Multiplexed, High Density Electrophysiology with Nanofabricated Neural Probes

Extracellular electrode arrays can reveal the neuronal network correlates of behavior with single-cell, single-spike, and sub-millisecond resolution. However, implantable electrodes are inherently invasive, and efforts to scale up the number and density of recording sites must compromise on device size in order to connect the electrodes. Here, we report on silicon-based neural probes employing nanofabricated, high-density electrical leads. Furthermore, we address the challenge of reading out multichannel data with an application-specific integrated circuit (ASIC) performing signal amplification, band-pass filtering, and multiplexing functions. We demonstrate high spatial resolution extracellular measurements with a fully integrated, low noise 64-channel system weighing just 330 mg. The on-chip multiplexers make possible recordings with substantially fewer external wires than the number of input channels. By combining nanofabricated probes with ASICs we have implemented a system for performing large-scale, high-density electrophysiology in small, freely behaving animals that is both minimally invasive and highly scalable

Experimental Lagos bat virus infection in straw-colored fruit bats: A suitable model for bat rabies in a natural reservoir species.

Rabies is a fatal neurologic disease caused by lyssavirus infection. Bats are important natural reservoir hosts of various lyssaviruses that can be transmitted to people. The epidemiology and pathogenesis of rabies in bats are poorly understood, making it difficult to prevent zoonotic transmission. To further our understanding of lyssavirus pathogenesis in a natural bat host, an experimental model using straw-colored fruit bats (Eidolon helvum) and Lagos bat virus, an endemic lyssavirus in this species, was developed. To determine the lowest viral dose resulting in 100% productive infection, bats in five groups (four bats per group) were inoculated intramuscularly with one of five doses, ranging from 100.1 to 104.1 median tissue culture infectious dose (TCID50). More bats died due to the development of rabies after the middle dose (102.1 TCID50, 4/4 bats) than after lower (101.1, 2/4; 101.1, 2/4) or higher (103.1, 2/4; 104.1, 2/4) doses of virus. In the two highest dose groups, 4/8 bats developed rabies. Of those bats that remained healthy 3/4 bats seroconverted, suggesting that high antigen loads can trigger a strong immune response that abrogates a productive infection. In contrast, in the two lowest dose groups, 3/8 bats developed rabies, 1/8 remained healthy and seroconverted and 4/8 bats remained healthy and did not seroconvert, suggesting these doses are too low to reliably induce infection. The main lesion in all clinically affected bats was meningoencephalitis associated with lyssavirus-positive neurons. Lyssavirus antigen was detected in tongue epithelium (5/11 infected bats) rather than in salivary gland epithelium (0/11), suggesting viral excretion via the tongue. Thus, intramuscular inoculation of 102.1 TCID50 of Lagos bat virus into straw-colored fruit bats is a suitable model for lyssavirus associated bat rabies in a natural reservoir host, and can help with the investigation of lyssavirus infection dynamics in bats

Pathogenesis of bat rabies in a natural reservoir: Comparative susceptibility of the straw-colored fruit bat (Eidolon helvum) to three strains of Lagos bat virus.

Rabies is a fatal neurologic disease caused by lyssavirus infection. People are infected through contact with infected animals. The relative increase of human rabies acquired from bats calls for a better understanding of lyssavirus infections in their natural hosts. So far, there is no experimental model that mimics natural lyssavirus infection in the reservoir bat species. Lagos bat virus is a lyssavirus that is endemic in straw-colored fruit bats (Eidolon helvum) in Africa. Here we compared the susceptibility of these bats to three strains of Lagos bat virus (from Senegal, Nigeria, and Ghana) by intracranial inoculation. To allow comparison between strains, we ensured the same titer of virus was inoculated in the same location of the brain of each bat. All bats (n = 3 per strain) were infected, and developed neurological signs, and fatal meningoencephalitis with lyssavirus antigen expression in neurons. There were three main differences among the groups. First, time to death was substantially shorter in the Senegal and Ghana groups (4 to 6 days) than in the Nigeria group (8 days). Second, each virus strain produced a distinct clinical syndrome. Third, the spread of virus to peripheral tissues, tested by hemi-nested reverse transcriptase PCR, was frequent (3 of 3 bats) and widespread (8 to 10 tissues positive of 11 tissues examined) in the Ghana group, was frequent and less widespread in the Senegal group (3/3 bats, 3 to 6 tissues positive), and was rare and restricted in the Nigeria group (1/3 bats, 2 tissues positive). Centrifugal spread of virus from brain to tissue of excretion in the oral cavity is required to enable lyssavirus transmission. Therefore, the Senegal and Ghana strains seem most suitable for further pathogenesis, and for transmission, studies in the straw-colored fruit bat

The challenges of transferring chronic illness patients to adult care: reflections from pediatric and adult rheumatology at a US academic center

<p>Abstract</p> <p>Background</p> <p>Little is known about the transfer of care process from pediatric to adult rheumatology for patients with chronic rheumatic disease. The purpose of this study is to examine changes in disease status, treatment and health care utilization among adolescents transferring to adult care at the University of California San Francisco (UCSF).</p> <p>Methods</p> <p>We identified 31 eligible subjects who transferred from pediatric to adult rheumatology care at UCSF between 1995–2005. Subject demographics, disease characteristics, disease activity and health care utilization were compared between the year prior to and the year following transfer of care.</p> <p>Results</p> <p>The mean age at the last pediatric rheumatology visit was 19.5 years (17.4–22.0). Subject diagnoses included systemic lupus erythematosus (52%), mixed connective tissue disease (16%), juvenile idiopathic arthritis (16%), antiphospholipid antibody syndrome (13%) and vasculitis (3%). Nearly 30% of subjects were hospitalized for disease treatment or management of flares in the year prior to transfer, and 58% had active disease at the time of transfer. In the post-transfer period, almost 30% of subjects had an increase in disease activity. One patient died in the post-transfer period. The median transfer time between the last pediatric and first adult rheumatology visit was 7.1 months (range 0.7–33.6 months). Missed appointments were common in the both the pre and post transfer period.</p> <p>Conclusion</p> <p>A significant percentage of patients who transfer from pediatric to adult rheumatology care at our center are likely to have active disease at the time of transfer, and disease flares are common during the transfer period. These findings highlight the importance of a seamless transfer of care between rheumatology providers.</p

Computational and Statistical Analyses of Amino Acid Usage and Physico-Chemical Properties of the Twelve Late Embryogenesis Abundant Protein Classes

Late Embryogenesis Abundant Proteins (LEAPs) are ubiquitous proteins expected to play major roles in desiccation tolerance. Little is known about their structure - function relationships because of the scarcity of 3-D structures for LEAPs. The previous building of LEAPdb, a database dedicated to LEAPs from plants and other organisms, led to the classification of 710 LEAPs into 12 non-overlapping classes with distinct properties. Using this resource, numerous physico-chemical properties of LEAPs and amino acid usage by LEAPs have been computed and statistically analyzed, revealing distinctive features for each class. This unprecedented analysis allowed a rigorous characterization of the 12 LEAP classes, which differed also in multiple structural and physico-chemical features. Although most LEAPs can be predicted as intrinsically disordered proteins, the analysis indicates that LEAP class 7 (PF03168) and probably LEAP class 11 (PF04927) are natively folded proteins. This study thus provides a detailed description of the structural properties of this protein family opening the path toward further LEAP structure - function analysis. Finally, since each LEAP class can be clearly characterized by a unique set of physico-chemical properties, this will allow development of software to predict proteins as LEAPs

Subjective response to antipsychotic treatment and compliance in schizophrenia. A naturalistic study comparing olanzapine, risperidone and haloperidol (EFESO Study)

BACKGROUND: In order to compare the effectiveness of different antipsychotic drugs in the treatment of schizophrenia it is very important to evaluate subjective response and compliance in patient cohorts treated according to routine clinical practice. METHOD: Outpatients with schizophrenia entered this prospective, naturalistic study when they received a new prescription for an antipsychotic drug. Treatment assignment was based on purely clinical criteria, as the study did not include any experimental intervention. Patients treated with olanzapine, risperidone or haloperidol were included in the analysis. Subjective response was measured using the 10-item version of the Drug Attitude Inventory (DAI-10), and treatment compliance was measured using a physician-rated 4 point categorical scale. RESULTS: A total of 2128 patients initiated treatment (as monotherapy) with olanzapine, 417 with risperidone, and 112 with haloperidol. Olanzapine-treated patients had significantly higher DAI-10 scores and significantly better treatment compliance compared to both risperidone- and haloperidol-treated patients. Risperidone-treated patients had a significantly higher DAI-10 score compared to haloperidol-treated patients. CONCLUSION: Subjective response and compliance were superior in olanzapine-treated patients, compared to patients treated with risperidone and haloperidol, in routine clinical practice. Differences in subjective response were explained largely, but not completely, by differences in incidence of EPS

Hepatitis Vaccination of Men Who Have Sex with Men at Gay Pride Events

Prevention researchers have advocated primary prevention such as vaccination in alternative venues. However, there have been major questions about both the attendance of, and the ability to, vaccinate high-risk individuals in such settings. The current study seeks to assess the feasibility of vaccinating high-risk men who have sex with men (MSM) at Gay Pride events. The research questions are: Do gay men who are sampled at Gay Pride events engage in more or less risky behavior than gay men sampled at other venues? Do the gay men who receive hepatitis vaccinations at Gay Pride engage in more or less risky behavior than gay men at Gay Pride who do not receive hepatitis vaccination? Of the 3689 MSM that completed the Field Risk Assessment (FRA), 1095/3689 = 29.68% were recruited at either the 2006 or 2007 Long Beach, California Gay Pride events. The remaining, 2594/3689 = 70.32% were recruited at Long Beach gay bars, gay community organizations and institutions, and through street recruitment in various gay enclaves in the Long Beach area. Logistic regression analysis yielded eight factors that were associated with non-attendance of Gay Pride: Age, had sex while high in the last 12 months, had unprotected anal intercourse (UAI) in the last 12 months, had sex for drugs/money in the last 12 months, been diagnosed with a sexually transmitted infection (STI) in the last 12 months, used nitrites (poppers) in the last 12 months, and used methamphetamine in the last 12 months. Identifying as White, Asian, or African American compared to Hispanic was also associated with non-attendance. Bivariate analysis indicated that, of the MSM sampled at Gay Pride, 280/1095 = 25.57% received a hepatitis vaccination there. The MSM sampled at Gay Pride who reported engaging in UAI or having used any stimulant (cocaine, crack-cocaine, or methamphetamine) in the last 12 months were more likely to receive hepatitis vaccination on-site. The results provide evidence for the viability of successfully vaccinating high-risk MSM at Gay Pride events. However, it is vital that no-cost vaccinations are also funded in other community settings such as STI clinics, drug treatment programs, prisons, universities, and other community resource centers in order to reach those additional high-risk MSM who do not attend Gay Pride

Age-Related Changes of Myelin Basic Protein in Mouse and Human Auditory Nerve

Age-related hearing loss (presbyacusis) is the most common type of hearing impairment. One of the most consistent pathological changes seen in presbyacusis is the loss of spiral ganglion neurons (SGNs). Defining the cellular and molecular basis of SGN degeneration in the human inner ear is critical to gaining a better understanding of the pathophysiology of presbyacusis. However, information on age-related cellular and molecular alterations in the human spiral ganglion remains scant, owing to the very limited availably of human specimens suitable for high resolution morphological and molecular analysis. This study aimed at defining age-related alterations in the auditory nerve in human temporal bones and determining if immunostaining for myelin basic protein (MBP) can be used as an alternative approach to electron microscopy for evaluating myelin degeneration. For comparative purposes, we evaluated ultrastructural alternations and changes in MBP immunostaining in aging CBA/CaJ mice. We then examined 13 temporal bones from 10 human donors, including 4 adults aged 38–46 years (middle-aged group) and 6 adults aged 63–91 years (older group). Similar to the mouse, intense immunostaining of MBP was present throughout the auditory nerve of the middle-aged human donors. Significant declines in MBP immunoreactivity and losses of MBP+ auditory nerve fibers were observed in the spiral ganglia of both the older human and aged mouse ears. This study demonstrates that immunostaining for MBP in combination with confocal microscopy provides a sensitive, reliable, and efficient method for assessing alterations of myelin sheaths in the auditory nerve. The results also suggest that myelin degeneration may play a critical role in the SGN loss and the subsequent decline of the auditory nerve function in presbyacusis

COPDGene® 2019: Redefining the Diagnosis of Chronic Obstructive Pulmonary Disease

Background:Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene®), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods:Four key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results:Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics. Conclusions:A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop