Argon plasma coagulation treatment of anal high-grade squamous intraepithelial lesions in men who have sex with men living with HIV: results of a 2-year prospective pilot study.

OBJECTIVES: Men who have sex with men (MSM) living with HIV are at high risk for anal high-grade squamous intraepithelial lesions (HSILs) and cancer. The best management of anal HSIL remains unclear. Our objective was to assess whether argon plasma coagulation (APC) could be safe, well tolerated and efficient to treat anal HSILs in MSM living with HIV. METHODS: A prospective phase II, open-label, pilot study was conducted to evaluate APC to treat anal HSILs in 20 HIV-positive MSM. Participants were followed for 2 years after their first treatment. RESULTS: Twenty men with persistent HSILs completed the 2-year study. Their baseline median CD4 count was 490 cells/µL and 85% had undetectable HIV viral loads. Overall, 65% (13/20) of participants were clear of HSILs at their 24-month visit. The initial response rates after the first, second and third APC treatments were 45%, 44% and 67%, respectively, but recurrences were common. The main side effect was pain during and within 1 week after the treatments. There were no long-term side effects, nor serious adverse events related to the procedure. Cost is a drawback. CONCLUSIONS: APC can be used to treat anal HSILs in HIV-seropositive MSM, and requires repeated treatment because of a high recurrence rate. As successful treatment of human papillomavirus (HPV) infection or eradication of the anal transitional zone remains impossible, HSIL treatment is challenging and requires long-term follow-up.

DNA methylation and gene expression changes in mouse mammary tissue during successive lactations: part II - the impact of lactation rank.

Mastitis is among the main reasons women cease breastfeeding. In farm animals, mastitis results in significant economic losses and the premature culling of some animals. Nevertheless, the effect of inflammation on the mammary gland is not completely understood. This article discusses the changes to DNA methylation in mouse mammary tissue caused by lipopolysaccharide-induced inflammation after in vivo intramammary challenges and the differences in DNA methylation between 1st and 2nd lactations. Lactation rank induces 981 differential methylations of cytosines (DMCs) in mammary tissue. Inflammation in 1st lactation compared to inflammation in 2nd lactation results in the identification of 964 DMCs. When comparing inflammation in 1st vs. 2nd lactations with previous inflammation history, 2590 DMCs were identified. Moreover, Fluidigm PCR data show changes in the expression of several genes related to mammary function, epigenetic regulation, and the immune response. We show that the epigenetic regulation of two successive physiological lactations is not the same in terms of DNA methylation and that the effect of lactation rank on DNA methylation is stronger than that of the onset of inflammation. The conditions presented here show that few DMCs are shared between comparisons, suggesting a specific epigenetic response depending on lactation rank, the presence of inflammation, and even whether the cells had previously suffered inflammation. In the long term, this information could lead to a better understanding of the epigenetic regulation of lactation in both physiological and pathological conditions.Abbreviations: RRBS, reduced representation bisulphite sequencing; RT-qPCR, real-time quantitative polymerase chain reaction; MEC, mammary epithelial cells; MaSC, mammary stem cell; TSS, transcription start site; TTS, transcription termination site; UTR, untranslated region; SINE, short interspersed nuclear element; LINE, long interspersed nuclear element; CGI, CpG island; DEG, differentially expressed gene; DMC, differentially methylated cytosine; DMR, differentially methylated region; GO term, gene ontology term; MF, molecular function; BP, biological process.

DNA methylation and gene expression changes in mouse mammary tissue during successive lactations: part I - the impact of inflammation.

Mastitis is among the main reasons women cease breastfeeding, which leads to them supplementing breast milk with artificial formula. In farm animals, mastitis results in significant economic losses and the premature culling of some animals. Nevertheless, researchers do not know enough about the effect of inflammation on the mammary gland. This article discusses the changes to DNA methylation in mouse mammary tissue caused by lipopolysaccharide-induced inflammation (4 h post-injection of lipopolysaccharide). We analysed the expression of some genes related to mammary gland function, epigenetic regulation, and the immune response. The analysis focused on three comparisons: inflammation during the first lactation, inflammation during second lactation with no history of inflammation, and inflammation during second lactation with previous inflammation. We identified differentially methylated cytosines (DMCs), differentially methylated regions (DMRs), and some differentially expressed genes (DEGs) for each comparison. The three comparisons shared some DEGs; however, few DMCs and only one DMR were shared. These observations suggest that inflammation is one of several factors affecting epigenetic regulation during successive lactations. Furthermore, the comparison between animals in second lactation with and without inflammation, with no inflammation history during first lactation showed a different pattern compared to the other conditions in this experiment. This indicates that inflammation history plays an important role in determining epigenetic changes. The data presented in this study suggest that lactation rank and previous inflammation history are equally important when explaining mammary tissue gene expression and DNA methylation changes.Abbreviations: RRBS, reduced representation bisulfite sequencing; RT-qPCR, real-time quantitative polymerase chain reaction; MEC, mammary epithelial cells; TSS, transcription start site; TTS, transcription termination site; UTR, untranslated region; SINE, short interspersed nuclear element; LINE, long interspersed nuclear element; CGI, CpG island; DEG, differentially expressed gene; DMC, differentially methylated cytosine; DMR, differentially methylated region; GO term, gene ontology term; MF, molecular function; BP, biological process.

Diagnosis and management of heart failure from hospital admission to discharge: A practical expert guidance.

Heart failure (HF) has high event rates, mortality, and is challenging to manage in clinical practice. Clinical management is complicated by complex therapeutic strategies in a population with a high prevalence of comorbidity and general frailty. In the last four years, an abundance of research has become available to support multidisciplinary management of heart failure from within the hospital through to discharge and primary care as well as supporting diagnosis and comorbidity management. Within the hospital setting, recent evidence supports sacubitril-valsartan combination in frail, deteriorating or de novo patients with LVEF≤40%. Furthermore, new strategies such as SGLT2 inhibitors and vericiguat provide further benefit for patients with decompensating HF. Studies with tafamidis report major clinical benefits specifically for patients with ATTR cardiac amyloidosis, a remaining underdiagnosed and undertreated disease. New evidence for medical interventions supports his bundle pacing to reduce QRS width and improve haemodynamics as well as ICD defibrillation for non-ischemic cardiomyopathy. The Mitraclip reduces hospitalisations and mortality in patients with symptomatic, secondary mitral regurgitation and ablation reduces mortality and hospitalisations in patients with paroxysmal and persistent atrial fibrillation. In end-stage HF, the 2018 French Heart Allocation policy should improve access to heart transplants for stable, ambulatory patients and, mechanical circulatory support should be considered to avoid deteriorating on the waiting list. In the community, new evidence supports that improving discharge education, treatment and patient support improves outcomes. The authors believe that this review fills the gap between the guidelines and clinical practice and provides practical recommendations to improve HF management.

The epigenetic landscape of mammary gland development and functional differentiation.

Most of the development and functional differentiation in the mammary gland occur after birth. Epigenetics is defined as the stable alterations in gene expression potential that arise during development and proliferation. Epigenetic changes are mediated at the biochemical level by the chromatin conformation initiated by DNA methylation, histone variants, post-translational modifications of histones, non-histone chromatin proteins, and non-coding RNAs. Epigenetics plays a key role in development. However, very little is known about its role in the developing mammary gland or how it might integrate the many signalling pathways involved in mammary gland development and function that have been discovered during the past few decades. An inverse relationship between marks of closed (DNA methylation) or open chromatin (DnaseI hypersensitivity, certain histone modifications) and milk protein gene expression has been documented. Recent studies have shown that during development and functional differentiation, both global and local chromatin changes occur. Locally, chromatin at distal regulatory elements and promoters of milk protein genes gains a more open conformation. Furthermore, changes occur both in looping between regulatory elements and attachment to nuclear matrix. These changes are induced by developmental signals and environmental conditions. Additionally, distinct epigenetic patterns have been identified in mammary gland stem and progenitor cell sub-populations. Together, these findings suggest that epigenetics plays a role in mammary development and function. With the new tools for epigenomics developed in recent years, we now can begin to establish a framework for the role of epigenetics in mammary gland development and disease.

Diet-induced modifications to milk composition have long-term effects on offspring growth in rabbits.

It has been clearly demonstrated that the maternal nutritional status during pregnancy and lactation has long-term effects on offspring health. In mammals, milk represents the first maternal support provided to the newborns so that its composition may play a major role in long-term programming. We therefore assessed the effects of maternal high-fat/high-sugar obesogenic (OD) or control (CD) diets on offspring growth and adiposity in the rabbit. Between 7 and 20 wk of age, the BW gain of OD milk-fed rabbits was higher than that of CD milk-fed rabbits ( < 0.05). Body fat mass measurements at 21 wk of age revealed a significant increase in body adiposity as a function of milk ingested during the neonatal period, in both female and male offspring ( < 0.05). A marked weight gain difference was observed according to the milk in both female and male offspring. Moreover, we investigated the composition in major proteins and leptin levels in milk from OD or CD diet-fed dams. Liquid chromatography-mass spectrometry analysis of individual CD skimmed milk samples enabled identification and quantification of the rabbit main milk proteins and of their main phosphorylated isoforms at 2 different stages of lactation (3 and 10 d). Here we show that the OD diet induced a reduction in the whey acidic protein content concomitantly with both an increase in serum albumin and lactoferrin contents and in the phosphorylated isoforms of the main milk proteins. Furthermore, a sharp rise in leptin levels was observed in the milk of OD diet-fed dams on Day 10 of lactation when compared with CD diet animals ( < 0.05). Taken together, these findings provide evidence that lactation is a critical window of development during which exposure to a deleterious diet is highly detrimental to long-term outcomes. Moreover, these insights suggest that it may be possible to prevent at least some of the adverse effects of inadequate maternal nutrition on the long-term metabolic outcomes of the offspring through nutritional interventions applied during the lactation period.

Milk from dams fed an obesogenic diet combined with a high-fat/high-sugar diet induces long-term abnormal mammary gland development in the rabbit.

Alterations to the metabolic endocrine environment during early life are crucial to mammary gland development. Among these environmental parameters, the initial nutritional event after birth is the consumption of milk, which represents the first maternal support provided to mammalian newborns. Milk is a complex fluid that exerts effects far beyond its immediate nutritional value. The present study, therefore, aimed to determine the effect of the nutritional changes during the neonatal and prepubertal periods on the adult mammary phenotype. Newborn rabbits were suckled by dams fed a high-fat/high-sugar obesogenic (OD) or a control (CON) diet and then subsequently fed either the OD or CON diets from the onset of puberty and throughout early pregnancy. Mammary glands were collected during early pregnancy (Day 8 of pregnancy). Rabbits fed with OD milk and then subjected to an OD diet displayed an abnormal development of the mammary gland: the mammary ducts were markedly enlarged (P < 0.05) and filled with abundant secretory products. Moreover, the alveolar secretory structures were disorganized, with an abnormal aspect characterized by large lumina. Mammary epithelial cells contained numerous large lipid droplets and exhibited fingering of the apical membrane and abnormally enlarged intercellular spaces filled with casein micelles. Leptin has been shown to be involved in modulating several developmental processes. We therefore analyzed its expression in the mammary gland. Mammary leptin mRNA was strongly expressed in rabbits fed with OD milk and subjected to an OD diet by comparison with the CON rabbits. Leptin transcripts and protein were localized in the epithelial cells, indicating that the increase in leptin synthesis occurs in this compartment. Taken together, these findings suggest that early-life nutritional history, in particular through the milking period, can determine subsequent mammary gland development. Moreover, they highlight the potentially important regulatory role that leptin may play during critical early-life nutritional windows with respect to long-term growth and mammary function.

[Destructive arthritis of the hip in Crohn disease. 10 cases]. / Coxites destructrices de la maladie de Crohn. 10 observations.

OBJECTIVES: Destructive arthritis of the hip joint is a rare manifestation of Crohn's disease. We evaluated its frequency and clinical features in comparison with spondylarthritis and assessed the clinical course. METHODS: One hundred patients with Crohn's disease were followed prospectively in search of destructive arthritis of the hip joint. Patients with both Crohn's disease and manifestations of inflammatory joint disease hospitalized in three rheumatology units were also evaluated retrospectively. RESULTS: The prevalence of destructive hip disease was 2% in patients with Crohn's disease. Ten patients had destructive arthritis of the hip. Three had ankylosing spondylitis, 5 had spondylarthritis not responding to the criteria of ankylosing spondylitis and 2 had no axial joint disease. In all patients, signs of hip joint disease were a narrowed intra-articular space, bone condensation, osteophytosis and features of joint destruction. Manifestations were similar to those in patients with hip joint disease related to idiopathic ankylosing spondylarthritis. The clinical course was poorly controlled by anti-inflammatory drugs or treatment of the inflammatory bowel disease. Synoviorthesis were required and were effective in most cases. Total hip replacement was required in 3 cases. CONCLUSION: Destructive arthritis of the hip in patients with Crohn's disease is a rare complication causing severe functional impairment further handicapping the patient with a chronic bowel disease.

[Present status of Poncet's tuberculous rheumatism. A new case]. / Actualité du rhumatisme tuberculeux de Poncet. Une nouvelle observation.

A case of noninfectious polyarthritis of over one year's duration with calcaneal enthesopathy in a patient with visceral tuberculosis is reported. This pattern, termed Poncet's disease, shares pathophysiologic mechanisms with Freund's complete adjuvant-induced arthritis. Future studies should include polymerase chain reaction studies to look for the tubercle bacillus in joint fluid or synovial biopsy specimens.

Dynamics of concentrated colloidal suspensions during drying--aging, rejuvenation and overaging.

We report on the slow dynamics of concentrated colloidal suspensions during drying and rewetting under conditions of reversible concentration changes without coalescence or aggregation. We used multispeckle diffusing-wave spectroscopy to monitor the slow dynamics of particles. We found that the alpha relaxation of the suspensions exhibits successively slowing-down, acceleration and a stationary regime during drying at constant rates. Under rewetting conditions, we observed slowing-down and a stationary regime. The characteristic time of the stationary regime is inversely proportional to the rate of concentration change and identical for both drying and rewetting. We explain these regimes as aging (overaging), rejuvenation and plastic flow of the suspensions induced by a deviatoric stress (a combination of compressive and elongational stresses) which is induced by the uniaxial compressive strain generated by evaporation.

Identification of a polymorphic microsatellite marker in the mouse Fas ligand gene.

We describe the characterization of a polymorphic microsatellite marker, located 1.8 kb downstream of exon 4 in the mouse Fas ligand gene. This (GT) repeat sequence allows the identification of four alleles which can very easily be distinguished by simple agarose electrophoresis.

Cutaneous vasculitis and IgA glomerulonephritis in ankylosing spondylitis.

Two patients with ankylosing spondylitis were found to have IgA nephropathy and leucocytoclastic cutaneous vasculitis. Immunofluorescence showed perivascular deposition of IgA in the skin of one patient and in the mesangium of both patients. Such an association has been reported only once before. This supports the concept of abnormal IgA immune stimulation in the pathogenesis of ankylosing spondylitis.

Early diagnosis of vertebral osteomyelitis due to a rare pathogen: Haemophilus parainfluenzae.

Bone and joint infections due to Haemophilus parainfluenzae are unusual. We describe a case of hematogenous vertebral osteomyelitis caused by this commensal microorganism of nose and oropharynx. Early diagnosis and therapy were possible within a week using sensitive radiologic methods: technetium bone scanning, computed tomography and magnetic resonance imaging.

Multidisciplinary day hospital treatment of rheumatoid arthritis patients. Evaluation after two years.

The availability of multidisciplinary care for rheumatoid arthritis is still limited. The Raoul Dufy Program offered by the Saint-Antoine Teaching Hospital in Paris provides one-on-one personalized care in a day hospital setting as an adjunct to conventional medical follow-up. Listening and providing information and education are major objectives of the nurse, rheumatologist and physical therapist participating in the program. The team also includes a social worker, a surgeon, a dietician, a podiatrist and a psychologist, who intervene as needed. Seventy patients attended the program between December 1993 and September 1995 and were asked to complete a baseline and a three-month questionnaire designed to evaluate the effects of the program in terms of new therapeutic interventions, patient knowledge and quality of life. The patient knowledge score increased significantly (P < 0.0001). Many therapeutic interventions were initiated after program attendance, especially in the fields of podiatry, psychology and physical therapy. However, the quality of life score failed to improve. These results and the substantial patient demand for appointments are encouraging. Further work is needed on the methodology of multidisciplinary care evaluation. Coping strategy evaluation tools may allow to identify some of the specific benefits provided by the multidisciplinary approach.