Antibiotic use during pregnancy is linked to offspring gut microbial dysbiosis, barrier disruption, and altered immunity along the gut-lung axis.

Antibiotic use during pregnancy is associated with increased asthma risk in children. Since approximately 25% of women use antibiotics during pregnancy, it is important to identify the pathways involved in this phenomenon. We investigate how mother-to-offspring transfer of antibiotic-induced gut microbial dysbiosis influences immune system development along the gut-lung axis. Using a mouse model of maternal antibiotic exposure during pregnancy, we immunophenotyped offspring in early life and after asthma induction. In early life, prenatal-antibiotic exposed offspring exhibited gut microbial dysbiosis, intestinal inflammation (increased fecal lipocalin-2 and IgA), and dysregulated intestinal ILC3 subtypes. Intestinal barrier dysfunction in the offspring was indicated by a FITC-dextran intestinal permeability assay and circulating lipopolysaccharide. This was accompanied by increased T-helper (Th)17 cell percentages in the offspring's blood and lungs in both early life and after allergy induction. Lung tissue additionally showed increased percentages of RORγt T-regulatory (Treg) cells at both time points. Our investigation of the gut-lung axis identifies early-life gut dysbiosis, intestinal inflammation, and barrier dysfunction as a possible developmental programming event promoting increased expression of RORγt in blood and lung CD4+ T cells that may contribute to increased asthma risk.

Low-dose perinatal supplementation with Enterococcus faecalis increases concentrations of short-chain fatty acids in the offspring but does not protect against allergic asthma.

Childhood allergic asthma is associated with a dysbiotic gut microbiome in early life, and maternal perinatal treatment with probiotics is a potential way alter the infant microbiome, which may improve asthma outcomes. This study used a mouse model to examine the effect of maternal supplementation with the probiotic Enterococcus faecalis on faecal short-chain fatty acid (SCFA) concentrations and asthma risk in the offspring. Pregnant/lactating mice were treated daily, from gestation day 6 to postnatal day 21, with an oral suspension of 106, 107 or 108 colony-forming units of a live preparation of the probiotic E. faecalis (Symbioflor®1). At weaning, offspring were subjected to an ovalbumin-induced experimental asthma protocol. Faeces were collected from the mothers and offspring at several different time points to determine SCFA concentrations. It was found that maternal supplementation with E. faecalis did not alter litter size, sex ratio or offspring weight, and was associated with an increase in SCFAs in offspring faeces at weaning and after allergy induction. However, allergic offspring from E. faecalis supplemented mothers showed no difference in asthma severity when compared with allergic offspring from control mothers. In conclusion, although maternal perinatal supplementation with low-dose E. faecalis was associated with increased faecal SCFAs in the offspring, it did not protect against offspring asthma. This is may be because SCFA concentrations were not increased to an immunoprotective level. We recommend that future studies concentrate on probiotic supplementation in high-risk cases, for instance, to repair gut dysbiosis resulting from antibiotic use in pregnant mothers or their infants.

Mouse milk immunoglobulin G Fc-linked N-glycosylation nano-LC-MS analysis in a model of vancomycin exposure during pregnancy.

Breast milk immunoglobulin G (IgG) plays an important role in the transfer of passive immunity in early life and in shaping the neonatal immune system through N-glycan-mediated effector functions. Currently, there are no protocols available to analyze breast milk IgG-Fc glycosylation in mouse models. Therefore, we developed and validated a glycoproteomic workflow for the medium-throughput subclass-specific nano-LC-MS analysis of IgG enriched from small milk volumes of lactating mice. With the established methods, the IgG glycopatterns in a mouse model of antibiotic use during pregnancy and increased asthma susceptibility in the offspring were analyzed. Pregnant BALB/c mice were treated with vancomycin during gestation days 8-17 and IgG1F, IgG2, and IgG3-Fc glycosylation was subsequently analyzed in maternal serum, maternal breast milk, and offspring serum on postnatal day 15. The IgG glycosylation profiles of mouse maternal milk and serum revealed no significant differences within the glycoforms quantified across subclasses. However, vancomycin use during pregnancy was associated with changes in IgG-Fc glycosylation in offspring serum, shown by the decreased relative abundance of the IgG1F-G1 and IgG3-G0 glycoforms, together with the increased relative abundance of the IgG3-G2 and S1 glycoforms. The workflow presented will aid in the emerging integrative multi-omics- and glycomics-oriented milk analyses both in rodent models and human cohorts for a better understanding of mother-infant immunological interactions.

Prenatal antibiotic exposure, asthma, and the atopic march: A systematic review and meta-analysis.

Antibiotic use during pregnancy may increase the risk for asthma in children. We performed a meta-analysis assessing prenatal antibiotic exposure and the risk for childhood wheeze or asthma, as well as for diseases associated with the atopic march. A systematic literature search protocol (PROSPERO-ID: CRD42020191940) was registered and searches were completed using Medline, Proquest, Embase, and the Cochrane central register of controlled trials. Screening for inclusion criteria: published in English, German, French, Dutch, or Arabic, intervention (use of any antibiotic at any time point during pregnancy), and disease (reporting atopic disease incidence in children with a primary outcome of asthma or wheeze), and exclusion criteria: reviews, preclinical data, and descriptive studies, yielded 27 studies. Study quality was assessed using the Newcastle-Ottawa Assessment Scale. Quality of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Our meta-analysis demonstrates that antibiotic use during pregnancy is associated with an increased relative risk (RR) of developing wheeze RR 1.51 (95% CI: 1.17-1.94) or asthma RR 1.28 (95% CI 1.22-1.34) during childhood. Assessment of the atopic march in association with asthma or wheeze revealed that antibiotic use during pregnancy also increases the risk for eczema/dermatitis RR 1.28 (95% CI: 1.06-1.53) and allergic rhinitis RR 1.13 (95% CI: 1.02-1.25). One study found an increase in food allergy RR 1.81 (95% CI: 1.11-2.95). Maternal antibiotic use during pregnancy is associated with an increased risk for wheeze or asthma development in children, as well as for diseases involved in the atopic march. There was high heterogeneity in the data, and the certainty of the evidence was determined to be low quality, highlighting the need for more high-quality studies on this topic. These results have importance for antibiotic stewardship throughout the prenatal period. This work was supported by the Deutsche Forschungsgemeinschaft and the Konrad Adenauer Foundation.

Antibiotic use during pregnancy increases offspring asthma severity in a dose-dependent manner.

BACKGROUND: The use of antibiotics during pregnancy is associated with increased allergic asthma risk in the offspring, and given that approximately 25% of pregnant women are prescribed antibiotics, it is important to understand the mechanisms contributing to this phenomenon. Currently, there are no studies that directly test this association experimentally. Our objective was to develop a mouse model in which antibiotic treatment during pregnancy results in increased offspring asthma susceptibility. METHODS: Pregnant mice were treated daily from gestation day 8-17 with an oral solution of the antibiotic vancomycin, and three concentrations were tested. At weaning, offspring were subjected to an adjuvant-free experimental asthma protocol using ovalbumin as an allergen. The composition of the gut microbiome was determined in mothers and offspring with samples collected from five different time points; short-chain fatty acids were also analyzed in allergic offspring. RESULTS: We found that maternal antibiotic treatment during pregnancy was associated with increased offspring asthma severity in a dose-dependent manner. Furthermore, maternal vancomycin treatment during pregnancy caused marked changes in the gut microbiome composition in both mothers and pups at several different time points. The increased asthma severity and intestinal microbiome changes in pups were also associated with significantly decreased cecal short-chain fatty acid concentrations. CONCLUSION: Consistent with the "Developmental Origins Hypothesis," our results confirm that exposure to antibiotics during pregnancy shapes the neonatal intestinal environment and increases offspring allergic lung inflammation.

Maternal asthma is associated with persistent changes in allergic offspring antibody glycosylation.

BACKGROUND: Maternal asthma during pregnancy is considered an environmental risk factor for asthma development in children. Immunoglobulin G (IgG) antibodies that are transferred from the mother to the fetus are known to act in a pro- or anti-inflammatory manner depending on their glycosylation status. OBJECTIVE: Using a mouse model, we examined how maternal allergic airway inflammation during pregnancy influenced offspring experimental asthma severity, as well as maternal and offspring serum IgG antibody glycosylation patterns. Additionally, the effects of maternal and offspring exposure to the same or different allergens were investigated. METHODS: Female mice were either sham sensitized or sensitized to casein (CAS) or ovalbumin (OVA) before mating. Subsequently, allergic lung inflammation was induced in pregnant dams via aerosol allergen challenge (sham, CAS or OVA). After weaning, pups were subjected to an experimental asthma protocol using OVA. Asn-297 IgG glycosylation was analysed in maternal and offspring serum. RESULTS: When mothers and offspring were sensitized to the same allergen (OVA-OVA), offspring had more severe experimental asthma. This was evidenced by altered antibody concentrations, increased bronchoalveolar lavage inflammatory cell influx and decreased lung tissue and lung draining lymph node regulatory T cell percentages. When mothers and offspring were sensitized to different allergens (CAS-OVA), this phenotype was no longer observed. Additionally, maternal serum from allergic mothers had significantly higher levels of pro-inflammatory IgG1, shown by decreased galactosylation and sialylation at the Asn-297 glycosylation site. Similar glycosylation patterns were observed in the serum of adult allergic offspring from allergic mothers. CONCLUSIONS AND CLINICAL RELEVANCE: We observed a strong association between maternal experimental asthma during pregnancy, increased offspring airway inflammation and pro-inflammatory IgG glycosylation patterns in mothers and offspring. IgG glycosylation is not a standard measurement in the clinical setting, and we argue that it may be an important parameter to include in future clinical studies.

p53 deficiency induces cancer stem cell pool expansion in a mouse model of triple-negative breast tumors.

Triple-negative breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Triple-negative tumors often display activated Wnt/ß-catenin signaling and most have impaired p53 function. We studied the interplay between p53 loss and Wnt/ß-catenin signaling in stem cell function and tumorigenesis, by deleting p53 from the mammary epithelium of K5ΔNßcat mice displaying a constitutive activation of Wnt/ß-catenin signaling in basal cells. K5ΔNßcat transgenic mice present amplification of the basal stem cell pool and develop triple-negative mammary carcinomas. The loss of p53 in K5ΔNßcat mice led to an early expansion of mammary stem/progenitor cells and accelerated the formation of triple-negative tumors. In particular, p53-deficient tumors expressed high levels of integrins and extracellular matrix components and were enriched in cancer stem cells. They also overexpressed the tyrosine kinase receptor Met, a feature characteristic of human triple-negative breast tumors. The inhibition of Met kinase activity impaired tumorsphere formation, demonstrating the requirement of Met signaling for cancer stem cell growth in this model. Human basal-like breast cancers with predicted mutated p53 status had higher levels of MET expression than tumors with wild-type p53. These results connect p53 loss and ß-catenin activation to stem cell regulation and tumorigenesis in triple-negative cancer and highlight the role of Met signaling in maintaining cancer stem cell properties, revealing new cues for targeted therapies.

[Giant epithelioid hemangioma of the hand]. / Hémangiome épithélioïde géant de la main.

Epithelioid vascular tumors are a heterogeneous group characterized by epithelioid-appearing endothelial cells. Included are benign vascular tumors (epithelioid haemangioma), borderline tumors (epithelioid haemangioendothelioma), and malignant tumors (epithelioid angiosarcoma). We describe a case of epithelioid haemangioma.

Role of nitric oxide and reduced glutathione in the protective effects of aminoguanidine, gadolinium chloride and oleanolic acid against acetaminophen-induced hepatic and renal damage.

The potential protective role of aminoguanidine (AG), gadolinium chloride (GdCl(3)) and oleanolic acid (OA) in acetaminophen (APAP)-induced hepatotoxicity and nephrotoxicity was investigated in rats. Pretreatment of rats with AG (50mg/kg) orally, GdCl(3) (10mg/kg) intramuscularly or OA (25mg/kg) intramuscularly protected markedly against hepatotoxicity and nephrotoxicity induced by an acute oral toxic dose of APAP (2.5g/kg) as assessed by biochemical measurements and by histopathological examination. None of AG-, GdCl(3)- or OA-pretreated animals died by the acute toxic dose of APAP. Concomitantly, pretreatment of rats with these agents suppressed the profound elevation of nitric oxide (NO) production and obvious reduction of intracellular reduced glutathione (GSH) levels in liver and kidney induced by the acute toxic dose of APAP. Similarly, daily treatment of rats with a smaller dose of AG (10mg/kg), GdCl(3) (3mg/kg) or OA (5mg/kg) concurrently with a smaller toxic dose of APAP (750mg/kg) for 1 week protected against APAP-induced hepatotoxicity and nephrotoxicity. This treatment also completely prevented APAP-induced mortality and markedly inhibited APAP-induced NO overproduction as well as hepatic and renal intracellular GSH levels reduction. These results provide evidence that inhibition of NO overproduction and consequently maintenance of intracellular GSH levels may play a pivotal role in the protective effects of AG, GdCl(3) and OA against APAP-induced hepatic and renal damages.

[Cystic lymphangiomas of the mesentery and the epiploon. About two cases]. / Le lymphangiome kystique du mésentère et de l'épiploon. A propos de deux cas.

Two cases of cystic lymphangiomas of the mesentery and the epiploon are hereby related. The authors underline the following points: first, the rarity of these tumors along with the absence of significant clinical features makes the differential diagnosis with ovary tumors a difficult task. Second, although abdominal ultra sonography, completed by CT scan, allows the hypothesis of lymphangioma, only histological examination will confirm the diagnosis. There is no other treatment but complete exeresis, with a good prognosis and exceptional recurrences.

[Pelvic lymphocele: report of a case and review of the literature]. / Lymphocèle pelvienne: un diagnostic à ne pas méconnaître! A propas d'un cas et revue de la littérature

Lymphadenectomy for pelvic cancer can lead to complications, particularly lymphocele. We report a case of pelvic lymphocele, which occurred in a patient who underwent surgery for stage IIa cervical carcinoma after preoperative radiotherapy. The intervention consisted in colpohysterectomy, with lymphadenectomy without peritonisation. Five months later she developed dysuria and pelvic pain. Ultrasound and computed tomography showed a pelvic lymphocele complicated by renal insufficiency. Kidney function was re-established after intraperitoneal marsupialisation. One year later the patient was in good clinical condition with no disorder of kidney function.

[Contribution of ultrasonography in thyroid diseases. Apropos of 100 cases]. / Apport de l'echographie dans la pathologie thyroïdienne. A propos de 100 cas.

Thyroid disease is a very common disease, essentially affecting women, and raises diagnostic and therapeutic problems. The objective of this study was to specify the value of ultrasonography in the diagnosis and aetiological orientation of these lesions, based on a retrospective study of 100 patients. The results of ultrasonography were compared to the histological results. The aetiologies detected were dominated by benign lesions, particularly adenomas (56 cases), dystrophic goitres (32 cases) and cancers (7 cases). Ultrasonography allowed the detection of clinically impalpable nodules with no isotope scan signs in 11% of cases. The ultrasonographic appearance of benign nodules was variable. Solitary nodules were detected in 63 cases. They were hyperechoic in 15 cases, isoechoic in 8 cases, cystic in 9 cases, and mixed in 31 cases. A peripheral clear halo was revealed in 25 cases and macrocalcifications were present in 17 cases. Malignant lesions were visualized in 7 cases and were solitary in 5 cases. Solitary lesions had a hypoechoic echostructure in 1 case, an isoechoic echostructure in 2 cases and a mixed echostructure in 2 cases. The margins were poorly demarcated in 3 cases, and circumscribed without peripheral halo in 2 cases. Cervical lymphadenopathy was detected in 2 cases. Graves' disease, diagnosed in 2 patients, showed a diffuse hypoechoic appearance of the entire thyroid gland. Ultrasonography is a sensitive morphological method for the diagnosis of thyroid lesions. A detailed and precise analysis of the ultrasound signs of the lesion can suggest that benign or malignant nature of the lesion, which can be completed by Doppler-ultrasound and especially ultrasound-guided needle biopsies.

Modulation of IgE production in the mouse by beta 2-adrenoceptor agonist.

The present study examined the in vitro and in vivo effect of salbutamol on IgE production in the mouse. The present results show that salbutamol potentiates the in vitro interleukin 4 (IL-4)-induced IgE production from lipopolysaccharide-activated murine B lymphocytes. This effect is dose-dependent and is observed at concentrations above 10 nM. In vivo, when ovalbumin (OA)-sensitized BALB/c mice were treated with a daily injection of salbutamol, an increase of the anti-OA IgE levels in the serum was observed as compared to sensitized animals. Such an effect was observed at doses above 1 microgram/kg and was maximal at 10 micrograms/kg. Treatment of sensitized mice with salbutamol increased the ex vivo production of IL-4, IL-5, IL-6 and IL-10 from concanavalin A-activated splenocytes whereas no modification of IFN-gamma synthesis was noticed as compared to nontreated sensitized control mice. These results demonstrate that beta 2-adrenoceptor agonist stimulation results in an increase in IgE production both in vitro and in vivo in the mice. At least in vivo, they also suggest that the effect of this drug could be explained by an increase of the production of Th2-type lymphokines.

[Hypertensive episode and arrhythmia with fatal outcome caused by pheochromocytoma discovered peroperatively]. / Poussées hypertensives et troubles du rythme à évolution fatale par phéochromocytome de découverte peropératoire.

The authors report a case of pheochromocytoma recognized during surgery, at the manipulation of the tumor resulting in severe arterial hypertension, arrhythmia and a final unresponsive ventricular fibrillation. The anatomopathological examination confirmed the diagnosis of the pheochromocytoma in ectopic localization.

[Heller's operation in the treatment of idiopathic megaesophagus. Apropos of 35 cases]. / L'intervention de Heller dans le traitement du mégaoesophage idiopathique. A propos de 35 cas.

The authors report 35 cases of idiopathic megaoesophagus in adult. They underline its clinical latency, often the patients come belatedey the insist upon the interest of Heller's procedure giving the best functional results.

[Krukenberg's tumor: still a somber prognosis. 4 cases]. / Tumeur de Krükenberg: un pronostic encore sombre. A propos de 4 observations.

The authors report four cases of Krukenberg's tumour. They point out its rarity and that the diagnosis can come as a surprise on histological examination. The tumour always has Signet ring cells. How the ovary comes to be involved is not known as yet. Treatment is mainly surgical with added chemotherapy but the prognosis is still very poor indeed.