We examined the reproducibility of DCM in healthy subjects (young 18-48 years, n = 27; old 50-80 years, n = 15) in the context of action selection. We then examined the effects of Parkinson’s disease (50-78 years, Hoehn and Yahr stage 1-2.5, n = 16) and dopaminergic therapy. Forty-eight models were compared, for each of 90 sessions from 58 subjects. Model-evidences clustered

according to sets of structurally similar models, with high correlations over two sessions in healthy older subjects. The same model was identified as most likely in healthy controls on both sessions and in medicated patients. In this most likely network model, the selection of action was associated with enhanced coupling between prefrontal cortex and the pre-supplementary motor area. However, the parameters for ON-01910 in vivo intrinsic connectivity and contextual modulation in this model were poorly correlated across sessions. A different model was identified in patients with Parkinson’s disease after medication withdrawal. In “off” patients, action selection was associated with enhanced connectivity from prefrontal to lateral premotor cortex. This accords with independent evidence of a dopamine-dependent find more functional disconnection of the SMA in Parkinson’s disease. Together, these results suggest that DCM model selection is robust and sensitive enough

to study clinical populations and their pharmacological treatment. For critical inferences, Selleckchem PF-6463922 model selection may be sufficient. However, caution is required when comparing groups or drug effects in terms of the connectivity parameter estimates, if there are significant posterior covariances among parameters. (C) 2009 Elsevier Inc. All rights reserved.”
“Background: Late-life depression encompasses both patients with late-life onset of depression ( bigger than 60

years) and older adults with a prior and current history of depression. The aim of the study was to analyze the impact of the economic condition and family relations in childhood as risk factors for late-life depression. Subjects and methods: This was an analytical cross-sectional study comprising 120 subjects, 60 patients with unipolar depression and 60 subjects without depressive disorders, diagnosed in accordance with the 10-th International Classification of Mental and Behavioural Disorders. All participants in the study were above the age of 60 and there was no significant statistical difference in the sex proportion in both groups (p bigger than 0.05). Data for the examination were taken from a self-reported questionnaire designed for our aim. The Geriatric Depression Scale was used to measure depressive symptoms. Results: Our results have shown that severe financial difficulties are important events in childhood and are risk factors for depression in the elderly (Chi-square=12.68, df=2, p=0.0018). Our investigation has found the association of family relations with late-life depression.

We propose a model algorithm for optimal dose finding using therapeutic drug monitoring (TDM) for MPA. Preemptive strategies depending on plasma MPA levels could yield more effective approaches to GvHD prophylaxis, alternative to MTX.”
“Catumaxomab is a trifunctional antibody (trAb) characterized by its unique ability to bind three different cell types: tumor cells, T-cells, and accessory cells. It has two different antigen-binding specificities: one for epithelial cell adhesion molecule (EpCAM) on tumor cells and one for the CD3 antigen on T-cells. Catumaxomab also binds to type I, IIa, and III Fc gamma receptors (Fc gamma R) on accessory cells, e.g. macrophages,

GPCR Compound Library dendritic cells, and natural killer cells, via its intact Fc region. Its anti-tumor activity results from T-cell-mediated lysis, antibody-dependent cell-mediated cytotoxicity,

and phagocytosis via activation of Fc gamma R-positive accessory cells. Importantly, no additional activation of immune cells is necessary for effective tumor eradication by catumaxomab, which represents a self-supporting system. Catumaxomab’s efficacy and safety have been demonstrated in a pivotal CYT387 inhibitor phase II/III study and supporting phase I/II studies. It is administered as four intraperitoneal (i.p.) infusions on days 0, 3, 7, and 10 at doses of 10. 20, 50, and 150 mu g, respectively. Catumaxomab has been approved in the European Union selleck compound since April 2009 for the i.p. treatment of malignant ascites (MA) in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible. Catumaxomab is the first trAb and the first drug worldwide to be approved specifically for the treatment of MA. It is

in clinical trials in a number of other indications including ovarian and gastric cancer. Alternative routes of administration are also under evaluation to further exploit the therapeutic potential of catumaxomab in EpCAM-positive carcinomas. (C) 2010 Elsevier Ltd. All rights reserved.”
“The development of a depression-like state in C57Bl/6J mice with repeated defeat experience (10 and 20 days) was accompanied by inhibition of the immune response (evaluated from the number of IgM antibody-producing cells). Activation of postsynaptic 5-HT1A receptors with a selective agonist 8-OH-DPAT (1.0 mg/kg) in these animals had no effect on the immune reaction. In mice without the experience of confrontations, stimulation of postsynaptic receptors caused a decrease in the number of IgM antibody-producing cells at the peak of the immune response induced by sheep erythrocytes (5×10(8) cells). However, the count of these cells remained unchanged in mice with a depression-like state (irrespective of the stage of disorder). Activation of presynaptic 5-HT1A receptors with 8-OH-DPAT (0.1 mg/kg) in control animals and mice with 10-day defeat experience was followed by immune stimulation.

“
“Social anhedonia Nepicastat datasheet is a promising indicator for the vulnerability towards developing schizophrenia-spectrum disorders and is an important determinant of the social impairment associated with these disorders. It is unknown if social anhedonia is associated with true deficits in experiential reactions or if lower social functioning in social anhedonia reflects behavioral deficits in social skill or initiation of social contact. Using a novel social interaction task, the current study compared controls (n=60) to individuals elevated on social anhedonia (n=49) on observer-rated social

skill and facial affect and participant self-reports of their experiential reactions to an affiliative interaction. Compared to the control group, the social anhedonia group was rated as behaviorally less affiliative and less socially skilled during the affiliative interaction. In response to the social interaction, the social anhedonia group reported less change in positive affect, less willingness to engage in future social interactions with the interaction partner, and less positive reactions toward the interaction partner compared to controls. There were no group differences in facial displays of emotion. Using a standardized affiliative stimulus, it was GDC 0068 demonstrated that individuals high

in social anhedonia have alterations in both their social skill and in their self-reported experiential reactions during a social interaction. (C) 2012 Elsevier Ireland Ltd. All rights reserved.”
“Various anatomical parameters affect

on intra-aneurysmal hemodynamics. Nevertheless, how the shapes of real patient aneurysms affect on their intra-aneurysmal hemodynamics remains unanswered.\n\nQuantitative computational fluid dynamics simulation was conducted using eight patients’ angiograms of internal carotid artery-ophthalmic artery aneurysms. The mean size of the intracranial aneurysms was 11.5 mm (range 5.8 to 19.9 mm). Intra-aneurysmal blood flow velocity and wall shear stress (WSS) were collected from three measurement planes in each aneurysm dome. The correlation coefficients (r) were obtained between AG-014699 molecular weight hemodynamic values (flow velocity and WSS) and the following anatomical parameters: averaged dimension of aneurysm dome, the largest aneurysm dome dimension, aspect ratio, and dome-neck ratio.\n\nNegative linear correlations were observed between the averaged dimension of aneurysm dome and intra-aneurysmal flow velocity (r = -0.735) and also WSS (r = -0.736). The largest dome diameter showed a negative correlation with intra-aneurysmal flow velocity (r = -0.731) and WSS (r = -0.496). The aspect ratio demonstrated a weak negative correlation with the intra-aneurysmal flow velocity (r = -0.381) and WSS (r = -0.501). A clear negative correlation was seen between the intra-aneurysmal flow velocity and the dome-neck ratio (r = -0.708).

Our model minimizes fixed costs, fuel costs, shortage costs, and emissions costs. A constraint set balances the load, imposes requirements on the way in which generators and storage devices operate, and tracks reserve requirements.

We capture cost functions with piecewise-linear and (concave) nonlinear constructs. We strengthen the formulation via cut addition. We then describe an underestimation approach to obtain an initial feasible solution to our model. Finally, we constitute a Benders’ master problem from the scheduling variables and a subset of those variables associated with the nonlinear constructs; the subproblem contains the storage and reserve selleck chemicals requirement quantities, and power from generators with convex (linear) emissions curves. We demonstrate that our strengthening techniques and Benders’ Decomposition approach solve our mixed integer, nonlinear version of the unit commitment model more quickly than standard global optimization algorithms. We present numerical results based on a subset of the Colorado power system that provide insights regarding

storage, renewable generators, and emissions.”
“The tissue structure of a bamboo stem (culm) differs from that of woody species, exhibiting a large cavity in the internode surrounded by a cortex with high silica concentration. Thus, to obtain an accurate estimation of the necromass, as well as carbon (C) and nitrogen (N) stocks in dead bamboo culms, we examined the basic characteristics of culm structure as well as the C and N concentrations of decomposing culms of Phyllostachys Selleck Smoothened Agonist bambusoides and P. heterocycla. We collected dead culms of the two bamboo species from 15 bamboo stands in central and southwestern Japan, and analyzed the relationship between the ratio of wall volume to culm disk volume and culm diameter, selleck inhibitor as well as

the changes of C and N concentrations in dead culms with wall density, which can be used as an indicator of the degree of decomposition. The ratio of wall volume to culm volume tended to decrease with increasing culm diameter for both species. The C concentration did not change, but the N concentration increased with decreasing wall density. The wall density was related to the C/N ratio, which is a chemical parameter of the degree of decomposition. The culm structure should be considered when estimating culm density. The mean C concentration can be used for estimating the C stock of decomposing culms irrespective of decomposition level. N concentration, however, should be determined according to decomposition level for N stock estimation.”
“The picoplanktonic cyanobacteria, Synechococcus spp., (Nageli) are important contributors to global ocean primary production that can be stressed by solar radiation, both in the photosynthetically active (PAR) and ultraviolet (UV) range.

03). A higher percentage of urologists from the ES recommended low animal protein intake to all stone formers than urologists from the

NCS (69% ES, 47% NCS; P < .05).\n\nCONCLUSIONS Urologists Angiogenesis inhibitor from both the NCS and the ES, despite differences in the type of practice, subspecialty interest in endourology and geographic location of practice, have similar medical and nutritional practices when counseling patients in the prevention of stone disease. UROLOGY 77: 291-294, 2011. (C) 2011 Elsevier Inc.”
“As recent chemotherapy regimens for metastatic colorectal cancer become more and more effective in a neoadjuvant setting before liver surgery, a “complete” clinical response is sometimes documented on imaging. Without operation though, metastatic recurrence is likely to commence within 12 months. Surgeons now face the problem to resect non-visualizable and non-palpable lesions.\n\nComputer-based virtual surgery planning can be used to fuse pre- and postchemotherapy computed tomography data to develop an operative strategy. This information is then intraoperatively transferred to the liver surface using an image-guided stereotactically

navigated ultrasound dissector. This enables the surgeon to perform a resection that is otherwise not possible.\n\nDuring operation, detection of the lesion through palpation Selleck BI-D1870 or ultrasound was impossible. After registering the virtual operation plan into the navigation system, the planned resection was performed without problems. Histopathologic workup showed vital tumor cells in the specimen.\n\nThe new image-guided stereotactic navigation technique combined with virtual surgery planning can solve the surgeon’s dilemma and yield a successful operation.”
“Aim Observed associations of alcohol with colorectal cancer are prone to distortion by confounding and reverse causation. A Mendelian randomization approach provides an unbiased estimate of the association using the aldehyde dehydrogenase

2 (ALDH2) variant as a surrogate of alcohol exposure.\n\nMethod A meta-analysis was performed to assess the association between the ALDH2 genotype and PHA-848125 molecular weight colorectal neoplasia, using the ALDH2 genotype as a marker of alcohol intake.\n\nResults The pooled odds ratio (OR) of colorectal neoplasia was 1.31 (95% CI, 1.01-1.70) for the Glu/Glu vs the Lys/Lys genotype. There was no evidence of interstudy heterogeneity (P = 0.12, I(2) = 42.7). The overall risk for Glu/Lys heterozygotes relative to Lys/Lys homozygotes (under a fixed-effects model) was 1.13 (95% CI, 0.86-1.48). There was no evidence of publication bias for Glu/Glu or Glu/Lys analysis.\n\nConclusion The result supports the role of alcohol in colorectal carcinogenesis based on a Mendelian randomization approach.

North American tertiary centers are more likely to see patients with CMT. Immune neuropathies and cryptogenic neuropathies selleck inhibitor were seen equally in North America and South America.”
“So far, in the motor control research field has been found that different muscle premovement activation, the so-called motor set, could influence reaction time. Contradictive RT results were published and studies were not focused primarily on the motor set as an RT correlate. The purpose of the present study was to reveal whether different muscle preactivation modes

of the primary movers and their antagonists cause an influence on RT. After a GO-signal, either an index finger isometric abduction or adduction, was performed on the background of

different premovement muscle activation modes. One way ANOVA showed significant influence of the premovement condition when isometric abduction was the response to the GO-signal. RT was always shorten when the first dorsal interosseous was preactivated with respect to the other conditions. The results support the hypothesis that preactivation of primary movers could shorten the reaction time.”
“Titanium oxide (TiO2) thin films were prepared by ion-assisted deposition (IAD) on glass substrates at various substrate temperatures. These films were re-baked and at the temperature of re-crystallization. Compound Library mouse The effects of the stability of the films on their optical properties, residual stress and surface roughness were studied. The

evolution of oxidation and the cause of the variation in the optical properties and residual stress during baking and re-baking were discussed. However, the optical constants, residual stress and surface roughness varied less in re-baking than in baking. During both baking and re-baking, at substrate temperatures of 150 degrees C, the extinction coefficients, residual stress and surface roughness fluctuated more than at substrate temperatures of 200 and 250 degrees C. These results all reveal that TiO2 films were more stable after re-baking than after baking, and it was especially useful for the IAD films deposited at substrate temperature of 150 degrees C. (C) 2010 The Japan Society of Applied Physics”
“Indian and Chinese carps, Labeo rohita, Catla catla; Ctenopharyngodon idella; Hypophthalmichthys Napabucasin ic50 molitrix and Aristichthys nobilis were obtained from Punjab University Fish Research farms Lahore. These fishes were examined for parasitic infection, lernaeasis. Lernaea cyprinacea (L.) was the most prevalent parasite infecting these five fish species (comprising 88.48-100% population). In addition to L. cyprinacea; Lernaea polymorpha (Yu, 1938); Lernaea oryzophila (Monod, 1932) were found on L. rohita and C. idella. Lernaea ctenopharyngodonis was found on C. idella only. Prevalence of Lernaea was 68.9% and 63.6% in L. rohita and C. catla respectively and 78.1% in C. idella; 66.7% in A. nobilis and 9.1% in H. molitrix. Mean intensity was 17.3; 9.2; 6.91; 1.

The goal of this study was to identify causal genes/variants within susceptibility loci associated with MDV3100 chemical structure COPD. In the discovery cohort, genome-wide gene expression profiles of 500 non-tumor lung specimens were obtained from patients undergoing lung surgery. Blood-DNA from the same patients were genotyped for 1,2 million SNPs. Following genotyping and gene expression quality control filters, 409 samples were analyzed.

Lung expression quantitative trait loci (eQTLs) were identified and overlaid onto three COPD susceptibility loci derived from GWAS; 4q31 (HHIP), 4q22 (FAM13A), and 19q13 (RAB4B, EGLN2, MIA, CYP2A6). Significant eQTLs were replicated in two independent datasets (n = 363 and 339). SNPs previously associated with COPD and lung function on 4q31 (rs1828591, rs13118928) were associated with the mRNA expression Stem Cells & Wnt inhibitor of HHIP. An association between mRNA expression level of FAM13A and SNP rs2045517 was detected at 4q22, but did not reach statistical significance. At 19q13, significant eQTLs were detected with EGLN2. In summary, this study supports HHIP, FAM13A, and EGLN2 as the most likely causal COPD genes on 4q31, 4q22, and 19q13, respectively. Strong lung eQTL SNPs identified in this study will need to be tested for association with COPD in case-control studies. Further functional studies will also be needed to understand the role of genes regulated by disease-related variants in COPD.”
“Infrared spectroscopy studies of beta-alkoxyvinyl

trifluoromethyl ketone, with structure C(2)H(5)O-C(C(CH(3))(3))=CH-COCF(3) (1), in twenty three different pure

organic solvents were undertaken to investigate the solvent-solute interactions and to correlate solvent properties such as Reichard’s parameter and solvatochromic parameters of Kamlet, Abbot, and Taft with carbonyl and vinyl stretching vibrations and their integrated intensities of existing spatial forms. It was shown that conjugation in C=C-C=O system of the (E-s-Z-o-Z) stereoisomer is higher than that in this system of the (Z-s-Z-o-Z) stereoisomer. From derived correlations Selleck LB-100 of the (v) over tilde (C=O) and (v) over tilde (C=C) wavenumbers with solvatochrornic parameters of Kamlet, Abbot, and Taft it is followed that the solvent polarity influences on the (v) over tilde (C=O) and (v) over tilde (C=C) wavenumbers more intense than the solvent HBD acidity, and, at the same time, the influence of these solvent properties is greater for the (E-s-Z-o-Z) stereoisomer. Analysis of derived KAT multiple regressions showed that the increase of the solvent polarity/polarizability (pi*) increased the conjugation in both stereoisomers, whereas the increase of the solvent HBD acidity (alpha) had opposite effect on conjugation in the (Z-s-Z-o-Z) and (E-s-Z-o-Z) stereoisomer. In the former case conjugation was weakened, whereas in the latter it was enhanced. These discrepancies were the consequence of different structure of H-bonded complexes between enone I and HBD solvents.

0% total Lys and 3.46 Mcal/ kg of ME and were fed from d 107 +/- 1.2 of gestation to weaning. Sows were allotted to dietary treatment based on breed, parity, and the date of d 107 of gestation. Litters were standardized within diet, and pigs were weaned

at an average age of 19 +/- 2.1 d. Sows were fed 3 times daily during lactation. After weaning, sows were fed a common gestation diet and checked twice daily for estrus. Sows were grouped by parity (young sows, <= 3; Nirogacestat mature sows, > 3) for statistical analysis. The data were analyzed as a 2 x 2 factorial arrangement of treatments; the factors were parity (<= 3 or > 3) and SDP (0 or 0.5%). Treatment differences were considered significant at P < 0.10. Mature sows had a greater BW on d 107 of gestation, on d 1 postfarrowing, and at weaning; greater lactation

ADFI; and greater litter BW after cross-fostering, but pig survival to weaning was decreased. Sows fed SDP had a greater gestation interval, litter BW at weaning, and litter ADG, with 1 less lactation day. The effect of SDP addition was dependent selleck chemicals on sow parity, as noted by numerous SDP x parity interactions. The addition of SDP increased lactation ADFI in mature sows but decreased ADFI in young sows. Mature sows fed SDP had a greater number of pigs weaned per litter, litter and pig weaning weights, pig survival to weaning, and number of pigs weaned per litter weighing more than 3.6 kg, but the SDP diet had little to no effect on these responses in young sows. Subsequent farrowing data were collected, but no dietary treatment effects (P > 0.10) were observed. The results of this research indicate that SDP increased

productivity of sows in parity 4 or greater.”
“In a previous work, the shape of Arabidopsis seed was described as a cardioid CCI-779 purchase modified by a factor of Phi. In addition, J index was defined as the similarity of the seed (in an orthogonal, bi-dimensional image) to a cardioid, thus allowing the quantitative comparison of seed shape in seeds of varieties and mutants at different stages of development. Here, J index is used for modeling changes in seed morphology during the dynamic process of seed imbibition before germination. The analysis was carried out by means of a general linear model with two fixed factors (genotype and time) applied to two Arabidopsis varieties: Columbia and Wassilewskija and two mutants in cellulose synthesis: prc1-1 (CESA6 in Columbia) and kor1-1 (in Wassilewskija). Equations representing the changes in seed form during imbibition are given. The analysis of changes in seed shape by this procedure provides (1) a quantitative method to record changes in seed shape and to compare between genotypes or treatments showing the time points with maximum differences, and (2) the observation of remarkable differences between wild-type seeds and mutants in cellulose biosynthesis, indicating new phenotypic characteristics previously unknown in the latter.

Results: Coping strategies were found to be associated with depression in patients with heart failure. Adaptive coping such as active coping, acceptance, and planning tended to be used by more patients and were associated with less depression. Those who used more maladaptive methods of coping such as denial and disengagement had higher levels of depression.

Conclusions: Further longitudinal research on depression and coping strategies and best treatment options for coping and depression in patients with heart failure are needed.”
“Objective Diagnosis and treatment of chronic hepatitis B (CHB) have improved in recent years with introduction of FDA approved Drug Library supplier new oral antiviral drugs. Aim of this study was to analyze general knowledge, therapeutic and diagnostic trends of physicians treating

CHB in Spain.\n\nMethods A questionnaire was distributed to 692 physicians of the Spanish Association for the Study of the Liver. The questionnaire assessed habits in CHB management and approach to a pair of hypothetical CHB cases: HBeAg positive and HBeAg negative.\n\nResults One hundred and nineteen (17%) physicians answered the questionnaire. Most of them correctly identified indications for CHB treatment (95%), and had experience AZD7762 concentration with lamivudine (89%), adefovir dipivoxil (84%) and interferon (76%), but only 45% knew the efficacy rate of these drugs. Seventy-six percent recommended pegylated interferon as initial treatment for HBeAg-positive patients, and 86% would treat HBeAg-negative patients with oral antiviral drugs (42% with lamivudine, 36% with adefovir dipivoxil, and 8% with entecavir). Hepatitis B virus (HBV)-DNA determination was used to monitor therapy by 74%, and only 24% used HBV drug resistance test. The only independent factor associated with adequate use of drugs and correct monitoring was experience of treating more than five patients per year. Antiviral prophylaxis for HBV carriers receiving immunosuppression

was indicated by 78% of physicians. Physicians working at university hospitals were significantly selleck chemicals more likely to recommend antiviral prophylaxis than physicians working at nonuniversity hospitals (86 vs. 65%; P=0.009).\n\nConclusion CHB management decisions are not always based on scientific evidence. Continuous medical education could improve knowledge and management of CH B. Eur J Gastroenterol Hepatol 21:1177-1183 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.”
“Triticum turgidum L var. dicoccoides has been a useful source of genes for high grain protein content (GPC) in wheat. The objective of this study was to test the agronomic and quality characteristics of 23 durum Langdon-T dicoccoides (LDN-DIC) substitutions based on T dicoccoides accessions PI 481521 (LDN521) and PI 478742 (LDN742), with emphasis on finding new genes for high GPC. The 23 LDN-DIC substitutions and checks were grown in replicated yield trials at Fargo and Prosper, ND in 2005-2006.

Five-week-old male Wistar rats (n = 35) were randomly assigned to five body weight-matched groups: tail-suspended group (SUS; n = 7); sedentary control group for SUS (S-CON; Silmitasertib clinical trial n = 7); spontaneous recovery group after tail suspension (S + R-CON, n = 7); jump exercise group after tail suspension (S + R-JUM; n = 7); and age-matched control group for S+R-CON

and S+R-JUM without tail suspension and exercise (S-CON+R-CON; n = 7). Rats in SUS and SCON were killed immediately after tail suspension for 14 days. The jump exercise protocol consisted of 10 jumps/day, 5 days/wk, and jump height was 40 cm. Bone mineral density (BMD) of the femur and three-dimensional trabecular bone architecture at the distal femoral metaphysis were measured. Tail suspension

induced a 13.6% decrease in total femoral BMD (P < 0.001) and marked deterioration of trabecular architecture. After 5 wk of free remobilization, femoral BMD, calf muscle weight, and body weight returned to age-matched control levels, but trabeculae remained thinner and less connected. On the other hand, S+R-JUM rats showed significant increases in trabecular thickness, number, and connectivity compared SB203580 datasheet with S+R-CON rats (62.8, 31.6, and 24.7%, respectively; P < 0.05), and these parameters of trabecular architecture returned to the levels of S-CON+R-CON. These results indicate that suspension-induced trabecular deterioration persists after remobilization, but jump exercise during remobilization can restore the integrity of trabecular architecture and bone mass FDA approved Drug Library in the femur in young growing rats.”
“Half a century ago, the apical ectodermal ridge (AER) at the distal tip of the tetrapod limb bud was shown to produce signals necessary for development along the proximal-distal (P-D) axis, but how these signals influence limb patterning is still much debated(1,2). Fibroblast growth factor (FGF) gene family members are key AER-derived signals(3,4), with Fgf4, Fgf8, Fgf9 and Fgf17 expressed specifically in the mouse AER(5). Here we demonstrate that mouse limbs lacking Fgf4, Fgf9 and

Fgf17 have normal skeletal pattern, indicating that Fgf8 is sufficient among AER-FGFs to sustain normal limb formation. Inactivation of Fgf8 alone causes a mild skeletal phenotype(6,7); however, when we also removed different combinations of the other AER-FGF genes, we obtained unexpected skeletal phenotypes of increasing severity, reflecting the contribution that each FGF can make to the total AER-FGF signal. Analysis of the compound mutant limb buds revealed that, in addition to sustaining cell survival, AER-FGFs regulate P-D-patterning gene expression during early limb bud development, providing genetic evidence that AER-FGFs function to specify a distal domain and challenging the long-standing hypothesis that AER-FGF signalling is permissive rather than instructive for limb patterning.