Reproducibility of three-dimensional posterior cranial base angles using low-dose computed tomography.

OBJECTIVES: One of the key aspects of three-dimensional (3D) craniofacial cephalometry is the measurement of posterior cranial base angle as this area is deeply involved in craniofacial development. The purpose of our retrospective study was to define the best reproducible 3D posterior cranial base angles among five 3D angles transposed from 2D cephalometry (Cousin, BL1 of Ross and Ravosa, Bjork, Delaire, CBA4 of Liberman) and seven 3D angles based on physical anthropology studies and on new concepts (R1 to R7). The null hypothesis was that all 3D posterior cranial base angles were equally reproducible. MATERIAL AND METHODS: We used a preoperative low-dose computed tomography (CT) data from 20 adult patients undergoing orthognathic surgery after approval by local ethical committee. Two independent observers performed two series of 23 3D landmark identifications on 3D CT surface rendering of each patient using Maxilim software. Then, the same observers performed twice 3D cephalometric analyses (23 landmarks, 4 midpoints, 19 planes) that provided the automatic measurement of 12 posterior cranial base angles. RESULTS: Inter-observer correlation coefficient varied from 0.545 (Cousin) to 0.695 (CBA4 of Liberman) and from -0.177 (R2) to 0.827 (R4). CONCLUSIONS: The null hypothesis was rejected. The most reproducible angle was 3D angle R4 based on "basion," "superior optic" (right, left), and "crista galli inferior" landmarks. CLINICAL RELEVANCE: R4 angle might be used as reference 3D posterior cranial base angle in further clinical studies involving 3D cephalometry as a diagnostic tool for orthodontics and for orthognathic surgery.

Effects of recombinant human prothrombin on thrombin generation in plasma from patients with hemophilia A and B.

BACKGROUND: The present study was carried out to investigate the impact of FII levels, and their increase, on the hemostatic potential in plasma from hemophilia A and B patients with and without inhibitors. METHOD: Recombinant human factor (F) II (rhFII) was added ex vivo to plasma from 68 patients with hemophilia A and B, with or without inhibitors. The hemostatic potential as measured by thrombin generation (calibrated automated thrombogram [CAT]) was focused on the endogenous thrombin potential (ETP) as it has been shown to correlate with the clinical phenotype of bleeding in hemophilia patients and has also been used to guide bypassing therapy in hemophilia patients with inhibitors before elective surgery. The factor eight inhibitor bypassing agent (FEIBA(®) ) was used as a reference to the clinical situation. RESULTS: The study shows that rhFII concentration-dependently increased ETP by a similar magnitude in hemophilia A and B, both with and without inhibitors. Compared with FEIBA, rhFII showed a shallower concentration-response curve. In both types of hemophilia 100 mg L(-1) of rhFII roughly doubled the ETP. A corresponding response was obtained by 0.5 U mL(-1) of FEIBA. CONCLUSION: These data support the theory that FII is one of the major components responsible for the efficacy of FEIBA. The data also indicate that rhFII may be useful, alone or in combination with other coagulation factors, in some of the conditions for which FEIBA is used today, although more data are needed to substantiate this.

[Management of plexiform neurofibroma isolated in childhood: four patients]. / Prise en charge du neurofibrome plexiforme isolé de l'enfant : à propos de quatre observations.

Plexiform neurofibroma is a rare and benign tumor often associated with type 1 neurofibromatosis (NF1) or Von Recklinghausen's disease. Present in one third of cases of NF1, there are isolated forms where the diagnosis should remain a diagnosis of exclusion. We report four cases of isolated plexiform neurofibromas found in children from topographies and we discuss the pretherapeutic assessment, the surgical management and the long-term follow-up.

Reproducibility of three-dimensional cephalometric landmarks in cone-beam and low-dose computed tomography.

OBJECTIVES: The purpose of this study is to compare the reproducibility of three-dimensional cephalometric landmarks on three-dimensional computed tomography (3D-CT) surface rendering using clinical protocols based on low-dose (35-mAs) spiral CT and cone-beam CT (I-CAT). The absorbed dose levels for radiosensitive organs in the maxillofacial region during exposure in both 3D-CT protocols were also assessed. MATERIALS AND METHODS: The study population consisted of ten human dry skulls examined with low-dose CT and cone-beam CT. Two independent observers identified 24 cephalometric anatomic landmarks at 13 sites on the 3D-CT surface renderings using both protocols, with each observer repeating the identification 1 month later. A total of 1,920 imaging measurements were performed. Thermoluminescent dosimeters were placed at six sites around the thyroid gland, the submandibular glands, and the eyes in an Alderson phantom to measure the absorbed dose levels. RESULTS: When comparing low-dose CT and cone-beam CT protocols, the cone-beam CT protocol proved to be significantly more reproducible for four of the 13 anatomical sites. There was no significant difference between the protocols for the other nine anatomical sites. Both low-dose and cone-beam CT protocols were equivalent in dose absorption to the eyes and submandibular glands. However, thyroid glands were more irradiated with low-dose CT. CONCLUSIONS: Cone-beam CT was more reproducible and procured less irradiation to the thyroid gland than low-dose CT. CLINICAL RELEVANCE: Cone-beam CT should be preferred over low-dose CT for developing three-dimensional bony cephalometric analyses.

[Validating a loading protocol for weakened mandibular models]. / Validation d'un protocole de mise en charge des modèles mandibulaires fragilisés.

INTRODUCTION: The purpose of this study was to validate an experimental model of weakened synthetic mandible loaded in a device simulating masticatory forces by studying the reproducibility of the fracture threshold. MATERIALS AND METHODS: Both sides of five synthetic mandibles were weakened by progressive synthetic bone resection. The synthetic mandibles were submitted, after each resection, to static chewing exercises in the simulator. The threshold fracture was recorded. RESULTS: The fracture threshold mean resection height was 19.33 mm with a percentage of error of 6.72%. DISCUSSION: The low percentage of error allowed us to validate this experimental model. A comparison with other experimental or finite element models confirmed our protocol and results. We plan to apply this protocol to fresh weakened mandibles.

[Soft tissue myxoma of the face]. / Tumeurs myxoïdes des tissus mous de la face.

Myxoid tumors are a group of heterogeneous lesions with a voluminous myxoid matrix, which may affect any tissue in the body. The frequency of these tumors depends on their localization. On the face, the localization is most often osseous. In this case, they are odontogenic myxoma. Localization in facial soft tissues is very rare. These tumors are benign but with a high potential for local aggressiveness and recurrence. They must be treated surgically with radical exeresis and long-term follow-up.

Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran.

AIMS: Causality assessment in drug-induced liver injury is often based on circumstantial evidence rather than a formal, systematic review. The Roussel Uclaf Causality Assessment Method (RUCAM) provides a more objective means of assessing causality of a suspected hepatotoxin but, to our knowledge, has never been used in the assessment of a single drug with unknown hepatotoxic potential in a clinical trial setting. METHODS: We studied the utility of RUCAM in assessing the hepatic events during the long-term clinical trials of the oral direct thrombin inhibitor ximelagatran, which has been associated with an increased incidence of alanine aminotransferase (ALT) elevations. A total of 233 subjects with elevated ALT values signalling possibly severe hepatic injury were eligible for RUCAM analysis (198 ximelagatran and 35 comparator anticoagulants). RESULTS: RUCAM scores, calculated independently by the assessors, using the existing numerical criteria provided in its methodology, suggested a possible or probable causal relationship between ALT and ximelagatran in 37 and 27% of cases, respectively. Causality was excluded or unlikely in the remaining 36% of cases. However, in the course of utilizing RUCAM, several limitations to the methodology came to light, including awarding additional points for age > 55 years, an unspecified use of alcohol, and a latency period of < 90 days, which may have had the unintentional effect of raising the overall score. Moreover, rechallenge is highly rewarded by RUCAM but is seldom done in clinical practice or in clinical trials. We also found ambiguities in the extent to which other causes of liver injury were excluded, what constitutes a significant hepatotoxic concomitant medication, and whether a clinical trial drug should be considered as having an unknown hepatotoxic potential for purposes of RUCAM scoring. Increasing familiarity with the RUCAM over the course of the study allowed for only a slight improvement in concordance between and among the assessors regarding the scoring. CONCLUSIONS: While the results indicate that RUCAM can provide for an objective assessment of causality of the hepatotoxicity of a drug under development in the clinical trial setting, this study highlights a number of problems with the current scoring system that should be addressed by future enhancements of the methodology.

Stroke event rates in anticoagulated patients with paroxysmal atrial fibrillation.

AIMS: To test the hypothesis that stroke and systemic embolic events (SEE) in the stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) III and V trials are different between paroxysmal and persistent atrial fibrillation (AF). METHODS: Data analysis from two cohorts of patients enrolled in the prospective SPORTIF III and V clinical trials (n = 7329); 836 subjects (11.4%) with paroxysmal AF [mean age 70.1 years (SD = 9.5)] were compared with 6493 subjects with persistent AF for this ancillary study. RESULTS: The annual event rates for stroke/SEE are 1.73% for persistent AF and 0.93% for paroxysmal AF. In a multivariate analysis, after adjusting for stroke risk factors, gender and aspirin usage, the differences remained statistically significant with a higher hazard ratio (HR) for stroke/SEE in persistent AF [vs. paroxysmal AF, HR 1.87, 95% confidence interval (CI) 1.04-3.36; P = 0.037]. In 'high risk' patients (with >or=2 stroke risk factors) annual event rates for stroke/SEE were 2.08% for persistent AF and 1.27% for paroxysmal AF (adjusted HR = 1.68, 95% CI 0.91-3.1, P = 0.098). Elderly patients had annual event rates for stroke/SEE of 2.38% for persistent AF and 1.13% for paroxysmal AF (adjusted HR = 2.27, 95% CI 0.92-5.59, P = 0.075). Vitamin K antagonist (VKA)-naive paroxysmal AF patients had a 1.89%/year stroke/SEE rate, compared with 0.61% for previous VKA takers (HR = 0.33, 95% CI 0.11-1.01, P = 0.052). CONCLUSION: In this large clinical trial cohort of anticoagulated AF patients, those with paroxysmal AF had stroke rates which were lower than for patients with persistent AF, although both groups had broadly similar stroke risk factors. Subjects with paroxysmal AF at 'high risk' had stroke/SEE rates that were not significantly different to persistent AF subjects.

Angiotensin converting enzyme inhibitor and angiotensin receptor blockade use in relation to outcomes in anticoagulated patients with atrial fibrillation.

BACKGROUND: The renin-angiotensin-aldosterone-system (RAAS) plays an important role in atrial fibrillation (AF). Evidence shows that blocking the RAAS with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has a definite role in preventing new onset AF and in maintaining sinus rhythm in recurrent AF. Our aim was to determine if ACEI/ARB treatment was associated with clinical outcomes [stroke/systemic embolic events (SEE), mortality] in a controlled, anticoagulated AF population. METHODS: An ancillary retrospective cross-sectional and longitudinal analysis of participants in the Stroke Prevention using an ORal Thrombin Inhibitor in AF (SPORTIF) III and V trials, in relation to use (or nonuse) of ACEI/ARBs. RESULTS: Rates of stroke/SEEs, mortality or major bleeding were no different between users and nonusers in the whole cohort, or in relation to the presence/absence of hypertension, coronary artery disease and previous stroke/transient ischaemic attack, nor amongst those aged <75 years. Patients aged > or = 75 years taking ACEIs or ARBs had lower mortality (HR 0.71, 95% CI 0.52-0.95), but no significant influence on other end-points was noted. Diabetics and those with left ventricular dysfunction on ximelagatran had a higher odds ratio of abnormal liver enzyme levels. There was no apparent benefit of ACEIs or ARBs on other event rates. CONCLUSIONS: This analysis from two large randomized trials of anticoagulation has not demonstrated a significant benefit of ACEI or ARB use amongst AF patients, except amongst elderly subjects.

Inhibitory activity of phosphates on molds isolated from foods and food processing plants.

Six commercial phosphates were evaluated for inhibition of the growth of 17 molds isolated from food sources. The assays were performed at neutral and natural (without pH adjustment) pH values, and the molds were streaked on plate count agar with added phosphates. Phosphate concentrations of 0.1, 0.3, 0.5, 1.0, and 1.5% (wt/vol) were used, and the MIC was determined. The resistance of molds to phosphates depended on the species. At a neutral pH, Aspergillus ochraceus and Fusarium proliferatum were resistant to all phosphates at all concentrations assayed, and Byssochlamys nivea, Aureobasidium pullulans, and Penicillium glabrum were most sensitive. The most inhibitory phosphates were those with chain lengths greater than 15 phosphate units and the highest sequestering power. At natural pH values (resulting from dissolving the phosphate in the medium), inhibitory activity changed dramatically for phosphates that produced alkaline or acidic pH in the medium. Phosphates with alkaline pH values (sodium tripolyphosphate of high solubility, sodium tripolyphosphate, and sodium neutral pyrophosphate) were much more inhibitory than phosphates at a neutral pH, but sodium acid pyrophosphate (acidic pH) had decreased inhibitory activity. The results indicate that some phosphates could be used in the food industry to inhibit molds linked to food spoilage.

A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I.

This randomized, controlled, multicentre study evaluated the efficacy and tolerability of the oral direct thrombin inhibitor ximelagatran, compared with a low-molecular-weight heparin (dalteparin) followed by warfarin, in the treatment of deep vein thrombosis (DVT) of the lower extremity. Patients with acute DVT received oral ximelagatran (24, 36, 48 or 60 mg twice daily) or dalteparin and warfarin for 2 weeks. Evaluation of paired venograms from 295 of 350 patients showed regression of the thrombus in 69% of patients treated with ximelagatran and 69% of patients treated with dalteparin and warfarin. Progression was observed in 8% and 3% of patients, respectively. Changes in thrombus size according to the Marder score were similar in all groups. Treatment discontinuation due to bleeding occurred in two patients receiving ximelagatran (24- and 36-mg groups) and in two patients receiving dalteparin and warfarin. Reduction in pain, edema and circumference of the affected leg was similar in all groups. Oral ximelagatran appears to be a promising alternative to current anticoagulant therapy to limit the progression of acute DVT, and it seems to possess a wide therapeutic window.

Factor V Leiden (G1691A) and prothrombin gene G20210A mutations as potential risk factors for venous thromboembolism after total hip or total knee replacement surgery.

Patients (n = 1600) from 12 European countries, scheduled for elective orthopaedic hip or knee surgery, were screened for Factor V Leiden and prothrombin gene G20210A mutations, found in 5.5% and 2.9% of the populations, respectively. All patients underwent prophylactic treatment with one of four doses of melagatran and ximelagatran or dalteparin, starting pre-operatively. Bilateral ascending venography was performed on study day 8-11. The patients were subsequently treated according to local routines and followed for 4-6 weeks postoperatively. The composite endpoint of screened deep vein thrombosis (DVT) and symptomatic pulmonary embolism (PE) during prophylaxis did not differ significantly between patients with or without these mutations. Symptomatic venous thromboembolism (VTE) during prophylaxis and follow-up (1.9%) was significantly over-represented among patients with the prothrombin gene G20210A mutation (p = 0.0002). A tendency towards increased risk of VTE was found with the Factor V Leiden mutation (p = 0.09). PE were few, but significantly over-represented in both the Factor V Leiden and prothrombin gene G20210A mutated patients (p = 0.03 and p = 0.05, respectively). However, since 90% of the patients with these genetic risk factors will not suffer a VTE event, a general pre-operative genotyping is, in our opinion, of questionable value.

Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT.

Forty-eight patients with acute proximal deep vein thrombosis (DVT) were randomised to intravenous infusions for 4 to 6 days with melagatran, a novel synthetic low molecular weight thrombin inhibitor, or unfractionated heparin adjusted by the activated partial thromboplastin time (APTT). The aim of the study was to investigate the pharmacokinetics, pharmacodynamics and the safety of melagatran therapy at three different doses. Steady-state plasma concentrations were rapidly achieved and maintained throughout the infusion period. The mean plasma concentrations in the low, medium and high dose groups were 0.17, 0.31 and 0.53 micromol/l, respectively. The prolongation of APTT was stable during the melagatran infusions and correlated to the plasma concentration. Phlebographically verified regression of thrombus size measured as decrease in Marder score was seen after 4 to 6 days in 8 of 12 patients, 6 of 12 patients and 5 of 11 patients in the low, medium and high dose groups of melagatran and in 5 of the heparin-treated patients. In the low dose group with melagatran, thrombus extension was seen in one patient. At the dose levels studied, melagatran was well tolerated with no clinically significant bleeding problems, suggesting that melagatran could safely be given to patients suffering from DVT.

Omeprazole and ranitidine in the prevention of relapse in patients with duodenal ulcer disease.

BACKGROUND: Although the eradication of Helicobacter pylori is of primary importance when initiating treatment, it is also important to have a strategy for patients who are H pylori-negative, fail to demonstrate eradication or have a tendency to become re-infected or relapse. PATIENTS AND METHODS: In a double-blind, parallel-group clinical trial of 928 patients (from 70 centres in 16 countries) with duodenal ulcers who after a short term study had relief of symptoms and healed ulcers proved endoscopically, 308 were randomly assigned to receive omeprazole 10 mg in the morning, 308 to receive omeprazole 20 mg in the morning and 312 to receive ranitidine 150 mg at bedtime for up to 12 months. Symptoms were assessed every three months and endoscopy repeated at three, six and 12 months, or more often if indicated by recurrence of symptoms. The safety screening included basal serum gastrin concentrations and gastric mucosal histopathology. RESULTS: The remission rates up to 12 months were 87% for the omeprazole 20 mg group, 71% for the omeprazole 10 mg group and 63% for the ranitidine group. Omeprazole 20 mg differed significantly from both omeprazole 10 mg (P=0.0001, 95% CI 9 to 23) and ranitidine (P=0.0001, 95% CI 17 to 31). There was no statistically significant difference between omeprazole 10 mg and ranitidine over the 12-month period, but the 95% confidence interval allowed differences between 0% and 16% in favour of omeprazole at 12 months. A Cox regression analysis revealed that longer treatment courses to heal, smoking, a long ulcer history and young age negatively contributed to the odds of staying in remission. The treatments were well tolerated. There was a slight increase in basal serum gastrin concentrations, reflecting the different degrees of acid inhibition induced by the three treatments. No dysplastic or neoplastic lesions were found in any biopsies. CONCLUSIONS: More duodenal ulcer patients are maintained in remission with omeprazole 20 mg daily than with omeprazole 10 mg daily or with ranitidine 150 mg at bedtime.

Prognostic factors influencing relapse of oesophagitis during maintenance therapy with antisecretory drugs: a meta-analysis of long-term omeprazole trials.

BACKGROUND: This meta-analysis investigated factors that may affect the risk of relapse of oesophagitis, and evaluated the predictive value of symptoms for the presence of relapse during long-term treatment. METHODS: Individual data from 1154 patients included in five independently conducted, randomized, long-term clinical trials of the efficacy of different dosage regimens of omeprazole, standard ranitidine treatment and placebo for the prevention of relapse of oesophagitis were pooled for this meta-analysis. The therapeutic regimens studied were omeprazole 20 mg o.m. (OME20) in 366 patients, omeprazole 10 mg o.m. (OME10) in 225 patients, omeprazole 20 mg weekends (OMEW) in 235 patients, ranitidine 150 mg b.d. (RAN) in 179 patients, or placebo (PLA) in 149 patients. RESULTS: OME20 maintained 82.4% (95% CI: 78.2-86.6%) of patients in endoscopic remission over the 6-month period compared to 71.9% (95% CI: 65.5-78.3%) for OME10, 52.3% (95% CI: 44.4-60.1%) for RAN, 42.7% (95% CI: 35.8-49.5%) for OMEW, and 10.6% (95% CI: 5.0-16.3%) for PLA. A Cox's regression analysis of time to recurrence of oesophagitis showed that four factors were associated with a higher relapse rate during placebo and active maintenance therapy: (a) pre-treatment severity of oesophagitis (P < 0.0001), (b) young age (P = 0.01), (c) non-smoking (P = 0.02) and (d) moderate/severe regurgitation before entry into the trials (P = 0.03). Asymptomatic relapse of oesophagitis was uncommon, being found in only 8.6% of the patients. CONCLUSIONS: Maintenance treatment with omeprazole 10 and 20 mg daily is superior to all other regimens tested, and is only marginally influenced by the pretreatment severity of oesophagitis. Age contributes to the factors that influence the outcome during long-term treatment with omeprazole. Symptom relief is highly predictive for the maintenance of healing.

Antibacterial activity of enterococci strains against Vibrio cholerae.

Thirty-seven strains of enterococci isolated from milk and milk products from Santa Fe (Argentina) region were tested for antagonistic activity against Vibrio cholerae 01 and non-01. Seven of 17 strains of Enterococcus faecalis, five of 10 strains of Enterococcus faecium and four of 10 strains of Enterococcus durans produced inhibition zones against the indicator species. The activity of the antibacterial compounds was completely destroyed by treatment with trypsin and pronase E in most cases (only the supernatant fluids of a few strains remained weakly active after the treatment), but was resistant to heat treatment at 100 degrees C during 10 and 30 min. When the 10-fold concentrated supernatant fluids were added to a fresh culture of sensitive cells it produced a rapid inactivation. According to these preliminary tests, different strains of enterococci produced compounds with slightly different antivibrio properties, and these compounds were heat-resistant and had a predominantly proteinaceous nature.

Linearly divergent treatment effects in clinical trials with repeated measures: efficient analysis using summary statistics.

In many randomized clinical trials with repeated measures of a response variable one anticipates a linear divergence over time in the difference between treatments. This paper explores how to make an efficient choice of analysis based on individual patient summary statistics. With the objective of estimating the mean rate of treatment divergence the simplest choice of summary statistic is the regression coefficient of response on time for each subject (SLOPE). The gains in statistical efficiency imposed by adjusting for the observed pre-treatment levels, or even better the estimated intercepts, are clarified. In the process, we develop the optimal linear summary statistic for any repeated measures design with assumed known covariance structure and shape of true mean treatment difference over time. Statistical power considerations are explored and an example from an asthma trial is used to illustrate the main points.