Innovative Therapy Combining Neck Muscle Vibration and Transcranial Direct Current Stimulation in Association with Conventional Rehabilitation in Left Unilateral Spatial Neglect Patients: HEMISTIM Protocol for a Randomized Controlled Trial.

Unilateral spatial neglect (USN) rehabilitation requires the development of new methods that can be easily integrated into conventional practice. The aim of the HEMISTIM protocol is to assess immediate and long-term recovery induced by an innovative association of left-side neck-muscle vibration (NMV) and anodal transcranial Direct Current Stimulation (tDCS) on the ipsilesional posterior parietal cortex during occupational therapy sessions in patients with left USN. Participants will be randomly assigned to four groups: control, Left-NMV, Left-NMV + sham-tDCS or Left-NMV + anodal-tDCS. NMV and tDCS will be applied during the first 15 min of occupational therapy sessions, three days a week for three weeks. USN will be assessed at baseline, just at the end of the first experimental session, after the first and third weeks of the protocol and three weeks after its ending. Our primary outcome will be the evolution of the functional Catherine Bergego Scale score. Secondary outcome measures include five tests that investigate different neuropsychological aspects of USN. Left NMV, by activating multisensory integration neuronal networks, might enhance effects obtained by conventional therapy since post-effects were shown when it was combined with upper limb movements. We expect to reinforce lasting intermodal recalibration through LTP-like plasticity induced by anodal tDCS.

Determinants of adherence to oral hygiene prophylaxis guidelines in patients with previous infective endocarditis.

BACKGROUND: Infective endocarditis (IE) is characterized by low incidence but high mortality. Patients with a history of IE are at highest risk. Adherence to prophylaxis recommendations is poor. We sought to identify determinants of adherence to oral hygiene guidelines on IE prophylaxis in patients with a history of IE. METHODS: Using data from the cross-sectional, single-centre POST-IMAGE study, we analysed demographic, medical and psychosocial factors. We defined patients as adherent to prophylaxis if they declared going to the dentist at least annually and brushing their teeth at least twice a day. Depression, cognitive status and quality of life were assessed using validated scales. RESULTS: Of 100 patients enrolled, 98 completed the self-questionnaires. Among these, 40 (40.8%) were categorized as adherent to prophylaxis guidelines, and were less likely to be smokers (5.1% vs. 25.0%; P=0.02) or have symptoms of depression (36.6% vs. 70.8%; P<0.01) or cognitive decline (0% vs. 15.5%; P=0.05). Conversely, they had higher rates of: valvular surgery since the index IE episode (17.5% vs. 3.4%; P=0.04), searching for information on IE (61.1% vs. 46.3%, P=0.05), and considering themselves as adherent to IE prophylaxis (58.3% vs. 32.1%; P=0.03). Tooth brushing, dental visits and antibiotic prophylaxis were correctly identified as measures to prevent IE recurrence in 87.7%, 90.8% and 92.8% of patients, respectively, and did not differ according to adherence to oral hygiene guidelines. CONCLUSIONS: Self-reported adherence to secondary oral hygiene guidelines on IE prophylaxis is low. Adherence is unrelated to most patient characteristics, but to depression and cognitive impairment. Poor adherence appears related more to a lack of implementation rather than insufficient knowledge. Assessment of depression may be considered in patients with IE.

Patients with Obstructive Sleep Apnea and Cardiovascular Diseases: What, When, and Why Is Mandibular Advancement Device Treatment Required? A Short Review.

Obstructive sleep apnea is a potentially dangerous condition with significant risks of comorbidities if left untreated. It represents a cardiovascular risk factor in the general population, and a higher prevalence is observed in patients already suffering from cardiovascular diseases. The gold standard treatment, continuous positive airway pressure, is not always accepted or tolerated. The mandibular advancement device represents an alternative treatment that we propose to implement in our study. The objective here is to first present a brief review of the topic. Due to poor evidence in the field, we propose a pilot study to evaluate the effect of a mandibular advancement device in patients with cardiovascular disease who are not treated for their sleep pathology in order to improve their therapeutic management.

Oral Kaposi Sarcoma in two patients living with HIV despite sustained viral suppression: New clues.

Kaposi sarcoma (KS) etiologically linked to Kaposi sarcoma-associated herpesvirus (KSHV) is the most common HIV associated cancer despite the generalization of antiretroviral therapy. Head, neck, and especially oral cavity are common and specific sites for lesions. Those oral lesions contain a high viral load of KSHV virus and are one of the signs of disease severity. The development of KS in HIV-infected patients is classically described in case of low CD4 count, but recently reported cases revealed oral KS despite a robust CD4 count, such observations being possibly linked to interactions between periodontal germs and the oncogenic KSHV virus. We present two cases of KS location on the oral mucosa in HIV patients with gingival inflammation despite efficient antiretroviral treatment and immune restoration. Those cases suggest that the diagnosis of oral KS lesions should be considered by oral surgeons, dermatologists, and infectious specialists, when managing any suspicious lesion in an HIV patient, even with undetectable HIV viral loads, or in a seronegative patient with unprotected sexual activity. Key words:Kaposi Sarcoma, KSHV, HIV infection, CD4 count, oral lesion, oral cancer, periodontal pathogens.

Genetic background influences hepcidin response to iron imbalance in a mouse model of hemolytic anemia (Congenital erythropoietic porphyria).

Clinical severity is heterogeneous among patients suffering from congenital erythropoietic porphyria (CEP) suggesting a modulation of the disease (UROS deficiency) by environmental factors and modifier genes. A KI model of CEP due to a missense mutation of UROS gene present in human has been developed on 3 congenic mouse strains (BALB/c, C57BL/6, and 129/Sv) in order to study the impact of genetic background on disease severity. To detect putative modifiers of disease expression in congenic mice, hematologic data, iron parameters, porphyrin content and tissue samples were collected. Regenerative hemolytic anemia, a consequence of porphyrin excess in RBCs, had various expressions: 129/Sv mice were more hemolytic, BALB/c had more regenerative response to anemia, C57BL/6 were less affected. Iron status and hemolysis level were directly related: C57BL/6 and BALB/c had moderate hemolysis and active erythropoiesis able to reduce iron overload in the liver, while, 129/Sv showed an imbalance between iron release due to hemolysis and erythroid use. The negative control of hepcidin on the ferroportin iron exporter appeared strain specific in the CEP mice models tested. Full repression of hepcidin was observed in BALB/c and 129/Sv mice, favoring parenchymal iron overload in the liver. Unchanged hepcidin levels in C57BL/6 resulted in retention of iron predominantly in reticuloendothelial tissues. These findings open the field for potential therapeutic applications in the human disease, of hepcidin agonists and iron depletion in chronic hemolytic anemia.

[Prevention of Infective endocarditis]. / Prévention de l'endocardite infectieuse.

Indications of antibiotic prophylaxis are restricted to the patients at highest risk of infective endocarditis undergoing at-risk dental procedures. Guidelines emphasize the importance of daily non-specific oral and cutaneous hygiene. Restorative dentistry, endodontic and periodontal therapy can be performed in patients at high risk of endocarditis, provided careful follow-up is effective. The use of dental implants is no longer contra-indicated in patients at high risk of endocarditis, but the decision be based on an individual analysis of risk factors of implant failure. Evaluations of practices show that prevention of endocarditis is not sufficiently implemented. All health professionals should be aware of the importance of prevention measures of heathcare-associated infective endocarditis. Endocarditis prophylaxis cards are made available to patients and health professionals to make them aware of the endocarditis prophylaxis.

Dental procedures, antibiotic prophylaxis, and endocarditis among people with prosthetic heart valves: nationwide population based cohort and a case crossover study.

Objective To assess the relation between invasive dental procedures and infective endocarditis associated with oral streptococci among people with prosthetic heart valves.Design Nationwide population based cohort and a case crossover study.Setting French national health insurance administrative data linked with the national hospital discharge database.Participants All adults aged more than 18 years, living in France, with medical procedure codes for positioning or replacement of prosthetic heart valves between July 2008 and July 2014.Main outcome measures Oral streptococcal infective endocarditis was identified using primary discharge diagnosis codes. In the cohort study, Poisson regression models were performed to estimate the rate of oral streptococcal infective endocarditis during the three month period after invasive dental procedures compared with non-exposure periods. In the case crossover study, conditional logistic regression models calculated the odds ratio and 95% confidence intervals comparing exposure to invasive dental procedures during the three month period preceding oral streptococcal infective endocarditis (case period) with three earlier control periods.Results The cohort included 138 876 adults with prosthetic heart valves (285 034 person years); 69 303 (49.9%) underwent at least one dental procedure. Among the 396 615 dental procedures performed, 103 463 (26.0%) were invasive and therefore presented an indication for antibiotic prophylaxis, which was performed in 52 280 (50.1%). With a median follow-up of 1.7 years, 267 people developed infective endocarditis associated with oral streptococci (incidence rate 93.7 per 100 000 person years, 95% confidence interval 82.4 to 104.9). Compared with non-exposure periods, no statistically significant increased rate of oral streptococcal infective endocarditis was observed during the three months after an invasive dental procedure (relative rate 1.25, 95% confidence interval 0.82 to 1.82; P=0.26) and after an invasive dental procedure without antibiotic prophylaxis (1.57, 0.90 to 2.53; P=0.08). In the case crossover analysis, exposure to invasive dental procedures was more frequent during case periods than during matched control periods (5.1% v 3.2%; odds ratio 1.66, 95% confidence interval 1.05 to 2.63; P=0.03).Conclusion Invasive dental procedures may contribute to the development of infective endocarditis in adults with prosthetic heart valves.

Position paper for the evaluation and management of oral status in patients with valvular disease: Groupe de Travail Valvulopathies de la Société Française de Cardiologie, Société Française de Chirurgie Orale, Société Française de Parodontologie et d'Implantologie Orale, Société Française d'Endodontie et Société de Pathologie Infectieuse de Langue Française.

Oral health is of particular importance in patients with heart valve diseases because of the risk of infective endocarditis. Recommendations for antibiotic prophylaxis before dental procedures have been restricted, but the modalities of oral evaluation and dental care are not detailed in guidelines. Therefore, a multidisciplinary working group reviewed the literature to propose detailed approaches for the evaluation and management of buccodental status in patients with valvular disease. Simple questions asked by a non-dental specialist may draw attention to buccodental diseases. Besides clinical examination, recent imaging techniques are highly sensitive for the detection of inflammatory bone destruction directly related to oral or dental infection foci. The management of buccodental disease before cardiac valvular surgery should be adapted to the timing of the intervention. Simple therapeutic principles can be applied even before urgent intervention. Restorative dentistry and endodontic and periodontal therapy can be performed before elective valvular intervention and during the follow-up of patients at high risk of endocarditis. The detection and treatment of buccodental foci of infection should follow specific rules in patients who present with acute endocarditis. Implant placement is no longer contraindicated in patients at intermediate risk of endocarditis, and can also be performed in selected high-risk patients. The decision for implant placement should follow an analysis of general and local factors increasing the risk of implant failure. The surgical and prosthetic procedures should be performed in optimal safety conditions. It is therefore now possible to safely decrease the number of contraindicated dental procedures in patients at risk of endocarditis.

Osteomyelitis of the Mandible after Dental Implants in an Immunocompetent Patient.

Dental implants are now broadly used to replace missing teeth, and the presence of infectious complications is rising. Dental implant therapy as a local risk factor for the onset of osteomyelitis and its management have not been widely explored. Here, we report an unusual case of mandibular suppurative osteomyelitis caused by Streptococcus intermedius in a healthy and immunocompetent patient secondary to mandibular implants. We describe how surgery combined with systemic application of antibiotics allowed conservation of the dental implants in the mandibular bone, discuss the probable source of contamination, and present the follow-up of the osteomyelitis.

Oral Streptococcal Endocarditis, Oral Hygiene Habits, and Recent Dental Procedures: A Case-Control Study.

BACKGROUND.: We aimed to compare oral hygiene habits, orodental status, and dental procedures in patients with infective endocarditis (IE) according to whether the IE-causing microorganism originated in the oral cavity. METHODS.: We conducted an assessor-blinded case-control study in 6 French tertiary-care hospitals. Oral hygiene habits were recorded using a self-administered questionnaire. Orodental status was analyzed by trained dental practitioners blinded to the microorganism, using standardized clinical examination and dental panoramic tomography. History of dental procedures was obtained through patient and dentist interviews. Microorganisms were categorized as oral streptococci or nonoral pathogens using an expert-validated list kept confidential during the course of the study. Cases and controls had definite IE caused either by oral streptococci or nonoral pathogens, respectively. Participants were enrolled between May 2008 and January 2013. RESULTS.: Cases (n = 73) were more likely than controls (n = 192) to be aged <65 years (odds ratio [OR], 2.85; 95% CI, 1.41-5.76), to be female (OR, 2.62; 95% CI, 1.20-5.74), to have native valve disease (OR, 2.44; 95% CI, 1.16-5.13), to use toothpicks, dental water jet, interdental brush, and/or dental floss (OR, 3.48; 95% CI, 1.30-9.32), and to have had dental procedures during the prior 3 months (OR, 3.31; 95% CI, 1.18-9.29), whereas they were less likely to brush teeth after meals. The presence of gingival inflammation, calculus, and infectious dental diseases did not significantly differ between groups. CONCLUSIONS.: Patients with IE caused by oral streptococci differ from patients with IE caused by nonoral pathogens regarding background characteristics, oral hygiene habits, and recent dental procedures, but not current orodental status.

Hemolytic anemia repressed hepcidin level without hepatocyte iron overload: lesson from Günther disease model.

Hemolysis occurring in hematologic diseases is often associated with an iron loading anemia. This iron overload is the result of a massive outflow of hemoglobin into the bloodstream, but the mechanism of hemoglobin handling has not been fully elucidated. Here, in a congenital erythropoietic porphyria mouse model, we evaluate the impact of hemolysis and regenerative anemia on hepcidin synthesis and iron metabolism. Hemolysis was confirmed by a complete drop in haptoglobin, hemopexin and increased plasma lactate dehydrogenase, an increased red blood cell distribution width and osmotic fragility, a reduced half-life of red blood cells, and increased expression of heme oxygenase 1. The erythropoiesis-induced Fam132b was increased, hepcidin mRNA repressed, and transepithelial iron transport in isolated duodenal loops increased. Iron was mostly accumulated in liver and spleen macrophages but transferrin saturation remained within the normal range. The expression levels of hemoglobin-haptoglobin receptor CD163 and hemopexin receptor CD91 were drastically reduced in both liver and spleen, resulting in heme- and hemoglobin-derived iron elimination in urine. In the kidney, the megalin/cubilin endocytic complex, heme oxygenase 1 and the iron exporter ferroportin were induced, which is reminiscent of significant renal handling of hemoglobin-derived iron. Our results highlight ironbound hemoglobin urinary clearance mechanism and strongly suggest that, in addition to the sequestration of iron in macrophages, kidney may play a major role in protecting hepatocytes from iron overload in chronic hemolysis.

Hepcidin as a Major Component of Renal Antibacterial Defenses against Uropathogenic Escherichia coli.

The iron-regulatory peptide hepcidin exhibits antimicrobial activity. Having previously shown hepcidin expression in the kidney, we addressed its role in urinary tract infection (UTI), which remains largely unknown. Experimental UTI was induced in wild-type (WT) and hepcidin-knockout (Hepc-/-) mice using the uropathogenic Escherichia coli CFT073 strain. Compared with infected WT mice, infected Hepc-/- mice showed a dramatic increase in renal bacterial load. Moreover, bacterial invasion was significantly dampened by the pretreatment of WT mice with hepcidin. Infected Hepc-/- mice exhibited decreased iron accumulation in the renal medulla and significant attenuation of the renal inflammatory response. Notably, we demonstrated in vitro bacteriostatic activity of hepcidin against CFT073. Furthermore, CFT073 repressed renal hepcidin, both in vivo and in cultured renal cells, and reduced phosphorylation of SMAD kinase in vivo, suggesting a bacterial strategy to escape the antimicrobial activities of hepcidin. In conclusion, we provide new mechanisms by which hepcidin contributes to renal host defense and suggest that targeting hepcidin offers a strategy to prevent bacterial invasion.

Efficacy and toxicity of intravenous iron in a mouse model of critical care anemia*.

OBJECTIVE: Anemia is common in critically ill patients, due to inflammation and blood loss. Anemia can be associated with iron deficiency and low serum hepcidin levels. However, iron administration in this setting remains controversial because of its potential toxicity, including oxidative stress induction and sepsis facilitation. The objective of this work was to determine the efficacy and toxicity of iron administration using a mouse model mimicking critical care anemia as well as a model of acute septicemia. DESIGN: Prospective, randomized, open label controlled animal study. SETTING: University-based research laboratory. SUBJECTS: C57BL/6 and OF1 mice. INTERVENTIONS: Intraperitoneal injection of zymosan inducing generalized inflammation in C57BL/6 mice, followed in our full model by repeated phlebotomies. A dose equivalent to 15 mg/kg of ferric carboxymaltose was injected intravenously on day 5. To assess the toxicity of iron in a septicemia model, OF1 mice were simultaneously injected with iron and different Escherichia coli strains. MEASUREMENTS AND MAIN RESULTS: To investigate the effect of iron on oxidative stress, we measured reactive oxygen species production in the blood using luminol-amplified chemiluminescence and superoxide dismutase 2 messenger RNA levels in the liver. These markers of oxidative stress were increased after iron administration in control mice but not in zymosan-treated mice. Liver catalase messenger RNA levels decreased in iron-treated control mice. Iron administration was not associated with increased mortality in the septicemia model or in the generalized inflammation model. Iron increased hemoglobin levels in mice fed with a low iron diet and subjected to phlebotomies and zymosan 2 wks after treatment administration. CONCLUSIONS: Adverse effects of intravenous iron supplementation by ferric carboxymaltose seem to be minimal in our animal models. Furthermore, iron appears to be effective in correcting anemia, despite inflammation. Studies of efficacy and safety of iron in critically ill patients are warranted.

Protoporphyrin retention in hepatocytes and Kupffer cells prevents sclerosing cholangitis in erythropoietic protoporphyria mouse model.

BACKGROUND & AIMS: Chronic, progressive hepatobiliary disease is the most severe complication of erythropoietic protoporphyria (EPP) and can require liver transplantation, although the mechanisms that lead to liver failure are unknown. We characterized protoporphyrin-IX (PPIX)-linked hepatobiliary disease in BALB/c and C57BL/6 (Fechm1Pas) mice with mutations in ferrochelatase as models for EPP. METHODS: Fechm1Pas and wild-type (control) mice were studied at 12-14 weeks of age. PPIX was quantified; its distribution in the liver, serum levels of lipoprotein-X, liver histology, contents of bile salt and cholesterol phospholipids, and expression of genes were compared in mice of the BALB/c and C57BL/6 backgrounds. The in vitro binding affinity of PPIX for bile components was determined. RESULTS: Compared with mice of the C57BL/6 background, BALB/c Fechm1Pas mice had a more severe pattern of cholestasis, fibrosis with portoportal bridging, bile acid regurgitation, sclerosing cholangitis, and hepatolithiasis. In C57BL/6 Fechm1Pas mice, PPIX was sequestrated mainly in the cytosol of hepatocytes and Kupffer cells, whereas, in BALB/c Fechm1Pas mice, PPIX was localized within enlarged bile canaliculi. Livers of C57BL/6 Fechm1Pas mice were protected through a combination of lower efflux of PPIX and reduced synthesis and export of bile acid. CONCLUSIONS: PPIX binds to bile components and disrupts the physiologic equilibrium of phospholipids, bile acids, and cholesterol in bile. This process might be involved in pathogenesis of sclerosing cholangitis from EPP; a better understanding might improve diagnosis and development of reagents to treat or prevent liver failure in patients with EPP.

Erythropoietin stimulates spleen BMP4-dependent stress erythropoiesis and partially corrects anemia in a mouse model of generalized inflammation.

Mouse bone marrow erythropoiesis is homeostatic, whereas after acute anemia, bone morphogenetic protein 4 (BMP4)-dependent stress erythropoiesis develops in the spleen. The aim of this work was to compare spleen stress erythropoiesis and bone marrow erythropoiesis in a mouse model of zymosan-induced generalized inflammation, which induces long-lasting anemia and to evaluate the ability of erythropoietin (Epo) injections to correct anemia in this setting. The effects of zymosan and/or Epo injections on erythroid precursor maturation and apoptosis, serum interferon-γ levels, hematologic parameters, and spleen BMP4 expression were analyzed, as well as the effect of zymosan on red blood cell half-life. We found that bone marrow erythropoiesis is suppressed by inflammation and does not respond to Epo administration, despite repression of erythroblast apoptosis. On the contrary, a robust erythropoietic response takes place in the spleen after Epo injections in both control and zymosan-induced generalized inflammation mice. This specific response implies Epo-mediated induction of BMP4 expression by F4/80(+) spleen macrophages, proliferation of stress burst-forming units-erythroid, and increased number of spleen erythroblasts. It allows only partial recovery of anemia, probably because of peripheral destruction of mature red cells. It is not clear whether similar BMP4-dependent stress erythropoiesis can occur in human bone marrow after Epo injections.

Phlebotomies or erythropoietin injections allow mobilization of iron stores in a mouse model mimicking intensive care anemia.

OBJECTIVE: Anemia in critically ill patients is frequent and consists of chronic disease associated with blood losses. These two mechanisms have opposite effects on iron homeostasis, especially on the expression of the iron regulatory hormone hepcidin. We developed a mouse model mimicking the intensive care anemia to explore iron homeostasis. DESIGN: Experimental study. SETTING: University-based research laboratory. SUBJECTS: C57BL/6 mice. INTERVENTIONS: Mice received either a single intraperitoneal injection of lipopolysaccharide followed 1 week later by zymosan, or were subjected to repeated phlebotomies by retro-orbital punctures, or both. Several subsets of mice were analyzed over a 14-day period to describe the mouse model of intensive care anemia. Additional mice received erythropoietin injections with or without the zymosan treatment and were killed at day 5, to perform a more detailed analysis. MEASUREMENTS AND MAIN RESULTS: We observed anemia as soon as 5 days after zymosan injection, together with increased messenger RNA (mRNA) levels for interleukin-6 and hepcidin. Phlebotomies alone fully suppressed hepcidin mRNA expression. Interestingly, in mice treated with zymosan and phlebotomies, hepcidin expression was suppressed, despite the persistent increase in interleukin-6. Stimulation of erythropoiesis by erythropoietin injections also led to a decrease in hepcidin mRNA in zymosan-treated mice. In these situations combining inflammation and erythropoiesis stimulation, there was no change in ferroportin, the membrane iron exporter, at the mRNA level, whereas ferroportin protein increased. Macrophage iron stores (assessed by histology using diaminobenzidine staining, or by quantification of nonheme iron and ferritin concentrations) were depleted in the spleen. CONCLUSIONS: These results suggest that the erythroid factor dominates over inflammation for hepcidin regulation, and that iron could be mobilized in these situations combining inflammation and erythropoiesis stimulation.

Labiomandibular paresthesia caused by endodontic treatment: an anatomic and clinical study.

Labiomandibular paresthesia after root canal treatment is an accident that is still too frequent despite the development of new endodontic techniques. The aim of this anatomical and clinical study is to advance the understanding of how accidents occur so as to avoid them. This anatomical study made it possible to determine the variability of proximity of the apex of the tooth root to the mandibular bundle, as well as the relationship between the nerve and its satellite artery, and to understand how endodontic filling material spreads into the cancellous bone. The clinical study, which included examination with conventional radiology as well as with imaging techniques, enabled us to identify the exact location of the filling material in relation to the mandibular bundle and to correlate this to the occurrence of clinical symptoms and their diverse manifestations.