Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial.

Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64.

Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent developmental disorder, associated with a range of long-term impairments. Variation in DNA methylation, an epigenetic mechanism, is implicated in both neurobiological functioning and psychiatric health. However, the potential role of DNA methylation in ADHD symptoms is currently unclear. In this study, we examined data from the Avon Longitudinal Study of Parents and Children (ALSPAC)-specifically the subsample forming the Accessible Resource for Integrated Epigenomics Studies (ARIES)-that includes (1) peripheral measures of DNA methylation (Illumina 450k) at birth (n=817, 49% male) and age 7 (n=892, 50% male) and (2) trajectories of ADHD symptoms (7-15 years). We first employed a genome-wide analysis to test whether DNA methylation at birth associates with later ADHD trajectories; and then followed up at age 7 to investigate the stability of associations across early childhood. We found that DNA methylation at birth differentiated ADHD trajectories across multiple genomic locations, including probes annotated to SKI (involved in neural tube development), ZNF544 (previously implicated in ADHD), ST3GAL3 (linked to intellectual disability) and PEX2 (related to perixosomal processes). None of these probes maintained an association with ADHD trajectories at age 7. Findings lend novel insights into the epigenetic landscape of ADHD symptoms, highlighting the potential importance of DNA methylation variation in genes related to neurodevelopmental and peroxisomal processes that play a key role in the maturation and stability of cortical circuits.

Maternal depression symptoms, unhealthy diet and child emotional-behavioural dysregulation.

BACKGROUND: Maternal depression and unhealthy diet are well-known risk factors for adverse child emotional-behavioural outcomes, but their developmental relationships during the prenatal and postnatal periods are largely uncharted. This study sought to examine the inter-relationships between maternal depression symptoms and unhealthy diet (assessed during pregnancy and postnatal periods) in relation to child emotional-behavioural dysregulation (assessed at the ages of 2, 4 and 7 years). METHOD: In a large prospective birth cohort of 7814 mother-child pairs, path analysis was used to examine the independent and inter-related associations of maternal depression symptoms and unhealthy diet with child dysregulation. RESULTS: Higher prenatal maternal depression symptoms were prospectively associated with higher unhealthy diet, both during pregnancy and the postnatal period, which, in turn, was associated with higher child dysregulation up to the age of 7 years. In addition, during pregnancy, higher maternal depression symptoms and unhealthy diet were each independently associated with higher child dysregulation up to the age of 7 years. These results were robust to other prenatal, perinatal and postnatal confounders (such as parity and birth complications, poverty, maternal education, etc.). CONCLUSIONS: Maternal depression symptoms and unhealthy diet show important developmental associations, but are also independent risk factors for abnormal child development.

Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study.

Youth with high callous-unemotional traits (CU) are at risk for early-onset and persistent conduct problems. Research suggests that there may be different developmental pathways to CU (genetic/constitutional vs environmental), and that the absence or presence of co-occurring internalizing problems is a key marker. However, it is unclear whether such a distinction is valid. Intermediate phenotypes such as DNA methylation, an epigenetic modification regulating gene expression, may help to clarify etiological pathways. This is the first study to examine prospective inter-relationships between environmental risk (prenatal/postnatal) and DNA methylation (birth, age 7 and 9) in the prediction of CU (age 13), for youth low vs high in internalizing problems. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously implicated in CU. Participants were 84 youth with early-onset and persistent conduct problems drawn from the Avon Longitudinal Study of Parents and Children. For youth with low internalizing problems (46%), we found that (i) OXTR methylation at birth associated with higher CU (age 13) as well as decreased experience of victimization during childhood (evocative epigenetic-environment correlation; birth-age 7), (ii) higher prenatal parental risks (maternal psychopathology, criminal behaviors, substance use) associated with higher OXTR methylation at birth and (iii) OXTR methylation levels were more stable across time (birth-age 9). In contrast, for youth with high internalizing problems, CU were associated with prenatal risks of an interpersonal nature (that is, intimate partner violence, family conflict) but not OXTR methylation. Findings support the existence of distinct developmental pathways to CU.

Control line failure in Angiostrongylus vasorum point-of-care serology test in dogs with angiostrongylosis due to suspected hook effect.

OBJECTIVES: Angiostrongylosis is a significant differential for a diverse range of clinical signs in dogs, many of whom present acutely and sometimes with fatal consequences. Point-of-care diagnostic assays include a commercially available Angiostrongylus vasorum qualitative direct lateral flow assay. MATERIALS AND METHODS: Case records from one referral centre from dogs with an invalid A. vasorum lateral flow assay, comprising an absent control line alongside a visible test line, were reviewed. As control line failure was hypothesised to be due to antigen excess; where available the A. vasorum lateral flow assay was repeated using dilutions of the original serum. RESULTS: Six dogs had an invalid A. vasorum lateral flow assay result. Five dogs had presented with acute-onset, severe clinical disease consistent with angiostrongylosis, and one dog was a clinically healthy in-contact. Clinical suspicion of angiostrongylosis was confirmed using alternative diagnostic testing and/or response to treatment. Repetition of the A. vasorum lateral flow assay, in four cases, using diluted plasma (10% to 12.5% v/v) resulted in the appearance of a control line alongside the visible test line. CLINICAL SIGNIFICANCE: A heavy burden of A. vasorum infection resulting in angiostrongylosis should be suspected in dogs with compatible clinical signs and an invalid A. vasorum lateral flow assay result due to control failure alongside a visible test line. Repetition of the test with a diluted serum may be considered to account for the hook effect, also known as the postzone phenomenon, as a possible cause.

Lack of correlation between predicted and actual off-target effects of short-interfering RNAs targeting the human papillomavirus type 16 E7 oncogene.

BACKGROUND: When designing therapeutic short-interfering RNAs (siRNAs), off-target effects (OTEs) are usually predicted by computational quantification of messenger RNAs (mRNAs) that contain matches to the siRNA seed sequence in their 3' UTRs. It is assumed that the higher the number of predicted transcriptional OTEs, the greater the size of the actual OTE signature and the more detrimental the phenotypic consequences in target-negative cells. METHODS: We tested this general assumption by investigating the OTEs of potential therapeutic siRNAs targeting the human papillomavirus (HPV) type-16 E7 oncogene. We studied HPV-negative squamous epithelial cells, from normal cervix (NCx) and skin (HaCaT), which would be vulnerable to 'bystander' OTEs following transfection in vivo. RESULTS: We observed no correlation between the number of computationally predicted OTEs and the actual number of seed-dependent OTEs (P=0.76). On average only 20.5% of actual transcriptional OTEs were seed-dependent (i.e., predicted). The unpredicted OTEs included stimulation of innate immune pathways, as well as indirect (downstream) effects of other OTEs, which affected important cancer-associated pathways. Although most significant OTEs observed were seen in both NCx and HaCaT cells, only 0-5.9% of differentially expressed genes overlapped between the two cell types. CONCLUSION: These data do not support the assumption that actual OTEs correlate well with predicted OTEs.

The duration and timing of maternal depression as a moderator of the relationship between dependent interpersonal stress, contextual risk and early child dysregulation.

BACKGROUND: Risk factors that are associated with depression in the mother also negatively affect the child. This research sought to extend current knowledge by examining the duration and timing of maternal depression as a moderator of: (1) the impact of dependent interpersonal stress (DIS), such as partner conflict or low social support, and contextual risk (e.g. poverty) on child dysregulation; and (2) continuity in early child dysregulation. METHOD: Mother-child pairs (n = 12 152) who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC) were examined between pregnancy and age 4 years. Data on maternal depression were collected five times between pregnancy and 33 months postpartum; on DIS and contextual risk three times between pregnancy and 33 months; and on child dysregulation at age 2 and 4 years. RESULTS: Longitudinal latent class analysis identified a class of mothers (10%) who evinced a chronic level of depression between pregnancy and 33 months. For chronic-depressed versus non-depressed mothers, the results indicate that: (1) DIS predicted higher child dysregulation if experienced between pregnancy and age 2; (2) contextual risk had a differential effect on child dysregulation if experienced during pregnancy; and (3) children had higher continuity in dysregulation between age 2 and age 4. CONCLUSIONS: Assessing the impact of the timing and duration of maternal depression, and different types of co-occurring risk factors, on child well-being is important. Maternal depression and associated DIS, in comparison to contextual risk, may be more responsive to intervention.

Intergenerational transmission of maltreatment and psychopathology: the role of antenatal depression.

BACKGROUND: Maternal experience of childhood maltreatment and maternal antenatal depression are both associated with offspring childhood maltreatment and offspring adjustment problems. We have investigated the relative impact of maternal childhood maltreatment and exposure to depression in utero on offspring maltreatment and psychopathology. METHOD: The sample included 125 families from the South London Child Development Study. A prospective longitudinal design was used. Data on maternal childhood maltreatment, maternal antenatal depression (36 weeks of pregnancy), offspring childhood maltreatment (age 11 years) and offspring adolescent antisocial behaviour and depression (ages 11 and 16 years) were obtained from parents and offspring through clinical interview. RESULTS: Mothers who experienced childhood maltreatment were significantly more likely to be depressed during pregnancy [odds ratio (OR) 10.00]. Offspring of mothers who experienced only childhood maltreatment or only antenatal depression were no more at risk of being maltreated or having psychopathology; however, offspring of mothers who experienced both maternal childhood maltreatment and antenatal depression were exposed to significantly greater levels of childhood maltreatment and exhibited significantly higher levels of adolescent antisocial behaviour compared with offspring not so exposed. Furthermore, maternal childhood maltreatment accounted for a significant proportion of the variance in offspring childhood maltreatment in only those offspring exposed to depression in utero. CONCLUSIONS: Maternal childhood maltreatment and maternal antenatal depression are highly associated. The co-occurrence of both insults significantly increases the risk of offspring adversity. The antenatal period is an optimum period to identify vulnerable women and to provide interventions.

A parsimonious model of lineage-specific expansion of MADS-box genes in Physcomitrella patens.

KEY MESSAGE: The MADS-box gene family expanded in the lineage leading to the moss, Physcomitrella patens , mainly as a result of polyploidisations and/or large-scale segmental duplication events and to a lesser extent by tandem duplications. Plant MADS-box genes comprise a large family best known for the roles of type II MIKC (C) genes in floral organogenesis, but also including type II MIKC* genes, some of which have been implicated in male gametophytic development, and type I genes, a few of which are involved in ontogeny of female gametophytes, seeds and embryos. Genome-wide analyses of the MADS-box family in angiosperms have revealed numeric predominance of type I and MIKC (C) genes and cross-species phylogenetic clustering of the Mα, Mß and Mγ subtypes of type I genes and of 12 major subgroups of MIKC (C) genes. The genome sequence of Physcomitrella patens has facilitated investigation of its full complement of 26 MADS-box genes, including 6 MIKC (C) genes, 11 MIKC* genes, seven type I genes and two pseudogenes. A much higher degree of similarity in sequence and architecture within the MIKC (C) and MIKC* gene subtypes exists in Physcomitrella than in Arabidopsis. Furthermore, MADS-box and K-box sequence is highly conserved between the MIKC (C) and MIKC* subgroups in Physcomitrella. Nine MIKC* genes and two MIKC (C) genes are located in pairs or triplets on individual DNA scaffolds. Phylogenetic gene clustering, gene architectures and gene linkages (directly determined from examination of the genome sequence) underpin a parsimonious model of two tandem duplications and three segmental duplication events, which can account for lineage-specific expansion of the MADS-box gene family in Physcomitrella from 4 members to 26. Two of these segmental duplication events may be indicative of polyploidisations, one of which has been postulated previously.

Prevalence and risk factors for common respiratory pathogens within a cohort of pet cats in the UK.

OBJECTIVES: Feline herpesvirus (FHV), feline calicivirus (FCV) and Chlamydia felis are common causes of upper respiratory tract disease (URTD) in cats. Their prevalence in the UK pet cat population has not been reported and little is known regarding the risk factors for their oral carriage. METHODS: Total nucleic acid was extracted from owner-collected buccal swabs (n=600) from cats enrolled in a self-selected longitudinal cohort study. Duplex quantitative PCRs for the detection of FHV and C. felis genomic DNA and reverse-transcriptase quantitative PCRs for the detection of FCV genomic RNA were performed. Duplicates, swabs with insufficient host DNA/RNA, and cats with missing data were excluded. Selected epidemiological data were interrogated using univariable and multi-variable logistic regression modelling to identify risk factors. RESULTS: Data from 430 cats were included in the final statistical model. Of these, 2.1% (n=9/430; 95% CI 1.0% to 3.9%) were positive for FHV, 13.3% (n=57/430; 95% CI 10.2% to 16.8%) positive for FCV and 1.2% (n=5/430; 95% CI 0.4% to 2.7%) positive for C. felis. FCV co-infection was present in five (44%) FHV-positive cats and three (60%) C. felis-positive cats. FCV carriage was more frequent in purebred cats (odds ratio 2.48; 95% CI 1.37 to 4.49) and in cats with current or historical clinical signs compatible with URTD (odds ratio 2.98; 95% CI 1.22 to 7.27). CLINICAL SIGNIFICANCE: FCV was the most frequently encountered URTD pathogen in this sample of cats; this should be noted for disinfectant choice. In cats suspected of having FHV or C. felis infection, assessment for co-infection with FCV is recommended.

Clinical presentation, diagnostic investigations, treatment protocols and outcomes of dogs diagnosed with tick-borne diseases living in the United Kingdom: 76 cases (2005-2019).

OBJECTIVES: To report the presence of tick-borne diseases in dogs living in the United Kingdom. MATERIALS AND METHODS: Dogs with a final diagnosis of tick-borne diseases made between January 2005 and August 2019 at seven referral institutions in the United Kingdom were included in the study. RESULTS: Seventy-six dogs were included: 25 were diagnosed with ehrlichiosis, 23 with babesiosis, eight with Lyme borreliosis and six with anaplasmosis. Fourteen dogs had co-infections with two or three pathogens. Except for those dogs with anaplasmosis and Lyme borreliosis, most dogs with tick-borne diseases had a history of travel to or from endemic countries. However, three dogs with ehrlichiosis, and one dog each infected with Babesia canis and Babesia vulpes did not have any history of travel. A variety of non-specific clinical signs and laboratory abnormalities were reported. Targeted treatment was successful at achieving clinical remission in 64 (84%) dogs. CLINICAL SIGNIFICANCE: Even in non-endemic areas, veterinary surgeons should consider tick-borne diseases in dogs with compatible clinical presentation and laboratory findings and especially where there is a history of travel. As autochthonous transmission of tick-borne-pathogens does occur, an absence of travel should not rule out tick-borne diseases. Specific diagnostic testing is required to confirm infection, and this enables prompt targeted treatment and often a positive outcome.

Adverse childhood experiences and global mental health: avenues to reduce the burden of child and adolescent mental disorders.

Mental disorders are one of the largest contributors to the burden of disease globally, this holds also for children and adolescents, especially in low- and middle-income countries. The prevalence and severity of these disorders are influenced by social determinants, including exposure to adversity. When occurring early in life, these latter events are referred to as adverse childhood experiences (ACEs).In this editorial, we provide an overview of the literature on the role of ACEs as social determinants of mental health through the lenses of global mental health. While the relation between ACEs and mental health has been extensively explored, most research was centred in higher income contexts. We argue that findings from the realm of global mental health should be integrated into that of ACEs, e.g. through preventative and responsive psychosocial interventions for children, adolescents and their caregivers. The field of global mental health should also undertake active efforts to better address ACEs in its initiatives, all with the goal of reducing the burden of mental disorders among children and adolescents globally.

Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study.

To investigate similarities and differences in the serotonergic diathesis for mood disorders and suicide attempts, we conducted a study in a cohort followed longitudinally for 22 years. A total of 1255 members of this cohort, which is representative of the French-speaking population of Quebec, were investigated. Main outcome measures included (1) mood disorders (bipolar disorder and major depression) and suicide attempts by early adulthood; (2) odds ratios and probabilities associated with 143 single nucleotide polymorphisms in 11 serotonergic genes, acting directly or as moderators in gene-environment interactions with childhood sexual or childhood physical abuse (CPA), and in gene-gene interactions; (3) regression coefficients for putative endophenotypes for mood disorders (childhood anxiousness) and suicide attempts (childhood disruptiveness). Five genes showed significant adjusted effects (HTR2A, TPH1, HTR5A, SLC6A4 and HTR1A). Of these, HTR2A variation influenced both suicide attempts and mood disorders, although through different mechanisms. In suicide attempts, HTR2A variants (rs6561333, rs7997012 and rs1885884) were involved through interactions with histories of sexual and physical abuse whereas in mood disorders through one main effect (rs9316235). In terms of phenotype-specific contributions, TPH1 variation (rs10488683) was relevant only in the diathesis for suicide attempts. Three genes contributed exclusively to mood disorders, one through a main effect (HTR5A (rs1657268)) and two through gene-environment interactions with CPA (HTR1A (rs878567) and SLC6A4 (rs3794808)). Childhood anxiousness did not mediate the effects of HTR2A and HTR5A on mood disorders, nor did childhood disruptiveness mediate the effects of TPH1 on suicide attempts. Of the serotonergic genes implicated in mood disorders and suicidal behaviors, four exhibited phenotype-specific effects, suggesting that despite their high concordance and common genetic determinants, suicide attempts and mood disorders may also have partially independent etiological pathways. To identify where these pathways diverge, we need to understand the differential, phenotype-specific gene-environment interactions such as the ones observed in the present study, using suitably powered samples.

DNA damage and metabolic activity in the preimplantation embryo.

BACKGROUND: Embryos with greater viability have a lower or 'quieter' amino acid metabolism than those which arrest. We have hypothesized this is due to non-viable embryos possessing greater cellular/molecular damage and consuming more nutrients, such as amino acids for repair processes. We have tested this proposition by measuring physical damage to DNA in bovine, porcine and human embryos at the blastocyst stage and relating the data to amino acid profiles during embryo development. METHODS: Amino acid profiles of in vitro-derived porcine and bovine blastocysts were measured by high-performance liquid chromatography and the data related retrospectively to DNA damage in each individual blastomere using a modified alkaline comet assay. Amino acid profiles of spare human embryos on Day 2-3 were related to DNA damage at the blastocyst stage. RESULTS: A positive correlation between amino acid turnover and DNA damage was apparent when each embryo was examined individually; a relationship exhibited by all three species. There was no relationship between DNA damage and embryo grade. CONCLUSIONS: Amino acid profiling of single embryos can provide a non-invasive marker of DNA damage at the blastocyst stage. The data are consistent with the quiet embryo hypothesis with viable embryos (lowest DNA damage) having the lowest amino acid turnover. Moreover, these data support the notion that metabolic profiling, in terms of amino acids, might be used to select single embryos for transfer in clinical IVF.

Spectrophotometry of pluto-charon mutual events: individual spectra of pluto and charon.

Time-resolved spectra of the 3 March and 4 April 1987 mutual events of Pluto and its satellite Charon were obtained with spectral coverage from 5,500 to 10,000 angstroms with 25 angstrom spectral resolution. Since both events were total occultations of Charon by Pluto, spectra were obtained of the anti-Charon-facing hemisphere of Pluto, with no contribution from Charon during totality. On 4 April, a combined spectrum of Pluto and Charon immediately before first contact was also obtained. The spectrum of the Pluto-facing hemisphere of Charon was extracted by differencing the pre-event and totality spectra. The spectra were reduced to reflectances by ratioing them to spectra of solar analog stars. Charon has a featureless reflectance spectrum, with no evidence of methane absorption. Charon's reflectance appears neutral in color and corresponds to a geometric albedo of approximately 0.37 at 6000 angstroms. The Pluto reflectance spectrum displays methane absorption bands at 7300, 7900, 8400, 8600, and 8900 angstroms and is red in color, with a geometric albedo of approximately 0.56 at 6000 angstroms. The signal-to-noise ratios of the eclipse spectra were not high enough to unambiguously identify the weaker methane band at 6200 angstroms.

Atomic hydrogen on Mars: measurements at solar minimum.

The Copernicus Orbiting Astronomical Observatory was used to obtain measurements of Mars Lyman-alpha (1215.671-angstrom) emission at the solar minimum, which has resulted in the first information on atomic hydrogen concentrations in the upper atmosphere of Mars at the solar minimum. The Copernicus measurements, coupled with the Viking in situ measurements of the temperature (170 degrees +/- 30 degrees K) of the upper atmosphere of Mars, indicate that the atomic hydrogen number density at the exobase of Mars (250 kilometers) is about 60 times greater than that deduced from Mariner 6 and 7 Lyman-alpha measurements obtained during a period of high solar activity. The Copernicus results are consistent with Hunten's hypothesis of the diffusion-limited escape of atomic hydrogen from Mars.

Mars: Detection of Atmospheric Water Vapor during the Southern Hemisphere Spring and Summer Season.

Water vapor was found to reappear in the atmosphere of Mars during its southern hemisphere spring and summer season, with a maximum vertical column abundance of 45 to 50 microns of precipitable water averaged over the entire planet. Although the spring-summer seasons for each hemisphere are generally symmetrical with respect to the appearance of water vapor, the data suggest that water vapor may appear later in the season and in slightly larger amounts during the southern hemisphere spring-summer.

Discovery of a main-belt asteroid resembling ordinary chondrite meteorites.

Although ordinary chondrite material dominates meteorite falls, the identification of a main-belt asteroid source has remained elusive. From a new survey of more than 80 small main-belt asteroids comes the discovery of one having a visible and near-infrared reflectance spectrum similar to L6 and LL6 ordinary chondrite meteorites. Asteroid 3628 BoZnemcová has an estimated diameter of 7 kilometers and is located in the vicinity of the 3:1 Jovian resonance, a predicted meteorite source region. Although the discovery of a spectral match may indicate the existence of ordinary chondrite material within the main asteroid belt, the paucity of such detections remains an unresolved problem.

Inflammatory Mediators in the Mesenteric Lymph Nodes, Site of a Possible Intermediate Phase in the Immune Response to Feline Coronavirus and the Pathogenesis of Feline Infectious Peritonitis?

Feline infectious peritonitis (FIP) is an almost invariably fatal feline coronavirus (FCoV)-induced disease thought to arise from a combination of viral mutations and an overexuberant immune response. Natural initial enteric FCoV infection may remain subclinical, or result in mild enteric signs or the development of FIP; cats may also carry the virus systemically with no adverse effect. This study screened mesenteric lymph nodes (MLNs), the presumed first site of FCoV spread from the intestine regardless of viraemia, for changes in the transcription of a panel of innate immune response mediators in response to systemic FCoV infection and with FIP, aiming to identify key pathways triggered by FCoV. Cats with and without FIP, the latter with and without FCoV infection in the MLN, were compared. Higher expression levels in FIP were found for toll-like receptors (TLRs) 2, 4 and 8. These are part of the first line of defence and suggest a response to both viral structural proteins and viral nucleic acid. Expression of genes encoding inflammatory cytokines and chemokines, including interleukin (IL)-1ß, IL-6, IL-15, tumour necrosis factor (TNF)-α, CXCL10, CCL8, interferon (IFN)-α, IFN-ß and IFN-γ, was higher in cats with FIP, consistent with inflammatory pathway activation. Expression of genes encoding transcription factors STAT1 and 2, regulating signalling pathways, particularly of the interferons, was also higher. Among cats without FIP, there were few differences between virus-positive and virus-negative MLNs; however, TLR9 and STAT2 expression were higher with infection, suggesting a direct viral effect. The study provides evidence for TLR involvement in the response to FCoV. This could open up new avenues for therapeutic approaches.