In the free-looking task (as part of the stable value procedure)

In the free-looking task (as part of the stable value procedure) that induced automatic saccades (Figure 1D), caudate tail neurons showed presaccadic activity that was significantly stronger to preferred value objects than to nonpreferred value objects (Figure 7B, bottom). Such

presaccadic activity was absent in caudate head neurons (Figure 7B, top). The caudate tail-specific activity preceding automatic saccades was confirmed using a free-viewing procedure (Figure S5) in which four objects, chosen SKI-606 mouse randomly on each trial, were presented simultaneously and the monkey looked at them with no reward consequence. To further test the flexible-stable dichotomy hypothesis, we selectively inactivated the caudate head or the caudate tail by injecting a GABAA receptor agonist, muscimol (Figure 8A). The inactivation of the caudate head disrupted the initiation of saccades in the flexible value task (which we call controlled saccades) (Figure 8B, top). Before the inactivation, the target acquisition time on single object trials was significantly shorter for high-valued objects than for low-valued objects (Figure 1B, Figure S6B, left). This bias of controlled saccades decreased significantly during the caudate head inactivation

(Figure 8B, top) but Selleckchem PF-06463922 only for contralateral saccades (from 69.7 ms to 20.4 ms; p < 0.01, paired t test). The bias decrease was largely due to earlier saccades to low-valued objects (Figure S6B, top). The caudate head inactivation also disrupted the choice of the high-valued objects in the flexible value task (Figure S7C, top), again only for contralateral saccades (p < 0.05, paired t test), when four, not two, objects were used. However, the caudate head inactivation did not affect saccades in the stable value procedure using either the free-looking task (Figure 8C,

aminophylline top) or the free-viewing procedure (Figure S8B). In contrast, the inactivation of the caudate tail specifically disrupted the initiation of saccades in the stable value task (free-looking task) (Figure 8C, bottom). Before the inactivation, the likelihood of saccades to the presented object (which we call automatic saccades) was higher for high-valued objects than for low-valued objects (Figure 1D, Figure S6D, left). This bias of automatic saccades disappeared during the caudate tail inactivation (Figure 8C, bottom) but only for contralateral saccades (from 19.9% to −1.2%; p < 0.01, paired t test). The bias decrease was largely due to more frequent saccades to low-valued objects (Figure S6D, bottom). Among the saccades made to the presented object, there was no change in latency.

Intrinsic autofluorescence imaging responses (Figures 1B and S1B)

Intrinsic autofluorescence imaging responses (Figures 1B and S1B) suggested that, of these three higher visual areas, areas AL and PM were strongly driven by different combinations of spatial and temporal frequencies, while area LM demonstrated a response profile more similar to that of area V1 (Figure 1B; see also Van den Bergh et al., 2010 and Wang and Burkhalter, 2007). For this reason, we targeted our calcium imaging experiments to areas

AL, PM, and V1 (Figures 1C and 1D). During calcium Dolutegravir price imaging—both widefield epifluorescence imaging of entire areas (Figures 1C and 1D) and two-photon laser-scanning microscopy of individual neurons (Figure 2, Figure 3 and Figure 4)—we presented stimuli at one of five spatial frequencies and seven temporal frequencies, corresponding to a range of stimulus speeds of almost three orders of magnitude. Figure 1D illustrates the average visual responses of GCaMP3-labeled neurons within areas AL and PM of an example mouse, using widefield calcium imaging. We observed clear differences in spatial and temporal frequency sensitivity across areas. Specifically, area AL preferred lower spatial and higher temporal frequencies (and thus, higher speeds), Selleckchem VE-821 while area PM preferred higher spatial and lower temporal frequencies (and lower speeds). While widefield imaging can reveal such population biases, it

cannot assess the diversity of tuning across individual neighboring neurons. Thus, we concentrated our efforts on two-photon cellular imaging of GCaMP3 fluorescence. To determine the diversity in stimulus preferences of neurons within and across areas in awake mouse, we recorded cellular calcium responses using two-photon imaging in layer II/III of cortical areas V1, AL, and PM (Figure 2A). We confirmed the precise location of the imaged volume by comparing surface vasculature in two-photon and widefield images (see Experimental Procedures). We recorded calcium signals simultaneously

from several dozen neurons in a volume spanning ∼ 200 μm new × 200 μm × 45 μm at a rate of 1 Hz (using a piezoelectric objective Z-scanner; Kerlin et al., 2010). By correcting for slow drifts in neuron location within the imaged volume (<10 μm), we were able to record robust evoked responses from the same neurons for several hours, allowing estimation of the spatial and temporal frequency tuning for individual neurons, as illustrated in Figures 2B and 2C (top panels). Responses in the spatial by temporal frequency plane were fit to oriented two-dimensional Gaussians (Figures 2B and 2C, bottom panels; see Priebe et al., 2006 and Experimental Procedures) to quantify the tuning for spatial and temporal frequency and speed. These estimates were obtained from trials when the mouse was either stationary or walking freely on the trackball.

These data suggest that Brm likely acts upstream of Sox14 to cont

These data suggest that Brm likely acts upstream of Sox14 to control its expression but appears to not directly regulate the expression of mical, a Sox14 target gene, in ddaC neurons. Thus, Brm appears to play a specific role in regulating the expression of Sox14, but not some other components of the EcR-B1/Sox14/Mical pathway. We next examined Brm expression and compared its expression pattern with EcR-B1. Brm was KPT-330 manufacturer expressed and localized in the nuclei of ddaCs and other dorsal da neurons (Figure S2B), whereas it was absent in brm MARCM ddaC clones ( Figure S2D). In contrast to drastic upregulation of EcR-B1 from the early third instar larval (eL3) stage to the

WP stage in ddaCs ( Kirilly et al., 2009), Brm levels remained largely constant ( Figures S2G and S2H). Consistently, inhibition of ecdysone signaling by EcRDN overexpression had no effect

on the expression levels of Brm in the WP ddaCs ( Figure S2F). These data indicate that Brm is expressed independently of ecdysone signaling. The observation that the Brm remodeler regulates dendrite pruning prompted us to systematically investigate the involvement of histone modifiers, including histone acetyltransferases/deacetylases and methyltransferases/demethylases in ddaC dendrite pruning. We examined 49 genes that potentially regulate enzymatic functions and assembly of various histone modification complexes click here (Table S1; also see Supplemental Experimental Procedures) via RNAi. From these HATs, CBP was the only gene we isolated that was required for ddaC dendrite pruning. CBP functions as a HAT as well as a transcriptional coactivator during gene activation ( Bantignies et al., 2000). Perturbation of its histone acetyltransferase activity is implicated in

neurological disorders, such as Rubinstein-Taybi syndrome (RTS) ( Wang et al., 2010) and polyglutamine expansion diseases ( Steffan et al., 2001). CBP RNAi knockdown with two independent RNAi lines, GD3787 (#1) and KK105115 (#2) ( Dietzl et al., 2007), resulted in severe dendrite pruning defects in ddaC neurons: an average of 9 (n = 21; Figures 3B, 3B′, and 3F) and 12 Ergoloid (n = 30; Figures 3C, 3C′, and 3F) primary and secondary dendrites, respectively, persisted at 18 hr APF. Using a third CBP RNAi line (#3) that was previously published ( Kumar et al., 2004), the knockdown of CBP exhibited a similarly strong dendrite pruning defect, with an average of 11.9 primary and secondary dendrites (n = 29; Figures 3D, 3D′, and 3F), whereas all dendrites were pruned in the wild-type ddaC neurons (n = 15; Figures 3A, 3A′, and 3F) at 18 hr APF. The larval dendrites of CBP RNAi ddaCs were largely removed by 30 hr APF (n = 6; Figure S3A), similar to those of BrmDN-overexpressing ddaCs.

, 2008), which makes the duration of its action too short for con

, 2008), which makes the duration of its action too short for convenient and compliant use as an oral monthly product. Spinosad, on the other hand, has a long plasma half-life of 7–10 days (Holmstrom et al., 2012) therefore preventing and treating flea infestations for one month. In contrast to the currently available oral antiparasitic agents for dogs, the ideal pharmacokinetic and efficacy profile would demonstrate both a rapid onset of action and monthly duration of efficacy against fleas and multiple tick species. These attributes are achieved with an easy-to-administer oral soft chewable formulation for dogs, as demonstrated by the afoxolaner pharmacokinetic profile and PK/PD correlation

SB203580 discussed herein and supported by both efficacy and safety data. Protein binding was determined via equilibrium dialysis using a Dianorm Multi-Equilibrium DIALYZER at 200, 500, 1000, 2000 and 10,000 ng/mL of afoxolaner in dog plasma Talazoparib cell line with buffer and plasma chambers separated by a semi-permeable cellulose membrane with a molecular weight cutoff of 10,000 Dalton. Incubations were performed for 2.5 h (37 °C), after which the afoxolaner concentrations were measured in the buffer and plasma compartments using LC–MS analysis (see below). For all in vivo studies, animals were treated with the final formulation of afoxolaner except when noted. All dogs were purpose-bred, ≥6 months of age, and weighed approximately 5–19 kg.

The number of dogs in each study and other study details are described in Table 1 and in the text below. All animal procedures in these studies were reviewed and approved by Merial Institutional Tryptophan synthase Animal Care and Use Committee (IACUC) and dogs were handled with due regard for their welfare (USDA, 2008, 9 CFR). Blood samples

were taken prior to treatment, and periodically until the end of each study. All blood samples were processed into plasma and stored frozen until analyzed. Afoxolaner plasma concentrations were determined using a validated LC–MS method (Nguyen, unpublished data) and pharmacokinetic analysis via noncompartmental and/or compartmental analysis was performed. All study times are relative to Day 0, the day of dosing. Six pharmacokinetic studies were performed. The purpose and study design details are given in Table 1. Some details of PK Study 6 and two efficacy studies are given below. Six male Beagles were studied to determine the renal and biliary clearance of afoxolaner when administered as a soft chewable formulation once, orally, at 30–45 mg/kg (PK Study 6). Four of the dogs underwent bile duct cannulation prior to study start to allow bile collection throughout the study. Hematology and serum chemistry samples from all dogs were evaluated prior to treatment to assure normal liver functioning. Dogs were fasted prior to treatment. Plasma, urine and bile samples were collected and stored frozen (−20 °C) until analysis.

Our findings reveal that the interaction of Sema6D, Plexin-A1, an

Our findings reveal that the interaction of Sema6D, Plexin-A1, and Nr-CAM on chiasm cells inverts the sign of Sema6D signaling and represents a switch mechanism crucial for chiasm crossing. The deployment of distinct receptor subunits has been shown to switch axonal responses to an individual guidance molecule in many different neural systems. As one example, Sema3E is a repulsive cue for distinct populations of forebrain axons that express Plexin-D1 alone, but when Neuropilin1 and Plexin-D1 are coexpressed by these axons, Sema3E signaling promotes rather than retards growth (Chauvet SB431542 in vivo et al., 2007). In an analogous manner the expression of the netrin receptor, unc5, and

its vertebrate counterparts (UNC5H1-3) can change the response of its coreceptor unc40/DCC to the guidance factor unc-6/netrin from attraction to repulsion (Chisholm and Tessier-Lavigne, 1999, Culotti and Merz,

1998 and Hong et al., 1999). In these and other instances, a change in the receptor complex expressed by axons underlies the switch in response to guidance cues. The scenario we describe in this study is conceptually different in that the expression of Nr-CAM and Plexin-A1 by ligand-presenting midline cells triggers the switch in axonal response. Although we recognize the existence of other conceivable strategies for switching the response of RGCs to Sema6D (Figure S8), our data can best be explained by a model in which Nr-CAM Selleckchem BI6727 and Plexin-A1 on chiasm cells modulate the interaction of the Sema6D ligand with Nr-CAM and Plexin-A1 receptors many on RGCs. The fact that Plexin-A1 and Nr-CAM are expressed by the ligand-presenting cells (midline glia and chiasm neurons) as well as by RGCs poses the question

of how they change RGC axon interactions with Sema6D. One possibility is that Nr-CAM and Plexin-A1 on chiasm cells alter the conformation of the Nr-CAM and Plexin-A1 receptor system on RGCs. This altered receptor state would then transduce Sema6D signals in a manner different from that of Sema6D alone. An alternative idea is that the conformation of Sema6D on midline glia is changed by its interaction with Nr-CAM on midline glia and with Plexin-A1 on chiasm neurons, such that Sema6D association with the Nr-CAM/Plexin-A1 receptor system on RGC axons triggers growth rather than inhibition (Figure 8D). Evaluation in vivo of the phenotype of Sema6Dflox/flox, Plexin-A1flox/flox, and Nr-CAMflox/flox mice will require the construction of new and more selective means of gene inactivation in chiasm cells. Furthermore, although the detailed organization of the Sema6D/Nr-CAM/Plexin-A1 receptor complex is not yet known, the structural characterization of semaphorin ligands bound to plexin receptors ( Janssen et al., 2010 and Nogi et al., 2010) could provide insights into such potential molecular interactions at the chiasm.

0 ± 11 8, n = 22, ApNLG overexpression + 5-HT 46 4 ± 14 6, n = 23

0 ± 11.8, n = 22, ApNLG overexpression + 5-HT 46.4 ± 14.6, n = 23, ApNLG mutant overexpression+ 5-HT 4.3 ± 12.9, n = 23, p < 0.001 versus ApNLG overexpression + 5-HT). Overexpression of wild-type

ApNLG or ApNLG mutant had no effect on basal transmission (% initial EPSP amplitude: no expression 3.5 ± 7.0, n = 21; ApNLG mutant overexpression alone –6.8 ± 8.9, n = 9; ApNLG overexpression alone –9.3 ± 7.0, n = 17). Previous studies of the sensory-to-motor neuron synapse in Aplysia have revealed the existence of an intermediate-term phase of facilitation that requires protein synthesis but does not require nuclear transcription ( Ghirardi et al., 1995 and Sutton and Carew, 2000). We therefore wondered whether the ApNLG autism-linked mutant might also have an effect on intermediate-term facilitation as

it precedes LTF and may serve to initiate the transsynaptic signaling required for the long-term process. Indeed, we found that similar to its affect on LTF, there MG-132 solubility dmso was a significant decrease in facilitation during the intermediate-term time domain measured at 1 hr after repeated pulses of 5-HT when the ApNLG autism-linked mutant was overexpressed in the postsynaptic motor neuron ( Figure 8A, % initial EPSP amplitude: 5-HT 74.4 ± 11.7, n = 22, ApNLG overexpression + 5-HT 76.2 ± 13.0, n = 23, ApNLG mutant overexpression+ 5-HT 24.8 ± 10.9, n = 23, p < 0.05 versus ApNLG overexpression + 5-HT). Overexpression of wild-type ApNLG or ApNLG mutant had no effect on basal transmission measured at 1 hr (% initial EPSP amplitude: no expression 7.1 ± 4.3, n = 21; ApNLG mutant overexpression alone 1.8 ± 9.1, n = 9; ApNLG overexpression alone 5.8 ± 4.3, n = 17). The findings that the ApNLG autism-linked mutant blocks both intermediate-term and long-term facilitation indicate that the transsynaptic interaction mediated by neurexin and neuroligin is a critical component of both memory phases and is essential for the normal progression of long-term memory storage. To investigate the role of the neurexin-neuroligin transsynaptic interaction in activity-dependent

synaptic plasticity, we have cloned Aplysia homologs of Isotretinoin neurexin (ApNRX) and neuroligin (ApNLG). We found that they are indeed necessary components of 5-HT-induced long-term facilitation and the associated presynaptic structural remodeling and growth of sensory-to-motor neuron synapses of the Aplysia gill-withdrawal reflex reconstituted in culture. The presence of neurexin and neuroligin in Aplysia as well as in the genomes of Drosophila and C. elegans further supports the view that the neurexin-neuroligin transsynaptic interaction is highly conserved throughout evolution ( Tabuchi and Südhof, 2002). Like other invertebrates, ApNRX has a domain structure similar to that of vertebrate α-neurexin with the likely absence of β-neurexin-like isoforms.

, 2007) These findings fit well with behavioral research showing

, 2007). These findings fit well with behavioral research showing a positivity bias when people remember simulations of positive, negative, and neutral future events: details associated with negative simulations

are remembered more poorly over time compared with details associated with positive or neutral simulations (Szpunar et al., 2012; see also, MI-773 mw Gallo et al., 2011). Emotional factors also play a role in the well-established finding that repeatedly simulating a future event makes that event seem more probable (for review of early studies, see Koehler, 1991). Szpunar and Schacter (2012) recently reported that after repeatedly simulating personal events that might occur in one’s future, the subjective plausibility of those events increases, but the effect was observed only for positive and negative events, and not for neutral events. Research investigating the neural basis of this cognitive

bias could benefit from studies that have begun to examine the neural underpinnings of emotional simulations (e.g., D’Argembeau et al., 2008b; Sharot et al., 2007). Another promising domain centers on the phenomenon of temporal discounting: people typically Bax protein devalue a future reward according to the extent of delay before the reward is delivered ( Green and Myerson, 2004). Boyer (2008) argued that a key adaptive function of the

ability to simulate future events based on past experience is to allow individuals to represent emotional aspects of future reward in a way that overrides temporal discounting so as to produce less impulsive and more farsighted decisions. Two recent studies have shown that when people imagine experiencing a reward in the future, they show Terminal deoxynucleotidyl transferase an increased tendency to favor reward that produce greater long-term payoffs, thereby countering the normal tendency to devalue delayed reward ( Benoit et al., 2011; Peters and Büchel, 2010; for related results, see Mitchell et al., 2011). Moreover, the results of fMRI scanning carried out during this procedure showed that the effects of episodic simulation on temporal discounting are associated with increased coupling between activity in the hippocampus and prefrontal ( Benoit et al., 2011) or anterior cingulate ( Peters and Büchel, 2010) regions involved in reward-related processing. These findings could provide a basis for investigating effects of simulation on discounting, and its neural underpinnings, in populations prone to impulsive decision making such as drug addicts (e.g., Bechara, 2005). Importantly, Kwan et al.

The Honourable Vice-Minister of Health of Vietnam, Mr Nguyen Tha

The Honourable Vice-Minister of inhibitors Health of Vietnam, Mr. Nguyen Thanh Long, stated that the Vietnamese Government and the Ministry of Health strongly support the vaccine manufacturing system in the country. Over the past 25 years, the National

Expanded Programme on Immunization has achieved significant results by changing disease patterns in children. There are now four major vaccine manufacturers in Selleck GSK1120212 Vietnam, namely VABIOTECH, POLYVAC, DAVAC, and IVAC. The local manufacturers supply so far ten out of eleven vaccines for the National Expanded Programme on Immunization in Vietnam including the licensed oral polio vaccine, DTP, BCG, Japanese encephalitis, hepatitis B, cholera, typhoid fever and measles vaccines. The vaccine manufacturers in Vietnam count many new vaccines under evaluation or licensure such as rotavirus, A/H5N1 influenza, seasonal Olaparib price influenza, dengue, and combination vaccines. B. Aylward, from WHO, gave a key note lecture focusing on the Global Polio Eradication strategy. Since the Polio Eradication programme started, in 1988, the number of polio-paralyzed children has decreased tremendously, from an estimated over 350,000 children paralyzed

every year to a few hundreds in 2013, due to vaccination, and poliovirus type 2 has been eradicated, in 1999. However, between 2000 and 2011, 14 countries reported circulating vaccine-derived (type 2) poliovirus outbreaks. While India stopped transmission in 2011, cases were alarmingly increasing in Nigeria, Afghanistan and Pakistan during the same period. Thus on 25th May 2012 the World Health Assembly declared polio eradication an emergency for global public health and urged WHO to rapidly finalize a Polio Endgame Strategy. A key element of the endgame is the removal of the type 2 component of the oral poliovirus vaccine, facilitated by the introduction of an affordable inactivated injectable polio vaccine (IPV) globally. A study conducted in Cuba reported a breakthrough in the search for an ‘affordable IPV’ with one fifth dose of IPV found to achieve 63% seroconversion, and 99% priming against poliovirus type 2 [1]. This result was crucial to a landmark SAGE recommendation that all countries should introduce

at least one dose of Endonuclease IPV into their routine immunization programmes to mitigate the risks associated with withdrawal of OPV2. To date in 2013, no type 3 polio virus cases have been detected for the first time in history, and there has been a nearly 50% decrease in endemic virus cases in Afghanistan, Nigeria and Pakistan. Still reports of spreading of viruses to Egypt, Israel, and Somalia are of concern and are challenging eradication resources. The Polio endgame goal is to complete eradication and containment of all wild and vaccine derived polio viruses, with a global plan that has four objectives [2], the second of which is particularly important for vaccine manufacturers: OPV2 withdrawal and IPV introduction in 125 countries within 24 months.

The methods of the retrieved papers were extracted and reviewed i

The methods of the retrieved papers were extracted and reviewed independently by two reviewers (RS and EP) using predetermined criteria ( Box 1). Disagreement or ambiguities were resolved by consensus after discussion with a third reviewer (LA). Design • Randomised trial or quasi-randomised trial Participants • Adults Intervention • Experimental intervention includes biofeedback using any signal (EMG, force, position) via any sensory system (visual, auditory, tactile) Outcome measures • Measure/s of lower limb activity (sitting, standing up, standing or walking) Quality: The quality of included inhibitors trials was assessed by extracting PEDro scores from the Physiotherapy Evidence Database. Rating of trials on this database is carried

KPT-330 mw out by two independent trained raters

and disagreements are resolved by a third rater. Where a trial was not included on the database, it was assessed independently by two reviewers who had completed the PEDro Scale training tutorial on the Physiotherapy Evidence Database. Participants: hypoxia-inducible factor pathway Trials involving adult participants of either gender, at any level of initial disability, at any time following stroke were included. Age, gender, and time since stroke were recorded to describe the trials. Intervention: The experimental intervention could be of any type of biofeedback, ie, using any signal (position, force, EMG) via any sense (visual, auditory, tactile). At least some of the intervention had to involve practice of the whole activity and practice of the activity had

to involve movement (such as reaching in sitting or weight shift in standing). The control intervention could be nothing, placebo, or usual therapy in any combination. Type of biofeedback, activity trained, and duration and frequency of the intervention were recorded to describe the trials. Outcome measures: Measures of lower limb activity congruent with the activity in which biofeedback was applied were used in the analysis. Where multiple measures for one activity were reported, a measure was chosen that best reflected the aim of the biofeedback intervention Thymidine kinase (eg, step length). The measures used to record outcomes and timing of measurement were recorded to describe the trials. Data were extracted from the included trials by one reviewer and cross-checked by a second reviewer. Information about the method (ie, design, participants, lower limb activity trained, intervention, measures) and data (ie, number of participants and mean (SD) of outcomes) were extracted. Authors were contacted where there was difficulty extracting and interpreting data from the paper. Post-intervention scores were used to obtain the pooled estimate of the effect of intervention in the short term (after intervention) and in the longer term (some time after the cessation of intervention). Since different outcome measures were used, the effect size was reported as Cohen’s standardised mean difference (95% CI). A fixed-effect model was used initially.

Interviews with a selection of countries from each group will be

Interviews with a selection of countries from each group will be conducted later to ascertain explanatory factors for increased or decreased distribution rates. The study’s results were compiled uniformly on a global basis from a standardized source. The vaccine producers that manufacture the majority of the world’s influenza vaccines (IFPMA IVS members)

accounted for approximately 79% of the global seasonal influenza vaccine production reported by a 2011 WHO survey [10], or 489 million doses out of 620 million doses, with the remainder manufactured by non-IFPMA IVS members. However, some limitations to the survey methods must be noted. Some error may have occurred due to inaccurate reporting by distributors, but this error should be small. It is also recognized that dose distribution is not synonymous with vaccination coverage rates, but provides a reasonable proxy to assess vaccine utilization. Also, increases in absolute selleck numbers of doses distributed

may in some cases reflect changes in PCI-32765 solubility dmso target populations (i.e., new target groups), and not increased coverage. Global distribution of IFPMA IVS seasonal influenza vaccine doses in 2011 represents an approximate 87% increase over absolute number of doses distributed in 2004 (489.1 versus 261.7 million doses) as seen in Fig. 1, but only an approximate 12% increase over doses distributed in 2008 (489.1 versus 436.5 million doses). Thus, while there is a positive trend in global distribution of doses, and a majority of countries (56%) have increased doses distributed per 1000 population between 2008 and 2011, the rate of growth has slowed

considerably. In 2011, only 24% of 115 countries had achieved or surpassed the hurdle rate of 159 doses per 1000 population. Using vaccine dose distribution as a proxy for vaccine coverage would therefore suggests that the majority of countries have not achieved inhibitors national or supranational targets for influenza vaccination where they exist. Low coverage rates cannot be attributed to lack of vaccine supply as global manufacturing capacity for influenza vaccines has grown steadily but remains underutilized with only about half the capacity being consumed annually [10]. Hence, many vulnerable patients are not protected against most the potential serious implications of an influenza infection. Furthermore, there are significant regional disparities in dose distribution. Increases in distributed doses have been predominantly steady in all WHO regions since 2004, except in EURO and EMRO where distributed doses have been declining since 2009. AFRO, SEARO and EMRO constitute 47% of the global population but account for only 14.1 million doses of the more than 489 million IFPMA IVS doses (3.7%) distributed in 2011. And within these 3 regions, further inequities in distribution exist with only 4 countries having distributions of >70 doses per 1000 population and the vast majority of countries having considerably lower per capita distributions.