Enamel matrix derivative (Emdogain®) for periodontal tissue regeneration in intrabony defects

Background: Periodontitis is a chronic infective disease of the gums caused by bacteria present in dental plaque. This condition induces the breakdown of the tooth supporting apparatus until teeth are lost. Surgery may be indicated to arrest disease progression and regenerate lost tissues. Several surgical techniques have been developed to regenerate periodontal tissues including guided tissue regeneration (GTR), bone grafting (BG) and the use of enamel matrix derivative (EMD). EMD is an extract of enamel matrix and contains amelogenins of various molecular weights. Amelogenins are involved in the formation of enamel and periodontal attachment formation during tooth development. Objectives: To test whether EMD is effective, and to compare EMD versus GTR, and various BG procedures for the treatment of intrabony defects. Search strategy: We searched the Cochrane Oral Health Group Trials Register, CENTRAL, MEDLINE and EMBASE. Several journals were handsearched. No language restrictions were applied. Authors of randomized controlled trials (RCTs) identified, personal contacts and the manufacturer were contacted to identify unpublished trials. Most recent search: February 2009. Selection criteria: RCTs on patients affected by periodontitis having intrabony defects of at least 3 mm treated with EMD compared with open flap debridement, GTR and various BG procedures with at least 1 year follow‐up. The outcome measures considered were: tooth loss, changes in probing attachment levels (PAL), pocket depths (PPD), gingival recessions (REC), bone levels from the bottom of the defects on intraoral radiographs, aesthetics and adverse events. The following time‐points were to be evaluated: 1, 5 and 10 years. Data collection and analysis: Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two authors. Results were expressed as random‐effects models using mean differences for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI). It was decided not to investigate heterogeneity, but a sensitivity analysis for the risk of bias of the trials was performed. Main results: Thirteen trials were included out of 35 potentially eligible trials. No included trial presented data after 5 years of follow‐up, therefore all data refer to the 1‐year time point. A meta‐analysis including nine trials showed that EMD treated sites displayed statistically significant PAL improvements (mean difference 1.1 mm, 95% CI 0.61 to 1.55) and PPD reduction (0.9 mm, 95% CI 0.44 to 1.31) when compared to placebo or control treated sites, though a high degree of heterogeneity was found. Significantly more sites had <2 mm PAL gain in the control group, with RR 0.53 (95% CI 0.34 to 0.82). Approximately nine patients needed to be treated (NNT) to have one patient gaining 2 mm or more PAL over the control group, based on a prevalence in the control group of 25%. No differences in tooth loss or aesthetic appearance as judged by the patients were observed. When evaluating only trials at a low risk of bias in a sensitivity analysis (four trials), the effect size for PAL was 0.62 mm (95% CI 0.28 to 0.96), which was less than 1.1 mm for the overall result. Comparing EMD with GTR (five trials), GTR showed statistically significant more postoperative complications (three trials, RR 0.12, 95% CI 0.02 to 0.85) and more REC (0.4 mm 95% CI 0.15 to 0.66). The only trial comparing EMD with a bioactive ceramic filler found statistically significant more REC (‐1.60 mm, 95% CI ?2.74 to ?0.46) at the EMG treated sites. Authors’ conclusions: One year after its application, EMD significantly improved PAL levels (1.1 mm) and PPD reduction (0.9 mm) when compared to a placebo or control, however, the high degree of heterogeneity observed among trials suggests that results have to be interpreted with great caution. In addition, a sensitivity analysis indicated that the overall treatment effect might be overestimated. The actual clinical advantages of using EMD are unknown. With the exception of significantly more postoperative complications in the GTR group, there was no evidence of clinically important differences between GTR and EMD. Bone substitutes may be associated with less REC than EMD. Plain language summary: Enamel matrix derivative (Emdogain®) for periodontal tissue regeneration in intrabony defects. Emdogain might have some advantages over other methods of regenerating the tissue supporting teeth lost by gum disease, such as less postoperative complications, but has not been shown to save more compromised teeth or that patients noticed any aesthetic improvement 1 year after its application. Bacteria in plaque can cause gum disease (periodontitis) that breaks down tissue supporting teeth. Surgical cleaning tries to stop the disease to save loose teeth. Bone grafting, guided tissue regeneration and enamel matrix derivatives (such as Emdogain) aim to regenerate support tissues. Emdogain contains proteins (derived from developing pig teeth) believed to regenerate tooth attachment. The review found that adjunctive application of Emdogain regenerates about 1 mm more tissue than surgical cleaning alone, although it is unclear to which extent such improvement is noticeable since patients did not find any difference in the aesthetic results. Emdogain showed similar clinical results to guided tissue regeneration, but is simpler to use and determines less complications. Bone substitutes may induce less gum retraction than Emdogain. No serious adverse reactions to Emdogain were reported in trials.     

Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine,Acetaminophen, and Alpha-Amanitin in Mice

We have recently observed that oral administration of d-glucose saves animals from lipopolysaccharide (LPS)-induced death. This effect is the likely consequence of glucose-induced activation of the sodium-dependent glucose transporter-1. In this study, we investigated possible hepatoprotective effects of glucose-induced, sodium-dependent, glucose transporter-1 activation. We show that oral administration of d-glucose, but not of either d-fructose or sucrose, prevents LPS-induced liver injury, as well as liver injury and death induced by an overdose of acetaminophen. In both of these models, physiological liver morphology is maintained and organ protection is confirmed by unchanged levels of the circulating markers of hepatotoxicity, such as alanine transaminase or lactate dehydrogenase. In addition, d-glucose was found to protect the liver from α-amanitin-induced liver injury. In this case, in contrast to the previously described models, a second signal had to be present in addition to glucose to achieve protective efficacy. Toll-like receptor 4 stimulation that was induced by low doses of LPS was identified as such a second signal. Eventually, the protective effect of orally administered glucose on liver injury induced by LPS, overdose of acetaminophen, or α-amanitin was shown to be mediated by the anti-inflammatory cytokine interleukin-10. These findings, showing glucose-induced protective effects in several animal models of liver injury, might be relevant in view of possible therapeutic interventions against different forms of acute hepatic injury.Liver failure is one of the most devastating syndromes observed in clinical practice. It is associated with high overall mortality, ranging from 30% to 80%, depending on the underlying etiology.^1,2 The most common etiologies are acute viral hepatitis, drug overdose, idiosyncratic drug reactions, and ingestion of other toxins.³ Insulting agents can cause hepatocyte death through different mechanisms of action, and when the amount of functioning cells decreases to a level at which the organ is no longer capable of fulfilling its metabolic and synthetic tasks, hepatic failure takes place.⁴Recently we demonstrated, in a murine model of septic shock, that oral administration of d-glucose saves mice from death, most likely as a result of glucose-induced activation of the intestinal sodium-dependent glucose transporter-1 (SGLT-1).⁵ Using this model, we made preliminary observations that the liver, one of the organs most severely affected by lipopolysaccharide and d-galactosamine (LPS/d-GalN) treatment, was protected by oral administration of d-glucose. The expression of SGLT-1 on the apical membrane of enterocytes and the observation that protection from LPS shock was observed only on oral administration of d-glucose, but not on i.p. administration, suggested an important role of intestinal epithelial cells in protection from LPS-induced injury to the liver and other organs.Here, we report on a more extensive investigation on the hepatoprotective effect of orally administered d-glucose. Glucose was evaluated in LPS-induced shock, as well as in two other models of acute liver failure, ie, acetaminophen (APAP)- and α-amanitin-induced hepatic toxicity. APAP overdose is a common cause of drug-induced liver injury⁶ since this drug, when administered at very elevated doses, generates the highly reactive intermediate, N-para-aminoquinonimine,⁷ which covalently binds to hepatocyte macromolecules, leading to cellular death.⁸ This can lead to a potentially fatal centrilobular hepatic necrosis.⁹ On the other hand, α-amanitin toxin, which provide the major morbidity and mortality associated with toxic mushroom ingestion, interact with RNA polymerase II and affected cells undergo apoptosis due to insufficient protein synthesis. Organs mainly affected by α-amanitin include the intestinal mucosa, hepatocytes, and proximal tubules of kidney. The most severely affected organ is the liver, and hepatic toxicity is the actual cause of α-amanitin-induced lethality.In the herein-described experiments, we show that in all three models it is possible to achieve liver protection by d-glucose-induced intestinal SGLT-1 activation. However, while in models of LPS shock and APAP overdosing, d-glucose is therapeutically active when administered alone, in the α-amanitin model the concomitant administration of a low dose of LPS was required to achieve protection.     

Palliative Benefits of the Multimodality Approach in the Re-treatment of Recurrent Malignant Glioma: Two Case Reports

Two young male patients treated seven and four years back, for malignant glioma, returned with recurrence at the same site, with a World Health Organization (WHO) Performance Score of four and two. Both underwent resurgery and received postoperative reirradiation of 5040 cGy in 28 fractions and concurrent Temozolomide 75 mg/m² body surface area (BSA) daily, and one patient received additional adjuvant Temozolomide 250 mg (150 mg/m² BSA). Both patients tolerated the treatment well with 16 and 14 months follow-up from the time of recurrence. They were symptom-free, with normal physical function and good mental state, and resumed their respective jobs.     

Endoscopic ultrasonography for upper gastrointestinal submucosal lesions: a cost minimization analysis with an international perspective

OBJECTIVES: Our prospective clinical study of prospectively compared physicians' management of submucosal tumors (SMTs) with and without endoscopic ultrasound (EUS). It showed that EUS reduced further tests by more than 50%, but it is unclear whether it reduced the overall costs. The aim of this study was to determine whether EUS would reduce costs. METHODS: Based on the data from the clinical study, a decision analysis was created to compare the direct hospital costs for diagnosing SMTs with and without EUS. Cost data from Germany, Canada, Japan, France, and the United States were used. Costs were expressed as a ratio of the cost of esophagogastroduodenoscopy (EGD). Average cost ratios for each procedure were as follows (sensitivity analysis ranges are 95% CIs): EGD = 1; large particle biopsy (LPB) 0.75 (0.22-1.24); endoscopic ultrasound (EUS) 2.0 (1.22-2.79); abdominal ultrasound (US) 0.77 (0.31-1.24); computed tomography (CT) 1.79 (0.64-2.95); magnetic resonance imaging (MRI) 3.54 (1.28-5.79); and ERCP 3.45 (0.82-6.07). RESULTS: Initial inputs show the "no EUS" strategy is less costly when cost data for all countries are averaged (expected cost 2.13 vs 2.71, expressed as a ratio of the cost of EGD]) and for all countries individually except Germany. In descending order, overall management costs were most sensitive to the relative costs of CT and EUS, the cost of LPB, and to the probability of no further testing when the "no EUS" strategy is used. However, threshold analysis showed that changes in only one variable, the ratio of the cost of EUS compared to CT (the "EUS/CT ratio"), were able to shift the optimal strategy from "no EUS" to "EUS." "EUS" becomes less costly only if the EUS/CT cost ratio is <0.85 (i.e., if the cost of EUS is <85% that of CT). If the potential for EUS to reduce severe complications caused by LPB of high risk lesions is incorporated, "EUS" is less costly if this risk is >2% (range 1-5%). CONCLUSIONS: When used to diagnose SMTs, EUS may reduce the need for further tests but not necessarily costs. For this indication, the relative cost of EUS compared with CT is what most limits its potential value as a cost-minimizing test. The costs, economic impact, and hence the relative appropriateness of EUS and other procedures may vary in different health care systems.