Antibodies Directed toward Neuraminidase N1 Control Disease in a Mouse Model of Influenza.

There is increasing evidence to suggest that antibodies directed toward influenza A virus (IAV) neuraminidase (NA) are an important correlate of protection against influenza in humans. Moreover, the potential of NA-specific antibodies to provide broader protection than conventional hemagglutinin (HA) antibodies has been recognized. Here, we describe the isolation of two monoclonal antibodies, N1-7D3 and N1-C4, directed toward the N1 NA. N1-7D3 binds to a conserved linear epitope in the membrane-distal, carboxy-terminal part of the NA and reacted with the NA of seasonal H1N1 isolates ranging from 1977 to 2007 and the 2009 H1N1pdm virus, as well as A/Vietnam/1194/04 (H5N1). However, N1-7D3 lacked NA inhibition (NI) activity and the ability to protect BALB/c mice against a lethal challenge with a range of H1N1 viruses. Conversely, N1-C4 bound to a conformational epitope that is conserved between two influenza virus subtypes, 2009 H1N1pdm and H5N1 IAV, and displayed potent in vitro antiviral activity mediating both NI and plaque size reduction. Moreover, N1-C4 could provide heterosubtypic protection in BALB/c mice against a lethal challenge with 2009 H1N1pdm or H5N1 virus. Glutamic acid residue 311 in the NA was found to be critical for the NA binding and antiviral activity of monoclonal antibody N1-C4. Our data provide further evidence for cross-protective epitopes within the N1 subtype and highlight the potential of NA as an important target for vaccine and therapeutic approaches.IMPORTANCE Influenza remains a worldwide burden on public health. As such, the development of novel vaccines and therapeutics against influenza virus is crucial. Human challenge studies have recently highlighted the importance of antibodies directed toward the viral neuraminidase (NA) as an important correlate of reduced influenza-associated disease severity. Furthermore, there is evidence that anti-NA antibodies can provide broader protection than antibodies toward the viral hemagglutinin. Here, we describe the isolation and detailed characterization of two N1 NA-specific monoclonal antibodies. One of these monoclonal antibodies broadly binds N1-type NAs, and the second displays NA inhibition and in vitro and in vivo antiviral activity against 2009 H1N1pdm and H5N1 influenza viruses. These two new anti-NA antibodies contribute to our understanding of the antigenic properties and protective potential of the influenza virus NA antigen.

Inflammatory monocytes regulate Th1 oriented immunity to CpG adjuvanted protein vaccines through production of IL-12.

Due to their capacity to skew T cell responses towards Th1 oriented immunity, oligonucleotides containing unmethylated CpG motifs (CpG) have emerged as interesting adjuvants for vaccination. Whereas the signalling pathways in response to CpG mediated TLR9 activation have been extensively documented at the level of the individual cell, little is however known on the precise identity of the innate immune cells that govern T cell priming and polarisation to CpG adjuvanted protein antigens in vivo. In this study, we demonstrate that optimal induction of Th1 oriented immunity to CpG adjuvanted protein vaccines requires the coordinated actions of conventional DCs and of monocytes. Whilst conventional DCs were required for antigen presentation and initial T cell priming, monocytes constitute the main source of the Th1 polarising cytokine IL-12.

Carbohydrate supplementation of horses during endurance exercise: comparison of fructose and glucose.

To delay the onset of fatigue, endurance horses are often fed at rest stops during races. The resulting increase in blood insulin may adversely inhibit lipolysis. In humans, ingestion of fructose produces a smaller insulin rise than glucose. This study compared glucose and fructose as carbohydrate supplements for endurance horses. Three Arabian geldings were given 300 g of fructose (F), glucose (G) or 50% glucose: 50% fructose (GF), in 1.5 L water, by stomach tube. In the Resting Test, carbohydrate was administered at rest. Following treatment, blood samples were taken every 30 min for 8 h, and feces were collected for 24 h. Treatment did not affect fecal weight or water content. Plasma glucose and insulin responses did not differ among treatments. Post-treatment (60 min), plasma L-lactate tended to be higher (P = 0.06) after the F and GF treatments than after the G treatment. In the Exercise Test, two treadmill exercise bouts at 0 degrees incline (Bout 1: 90 min; Bout 2: 120 min) were separated by a 1-h rest period. A total distance of 36.84 km was covered at a mean speed of 2.9 m/s. Carbohydrate was administered 45 min before Bout 2. Plasma glucose and insulin at the start of Bout 2 were higher (P = 0.02 and 0.03, respectively) with the GF treatment than with the F treatment. However, during exercise, plasma glucose concentrations did not differ among treatments. We conclude that fructose is well-absorbed by horses and rapidly converted to glucose.

Risperidone (R64 766) in psychotic patients. A first clinical therapeutic exploration.

Seventeen therapy-resistant adult male psychotic inpatients were treated in an exploratory open study with the new combined serotonin-S2 and dopamine-D2 antagonist risperidone (R 64 766). The mean daily dose was 4.5 mg orally, and the mean duration of treatment 6 months. There were 11 responders, 5 non-responders and 1 drop-out. Risperidone combined an effective antidelusional potency with important contact- and mood-improving properties, while at the same time it reduced existing extrapyramidal symptoms (EPS). Three out of the 5 non-responders were probably underdosed. Risperidone was very well tolerated, reported side effects were mild and transient, and no reason for premature interruption of the therapy.

Haloperidol decanoate as a replacement for maintenance therapy with intramuscular fluphenazine decanoate in schizophrenia and other chronic psychoses.

Thirty-five psychotic male inpatients receiving optimal neuroleptic maintenance therapy, with fluphenazine decanoate (once every 3-weeks), and one receiving chlorpromazine entered a 24-week study with haloperidol decanoate administered once every 4 weeks, at a dose based on mg equivalence between fluphenazine decanoate and haloperidol decanoate; as regards the latter, this dose was estimated to be comparable with 20 times a daily haloperidol dose. Psychotic symptom severity, evaluated at the end of each treatment period by 8 out of 9 assessed symptoms from the Brief Psychiatric Rating Scale, showed haloperidol decanoate to be of similar efficacy to previously used maintenance medication. The symptom emotional withdrawal was significantly improved by the end of the study. In addition, 18 patients out of 20 were successfully withdrawn from antiparkinsonian therapy without experiencing an enhancement of extrapyramidal side-effects.