A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity

BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract–immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4⁺ and CD8⁺ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01443936","term_id":"NCT01443936"}}NCT01443936 and {"type":"clinical-trial","attrs":{"text":"NCT01806909","term_id":"NCT01806909"}}NCT01806909.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C).     

Muscle fatigue in some neurological disorders

Fatigue of tibialis anterior (TA) was induced by repetitive electrical stimulation. Using this test, patients with upper motor neuron muscle weakness owing to multiple sclerosis (MS) and injuries to the spinal cord showed greater fatigability of their TA muscles, suggesting that the muscle fiber population changed toward that typical of fatigable motor units. During repetitive stimulation, in addition to the decrement in tension there was an increase in half-relaxation time of tetanic contractions at 40 Hz in both subjects and patients. The increase in half relaxation during repeated activity was greater in patients with MS and spinal cord injury than in healthy subjects, suggesting that the long-term inactivity affected the efficiency of the Ca2+ uptake mechanism of their muscle fibers. Thus long-term inactivity of patients with upper motoneuron dysfunction leads to increased fatigability of their muscles and exaggerates the slowing of muscle relaxation after prolonged exercise.     

Regularity and latency of units in ventral cochlear nucleus: implications for unit classification and generation of response properties

1. The responses of neurons in the ventral cochlear nucleus (VCN) of decerebrate cats are described with regard to their regularity of discharge and latency. Regularity is measured by estimating the mean and standard deviation of interspike intervals as a function of time during responses to short tone bursts (25 ms). This method extends the usual interspike-interval analysis based on interval histograms by allowing the study of temporal changes in regularity during transient responses. The coefficient of variation (CV), equal to the ratio of standard deviation to mean interspike interval, is used as a measure of irregularity. Latency is measured as the mean and standard deviation of the latency of the first spike in response to short tone bursts, with 1.6-ms rise times. 2. The regularity and latency properties of the usual PST histogram response types are shown. Five major PST response type classes are used: chopper, primary-like, onset, onset-C, and unusual. The presence of a prepotential in a unit's action potentials is also noted; a prepotential implies that the unit is recorded from a bushy cell. 3. Units with chopper PST histograms give the most regular discharge. Three varieties of choppers are found. Chop-S units (regular choppers) have CVs less than 0.35 that are approximately constant during the response; chop-S units show no adaptation of instantaneous rate, as measured by the inverse of the mean interspike interval. Chop-T units have CVs greater than 0.35, show an increase in irregularity during the response and show substantial rate adaptation. Chop-U units have CVs greater than 0.35, show a decrease in irregularity during the response, and show a variety of rate adaptation behaviors, including negative adaptation (an increase in rate during a short-tone response). Irregular choppers (chop-T and chop-U units) rarely have CVs greater than 0.5. Choppers have the longest latencies of VCN units; all three groups have mean latencies at least 1 ms longer than the shortest auditory nerve (AN) fiber mean latencies. 4. Chopper units are recorded from stellate cells in VCN (35, 42). Our results for chopper units suggest a model for stellate cells in which a regularly firing action potential generator is driven by the summation of the AN inputs to the cell, where the summation is low-pass filtered by the membrane capacitance of the cell.(ABSTRACT TRUNCATED AT 400 WORDS)     

Synergistic effects of dopamine agonists and centrally administered neurotensin on feeding

Several lines of evidence indicate that neurotensin may modulate the activity of dopamine systems in the central nervous system. The present study investigated the possibility that intraperitoneal injections of the dopamine agonists l-dopa and bromocriptine would alter the aphagia produced by central administration of neurotensin. It was found that neurotensin suppressed feeding in food-deprived rats when injected into the lateral ventricle or the ventromedial hypothalamus. Food intake was not affected, however, when the peptide was placed in the lateral hypothalamus. A dose-dependent aphagia was also observed following peripheral injections of l-dopa and bromocriptine. Additionally, the anorectic effect of centrally administered neurotensin was potentiated by concurrent administration of doses of l-dopa or bromocriptine which, when given alone, had no effect on food intake. The data suggest that neurotensin aphagia may be mediated by the peptide's ability to increase the activity of dopamine systems in the central nervous system.     

A simple stereotactic method for frameless deep brain stimulation

BACKGROUND: Deep brain stimulation (DBS) is widely used to treat advanced Parkinson's disease, other movement and psychiatric disorders. DBS implantation requires application of a stereotactic frame throughout a lengthy procedure, making it uncomfortable and tiring. We designed a stereotactic cube to stage the operation, perform frameless microelectrode recording (MER) and fix the DBS. METHODS: The 15-mm cube is implanted in a burr hole using bone cement. It contains 5 parallel trajectories (central + 4 around). It is aligned by stereotactic frame so that central trajectory reaches the target. Frameless MER is performed by attaching a micro-driver to the cube using 2-5 cannulae (4 cm). The DBS is fixed to the cube by a mini-plate and 1 screw. Ninety-six cubes were compared with 43 Bennet spheres (BS). RESULTS: No cube moved compared to 2 (5%) BS (p < 0.05). The final trajectory was central in 64.4% of cubes compared to 47.5% of BS, and the final target was >2 mm out in no cubes compared to 12.5% of BS (p < 0.01). Infection and haemorrhage were observed in 2.5% and 3.3% of cubes, respectively, while 5% of BS developed infection, 5% haemorrhage and 7.5% skin erosion. CONCLUSIONS: This method is simple and effective in staging DBS procedures, performing frameless MER and DBS implantation, fixation and revision.