GASTRIC CARCINOMA WITH OSSEOUS METAPLASIA IN A DOG

This report describes an unprecedented case of a gastric carcinoma with osseous metaplasia in a 8-year-old male standard poodle. An exploratory laparotomy revealed a firm yellowish nodular mass in the pyloric region. The lesion was surgically removed and submitted for current histological examination. Immunohistochemistry was performed employing monoclonal antibodies for pan-cytokeratin, vimentin, smooth muscular a-actin and BMP-2/4. The mass consisted in neoplastic proliferation of epithelial cells, arranged in a tubular or acinar pattern and supported by scirrhous stroma, with mucin production and multiple foci of heterotopic ossification. Neoplastic epithelial cells showed strong positive immunostaining for AE1/AE3 and BMP-2/4, although they were negative for both vimentin and a-actin. Histopathological findings suggested that the bone tissue may be primarily originated from neoplastic epithelial cells which directly circumscribe the osseous metaplasia foci

Pathogenic Rickettsia in ticks of spur-thighed tortoise (Testudo graeca) sold in a Qatar live animal market

Research Areas: Infectious Diseases ; Veterinary SciencesThe dissemination of vector arthropods harbouring zoonotic pathogens through the uncontrolled transboundary trade of exotic and pet animals poses an important threat to Public Health. In the present report, we describe the introduction of pathogenic Rickettsia africae and R. aeschlimanni in ticks removed from imported tortoises in Qatar. A total of 21 ticks were collected from pet spur‐thighed tortoises (Testudo graeca) from Doha, May 2018, and studied for species identification and characterization of Rickettsia spp. Morphological and molecular analysis of ticks allowed their identification as Hyalomma aegyptium. Molecular analysis of partial ompA and gltA genes showed that Rickettsia sequences found on these ticks clustered with sequences classified as R. aeschilimanii and R. africae. Since pre‐adult stages of H. aegyptium also feed on humans, this tick species may play a role in the transmission of R. aeschilimanii and R. africae. We alert for the introduction of non‐native pets as vehicles for tick importation, known vectors for animal and human pathogenic agents. Importation of exotic species into non‐autochthonous countries deserves strict control to enforce robust surveillance and mitigate potential exotic diseases epidemics.info:eu-repo/semantics/publishedVersio

HIV-1 Residual Viremia Correlates with Persistent T-Cell Activation in Poor Immunological Responders to Combination Antiretroviral Therapy

BACKGROUND:The clinical significance and cellular sources of residual human immunodeficiency virus type 1 (HIV-1) production despite suppressive combination antiretroviral therapy (cART) remain unclear and the effect of low-level viremia on T-cell homeostasis is still debated. METHODOLOGY/PRINCIPAL FINDINGS:We characterized the recently produced residual viruses in the plasma and short-lived blood monocytes of 23 patients with various immunological responses to sustained suppressive cART. We quantified the residual HIV-1 in the plasma below 50 copies/ml, and in the CD14(high) CD16(-) and CD16+ monocyte subsets sorted by flow cytometry, and predicted coreceptor usage by genotyping V3 env sequences. We detected residual viremia in the plasma of 8 of 10 patients with poor CD4+ T-cell reconstitution in response to cART and in only 5 of 13 patients with good CD4+ T-cell reconstitution. CXCR4-using viruses were frequent among the recently produced viruses in the plasma and in the main CD14(high) CD16(-) monocyte subset. Finally, the residual viremia was correlated with persistent CD4+ and CD8+ T-cell activation in patients with poor immune reconstitution. CONCLUSIONS:Low-level viremia could result from the release of archived viruses from cellular reservoirs and/or from ongoing virus replication in some patients. The compartmentalization of the viruses between the plasma and the blood monocytes suggests at least two origins of residual virus production during effective cART. CXCR4-using viruses might be produced preferentially in patients on cART. Our results also suggest that low-level HIV-1 production in some patients may contribute to persistent immune dysfunction despite cART

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Adhesion of helicobacter species to the human gastric mucosa : a deep look into glycans role

Helicobacter species infections may be associated with the development of gastric disorders, such as gastritis, peptic ulcers, intestinal metaplasia, dysplasia and gastric carcinoma. Binding of these bacteria to the gastric mucosa occurs through the recognition of specific glycan receptors expressed by the host epithelial cells. This review addresses the state of the art knowledge on these host glycan structures and the bacterial adhesins involved in Helicobacter spp. adhesion to gastric mucosa colonization. Glycans are expressed on every cell surface and they are crucial for several biological processes, including protein folding, cell signaling and recognition, and host-pathogen interactions. Helicobacter pylori is the most predominant gastric Helicobacter species in humans. The adhesion of this bacterium to glycan epitopes present on the gastric epithelial surface is a crucial step for a successful colonization. Major adhesins essential for colonization and infection are the blood-group antigen-binding adhesin (BabA) which mediates the interaction with fucosylated H-type 1 and Lewis B glycans, and the sialic acid-binding adhesin (SabA) which recognizes the sialyl-Lewis A and X glycan antigens. Since not every H. pylori strain expresses functional BabA or SabA adhesins, other bacterial proteins are most probably also involved in this adhesion process, including LabA (LacdiNAc-binding adhesin), which binds to the LacdiNAc motif on MUC5AC mucin. Besides H. pylori, several other gastric non-Helicobacter pylori Helicobacters (NHPH), mainly associated with pigs (H. suis) and pets (H. felis, H. bizzozeronii, H. salomonis, and H. heilmannii), may also colonize the human stomach and cause gastric disease, including gastritis, peptic ulcers and mucosa-associated lymphoid tissue (MALT) lymphoma. These NHPH lack homologous to the major known adhesins involved in colonization of the human stomach. In humans, NHPH infection rate is much lower than in the natural hosts. Differences in the glycosylation profile between gastric human and animal mucins acting as glycan receptors for NHPH-associated adhesins, may be involved. The identification and characterization of the key molecules involved in the adhesion of gastric Helicobacter species to the gastric mucosa is important to understand the colonization and infection strategies displayed by different members of this genus

Helicobacter species binding to the human gastric mucosa

Helicobacter pylori infects half of the world population, being associated with several gastric disorders, such as chronic gastritis and gastric carcinoma. The Helicobacter genus also includes other gastric helicobacters, such as H. heilmannii, H. ailurogastricus, H. suis, H. felis, H. bizzozeronii, and H. salomonis. These gastric helicobacters colonize both the human and animal stomach. The prevalence of gastric non-Helicobacter pylori Helicobacter (NHPH) species in humans has been described as low, and the in vitro binding to the human gastric mucosa was never assessed. Herein, human gastric tissue sections were used for the evaluation of the tissue glycophenotype and for the binding of gastric NHPH strains belonging to different species. Histopathological evaluation showed that 37.5% of the patients enrolled in our cohort presented chronic gastritis, while the presence of neutrophil or eosinophilic activity (chronic active gastritis) was observed in 62.5% of the patients. The secretor phenotype was observed in 68.8% of the individuals, based on the expression of Lewis B antigen and binding of the UleX lectin. The in vitro binding assay showed that all the NHPH strains evaluated were able to bind, albeit in low frequency, to the human gastric mucosa. The H. heilmannii, H. bizzozeronii, and H. salomonis strains displayed the highest binding ability both to the gastric superficial epithelium and to the deep glands. Interestingly, we observed binding of NHPH to the gastric mucosa of individuals with severe chronic inflammation and intestinal metaplasia, suggesting that NHPH binding may not be restricted to the healthy gastric mucosa or slight chronic gastritis. Furthermore, the in vitro binding of NHPH strains was observed both in secretor and non-secretor individuals in a similar frequency. In conclusion, this study is the first report of the in vitro binding ability of gastric NHPH species to the human gastric mucosa. The results suggest that other glycans, besides the Lewis antigens, could be involved in the bacterial adhesion mechanism; however, the molecular intervenients remain unknown

Helicobacter spp. in the Stomach of Cats: Successful Colonization and Absence of Relevant Histopathological Alterations Reveals High Adaptation to the Host Gastric Niche

In addition to Helicobacter pylori, many non-Helicobacter pylori Helicobacters (NHPH) are able to cause gastric disease in humans. Cats are a natural reservoir for many of these species. Accordingly, living in close and intimate contact with animals has been identified as a risk factor, and an important zoonotic significance has therefore been attributed to NHPH. To determine the prevalence and associated gastric histopathological changes of Helicobacter species, the gastric mucosa of 71 cats were evaluated. Only four presented normal histopathological mucosa with the absence of spiral-shaped organisms. Normal gastric mucosa and the presence of spiral-shaped bacteria were observed in 13 cats. The remaining animals presented histopathological changes representative of gastritis. Helicobacter species were detected in 53 cats (74.6%) by at least one detection method. None of the animals were positive for H. pylori or for H. ailurogastricus. Helicobacter heilmannii organisms were identified in 20 animals, predominantly in the body gastric region. Helicobacter salomonis was the second most prevalent species (57.1%), although it was mainly found in association with other NHPH. Helicobacter felis and H. bizzozeronii were less frequently detected. The great majority of the Helicobacter spp. PCR-positive animals presented normal features regarding fibrosis/mucosal atrophy, neutrophils, eosinophils, or other inflammatory cells and lymphofollicular hyperplasia. Given the controversy and the strong evidence of absence of significant histopathological alterations associated with the presence of Helicobacter spp. in cats, it is possible to hypothesize that these bacteria may be able to adapt to the feline gastric microenvironment or even to comprise part of the gastric microbiome of this animal species. Thus, prudency must be taken when prescribing an antibiotic therapy based solely on the presence of these bacteria in the feline stomach

Antimicrobial susceptibility pattern of helicobacter heilmannii and Helicobacter ailurogastricus isolates

A combined agar and broth dilution method followed by qPCR was used to determine the antimicrobial susceptibility of felineH. heilmanniiandH. ailurogastricusisolates. AllH. ailurogastricusisolates showed a monomodal distribution of MICs for all the antimicrobial agents tested. ForH. heilmannii, a bimodal distribution was observed for azithromycin, enrofloxacin, spectinomycin, and lincomycin. Single nucleotide polymorphisms (SNPs) were found in 50S ribosomal proteins L2 and L3 of theH. heilmanniiisolate not belonging to the WT population for azithromycin, and in 30S ribosomal proteins S1, S7, and S12 of the isolate not belonging to the WT population for spectinomycin. The antimicrobial resistance mechanism to enrofloxacin and lincomycin remains unknown (2 and 1H. heilmanniiisolate(s), resp.). Furthermore,H. heilmanniiisolates showed higher MICs for neomycin compared toH. ailurogastricusisolates which may be related to the presence of SNPs in several 30S and 50S ribosomal protein encoding genes and ribosomal RNA methyltransferase genes. This study shows that acquired resistance to azithromycin, spectinomycin, enrofloxacin, and lincomycin occasionally occurs in felineH. heilmanniiisolates. As pets may constitute a source of infection for humans, this should be kept in mind when dealing with a human patient infected withH. heilmannii