Oral lichen planus (OLP), oral lichenoid lesions (OLL), oral dysplasia, and oral cancer: retrospective analysis of clinicopathological data from 2002-2011.

INTRODUCTION: This 10-year retrospective study analyzed the incidence of malignant transformation of oral lichen planus (OLP). The study also included dysplasia and oral lichenoid lesion (OLL) in the initial biopsy as a potential differential diagnosis. MATERIAL AND METHODS: A total of 692 scalpel biopsies were taken from 542 patients (207 [38.2%] men and 335 [61.8%] women). Clinical and histopathological parameters were analyzed. RESULTS: The parameters gender (p = 0.022) and smoking behavior (p < 0.001) were significantly associated with the severity of diagnosis. Mucosal lesions with an ulcerative appearance (p = 0.006) and those located on the floor of the mouth (p < 0.001) showed significantly higher degrees of dysplasia or were diagnosed as oral squamous cell carcinoma (OSCC). Smoking and joint disease appeared to be significant risk factors. Treatment with tretinoin in different concentrations (0.005-0.02%) significantly improved diagnosis. Twelve patients (8 female, 4 male) showed malignant transformation to OSCC within an average period of 1.58 years. The malignant transformation rate (MTR) was higher for OLL (4.4%) than OLP (1.2%). If the first biopsy showed intraepithelial neoplasia, the risk of developing OSCC increased (by 3.5% for squamous intraepithelial neoplasia (SIN) II and by 6.7% for SIN III). CONCLUSION: Although we cannot rule out that OLP is a premalignant oral condition, we can confirm that OLP had the lowest MTR of all diagnoses.

Pregnancy and Birth After a Two-Step PGD: Polar Body Diagnosis for Hemophilia A and Array CGH on Trophectoderm Cells for Chromosomal Aberrations.

Objective: To demonstrate that a PGD program can be successfully established after the 2011 verdict of the German Bundestag concerning PGD. Material and Method: Eight years previously, the couple had had a daughter who suffered from clinically manifest hemophilia A due to an unbalanced X-inactivation, as well as microdeletion syndrome resulting in severe physical and mental disability. The couple wished to have a second child but refused the idea of a "trial" pregnancy. Given the indications for both, it was necessary to carry out polar body diagnosis (PBD) to rule out hemophilia A and, during the same cycle, a subsequent PGD on the blastocysts to rule out genetic aberrations. The PBD and PGD (trophectoderm biopsy, TEB) were performed after high-dosage ovarian stimulation and ICSI fertilization of the oocytes. A blastocyst was successfully transferred on day 6. Results: The patient conceived immediately. The pregnancy developed normally and the patient gave birth to a girl in the 40th week of pregnancy. Post-natal examinations showed that the baby is free from hemophilia A and is developing normally both physically and mentally. Conclusion: Establishment of a PGD program is now possible after legalization of PGD in Germany. It is possible to apply two investigative techniques in a single treatment cycle if multifactorial diagnosis is required.

Effects of tryptophan supplementation on plasma tryptophan and related hormone levels in heifers and dairy cows.

This study was conducted to investigate the effects of rumen-protected tryptophan (125 g tryptophan per day) in heifers and dairy cows. Blood samples from dairy cows and heifers were collected for 24h in 3-h intervals on the day before tryptophan supplementation, on day 2, 5 and 7 of tryptophan supplementation, and in heifers additionally on d 14 after tryptophan supplementation was ceased. Plasma tryptophan, melatonin, serotonin, and prolactin concentrations were determined. Tryptophan plasma concentrations on d 5 were augmented at day (11:00 h) and nighttime (02:00 h), (P<0.05) in response to tryptophan supplementation in heifers by 119% and in dairy cows by 47%, respectively, as compared with d 0. Melatonin increased (P<0.05) in response to tryptophan supplementation in heifers, but not in cows. The effect of tryptophan supplementation on plasma tryptophan and melatonin was reversible as demonstrated in heifers on d 14 after cessation of tryptophan supplementation. Serotonin and prolactin in plasma did not respond to tryptophan supplementation. However, milk yield during morning milking increased significantly in tryptophan supplemented cows on d 1, 3 and 4 as compared to the day before tryptophan supplementation. Additional blood samples were taken during afternoon milking in cows at 1-min intervals for the analyses of oxytocin and prolactin on the day before the start and on d 7 of tryptophan supplementation. Milk flow curves were recorded during milking. No effect of tryptophan supplementation on the milking related release of oxytocin and prolactin and on any characteristic of milk flow was observed. In conclusion, tryptophan supplementation caused increased plasma tryptophan in cows and heifers and plasma melatonin in heifers. However, plasma serotonin, prolactin and oxytocin release in cows remained unchanged by tryptophan supplementation. Milk yield at morning milking increased slightly and transiently in response to tryptophan supplementation.

A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matalpha2 repressor degradation.

Substrate discrimination in the ubiquitin-proteasome system is believed to be dictated by specific combinations of ubiquitin-protein ligases (E3s) and ubiquitin-conjugating enzymes (E2s). Here we identify Doa10/Ssm4 as a yeast E3 that is embedded in the endoplasmic reticulum (ER)/nuclear envelope yet can target the soluble transcription factor Matalpha2. Doa10 contains an unusual RING finger, which has ubiquitin-ligase activity in vitro and is essential in vivo for degradation of alpha2 via its Deg1 degradation signal. Doa10 functions with two E2s, Ubc6 and Ubc7, to ubiquitinate Deg1-bearing substrates, and it is also required for the degradation of at least one ER membrane protein. Interestingly, different short-lived ER proteins show distinct requirements for Doa10 and another ER-localized E3, Hrd1. Nevertheless, the two E3s overlap in function: A doa10Delta hrd1Delta mutant is far more sensitive to cadmium relative to either single mutant and displays strong constitutive induction of the unfolded protein response; this suggests a role for both E3s in eliminating aberrant ER proteins. The likely human ortholog of DOA10 is in the cri-du-chat syndrome critical region on chromosome 5p, suggesting that defective ubiquitin ligation might contribute to this common genetic disorder.

Theory of controlling stochastic resonance

The concept of controlling stochastic resonance has been recently introduced [L. Gammaitoni et al., Phys. Rev. Lett. 82, 4574 (1999)] to enhance or suppress the spectral response to threshold-crossing events triggered by a time-periodic signal in background noise. Here, we develop a general theoretical framework, based on a rate equation approach. This generic two-state theory captures the essential features observed in our experiments and numerical simulations.

Determination of retigabine and its acetyl metabolite in biological matrices by on-line solid-phase extraction (column switching) liquid chromatography with tandem mass spectrometry.

A HPLC assay with tandem mass spectrometric detection in the positive-ion atmospheric pressure chemical ionisation (APCI) mode for the sensitive determination of retigabine [(I), D-23129] and its acetyl metabolite [(II), ADW 21-360] in plasma was developed, utilising the structural analogue (D-10328), (III), as internal standard. Automated on-line solid-phase extraction of diluted plasma samples, based on 200-microl plasma aliquots, at pH 6.5, allowed a reliable quantification of retigabine and the acetyl metabolite down to 1 ng/ml. Injection of 500 microl of diluted plasma onto a C2 stationary phase-based column switching system in combination with a 75 mm x 4 mm reversed-phase analytical column at a flow-rate of 0.5 ml/min provided cycle times of 4 min per sample. The standard curves were linear from 1 to 1000 ng/ml using weighted linear regression analysis (1/x2). The method is accurate (mean accuracy < or = +/- 10%), precise (RSD < +/- 15%) and sensitive, providing lower limits of quantification in plasma of 1 ng/ml for retigabine (I), and 2.5 ng/ml for the metabolite (II) with limits of detection of 0.5 ng/ml for both analytes. Up to 200 unknowns may be analysed each 24 h per analyst.

Noise sustained propagation: local versus global noise

We expand on prior results on noise supported signal propagation in arrays of coupled bistable elements. We present and compare experimental and numerical results for kink propagation under the influence of local and global fluctuations. As demonstrated previously for local noise, an optimum range of global noise power exists for which the medium acts as a reliable transmission "channel." We discuss implications for propagation failure in a model of cardiac tissue, and present a general theoretical framework based on discrete kink statistics. Valid for generic bistable chains, the theory captures the essential features observed in our experiments and numerical simulations.

Pharmacokinetic-pharmacodynamic modeling of testosterone and luteinizing hormone suppression by cetrorelix in healthy volunteers.

Cetrorelix (CET), a potent luteinizing hormone-releasing hormone (LH-RH) antagonist, was recently approved for the prevention of premature ovulation in patients undergoing a controlled ovarian stimulation (COS), followed by oocyte pickup and assisted reproductive techniques (ART), and is currently under clinical trials for benign prostate hyperplasia, endometriosis, and tumors sensitive to sex hormones. CET suppresses luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) in men. The purpose of this study was to evaluate the pharmacokinetics and absolute bioavailability of 3 mg intravenously and subcutaneously administered CET in healthy male and female volunteers and to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to link the plasma concentrations of CET to the T and LH suppression in males. Following intravenous (IV) (n = 5) and subcutaneous (SC) (n = 6) administration of CET acetate, CET and hormone plasma levels were measured by radioimmunoassay (RIA) and enzyme immunoassay (EIA) methods, respectively. Pharmacokinetics of CET was explained by a three-compartment model for the IV route and by a two-compartment model with first-order absorption for the SC route. Average absolute bioavailability after SC administration was 85%. There were no differences in the pharmacokinetics between male and female subjects (ANOVA, p > 0.05). Single IV and SC doses of CET caused immediate and distinct suppression of LH, FSH, and T levels by 80%, 45% and 95% of their baseline levels, respectively. The duration of hormone suppression was longer for the SC route. An indirect-response PK-PD Emax model was developed to link the measured CET plasma concentrations with the respective T or LH levels. In addition, the circadian rhythm of T levels was accounted by including a cosine function in a second separate PD model. The PD model with cosine function was applied to T baseline levels as well as to the suppressed concentrations after CET dosing. The two models adequately described the PK-PD relationship between plasma levels of CET and T suppression following IV and SC dosing. The EC50 values (mean +/- SD) for the suppression of T were similar (p > 0.05) between the two routes of administration and the two models.

Disposition and metabolism of cetrorelix, a potent luteinizing hormone-releasing hormone antagonist, in rats and dogs.

Disposition and metabolism of cetrorelix was studied in intact and bile duct-cannulated rats and dogs after s.c. injection. An s.c. dose of 0.1 mg/kg [(14)C]cetrorelix was rapidly and completely absorbed in rats. T(max) in plasma and most tissues was at 2 h. Radioactivity at the injection site in rats declined to 10% by 24 h. The extent of (14)C absorption in rats calculated from excretion until 264 h was 94%. Exposure of the target organ pituitary gland was demonstrated with a time course similar to plasma but on a higher level. Rats excreted 69.6% of radioactivity via feces and 24. 3% into urine. Excretion was nearly complete within 48 h. No enteral reabsorption was detected. In dogs t(max) in plasma was 1.3 h. (14)C- and cetrorelix-plasma levels were similar until 24 h, indicating a negligible amount of metabolites. A dose of 1 mg/kg in dogs showed an increasing influence of a slow absorption phase (flip-flop). In dogs equal amounts of the (14)C dose were found within 192 h in feces and urine, 46 and 48%, respectively. In urine of both species, only intact cetrorelix was detected. In bile and feces of both species qualitatively the same metabolites were found, characterized as truncated peptides of the parent decapeptide. The major metabolite occurring in bile of both species was the (1-7)heptapeptide. The amounts of the (1-4)tetrapeptide in feces of rats but not in that of dogs increase with time, suggesting additional degradation of the peptide in the gastrointestinal tract of rats by enteric metabolization.

Quantification of perifosine, an alkylphosphocholine anti-tumour agent, in plasma by pneumatically assisted electrospray tandem mass spectrometry coupled with high-performance liquid chromatography.

An HPLC assay with tandem mass spectrometric detection in the positive-ion Turbo-Ion-Spray (TISP) mode for the fast and sensitive determination of perifosine ((I), D-21266) in human plasma was developed, utilising the structural analogue, miltefosine ((II), D-18506), as internal standard. Automated solid-phase extraction of diluted plasma samples, based on 250-microl plasma aliquots, at pH 6.5, allowed a reliable quantification of perifosine down to 4 ng/ml. Injection of 200 microl of plasma extracts onto a 100x3 mm normal-phase analytical column at a flow-rate of 0.5 ml/min provided retention-times of 2.4 and 2.1 min for perifosine (I) and the internal standard (II), respectively. The standard curves were linear from 4 to 2000 ng/ml using weighted linear regression analysis (1/Y2). The inter-assay and intra-assay accuracies for the calibration standards were within +0.9% and -0.2%, exhibiting precisions (C.V.) of +/-6.5 and +/-7.3%, respectively. Up to 100 unknowns may be analysed each 24 h per analyst.

Development of the frontal sinus following bilateral fronto-orbital osteotomies.

The presence of frontal sinuses following bilateral fronto-orbital advancement is discussed controversially in the literature. In a retrospective study, 33 patients (18 male and 15 female) were operated on between 1982 and 1993, with at least one year postoperative follow-up and with a minimum age of 6 years at the end of the follow-up period following bilateral fronto-orbital remodelling, were included. The average age at which the procedure was performed was 29 months with a minimum of 3 months and a maximum of 7.8 years. The study presented shows a pneumatization of the frontal sinus in 72.7% of 33 patients following bilateral fronto-orbital advancement. The first radiographic signs of sinus development were detected between the ages of 4 and 11, average 8.3 years. There were no statistically proven correlations between frontal sinus pneumatization and age at operation or the amount of advancement or sex of the patients. Surgical enlargement of the cranium by frontal advancement with adequate stabilization results in an enlargement of the neurocranium, thereby decreasing pressure on the inner frontal cortex and allowing frontal sinus pneumatization to proceed normally. Hence, the development of a frontal sinus may be a reflection of the effectiveness of the surgical therapy.

[Preoperative diagnosis of complex craniofacial syndromes]. / Präoperative Diagnostik komplexer kraniofazialer Syndrome.

The aim of this study was to evaluate stereolithography as a tool in craniofacial surgery. The indications were classified according to the usefulness of stereolithography for different craniofacial pathologies. Stereolithography models of 21 patients were built; in three cases two models were made. The age of the 7 male and 14 female patients was 17 years on average (range: 15 months-44 years). First a helical volume CT scan of the anatomical region was performed. After transformation of the data set, the models were built by an SLA 250 stereolithography apparatus (3D-Systems, Valencia, Calif., USA), steered by FORM-IT/DCS-Software (University of Zurich, Switzerland). The stereolithography models were constructed by superposition of epoxy resin slices of 0.05 mm thickness, which were polymerized by a helium-cadmium laser. These models were classified according to the indication for stereolithography, the operation performed, the relevance for surgical planning and the usefulness for the fabrication of implants and protheses. In craniofacial syndromes, severe asymmetries of the viscerocranium, large skull defects and before surgical correction of hypertelorism these models provided important additional information for the surgeon. Before complex interventions in these fields the construction of a stereolithography model should be considered. In multiple fractures consolidated in dislocation, the models proved to be less useful.

[Fronto-orbital corrections and development of the frontal sinus]. / Frontoorbitale Korrekturen und Stirnhöhlenentwicklung.

The development of frontal sinuses following bilateral fronto-orbital advancement is a topic of controversial discussion in the literature. In a retrospective study on 33 patients (15 girls and 18 boys) the development of the frontal sinus was examined radiologically. Only patients with a minimum age of 6 years and with at least 1 year of postoperative follow-up were included. The radiological reference for the frontal sinus development consisted of pneumatisation at or above the level of the supraorbital rims, as projected din postero-anterior cephalograms. According to these criteria a frontal sinus development was seen in 72.7% of our patients. There was no statistically proven correlation between sinus development and the sex of the patient, age at surgery or the amount of advancement. With the exception of severe cases of Crouzon's disease we usually expect normal development of the frontal sinus following bilateral fronto-orbital correction.

[Cranial development after corrective skull surgery in craniosynostosis]. / Wachstumsverhalten nach Schädelkorrekturen bei Kraniosynostosen.

Craniofacial development may be potentially implicated after vault corrections in cases of craniosynostosis. The aim of this prospective study was the investigation of the surgical effect on calvaria growth, correlating the percentiles of a group of patients before and after craniosynostosis correction in relation to the normal percentiles of growth. The patient population consisted of 71 children; the postoperative follow-up time in 57 patients was more than 12 months. Of the children followed up, 36 were male and 21 female. Thirty-six cases involved untreated non-syndromic craniosynostosis; the remaining 21 were syndrome cases. The patient ages ranged from 16 to 27 months. In 11 cases correction of an occipital craniosynostosis was carried out. The fronto-occipital circumference was registered in accordance with Prader's percentile table. The operative method included a fronto-parietal craniotomy, the temporary removal and shaping of the fronto-orbital band and a vault cranioplasty. During follow-up 13 patients treated with fronto-orbital advancement in cases of isolated craniosynostosis remained in the registered percentile curve. In 13 patients a change to a lower percentile curve was confirmed; 1 patient changed to a higher curve. In cases of syndromic craniosynostosis 10 patients remained in the post-operatively registered percentile curve; 8 patients changed to a lower and 1 patient to a higher percentile curve. No growth restriction of the reshaped calvaria after surgical correction of craniosynostosis was observed. No significant difference was found in the potential calvaria growth between syndromic and isolated craniosynostosis.

[Occipital correction in scapho- and plagiocephaly]. / Okzipitale Korrektur bei Skapho- und Plagiozephalie.

The operation technique and the results after occipital correction in children with plagiocephaly and scaphocephaly are reported. The indication for the intervention is provided by aesthetic and functional considerations. The outcome is very good; the growth of the skull follows the same range of percentiles as preoperatively and normal mental development is seen.

[Allo-transfusion saving measures in maxillofacial surgery]. / Fremdblutsparende Massnahmen in der Kiefer-und Gesichtschirurgie.

In terms of a prospective clinical study between June 1994 and May 1996, in 204 patients undergoing maxillo-facial surgeries with a expected blood loss of more than 500 ml a protocol of bloodsaving measures was followed. By means of an additional retrospective study, the consumption of homologous blood and the amount of bloodsaving measures between June 1990 and May 1994 was evaluated. Bloodsaving measures were consisting from acute normovolemic hemodilution, controlled moderate hypotension, cell saving, preoperative autologous blood donation, and administration of rh-erythropoetine. The methoda were applied isolated as well as in combination. Special concerns were given to a stable intraoperative homeostasis and to the acceptance of a low hematocrit perioperatively. Aim of the study was to investigate if, following the protocol, even in major maxillofacial procedures homologous blood transfusions almost completely can be avoided. Out of the 204 patients in the prospective study, only 30 received homologous blood. For the period June 94 to May 96, the reduction of the number of patients receiving homologous blood in relation to the period June 90 to May 94 was 83%. The results indicate that in the years 94 to 96 twice as much patients received bloodsaving measures. These led to a reduction of homologous blood consumption for 427 units in 1990 to 56 units 1996 (p < 0.001). If three measures, i.e. normovolemic hemodilution, cell saving, and hypotension were combined, the need of blood transfusion was at the minimum level. The effective reduction of homologous blood transfusion by consequent application of bloodsaving measures can with these data obviously be demonstrated.

[Pre-operative diagnosis of complex craniofacial syndromes]. / Präoperative Diagnostik komplexer kraniofazialer Syndrome.

The aim of this study was to evaluate stereolithography as a tool in craniofacial surgery. The indications were classified according to the usefulness of stereolithography for different craniofacial pathologies. Stereolithography models of 21 patients were built; in three cases two models were made. The age of the 7 male and 14 female patients was 17 years on average (range: 15 months-44 years). First a helical volume CT scan of the anatomical region was performed. After transformation of the data set, the models were built by an SLA 250 stereolithography apparatus (3D-Systems, Valencia, Calif., USA), steered by FORM-IT/DCS-Software (University of Zurich, Switzerland). The stereolithography models were constructed by superposition of epoxy resin slices of 0.05 mm thickness, which were polymerized by a helium-cadmium laser. These models were classified according to the indication for stereolithography, the operation performed, the relevance for surgical planning and the usefulness for the fabrication of implants and protheses. In craniofacial syndromes, severe asymmetries of the viscerocranium, large skull defects and before surgical correction of hypertelorism these models provided important additional information for the surgeon. Before complex interventions in these fields the construction of a stereolithography model should be considered. In multiple fractures consolidated in dislocation, the models proved to be less useful.

[Fronto-orbital correction and frontal sinus development]. / Frontoorbitale Korrekturen und Stirnhöhlenentwicklung.

The development of frontal sinuses following bilateral fronto-orbital advancement is a topic of controversial discussion in the literature. In a retrospective study on 33 patients (15 girls and 18 boys) the development of the frontal sinus was examined radiologically. Only patients with a minimum age of 6 years and with at least 1 year of postoperative follow-up were included. The radiological reference for the frontal sinus development consisted of pneumatisation at or above the level of the supraorbital rims, as projected in postero-anterior cephalograms. According to these criteria a frontal sinus development was seen in 72.7% of our patients. There was no statistically proven correlation between sinus development and the sex of the patient, age at surgery or the amount of advancement. With the exception of severe cases of Crouzon's disease we usually expect normal development of the frontal sinus following bilateral fronto-orbital correction.

[Cranial development and growth following treatment of craniosynostosis skull deformities]. / Wachstumsverhalten nach Schädelkorrekturen bei Kraniosynostosen.

Craniofacial development may be potentially implicated after vault corrections in cases of craniosynostosis. The aim of this prospective study was the investigation of the surgical effect on calvaria growth, correlating the percentiles of a group of patients before and after craniosynostosis correction in relation to the normal percentiles of growth. The patient population consisted of 71 children; the postoperative follow-up time in 57 patients was more than 12 months. Of the children followed up, 36 were male and 21 female. Thirty-six cases involved untreated non-syndromic craniosynostosis; the remaining 21 were syndrome cases. The patient ages ranged from 16 to 27 months. In 11 cases correction of an occipital craniosynostosis was carried out. The fronto-occipital circumference was registered in accordance with Prader's percentile table. The operative method included a fronto-parietal craniotomy, the temporary removal and shaping of the fronto-orbital band and a vault cranioplasty. During follow-up 13 patients treated with fronto-orbital advancement in cases of isolated craniosynostosis remained in the registered percentile curve. In 13 patients a change to a lower percentile curve was confirmed; 1 patient changed to a higher curve. In cases of syndromic craniosynostosis 10 patients remained in the post-operatively registered percentile curve; 8 patients changed to a lower and 1 patient to a higher percentile curve. No growth restriction of the reshaped calvaria after surgical correction of craniosynostosis was observed. No significant difference was found in the potential calvaria growth between syndromic and isolated craniosynostosis.

[The occipital correction in plagiocephaly and scaphocephaly]. / Okzipitale Korrektur bei Skapho- und Plagiozephalie.

The operation technique and the results after occipital correction in children with plagiocephaly and scaphocephaly are reported. The indication for the intervention is provided by aesthetic and functional considerations. The outcome is very good; the growth of the skull follows the same range of percentiles as preoperatively and normal mental development is seen.