Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients. However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data. Moreover, the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question. Using quantitative electroencephalography (qEEG) to objectively align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to that of ketamine, we demonstrate the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects. Furthermore, using placebo-controlled data, we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration. Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders.

Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers.

OBJECTIVE: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline. METHODS: 81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT). RESULTS: Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects. CONCLUSIONS: With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time.

Experience-dependent asymmetric shape of hippocampal receptive fields.

We propose a novel parameter, namely, the skewness, or asymmetry, of the shape of a receptive field to characterize two properties of hippocampal place fields. First, a majority of hippocampal receptive fields on linear tracks are negatively skewed, such that during a single pass the firing rate is low as the rat enters the field but high as it exits. Second, while the place fields are symmetric at the beginning of a session, they become highly asymmetric with experience. Further experiments suggest that these results are likely to arise due to synaptic plasticity during behavior. Using a purely feed forward neural network model, we show that following repeated directional activation, NMDA-dependent long-term potentiation/long-term depotentiation (LTP/LTD) could result in an experience-dependent asymmetrization of receptive fields.

Disseminated cytomegalovirus infection. Molecular analysis of virus and leukocyte interactions in viremia.

Viremia is a hallmark of disseminated cytomegalovirus (CMV) infection and disease. Using conventional virus culture and a subgenomic cloned CMV DNA probe to detect viral DNA within leukocytes, we studied the virus-cell interactions involved in immunocompromised patients with viremic CMV infection. CMV was recovered by culture in 17/17 samples enriched for polymorphonuclear leukocytes. Viral DNA was detected by dot-blot hybridization in 16/17 (94%). In contrast, samples enriched for mononuclear cells yielded infectious CMV in culture in only 7/15 (47%) instances; nonetheless, viral DNA was present in 16/17 samples probed. The quantity of CMV DNA in polymorphonuclear cells was significantly greater than in mononuclear leukocytes (mean 13.1 vs. 9.1 estimated viral genome equivalents per 100 cells, respectively), and CMV was always recovered from these cells regardless of the amount of viral DNA present. Yet, when the amounts of CMV DNA were virtually identical in granulocytes and mononuclear cells (6.3 and 7.1 genomic equivalents, respectively) collected simultaneously, infectious CMV could not be recovered from mononuclear cells. Although several interpretations are possible, these data are consistent with the view that CMV exists within granulocytes in a mature infectious form during viremia. The virus interactions with mononuclear cells appear to be more complex, particularly in those cells that contain CMV DNA but do not yield infectious virus.

High levels of circulating cytomegalovirus DNA reflect visceral organ disease in viremic immunosuppressed patients other than marrow recipients.

Although viremia is a hallmark of disseminated cytomegalovirus (CMV) infection, not all viremic patients have visceral organ CMV disease. We used blot hybridization with a cloned subgenomic probe to quantitate viral DNA in blood leukocytes of 60 viremic patients (25 with solid organ transplants, 20 with AIDS, and 15 marrow recipients) who had different clinical manifestations of CMV infection. The results are expressed as pg of viral DNA/10 micrograms of leukocyte DNA. Patients with AIDS or with solid organ transplants who had CMV visceral organ disease had the largest amounts of viral DNA in their granulocytes (median 632 and 237 pg, respectively). These amounts were significantly greater than those in similar viremic patients without CMV visceral disease (17 and 21 pg; P < 0.005 and 0.002, respectively). All patients in the study with > 150 pg of CMV DNA in their granulocytes had visceral CMV disease. The amounts of viral DNA in granulocytes of AIDS and organ transplant patients with CMV retinitis were low (median 22 pg). Marrow transplant patients were unique in that the amounts of CMV DNA in granulocytes were low whether CMV visceral organ disease was present (17 pg) or absent (14 pg). We conclude that high levels of circulating CMV DNA in viremic AIDS and solid organ transplant patients reflect viral involvement of visceral organs but not the retina. In marrow recipients, the severity of CMV disease, even when fatal, is not reflected quantitatively in peripheral blood leukocytes.

Hemodynamic analysis of edge stenosis in peripheral artery stent grafts.

PURPOSE: The purpose of this study was to characterize the hemodynamics of peripheral artery stent grafts to guide intelligent stent redesign. MATERIALS AND METHODS: Two surgically explanted porcine arteries were mounted in an ex vivo system with subsequent deployment of an Xpert self-expanding nitinol stent or Viabahn stent graft. The arteries were casted with radiopaque resin, and the cast then scanned using micro-computed tomography at 8µm isotropic voxel resolution. The arterial lumen was segmented and a computational mesh grid surface generated. Computational fluid dynamics (CFD) analysis was subsequently performed using COMSOL Multiphysics 5.1. RESULTS: CFD analysis demonstrated low endothelial shear stress (ESS) involving 9.4 and 63.6% surface area of the central stent graft and bare metal stent, respectively. Recirculation zones were identified adjacent to the bare metal stent struts, while none were identified in the central stent graft. However, the stent graft demonstrated malapposition of the proximal stent graft edge with low velocity flow between the PTFE lining and arterial wall, which was associated with longitudinally and radially oriented recirculation zones and low ESS. CONCLUSION: Computational hemodynamic analysis demonstrates that peripheral artery stent grafts have a superior central hemodynamic profile compared to bare metal stents. Stents grafts, however, suffer from malapposition at the proximal stent edge which is likely a major contributor to edge stenosis.

Differential behavioral state-dependence in the burst properties of CA3 and CA1 neurons.

Brief bursts of fast high-frequency action potentials are a signature characteristic of CA3 and CA1 pyramidal neurons. Understanding the factors determining burst and single spiking is potentially significant for sensory representation, synaptic plasticity and epileptogenesis. A variety of models suggest distinct functional roles for burst discharge, and for specific characteristics of the burst in neural coding. However, little in vivo data demonstrate how often and under what conditions CA3 and CA1 actually exhibit burst and single spike discharges. The present study examined burst discharge and single spiking of CA3 and CA1 neurons across distinct behavioral states (awake-immobility and maze-running) in rats. In both CA3 and CA1 spike bursts accounted for less than 20% of all spike events. CA3 neurons exhibited more spikes per burst, greater spike frequency, larger amplitude spikes and more spike amplitude attenuation than CA1 neurons. A major finding of the present study is that the propensity of CA1 neurons to burst was affected by behavioral state, while the propensity of CA3 to burst was not. CA1 neurons exhibited fewer bursts during maze running compared with awake-immobility. In contrast, there were no differences in burst discharge of CA3 neurons. Neurons in both subregions exhibited smaller spike amplitude, fewer spikes per burst, longer inter-spike intervals and greater spike amplitude attenuation within a burst during awake-immobility compared with maze running. These findings demonstrate that the CA1 network is under greater behavioral state-dependent regulation than CA3. The present findings should inform both theoretic and computational models of CA3 and CA1 function.

Experience-dependent changes in extracellular spike amplitude may reflect regulation of dendritic action potential back-propagation in rat hippocampal pyramidal cells.

Activity-dependent attenuations in extracellular spike amplitude have been shown to correlate with a decrease in the effectiveness with which somatic action potentials back-propagate into the dendritic arbor of hippocampal pyramidal cells. In this paper we demonstrate that activity-dependent attenuations in amplitude occur during behavior and that the amount of attenuation is reduced with an animal's experience in an environment. The observed reductions are caused by an animal's experience within a specific environmental context, are dependent on functional NMDA receptors, and are accompanied by an increase in the effective coupling of pyramidal cells and interneurons. These results provide an important step in linking together in vivo studies with in vitro data and suggest that mechanisms of plasticity engaged during behavior may be sufficient to alter the biophysical and integrative properties of hippocampal pyramidal cells.

A residents' training program for the development of smoking intervention skills.

This article describes the results of a three-hour training program that teaches residents a patient-centered counseling approach to smoking cessation, emphasizing questioning and exploring feelings, rather than providing information. Fifty internal medicine and family practice residents affiliated with a university medical center were assessed before and after training using questionnaires and videotape documenting changes in their knowledge about smoking, attitudes concerning intervention, and intervention skills. The residents showed a significant increase in knowledge and perceived themselves as having significantly more influence on their patients who smoke after completion of the training program. Counseling skills improved significantly in the use of questions and exploring feelings as judged by blind evaluation of videotapes. The results of this three-hour training program suggest that physicians in training are responsive to the teaching of specialized skills deemed important for promoting health behavior changes in their patients.

Mechanisms of anemia in protein-energy malnutrition in Johannesburg.

Studies of red cell metabolism, erythropoeitin concentration, iron and folate status were made in 48 children with protein-energy malnutrition in Johannesburg (altitude 1800 m). Biochemical evidence of iron deficiency was presented in 26% cases on admission and developed in 90% during recovery. Biochemical evidence of folate deficiency was present in 14% of cases on admission and resolved on dietary therapy alone. Serum erythropoeitin was increased on admission and remained elevated during recovery. There was no relationship between serum erythropoeitin and Hb concentrations. Key enzymes in the red cell glycolytic and hexose monophosphate pathways and red cell membrane showed increased activity. Red cell adenosine triphosphate concentration was increased and unstable. Red cell potassium was decreased and, in the fatal cases, red cell sodium was increased. The possible significance and practical implications of these findings are discussed.

Interaction between spike waveform classification and temporal sequence detection.

In vivo extracellular recordings have allowed researchers to study the response properties of neurons to behaviorally relevant stimuli. In this paper we use multiple tetrode recordings from the hippocampus of the freely behaving rat to show that the action potential amplitude of a given cell can vary in a systematic and activity dependent manner over behaviorally relevant time scales. Since the discrimination algorithms used by experimenters to isolate cells from extracellular recordings are based on differences in waveforms, we show how these systematic changes in waveform shape can lead to non-random errors in single cell isolation. We further demonstrate that these non-random errors can lead to apparent temporal ordering effects between neurons in the absence of any specific temporal relationship. A firm understanding of these naturally occurring physiological changes is therefore critical for the evaluation of higher order phenomena such as the temporally correlated firing of ensembles of neurons.

Construction and analysis of non-Poisson stimulus-response models of neural spiking activity.

A paradigm for constructing and analyzing non-Poisson stimulus-response models of neural spike train activity is presented. Inhomogeneous gamma (IG) and inverse Gaussian (IIG) probability models are constructed by generalizing the derivation of the inhomogeneous Poisson (IP) model from the exponential probability density. The resultant spike train models have Markov dependence. Quantile-quantile (Q-Q) plots and Kolmogorov-Smirnov (K-S) plots are developed based on the rate-rescaling theorem to assess model goodness-of-fit. The analysis also expresses the spike rate function of the neuron directly in terms of its interspike interval (ISI) distribution. The methods are illustrated with an analysis of 34 spike trains from rat CA1 hippocampal pyramidal neurons recorded while the animal executed a behavioral task. The stimulus in these experiments is the animal's position in its environment and the response is the neural spiking activity. For all 34 pyramidal cells, the IG and IIG models gave better fits to the spike trains than the IP. The IG model more accurately described the frequency of longer ISIs, whereas the IIG model gave the best description of the burst frequency, i.e. ISIs < or = 20 ms. The findings suggest that bursts are a significant component of place cell spiking activity even when position and the background variable, theta phase, are taken into account. Unlike the Poisson model, the spatial and temporal rate maps of the IG and IIG models depend directly on the spiking history of the neurons. These rate maps are more physiologically plausible since the interaction between space and time determines local spiking propensity. While this statistical paradigm is being developed to study information encoding by rat hippocampal neurons, the framework should be applicable to stimulus-response experiments performed in other neural systems.

Quantitation of cytomegalovirus DNA by blot hybridization in blood leukocytes of viremic patients.

We describe a technique for quantitation of viral DNA in blood leukocytes during viremic infection with human cytomegalovirus (CMV). Using a cloned subgenomic DNA probe and a blot hybridization assay, small amounts of viral DNA within samples of leukocyte DNA could be quantitated reproducibly using a videodensitometer. Critical components of the assay were: (1) a direct relationship between optical density and known amounts of viral DNA diluted in cellular DNA as positive standard samples and, (2) determination of the proper duration of autoradiographic exposure. The technique was sufficiently sensitive to detect 10 picograms of CMV DNA in the presence of microgram quantities of host cell DNA. In addition, samples containing minute amounts of CMV DNA could reliably be distinguished from samples that were negative. We have used the technique to characterize the pathogenesis of CMV viremia and to monitor the effects of antiviral chemotherapy. This procedure could easily be applied to pathogenetic studies of a variety of other infectious agents.

Quantitation of human cytomegalovirus glycoprotein H gene in cells using competitive PCR and a rapid fluorescence-based detection system.

A technique is described for quantitation of the human cytomegalovirus (HCMV) glycoprotein H (gH) gene in cells using a quantitative-competitive polymerase chain reaction (QC-PCR). Two recombinant DNA molecules, differing in size due to a 92-bp deletion within the HCMV gH sequence, were used in co-amplification studies to construct a standard curve from which the copy number of the gH gene present in clinical samples could be interpolated. The use of primers labeled with a fluorescent dye allowed direct detection of the amplified products by measuring the amount of fluorescence emitted by each specific PCR fragment with an automated DNA sequencer coupled to a software program. This system was validated subsequently using bronchoalveolar lavage cells obtained from immunocompromised patients and found to be highly sensitive and reproducible over a range of 5-50,000 HCMV gH copies. This rapid procedure could easily be applied to study the pathogenesis of HCMV infection, identify the patients at high risk of developing HCMV disease, and monitor the effects of antiviral therapy at the molecular level.

Propagation and titration of murine cytomegalovirus in a continuous bone marrow-derived stromal cell line (M2-10B4).

Murine cytomegalovirus (MCMV) can only be propagated effectively in mouse embryo fibroblast (MEF) cells. We demonstrate that MCMV replicates significantly better in M2-10B4 cells, a continuous line of murine bone marrow stromal cells. M2-10B4 cells were also comparable to MEF cells for detection of small amounts of MCMV reactivating from latently infected spleen explants. M2-10B4 cells will be very useful for studies of MCMV pathogenesis.

Evaluation of two AIDS prevention interventions for inner-city adolescent and young adult women.

Two hundred and fourteen young women received acquired immunodeficiency syndrome (AIDS) prevention interventions at an inner-city family health center serving minority patients predominantly. The community in which the health center is located has a high incidence of intravenous (IV) drug abuse. Either a peer or a health care provider delivered the intervention. In the peer-delivered intervention, a trained peer educator reviewed with patients an AIDS "Rap" videotape and several AIDS brochures, which imparted information about human immunodeficiency virus (HIV), its transmission, and prevention. In the provider-delivered intervention, family practice residents, attending physicians, and nurse practitioners used a patient-centered counseling approach to convey the same information. Questionnaires administered immediately before and after the intervention and at one month follow-up evaluated changes in knowledge, attitudes, and behavior. Analyses of data from both combined intervention groups revealed significant improvements in several areas of knowledge, including the effectiveness of using a condom and cleaning IV drug implements with bleach to prevent transmission of HIV. Many improvements were retained at the one-month follow-up. In addition, subjects in both groups who were sexually active stated immediately after the intervention that asking a sexual partner about past sexual experience would now be less difficult, and at one-month follow-up they reported a significant decrease in the frequency of vaginal sex. Our findings suggest that counseling by physicians can achieve more changes in knowledge of sexual risks, whereas peer education can achieve greater changes in knowledge about IV drug use. Results show that both approaches to AIDS prevention used in this study can significantly affect knowledge, attitudes, and sexual behavior.

PIP: 214 women of average age 20.3 years were subject to an AIDS prevention intervention at a family health center in a high IV drug use community in Worcester, Massachusetts. 116 of the women learned about HIV, its transmission, and prevention with trained peer educators in a review of an AIDS "Rap" video and several AIDS brochures. The remaining 98 women were exposed to the same information, but in a patient-centered counseling approach with family practice residents, attending physicians, and nurse practitioners. 25 women were African-American, 105 Caucasian, 76 Hispanic, and 8 of other ethnic backgrounds. They answered questionnaires regarding their AIDS-related knowledge, attitudes, and practices immediately before, immediately after, and 1 month after exposure to either the peer educator or provider-based education sessions; only 97 completed the follow-up survey. The authors found knowledge on the effectiveness of using condoms and cleaning IV drug implements with bleach to prevent HIV transmission to have significantly improved following the interventions. Many improvements remained at the 1-month follow-up. Moreover, sexually active subjects in both groups noted immediately after the interventions that they would find it easier to ask sex partners about past sexual experiences. A significant decrease was also reported in the amount of vaginal sex at the 1-month follow-up. The authors conclude that while physician counseling may effect more change in the knowledge of sexual risks, peer education may better effect change in knowledge about IV drug use.

The impact of JRA on children, adolescents, and their families. Current research and implications for future studies.

This article focusses on the impact of Juvenile Rheumatoid Arthritis (JRA) on children, adolescents, and their families. Investigations reported in the literature that consider the etiologic role of psychopathology and JRA, psychologic adjustment/maladjustment of adolescents with JRA, family adaptation to chronic illness, and changes in the family that affect health outcomes and treatment compliance are critically reviewed. Methodologic and research design issues are discussed in relation to previous investigations, and implications for future research are presented.

The patient exit interview as an assessment of physician-delivered smoking intervention: a validation study.

In evaluating the efficacy of physician-delivered counseling interventions for health behavior changes such as smoking cessation, a major challenge is determining the degree to which interventions are implemented by physicians. The Patient Exit Interview (PEI; J. Ockene et al., 1991) is a brief measure of a patient's perception of the content and quantity of smoking cessation intervention received from his or her physician. One hundred eight current smokers seen in a primary care clinic completed a PEI following their physician visit. Participants were 45% male, 95% Caucasian, with a mean age of 42 years and an average of 22 years of smoking. The PEI correlated well with a criterion measure of an audiotape assessment of the physician-patient interaction (r = .67, p < .001). When discrepancy occurred, in general it was due to patients' over-reporting of intervention as compared with the criterion measure. Implications and limitations of these findings are discussed.

Evaluation of primary care futures: a faculty development program for community health center preceptors.

PURPOSE: To assess the impact of a national series of faculty development workshops for community health center preceptors. METHOD: Two hundred and twenty-three community health center preceptors from a variety of disciplines attended one of five workshops conducted in different regions of the country. The workshops emphasized active learning using role-play to provide skills in educational planning, teaching styles, evaluation, and feedback. The preceptors were evaluated before and immediately after the workshop, and again three months later. They were also asked to assess the quality of the workshop. RESULTS: The preceptors demonstrated significant increases in the use of five of seven teaching concepts while analyzing a role-play interaction. In addition, there were significant positive, immediate changes in familiarity with nine of 11 concepts, which were retained for at least three months. The preceptors also reported that they continued to use six of the effective teaching behaviors they had learned three months after the workshop. They were extremely positive in their assessments of the workshops. CONCLUSION: This preliminary study suggests that preceptors from a variety of backgrounds can improve their teaching knowledge and skills by participating in a brief faculty development program that emphasizes active learning.

Faculty development for community-based physicians at the University of Massachusetts and SUNY-Buffalo.

Community-based faculty development (CBFD) is becoming increasingly important as medical education moves into the ambulatory/office-based setting CBFD provides preceptors with essential knowledge, skills, and attitudes directly related to teaching while providing a sense of identity as teachers to a diverse group of practitioners in a variety of settings. This article reviews the structure and function of successful community-based faculty development, using as examples programs from the University of Massachusetts Medical School and the State University of New York at Buffalo that were supported by The Robert Wood Johnson Foundation's Generalist Physician Initiative. After reviewing the literature on successful implementation of programs dedicated to community-based precepting, the authors investigate the educational concepts, instructional designs, and operational characteristics that are the framework for providing successful faculty development to community-based preceptors. They list rationales and examples of the educational methods used and compare structural components of the programs at both institutions. Last, they explore future directions in the rapidly changing medical education environment that need to be addressed in CBFD in the areas of outcome/program evaluation, comprehensive needs assessment, and regionalization.