For 12-month-old brain sections, the numbers of Aβ plaque in cortex and hippocampus were counted without the genotype

information. For 18- to 20-month-old mice, the area covered by Aβ was analyzed selleckchem by ImageJ. The numbers of Thioflavin S-stained neuritic plaques were also analyzed by ImageJ. See Supplemental Experimental Procedures for details. Mice were injected once daily with BrdU (100 mg/kg, i.p.) for 3 consecutive days. Half of the mice in each group were sacrificed 1 day after the final injection of BrdU to identify proliferating neural progenitor cells (NPCs). The remaining mice were sacrificed 2 weeks after the final injection of BrdU to determine survival and neuronal differentiation of the newborn cells. See Supplemental Experimental Procedures for details. Data are presented as the mean ± SEM. Comparisons between two groups were performed with the independent-samples t test, and those among more than two groups were performed with

ANOVA followed by Tukey’s test. All analyses were performed with SPSS version 12.0. p value of <0.05 was considered statistically high throughput screening assay significant. We thank Dr. Lin Wu for her scientific expertise and technical assistance in generating ADAM10 transgenic mice. We also thank Dr. Jorg Bartsch for providing ADAM10 prodomain antibody; Dr. Sam Sisodia for providing MoPrP.XhoI plasmid; Dr. Matthew Frosch for providing Tg2576 mice; Dr. Basavaraj Hooli and Dr. Can Zhang for helpful discussions; and William Wisdom for mouse tail genotyping. This study was supported by the Cure Alzheimer’s Fund, grants from the NIA, NIMH (R.E.T.), and the American Health Assistance Foundation (J.S.). “
“Tau

is a microtubule-associated protein that forms intracellular aggregates in several neurodegenerative diseases collectively termed tauopathies. These include Alzheimer’s disease (AD), progressive supranculear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia (FTD) (Mandelkow and Mandelkow, 2012). Tau is a highly soluble and natively unfolded protein (Jeganathan et al., 2008) that binds and promotes the assembly almost of microtubules (Drechsel et al., 1992 and Witman et al., 1976). In tauopathies, tau accumulates in hyperphosphorylated neurofibrillary tangles (NFTs) that are visualized within dystrophic neurites and cell bodies (Mandelkow and Mandelkow, 2012). The amount of tau pathology correlates with progressive neuronal dysfunction, synaptic loss, and functional decline in humans and transgenic mouse models (Arriagada et al., 1992, Bancher et al., 1993, Polydoro et al., 2009 and Small and Duff, 2008). In human tauopathies, pathology progresses from one brain region to another in disease-specific patterns (Braak and Braak, 1997, Raj et al., 2012, Seeley et al., 2009 and Zhou et al., 2012), although the underlying mechanism is not yet clear.

This work was supported by NIH (R01 EY10115, R01 NS075436, and RC2 NS069407). “
“When Hubel and Wiesel published their first landmark papers on the primary visual cortex of the cat,

they revealed that its neurons are exquisitely selective for stimulus attributes and that this selectivity defines orderly maps of functional architecture (Hubel and Wiesel, 1959, 1962). These discoveries echoed those made a few years earlier in somatosensory cortex (Mountcastle, 1957) and cemented a view of sensory cortex in which sharply tuned neurons arranged in vertical columns signal substantially different attributes from their neighbors displaced along the horizontal dimension. This view has been extremely fruitful in the subsequent 50 years and was further supported by advances in two-photon imaging. These revealed that maps high throughput screening of functional selleck screening library architecture are organized with crystalline precision down to the resolution of single cells (Ohki et al., 2005, 2006). Soon after these features were discovered, however, an apparently contradictory aspect of the responses began to emerge, suggesting that focal visual stimuli cause cortical activity that spreads over time to a large region of cortex, appearing earlier in the retinotopically appropriate cortical locations and progressively later in more distal

locations. This horizontal spread of neural activity constitutes a traveling wave. Traveling waves are evident in subthreshold potentials and are thus poised to influence the spike responses and thereby the output of area V1. They appear to work against the precise selectivity and orderly arrangement of V1 neurons along the cortical surface. Here we review data that point to traveling much waves as a prominent feature of area V1, both in the presence and in the absence of visual stimuli. We speculate briefly on the possible roles of these traveling waves in sensory

processing and on the possible circuits underlying their propagation, and we discuss how the traveling waves can coexist with the crystalline precision of the cortex. The traveling waves constitute a mode of operation that is mostly engaged when visual stimuli are weak or absent. When a sufficiently high contrast is presented sufficiently often over a sufficiently large region, the waves disappear. In those conditions, primary visual cortex does operate in the highly selective and orderly fashion that had been described by Hubel and Wiesel. We focus on traveling waves that propagate in the mammalian visual cortex, in the horizontal dimension, and at fairly high speeds (about 0.1–0.4 m/s). Other waves travel much slower, for instance, in binocular rivalry (∼0.018 m/s; Lee et al., 2005) or in spreading depression (∼0.00007 m/s; Lauritzen, 2001). We do not review the large literature on traveling waves in turtle cortex (Nenadic et al., 2003) or in nonvisual sensory or motor cortices of mammals (Ferezou et al., 2007; Fukunishi et al., 1992; London et al.

We did not notice significantly different seizure stages in WT and AKAP150−/− mice as previously reported by Tunquist et al. (2008), except in response to the first dose of KA ( Figure S2). Hippocampi were isolated from mice 16–20 hr after intrapleural administration of either pilocarpine or KA, or only vehicle as a control, total RNA was extracted, and qPCR was performed. Indeed, a profound augmentation of both KCNQ2 and KCNQ3 mRNA was observed in mice after

buy Talazoparib seizures induced by pilocarpine (27.9 ± 6.7-fold and 9.3 ± 2.2-fold, n = 18) or KA (8.7 ± 2.3-fold and 3.1 ± 0.6-fold, n = 25), compared with control mice injected with vehicle (1.1 ± 0.05-fold and 1.1 ± 0.10-fold, n = 17) ( Figures 10D and 10E). This profoundly increased mRNA of both KCNQ2 and KCNQ3 in hippocampi from mice subjected to seizures is much greater than that seen from 50 K+ or ACh treatment in cultured sympathetic neurons, suggesting that seizures induce exaggeration of this transcriptional regulation and could be conserved throughout the nervous system as a protective mechanism against hyperexcitability disorders such as epilepsy. Our mechanism predicts that this profound increase induced by seizures should learn more likewise be dependent on AKAP150. Indeed, in AKAP150−/− mice, there was almost

no upregulation of KCNQ2 and KCNQ3 mRNA after pilocarpine-induced (1.5 ± 0.1 and 1.4 ± 0.1, n = 14) or KA-induced (1.8 ± 0.4 and 1.6 ± 0.2, n = 18) seizures ( Figures 10D and 10E), confirming the central role of

AKAP150 in this phenomenon. Here, we show neuronal activity all to closely regulate M-channel transcription, likely as a negative feedback loop that limits neuronal hyperexcitability. AKAP79/150 associates with L-type (CaV1.3) Ca2+ channels and orchestrates a signaling complex that includes bound PKA, CaM, and CaN in this microdomain. CaV1.3 channels serve as the critical “sensor” of activity and depolarization, and their opening creates an elevated local Ca2+i signal, which activates CaN bound to AKAP79/150 in the microdomain of elevated local [Ca2+]i. Upon Ca2+i/CaN signals, both NFATc1 and NFATc2 are dephosphorylated and translocate from the cytoplasm to the nucleus, where they act on KCNQ2 and KCNQ3 gene regulatory elements, upregulating IM, thus reducing excitability ( Figure 10F). In a variety of neurons, AKAP79/150 orchestrates PKA to phosphorylate and upregulate the activity of L-type Ca2+ channels, amplifying the responses to depolarization induced by neuronal activity. In the hippocampus, CaN counterbalances PKA actions since the Ca2+ ions that enter the cell through L channels participate in inactivating those same channels via CaN ( Hall et al., 2007; Oliveria et al., 2007).

6 ± 0.8, p < 0.0001 paired Student's t test; HgfpH 3.6 ± 0.7, p < 0.05 paired Student's t test; Figure 2C). Similar results were observed when reporter expression

was compared in all DD and VD neurons (DD/VD fluorescence ratios: HgfpC 5.6 ± 0.5, p < 0.0001 paired Student's t test; HgfpH 2.6 ± 0.4, p < 0.005 paired Student's t test; Figures 2A and 2B and Figures S2B and S2D). learn more These results indicate that the hbl-1 promoter is expressed at significantly higher levels in DD neurons than in VD neurons. The decreased hbl-1 reporter expression in VD neurons could result from UNC-55 mediated repression of the hbl-1 promoter. To test this possibility, we analyzed expression of the HgfpC reporter in unc-55 mutants. HgfpC expression in VD neurons was significantly increased in unc-55 mutants (197% wild-type levels, p < 0.001 Student's t test), indicating increased transcription of the hbl-1 promoter in unc-55 mutant VD neurons ( Figure 2D and Figures S2B–S2D). The magnitude of the increased HgfpC expression differed in individual VD neurons. For VD10, HgfpC

expression in unc-55 mutants rose to the same level observed in DD5 neurons ( Figure 2D); however, in most cases, HgfpC expression in unc-55 mutant VD neurons remained significantly lower than that observed in DD neurons (DD/VD fluorescence ratio in unc-55: HgfpC 2.3 ± 0.4, p < 0.001 Student's t test; Figures S2C Y-27632 and S2D). By contrast, HgfpC expression in DDs did not increase in unc-55 mutants and instead was modestly decreased ( Figure 2D and Figure S2D). This is unlikely to be a direct effect of UNC-55 on the hbl-1 promoter because unc-55 is not expressed in DD neurons

( Zhou and Walthall, 1998). Taken together, these data support the idea that UNC-55 inhibits expression of the hbl-1 promoter in VD neurons and that hbl-1 expression in D neurons is likely regulated by additional factors beyond UNC-55. In Drosophila, the UNC-55 ortholog (Sevenup) represses Hunchback (Hb) transcription ( Kanai et al., 2005 and Mettler et al., 2006). As in Drosophila, the C. elegans hbl-1 promoter contains four predicted UNC-55 binding sites, suggesting the hbl-1 could be a direct target for UNC-55 repression. To test this idea, we mutated the UNC-55 binding sites in the almost hbl-1 promoter, and assayed its expression pattern. The mutant hbl-1 promoter (HmutgfpC) had a significantly reduced DD5/VD10 expression ratio (HgfpC 6.6 ± 0.8; HmutgfpC 2.7 ± 0.3, p < 0.0001 Student’s t test) ( Figure 2E), which was not significantly different from the ratio observed for the wild-type reporter (HgfpC) in unc-55 mutants (1.8 ± 0.3, p = 0.17, Student’s t test) ( Figure 2F). Thus, the UNC-55 binding sites are required for differential expression of the hbl-1 promoter in VD and DD neurons. If UNC-55 repression of hbl-1 prevents VD remodeling, we would expect that mutations reducing hbl-1 activity would diminish ectopic remodeling of VD synapses in unc-55 mutants.

, 2007 and Khodosevich MG-132 et al., 2009). While the role of CTGF in wound healing and fibrosis is established, little is

known about its role under normal physiological conditions (Shi-Wen et al., 2008). In the OB, CTGF is detected in the glomerular layer at postnatal day 3 (P3), peaks at P5, and continues to be expressed in into adulthood (Khodosevich et al., 2013). This coincides with a time of rapid cellular and anatomical expansion of the sensory epithelium. The CTGF-positive cells coexpress cholecystokinin (CCK) and are glutamatergic, characteristic of external tufted cells (Liu and Shipley, 1994 and Ohmomo et al., 2009). Although CTGF was detected primarily postnatally, the external tufted cells are primarily born embryonically during bulb development. Consistent with their identification as external tufted cells, CTGF-positive neurons were generated during the peak of OB development (E16–18), and their birth completed by P0. Together these observations suggest that earlier-born external tufted cells adopt a new and selective role that involves CTGF in the postnatal and adult animal. Rather than depend on tissue-specific conditional knockouts, the authors utilized adeno-associated virus (AAV) that robustly

infects all cell types—dividing and nondividing in the OB. Their experiments have revealed an interesting intercellular control mechanism Ferroptosis inhibitor that modulates the number of inhibitory interneurons. The authors combined expression manipulations that decreased CTGF expression with retroviral EGFP reporter-marking of SVZ neuroblasts at P3 and observed an increase in the number of EGFP-positive cells in the glomerular layer. This effect was reversed when a shRNA-resistant form of CTGF was injected. Morphological analysis identified EGFP-positive cells in the glomerular layer as periglomerular neurons. Why were more periglomerular cells present in the CTGF knockdown brains? During the first few weeks

after the newborn neurons reach the OB, roughly half of them undergo apoptosis. The authors hypothesized that knockdown of CTGF selectively altered apoptosis of periglomerular Terminal deoxynucleotidyl transferase but not granule cells. The number of apoptotic cells in the glomerular layer but not the granule cell layer decreased in the CTGF knockdown mice. Injecting shRNA-resistant CTGF increased the number of apoptotic cells. Thus, CTGF seemed to play a role in promoting apoptosis of periglomerular cells. Although the role of CTGF in inhibitory interneuron survival was clear, the signaling pathway that mediated the effects of the tufted cell-derived factor was more enigmatic. In particular, the receptors for canonical CTGF signaling are not expressed in the maturing neuroblasts of the olfactory bulb. CTGF is also known to bind to other growth factors and modulate their activity (Cicha and Goppelt-Struebe, 2009).

In fact, the late suppression (starting ∼140 ms after stimulus onset) as well as the link to perceptual processes fit well with late effects of a top-down feedback into V1. It is commonly thought that feedback connections from higher visual areas (Bullier et al., 2001; Li et al., 2006) are mainly excitatory. Some of these excitatory feedback input can influence local inhibitory neurons and thus induce a feedback inhibition (Isaacson and Scanziani, 2011). Another possible explanation is that background suppression is mediated

by a decreased excitatory feedback: a background input whose role is to reduce the gains of single neurons (Chance et al., 2002). Additional studies are required to better understand the source of the background suppressive phenomenon. In summary, we have shown that during contour integration there is a strong divergence of V1 population responses processing the contour or the noisy background. GS-7340 solubility dmso The neuronal population in the contour area increases its response amplitude and is positively correlated with behavior, while the background displays opposing characteristics, suppressed activity, and a negative correlation with behavior. These opposing 3-Methyladenine molecular weight processes increase the difference in neuronal activity between the contour and the noisy background and thus

may improve contour segregation from a noisy background and facilitate its perception. Additional information appears in Supplemental Experimental Procedures. Two adult monkeys (Macaca fascicularis; S, L) were Thalidomide trained on a contour-detection task. The trial started when the animal fixated on a small fixation point displayed on a uniform gray background. After a random fixation interval, a contour or noncontour stimulus appeared on the screen for 250–1,000 ms. The animal maintained fixation until the stimulus and fixation point were turned off. At this point, two small lateral targets appeared, one on each side

of the screen, and the animal was required to indicate its visual perception by performing a rightward saccade for a contour report and leftward saccade for noncontour report. A trial was classified as correct only if the animal maintained fixation throughout the trial, responded with a saccade to the correct target, and fixated on the target for an additional 400 ms. The animal was rewarded with a drop of juice for each correct trial. In each recording session, the contour and noncontour stimuli appeared in 80% of the trials, while the remaining 20% trials were fixation-alone trials (no stimulus presentation, blank condition). These trials were used to remove the heart beat artifact in the VSDI analysis (see VSDI analysis below). Detection performance is defined as the number of correct trials divided by total number of trials (sum of contour and noncontour trials). The average detection performance was 91% (2% misses, i.e.

, 2009). Because of this sensitivity, Ipatasertib price it was noticed that is important to keep good control by removing all possible agents that can negatively affect the

regular life cycle of trichostrongylids. Regarding water solubility, although desirable, it might not be required in some cases. For instance, tests in dogs using carbon tetrachloride against hookworms showed that the efficacy of the tested compounds increased as solubility in water decreased (Bennet-Jenkins and Bryant, 1996). Another point of difficulty found in in vitro tests was the contamination. Álvarez-Sánchez et al. (2005) used the LFIA to detect anthelmintic resistance to ivermectin and levamisole and reported that such assay offers the advantage of simplicity and rapidity in

comparison to the LDA. LDA takes a long time to be performed and problems related to contaminations frequently occur. These problems reflected in fewer laboratories using the assay as the primary screen for activity in vitro ( Jackson and Hoste, 2010). In our work we dealt with both bacterial and fungal contamination by using sterile techniques as much as possible because development stages could not stand higher quantities of antibiotics than found in nutritive medium ( Hubert and Kerboeuf, 1992). In addition, instead of seven days of incubation at 23 °C ( Bizimenyera et al., 2006), we increase temperature to 27 °C and decreased incubation time to five days. This modification allowed larval development KU-55933 ic50 at higher rates and more Edoxaban reproducible results. It also decreased fungal and bacterial contamination in the plates. Different LC50 values found between assays can be attributed to the sensitivity of each stage. Eggs are more resistant than L1 due to its hard and resistant shell. On the other hand, L3 were more resilient due to their double sheath. L1 was the most sensitive stage due to its pharynx that is more sensitive to the paralysis caused by drugs than the axial muscles (Molan et al., 2002).

These facts lead to higher or lesser volumes of active compound to achieve LC50 for each test. Várady et al. (2007) used the criterion of LC99 concentration to evaluate the sensitivity to thiabendazole under field screening. Those authors found in egg hatch and larval development assay the comparison of LC50 values was not significantly different, however the LC99 concentration is able to differentiate susceptible group, susceptible heterozygote group and resistant group in test for resistance diagnosis. Our LC99 results in EHA, LDA and LEA showed the same pattern of activity found in LC50 values. For trichostrongylids, the L3 exsheathment is a key process in the life cycle because it is the transition step between the free living and the parasitic stages (Hertzberg et al., 2002).

, 2010, Kong et al., 2010, Krashes et al., Dabrafenib chemical structure 2009, Lebestky et al., 2009 and Mao and Davis, 2009). Our work demonstrates that a single dopaminergic neuron in the SOG potently modulates

proboscis extension behavior. Other dopaminergic neurons have cell bodies near TH-VUM and extensive projections in the SOG, yet activation of these neurons is not associated with proboscis extension. It is possible that additional dopaminergic neurons regulate other aspects of taste behavior, but they are insufficient to drive proboscis extension. In mammals, dopamine levels in the nucleus accumbens, the target of the mesolimbic pathway, increase upon sugar detection in the absence of consumption (Hajnal et al., 2004) or upon nutrient consumption in the absence of detection (de Araujo et al., 2008), suggesting that dopamine encodes multiple rewarding aspects of sugar: intensity on the tongue and nutritional value. Recent studies in Drosophila also show that they sense nutritional content independent of taste detection, and this influences ingestion (

Burke and check details Waddell, 2011, Dus et al., 2011 and Fujita and Tanimura, 2011). It will be interesting to determine whether dopamine plays a role in sensing internal nutritional state and regulates other aspects of ingestion in addition to its role in proboscis extension. The anatomical location of the dopaminergic interneuron highlights the central role of the SOG in taste processing and suggests that local SOG circuits

may control proboscis extension behavior. Future studies identifying the downstream targets of TH-VUM will ultimately enable a deeper understanding of how dopamine achieves spatial and temporal modulation of extension probability. Our current study identifies an essential role for dopamine in gain control of proboscis extension to sucrose and underscores the exquisite PAK6 specificity of single neurons as thin threads to behavior. w1118 flies were used as control wild-type flies. The following Gal4 lines were used: Akh-Gal4 ( Lee and Park, 2004), dilp3-Gal4 ( Buch et al., 2008), tdc2-gal4 ( Cole et al., 2005), hugin-Gal4 ( Melcher and Pankratz, 2005), TH-Gal4 ( Friggi-Grelin et al., 2003), hs-flp, MKRS (Bloomington stock collection), Npf-Gal4 ( Wu et al., 2003), UAS-Kir2.1 ( Baines et al., 2001), tub-Gal80ts ( McGuire et al., 2004), ptub-FRT-Gal80-FRT and Gr5a-lexA ( Gordon and Scott, 2009), UAS-mCD8::GFP ( Lee and Luo, 1999), and UAS-dTRPA1 ( Hamada et al., 2008). DopR mutants (f02676) and D2R mutants (f06521) were obtained from the Exelixis collection ( Bellen et al., 2004 and Thibault et al., 2004). Flies were grown on standard fly food. Measurement of PER was performed as described using females (Wang et al., 2004), except that flies were glued to glass slides using nail polish. Flies were stimulated with water on their tarsi and allowed to drink ad libitum.

In particular, an insomniac-Gal4 reporter is expressed in regions of the Drosophila brain that are implicated in regulating sleep, including the mushroom bodies and the pars intercerebralis ( Pitman et al., 2006, Joiner et al., 2006 and Foltenyi et al., 2007), although driving insomniac expression in these areas individually does not rescue the sleep defect of insomniac mutants, with the exception of a weak rescue provided by the pars-intercerebralis-specific Mai301-Gal4 driver. Further manipulations of insomniac within the nervous system are necessary to understand the neuroanatomical basis by which it regulates sleep. Several lines of

evidence indicate that insomniac exerts its effects on sleep by a mechanism functionally distinct from the circadian clock. The circadian clock is intact in insomniac mutants, and insomniac expression is not regulated in a circadian fashion. Furthermore, the expression

of insomniac Carfilzomib price this website in clock neurons is unable to restore normal sleep patterns in insomniac mutant backgrounds. Consistent with these data, daily sleep profiles indicate that the circadian control of sleep is intact in insomniac mutants. As is the case for wild-type animals, the highest probability of sleep during the dark phase is observed soon after the onset of darkness, with a decreasing sleep drive as the dark phase proceeds. The profile of sleep probability during the light phase is similarly intact. The principal alteration of sleep in insomniac animals is a reduced likelihood of sleeping throughout the day and night, consistent with the inference that insomniac may contribute to homeostatic

mechanisms that regulate sleep need. Cullins are scaffold proteins that assemble multisubunit E3 ubiquitin ligase complexes that ubiquitinate and degrade a variety of protein substrates in diverse only biological contexts (Petroski and Deshaies, 2005). The C termini of cullins interact with RING-domain ubiquitin ligases, while the N termini interact with adaptor proteins that recruit substrates for ubiquitination. Cul3 complexes utilize proteins of the BTB superfamily as their adaptors (Pintard et al., 2003, Xu et al., 2003 and Geyer et al., 2003), including members of the nonchannel KCTD subfamily (Chen et al., 2009 and Canettieri et al., 2010). In addition to the KCTD proteins that are known to function as Cul3 adaptors, more than half of the non-channel KCTD proteins, including the three vertebrate orthologs of Insomniac, are candidate Cul3 adaptors, as they copurify specifically with Cul3, but not with other cullins (Bennett et al., 2010). For several of these candidate adaptors, including KCTD5 and TAG-303, the C. elegans ortholog of Insomniac, independent biochemical evidence confirms their ability to associate physically with Cul3 ( Xu et al., 2003, Bayón et al., 2008 and De Smaele et al., 2011).

Samples can also be taken to test for BMN 673 the presence of virus, including oesophagopharyngeal mucus scrapings

collected with a probang cup to detect virus carriers. An epidemiological enquiry is also required. At the end of these investigations the herd/flock must be categorised as to whether or not infected animals are present. The OIE Code clearly describes in Article 8.61 that the occurrence of FMDV infection is confirmed if FMDV is isolated from an animal [19]. The culling strategies for post-outbreak eradication to recover the FMD-free status are summarised in Article 8.6.47 as “the slaughter of all clinically affected and in-contact susceptible animals, but there is no discussion of the requirements to remove subclinically affected animals (that could be cases of recent, historic or carrier infection) if identified only by serology, in the absence of clinically affected companion animals. The EU Directive requires the stamping out of holdings AZD5363 mouse containing at least one animal where the

presence of FMDV is confirmed [9]. As well as depopulation of the susceptible species present, animal products must be treated or disposed of and holdings must be cleansed and disinfected before restocking. Control zones must be established to monitor and regulate animals in surrounding herds. On holdings containing NSP reactors but where further testing confirms the absence of circulating FMDV, the NSP positive animals must be culled. Other test-negative animals in the herd should also be killed but may be slaughtered under

controlled conditions and their meat is subject to deboning and maturation Isotretinoin (ruminants) or processing into meat products. In case of pork their carcasses can go for consumption (Supplementary Table 2). Cleansing and disinfection of the premises is still required, but no control zones are imposed on neighbouring premises. Thus, the actions required are clearly distinct where acutely infected animals are confirmed (after their detection by virological means or paired serology) compared to other situations where NSP seroreactors are found. However, for both OIE and EU, the presence of a carrier animal (confirmed by virus detection) would invoke the full implications of a new outbreak [9] and [19]. The requirement to kill the whole herd, including seronegative animals, when FMD infection is confirmed only by serology, could be modified to meet the recommendations of Arnold et al. [43], by selectively removing only the seropositive animals. But the compatibility of this alteration with the requirements of the Directive for cleansing, disinfection and controlled restocking of the herd would also have to be considered. The declaration of an outbreak has important implications for trade.