to the cortex. Within the lateral geniculate nucleus, the ascending visual signals are modified by the actions of a number of afferent pathways. One such projection originates in the pretectum and appears to be active in association with oculomotor activity. Much remains unknown about the pretectal-geniculate projection. Our purpose was to examine for the first time individual axon arbors from the pretectum that project to the lateral geniculate nucleus, describing their topography and nuclear and laminar targets. We made injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin into the cat pretectum, targeting the nucleus of the optic tract. Serial 40 microns coronal sections were processed by using immunohistochemistry to reveal labeled axons that were then serially reconstructed using light microscopy. Pretectal-geniculate axons appeared morphologically heterogeneous in terms of swelling size, branching patterns, and laminar target. Most axons innervated the geniculate A laminae. A separate, smaller population innervated the C laminae. All axons exhibited substantially greater spread medial-laterally than rostral-caudally in the lateral geniculate nucleus, displaying a topographical organization for visual field elevation, but not azimuth. Many pretectal axons that projected to the LGN also innervated adjacent structures, including the medial interlaminar nucleus, the perigeniculate nucleus, and/or the pulvinar. These results indicate that the projection from the pretectum to the dorsal lateral geniculate nucleus is heterogeneous, is semitopographical, and may coordinate neural activity in the lateral geniculate nucleus and in neighboring visual thalamic structures in association with oculomotor events.

Mast cells and their location in the cat lateral geniculate complex of the thalamus were examined by means of histamine immunohistochemistry and the mast cell stain pinacyanol erythrosinate. Brain sections from seven normal adult pigmented cats were processed for light or electron microscopy. Histamine-containing and pinacyanol erythrosinate-stained mast cells were widespread throughout the dorsal and ventral lateral geniculate nuclei and the surrounding regions. Mast cells were especially numerous rostrally in the complex and in the geniculate C laminae. The cells were found consistently in association with blood vessels, ranging from capillary size to vessels c. 150 microns diameter, and twice as often with arterioles as with venules. Large clusters of many mast cells associated with single blood vessels were seen. Individual mast cells were typically 8 microns in diameter and somewhat oval, although multipolar and crescent-shaped cells were also seen, up to twice as long. The amount of histamine labeling varied across cells. When histamine-labeled material was secondarily stained with pinacyanol erythrosinate, many mast cells were double labeled. In addition, there was a small population of mast cells that stained only with pinacyanol erythrosinate, but was otherwise identical to the histamine-immunoreactive mast cells. Electron microscopic examination showed that the mast cells lie on the brain side of the blood-brain barrier. Mast cells were found in close proximity to the thalamic neuropil, primarily apposed to the processes of astrocytes, but also apposed to neural elements. The distinctive electron-dense cytoplasmic granules in the fully granulated, mature state were largely amorphous in appearance and as large as 700 nm in diameter. Histamine was dispersed throughout some granules and contained within restricted areas of other granules. In degranulated mast cells, large, irregularly shaped, electron-lucent granules were seen fused with the cell membrane on the neuropil side, as well as the lumen side of the mast cell. More mast cells were observed at the electron microscopic level than were expected from the light level observations, which suggests that, despite the numbers of mast cells labeled, these results may still underestimate the total mast cell population present in this region of the thalamus. Mast cells, by their numbers, their distribution and the potent chemical substances they contain, may significantly influence vascular and neural function, directly and indirectly, in the cat lateral geniculate complex.

Many vertebrates generate blinks as a component of saccadic gaze shifts. We investigated the nature of this linkage between saccades and blinking in normal humans. Activation of the orbicularis oculi, the lid closing muscle, EMG occurred with 97% of saccadic gaze shifts larger than 33 degrees. The blinks typically began simultaneously with the initiation of head and/or eye movement. To minimize the possibility that the blinks accompanying saccadic gaze shifts were reflex blinks evoked by the wind rushing across the cornea and eye-lashes as the head and eyes turned, the subjects made saccadic head turns with their eyes closed. In this condition, orbicularis oculi EMG activity occurred with all head turns greater than 17 degrees in amplitude and the EMG activity began an average of 39.3 ms before the start of the head movement. Thus, one component of the command for large saccadic gaze shifts appears to be a blink. We call these blinks gaze-evoked blinks. The linkage between saccadic gaze shifts and blinking is reciprocal. Evoking a reflex blink prior to initiating a voluntary saccadic gaze shift dramatically reduces the latency of the initiation of the head movement.

The relationship between scores on two widely used measures of dependency--one objective and one projective--was examined in a sample of 102 undergraduate subjects (60 women and 42 men). Consistent with previous studies in this area, significant sex differences were found on the objective measure of dependency, with women obtaining higher dependency scores than men. However, as predicted, men and women obtained comparable scores on the projective measure of dependency. Additional analyses confirmed that scores on the objective and projective measures of dependency were significantly intercorrelated in both men and women, although the magnitudes of these correlations were somewhat larger in women than in men. Implications of these results for the assessment of dependent personality traits in research and clinical settings are discussed.

The histaminergic projection from the hypothalamus to the superior colliculus was examined immunohistochemically in the cat brain using an antibody to histamine. The source of histaminergic fibers in the brain is a group of neurons in the posterior hypothalamus, located primarily in ventrolateral and periventricular regions and collectively referred to as the tuberomammillary nucleus. All laminae of the superior colliculus--including the superficial, intermediate, and deep layers, as well as the central gray--were blanketed with histamine-immunoreactive axonal fibers. Overall, labeling in the superior colliculus was moderately dense compared to other locations in the cat brain, with some variation in fiber density. Individual labeled fibers resembled histaminergic fibers described previously in the brain. Labeled axonal fibers showed infrequent branching and were beaded with numerous en passant varicosities that were typically 1 micron or smaller, but as large as 2.5 micron in diameter. Varicosity size differed significantly at different depths in the colliculus. The histaminergic projection appears to be separate from a previously reported, apparently non-histaminergic projection from neurons in the dorsal hypothalamic area to discrete regions of intermediate and deep colliculus. These results indicate that the histaminergic projection from the tuberomammillary nucleus of the hypothalamus projects extensively throughout the superior colliculus. Histamine, which is believed to act as a neuromodulator in the brain, is in a position to influence sensory and motor-related processes in every layer of the cat superior colliculus.

The histaminergic innervation of the thalamic dorsal and ventral lateral geniculate nuclei and the perigeniculate nucleus of the cat was examined immunohistochemically by means of an antibody to histamine. We find histamine-immunoreactive neurons in the cat brain are concentrated in the ventrolateral portion of the posterior hypothalamus, confirming a previous report. However, this cell group also spreads into medial, dorsal, and extreme lateral regions of the posterior hypothalamus and extends as far rostral as the optic chiasm. Histamine-labeled fibers cover all regions of the lateral geniculate complex, but the density of labeling varies. The ventral lateral geniculate nucleus (vLGN) is most densely labeled, the A laminae of the dorsal lateral geniculate are sparsely labeled, and the geniculate C laminae and the perigeniculate nucleus show intermediate amounts of label. Thus, histaminergic fibers demonstrate a predilection for zones innervated by the W-cell system. Labeled fibers exhibit few branchings and numerous en passant swellings, lending a beaded appearance. The vLGN showed more instances of fibers with larger-sized swellings (up to 2 microns). Following injections of biotinylated tracers into the hypothalamus, we find labeled fibers throughout the lateral geniculate complex. The anterogradely labeled fibers resemble the histaminergic fibers in morphology, distribution, and relative bouton size. Thus, the hypothalamus appears to be the source of the histaminergic fibers in the lateral geniculate complex. Histamine-labeled fibers in the dorsal lateral geniculate nucleus (dLGN) exhibit uncommon ultrastructural morphology. Many extremely large, round, or elliptical vesicles fill the fiber swellings. Swellings are directly apposed to a variety of other dendritic and axonal profiles, but thus far no convincing synaptic contacts have been seen. The distribution and appearance of these histaminergic fibers resembles those reported for serotonergic fibers. Our results support the idea that histamine works nonsynaptically as a neuromodulator in the lateral geniculate complex, affecting the level of visual arousal.

Studies in humans and rabbits suggest that cocontraction of extraocular muscles occurs with reflex and voluntary blinks. We determined the pattern of extraocular muscle activity elicited by blink-evoking visual and trigeminal stimuli by electromyographically recording antagonistic pairs of extraocular muscles in alert rabbits. In addition, we recorded the activity of antidromically identified oculomotor motoneurons in response to the same stimuli in alert rabbits. The data demonstrate that all extraocular muscles except the superior oblique transiently increase their activity in response to blink-evoking stimuli. The pattern of extraocular muscle activity with reflex blinks mirrors that occurring in the lid-closing muscle, orbicularis oculi, but the latency of extraocular muscle activation is longer.

In humans and rats we found that nicotine transiently modifies the blink reflex. For blinks elicited by stimulation of the supraorbital branch of the trigeminal nerve, nicotine decreased the magnitude of the orbicularis oculi electromyogram (OOemg) and increased the latency of only the long-latency (R2) component. For blinks elicited by electrical stimulation of the cornea, nicotine decreased the magnitude and increased the latency of the single component of OOemg response. Since nicotine modified only one component of the supraorbitally elicited blink reflex, nicotine must act primarily on the central nervous system rather than at the muscle. The effects of nicotine could be caused by direct action on lower brainstem interneurons or indirectly by modulating descending systems impinging on blink interneurons. Since precollicular decerebration eliminated nicotine's effects on the blink reflex, nicotine must act through descending systems. Three lines of evidence suggest that nicotine affects the blink reflex through the basal ganglia by causing dopamine release in the striatum. First, stimulation of the substantia nigra mimicked the effects of nicotine on the blink reflex. Second, haloperidol, a dopamine (D2) receptor antagonist, blocked the effect of nicotine on the blink reflex. Third, apomorphine, a D2 receptor agonist, mimicked the effects of nicotine on the blink reflex.

We studied the eyelid movements of six patients with unilateral, isolated, facial paralysis using the magnetic search coil. The most significant abnormality consisted of a reduction in the magnitude of the orbicularis oculi contraction with slowing of the peak velocity of the closing phase of the blink. The closing phase blink velocity, which normally increases linearly as a function of amplitude (main sequence), in our patients displayed a relationship characterized by a slow saturating power function that fell off the main sequence. The contralateral normal lid in some cases can show adaptive signs of hyperactivity during the closing phase of the blink. Lid saccades showed a small but consistent decrease in amplitude and velocity compared with the contralateral unaffected eyelid. Unlike the closing phase of the blink, peak velocities of lid saccades stayed on the main sequence. In this study, we discuss how the eyelid executes downward lid saccades based purely on a passive mechanism.

Heat shock, cold shock, ethanol, and alkaline shift, but not hydrogen peroxide, stimulate the accumulation of monoacetylspermidine in Escherichia coli. Acetylation occurs with nearly equal frequencies at both the N1 and N8 positions of this ubiquitous polycation. Spermidine acetylation does not appear to be associated with known stress regulons, such as htpR, oxyR, and SOS. E. coli, capable of acetylating spermidine, constitutively express a spermidine acetyltransferase activity during all phases of growth, and this activity is unaffected by cold shock. A mutant strain, incapable of acetylating spermidine, does not express this enzyme activity but grows at an identical rate as the parent strain at 37 degrees C. These results demonstrate that the monoacetylation of spermidine in E. coli is regulated by some mechanism other than a stress-inducible acetyltransferase and is not essential for growth of these cells. They suggest that polyamine acetylation is involved in the responses of these organisms to a variety of chemical and physical stresses.

This study provides a comprehensive description of upper eyelid movement in normal human subjects. Using the magnetic search coil technique to monitor lid position and modified skin electrodes to record orbicularis oculi electromyographic (EMG) activity, the authors found that the basic eyelid movements, blinks, and saccadic lid movements, can be uniquely and reliably characterized by their amplitude-maximum velocity relationships. The data show that similar increases in levator palpebrae activity produce the upward lid movements that accompany upward saccadic eye movements as well as the upward phase of a blink. The lid movements that accompany downward saccadic eye movements arise almost exclusively from the passive downward forces and relaxation of the levator palpebrae muscle. In contrast, active orbicularis oculi contraction and the passive downward forces act together to generate lid closure with a blink. These normative data and techniques provide the basis for the clinical analysis of lid motility by which abnormal lid movements can be compared with normal lid kinematics.

Quantitative analysis of lid motility is presented for 4 individuals with hemifacial spasm and 1 with Meige's syndrome. The data were obtained, by means of a magnetic search coil technique, prior to and 1 week after injection of botulinum toxin into the orbicularis oculi muscle. Before treatment, the peak velocity of blink-related lid lowering and lid raising was slower than normal, yet lid saccades were normal. After botulinum treatment, significant decreases occurred in (1) the amplitude of blinks and lid saccades, and (2) the peak velocity of the blink down-phase. Botulinum treatment significantly alters blink lid-lowering kinematics, while saccadic lid-lowering kinematics are normal, providing further evidence that the orbicularis oculi muscle does not play a primary role in downward lid saccades.

The atoxic fragment C of tetanus toxin reliably undergoes retrograde direct and transneuronal transport, but the full extent of its transport capabilities has not been examined. The primary visual pathways provide an excellent system for investigating, for the first time, the possibility of anterograde direct and transneuronal transport of fragment C. Following injection into the eye of the rat and rabbit, fragment C, localized with a monoclonal antibody, underwent anterograde direct transport to all retinorecipient areas. From these areas, fragment C exhibited retrograde transneuronal transport, strongly and reliably labeling regions that project to retinorecipient areas, including layers V and VI of visual cortex, the parabigeminal nucleus, the suprageniculate nucleus, and the reticular thalamus. In contrast, the absence of fragment C in regions receiving only input from, but not projecting to, retinorecipient areas, most notably layer IV of visual cortex, provides strong evidence for the lack of anterograde transneuronal transport. Thus, while fragment C can be induced to undergo anterograde direct transport by injection into the eye, it exhibits only retrograde transneuronal transport. These characteristics suggest that fragment C of tetanus toxin is a consistent and reliable retrograde transneuronal marker for the elucidation of central nervous pathways.

The purpose of this paper is to examine blink kinematics and the neural basis of blinks evoked reflexively by different kinds of stimuli. The kinematics of the upper lid movement and the electromyographic response of lid muscles levator palpebrae and orbicularis oculi were recorded in the rabbit during trigeminally and visually-evoked blinks. We find that there is a basic, kinematic difference between blinks. A blink in response to an airpuff is more rapidly accomplished and achieves a higher velocity than does an equal amplitude blink in response to a flash of light. The two forms of the reflex blink result from differences in the nature and timing of activity in antagonistic lid muscle motoneurons. Nevertheless, most characteristics of blink neural control are common to both reflex blinks. Most importantly, it appears that blinks are produced by two-stage neural control, an early component that is preprogrammed and a late component that is under stimulus control.

We have measured the impairment of vision that accompanies a saccadic eye movement under whiteout conditions. Translucent plastic diffusers were fitted around the eyes to provide a luminous field without perceivable contours. Visual sensitivity of three subjects was tested by means of 10 msec luminance decrements of variable amplitude. We found that sensitivity was lower, by 0.7 to 1.1 log units, when the eyes were making 16 degree saccades than when they were at rest. Comparable amounts of saccadic suppression occurred under more usual Ganzfeld conditions. We therefore conclude that such minimal contours as are present in the Ganzfeld--fixation guides, minor surface blemishes, and the blurred outlines of the subject's nose and brow--have little effect on suppression. These results are consistent with the hypothesis that a centrally originating inhibitory process accompanies the initiation of the saccade.

This paper reviews the course of development of visual acuity in human infants and young children. Researchers have devised methods based on optokinetic nystagmus, visually evoked cortical potentials and preferential looking to assess visual acuity in infants and preverbal youngsters. During the first postnatal year and early childhood, acuity, measured by any of these methods, improves with increasing age. Each of these methods, has now been applied to the evaluation of clinical cases. Also presented are the results of a quick and simple test based on preferential looking, which has been incorporated into our clinical evaluation of infants. The data so far indicate that infants with normal eyes pass the test while infants with ocular problems which would interfere with vision fail. For evaluation of large numbers of infants this test appears to have the potential to assist nonspecialized personnel in the early identification of ophthalmic abnormalities.

Visual sensitivity was measured during vergence eye movements in order to determine whether a suppression of vision similar to that associated with saccades is also present during vergence. Suppression was evaluated psychophysically by determining sensitivity to briefly presented, full-field decrements of light in a Ganzfeld. Subjects were rougly 0.5 log unit less sensitive when stimuli were presented at the beginning of a 2-3 deg convergent or divergent eye movement, than during steady fixation. Thus, the concept of saccadic suppression must be broadened to include visual suppression that also accompanies nonsaccadic eye movements. These results support the hypothesis that vision is affected by signals that accompany initiation of oculomotor activity.

It has recently been shown that tobacco smoking in normal human subjects induces a transient primary-position upbeat nystagmus. We studied the effects of tobacco smoking on smooth pursuit eye movements and found defects in both vertical and horizontal tracking during the first 5 minutes after smoking one cigarette. The smooth pursuit defect consisted of a reduction in upward tracking velocity and the superposition of saccadic square-wave jerks on both vertical and horizontal tracking eye movements. The degree of impairment in upward smooth pursuit correlated with the intensity of tobacco-induced nystagmus present when recording in darkness. We suggest that these alterations are due to summation of nystagmus on normal tracking eye movements rather than primary defects in the smooth pursuit system.

In three, normal, human subjects, tobacco smoking was used as a pharmacological probe to modify differentially the direct and indirect pathways underlying the blink reflex. The latency of the indirect R2 component of the orbicularis oculis electromyogram evoked by electrical stimulation of the trigeminal supraorbital nerve transiently increased 20-80% after smoking, while the latency of the shorter latency, direct R1 component remained constant. The magnitude of both components of the blink reflex transiently decreased. The data demonstrate that tobacco smoking can differentially alter the long and short latency components of the blink reflex, and suggest that these effects result from modifications of central pathways sensitive to nicotine.

We studied the application of preferential looking (PL) procedures to evaluation of visual performance of 59 prematurely born infants and young children. Neurological abnormalities were present in 29 of the 59 patients. Ophthalmic examination revealed normal eyes in 20 of the patients; retinopathy of prematurity (20 patients) and strabismus (13 patients) were the most prevalent ophthalmological disorders; the remaining 6 patients had a variety of ophthalmic anomalies. Results indicate that PL testing of such patients is best accomplished after age 2 months. Patients with developmental delays can be tested, but they may have poor PL performance that is not accounted for by ophthalmic abnormalities. Differences in PL acuities between right and left eyes were indicative of amblyopia in some of the strabismic patients; sequential PL acuities monitored occlusion therapy in these pre-verbal youngsters.