Clinical safety of enamel matrix derivative (EMDOGAIN®) in the treatment of periodontal defects

Abstract The aim of the present clinical trial was to test tolerability during 2 treatments with EMDOGAIN® in a large number of patients. An open, controlled study design in 10 Swedish specialist clinics was chosen, with a test group of 107 patients treated with EMDOGAIN® in connection with periodontal surgery at 2 surgical test sites per patient. The procedures were performed 2 to 6 weeks apart on one-rooted teeth with at least 4 mm deep intraosseous lesions. A control group of 33 patients underwent flap surgery without EMDOGAIN® at I comparable site. In total 214 test and 33 control surgeries were performed. Serum samples were obtained from test patients for analysis of total and specific antibody levels. 10 of the patients had samples taken before and after the first surgery. 56 other samples were taken after one treatment with EMDOGAIN®, and 63 after 2 treatments. None of the samples, not even from allergy-prone patients after 2 treatments, indicated deviations from established baseline ranges. This indicates that the immunogenic potential of EMDOGAIN® is extremely low when applied in conjunction with periodontal surgery. Comparison between the test and control groups demonstrated the same type and frequency of post-surgical experiences, i.e., reactions caused by the surgical procedure itself. Clinical probing and radiographic evaluation was performed at baseline and 8 months postsurgery. About half of the patients (44 test and 21 control) were also evaluated after 3 years. There was a significant difference between the test and control results at 8 months post surgery. and this difference had increased further at the 3 year follow-up. The 2.5–3 mm increase in attachment and bone level after treatment with EMDOGAIN® was of the same magnitude as seen in the studies with split-mouth design aiming for lest of effectiveness of EMDOGAIN®.     

Penetration and distribution of three lipophilic probes in vitro in human skin focusing on the hair follicle.

Fluorescent model substances of increasing lipophilicity (Oregon Green) 488, Bodipy, FL C5 and Bodipy 564/570 C5) were selected to enable the visualization in the skin using confocal laser scanning microscopy. After measuring the penetration for 18 h, the nonfixed human scalp skin was imaged from the bottom parallel to the stratum corneum and in a cross-section view perpendicular to the skin surface. The images were evaluated by calculating relative accumulation values for different penetrants. The studies indicate that the penetrated amount is highest for Bodipy FL C5 (medium lipophilicity) and lowest for Bodipy 564/570 C5 (high lipophilicity) whereas Bodipy 564/570 C5 (high lipophilicity) reveals the highest relative accumulation in parts of the hair follicle compared to Oregon Green 488 (low lipophilicity). The addition of 30% (v/v) ethanol to the donor phase of substance with a low lipophilicity increases the follicular delivery. From our results we conclude that delivery to the hair follicle can be improved by increasing the drugs lipophilicity and optimizing the composition of the donor phase. However, no conclusion can be drawn about the actual route of transport to the hair follicle.     

Effects of repeated doses of benzodiazepines on arterial blood gases and transcutaneous Po2

The effects of repeated doses of benzodiazepines, diazepam and midazolam in combination with meperidine on arterial blood gases and transcutaneous PO2 were studied in eight healthy volunteers. The study was designed to mimic a clinical situation. Initially two doses of either midazolam 0.05 mg/kg or diazepam in fat emulsion 0.15 mg/kg were given in a randomized crossover fashion with a 20-min interval, followed by meperidine 0.5 mg/kg another 20 min later. The opioid effects were then antagonized by naloxone 0.4 mg. The initial doses of benzodiazepines caused an increase in PaCO2 and a decrease in PaO2. The changes in PaO2 were of short duration and recovered to baseline levels between injections. However, they came sooner and were more pronounced after midazolam. The changes in PtcO2 paralleled those in PaO2. The PtcO2 index as a measure of cardiac output and peripheral blood flow adequacy was increased immediately after the first injection of midazolam but was otherwise not different from control. There were no differences between the drugs concerning PtcO2 index. PaCO2 increased after the first benzodiazepine injection and remained so throughout the study. Addition of meperidine caused only small changes in PaO2 and PaCO2. These changes were reversed by naloxone. In spite of different elimination kinetics there was no difference in the duration of respiratory depression between the two benzodiazepines.     

Effect of temperature on blood flow and metabolism in a neurovascular island skin flap

Using the buttock flap in 29 white Yorkshire pigs, blood flow and O2 consumption were measured at dermal temperatures between 35 degrees C and 15 degrees C. Flow was measured with an electromagnetic flowmeter and O2 consumption was calculated as the product of blood flow and the difference in flap A-VO2. Baseline flow was 6.6 +/- .9 (SE) ml/100 g/min at 35 degrees C and 3.1 +/- .02 (SE) ml/10 g/min at 15 degrees C. Blood flow through the flap stopped completely at a dermal temperature of 14 degrees C. Oxygen consumption was 0.16 +/- .02 (SE) ml/100 g/min at 35 degrees C and 0.04 +/- 0.01 (SE) ml/100 g/min at 15 degrees C. At 20 degrees C blood flow was 4.3 ml/100 g/min and metabolism was .04 ml/100 g/min. In other words, blood flow was 65% of baseline, while O2 consumption was only 25% of baseline. The therapeutic effect of local cooling at 20 degrees C deserves further investigation. The cessation of flow at 14 degrees C may be caused by increased plasma viscosity.     

Acute and chronic whiplash disorders--a review.

OBJECTIVE: This review examines acute and chronic whiplash-associated disorders to facilitate assessment, treatment and rehabilitation for further research and evidence-based practices. DESIGN: A review of the literature. RESULTS AND CONCLUSION: Whiplash-associated disorders account for a large proportion of the overall impairment and disability caused by traffic injuries. Rarely can a definite injury be determined in the acute (or chronic) phase. Crash-related factors have been identified, and several trauma mechanisms possibly causing different injuries have been described. Most whiplash trauma will not cause injury, and the majority of patients (92-95%) will return to work. Litigation is not a major factor. Cognitive impairments are not the same as brain injury. Variables such as pain intensity, restricted motion, neurological symptoms and signs, together with central nervous system symptoms can be used to predict a situation with risk of remaining complaints. Influences of other factors--the same as for other chronic pain conditions--also exist. Persistent/chronic pain is not merely acute pain that persists over time; changes occur at different levels of the pain transmission system. Chronic whiplash-associated disorders are associated with problems concerning social functioning, daily anxieties and satisfaction with different aspects of life. Adequate information, advice and pain medication together with active interventions might be more effective in the acute stage. Early multidisciplinary rehabilitation focusing on cognitive-behavioural changes might be of value. To develop specific treatment and rehabilitation, it is important to identify homogenous subgroups.     

Urticaria is associated with birch-pollen sensitization

Urticaria is a common condition, seldom of allergic origin. It is however not always possible to find the provoking allergen. The aim of the present study was to analyze if there was a relationship between urticaria and sensitization to common airborne allergens. A representative sample of 402 12 to 13-yr-old children answered a questionnaire on allergic diseases, 397 were interviewed by the study nurse and 371 underwent skin prick tests to cat, dog, horse, birch, timothy-grass, house dust mites and Cladosporium mould. Specific IgE-antibodies were analyzed to birch pollen and cat dander. Urticaria was more common in sensitized children, but the relationship between urticaria and sensitization was only statistically significant for birch pollen sensitization (OR 1.99, 95% CL 1.04-3.83), when tested in a multiple logistic regression model with the specified allergens as independent variables. A similar pattern was seen for birch-specific IgE-antibody levels, which was higher in children reporting urticaria than in those without. IgE-levels to cat dander did not show such a difference. Urticaria was statistically significantly associated with sensitization to birch-pollen, but not to other common inhalant allergens. We propose that intake of birch-pollen cross-reactive food-stuffs may be a neglected cause of urticaria and relapsing urticaria, in birch-pollen sensitized subjects.     

Distinct Pharmacologic Properties of Neuromuscular Blocking Agents on Human Neuronal Nicotinic Acetylcholine Receptors: A Possible Explanation for the Train-of-four Fade

Background: Nondepolarizing neuromuscular blocking agents (NMBAs) are extensively used in the practice of anesthesia and intensive care medicine. Their primary site of action is at the postsynaptic nicotinic acetylcholine receptor (nAChR) in the neuromuscular junction, but their action on neuronal nAChRs have not been fully evaluated. Furthermore, observed adverse effects of nondepolarizing NMBAs might originate from an interaction with neuronal nAChRs. The aim of this study was to examine the effect of clinically used nondepolarizing NMBAs on muscle and neuronal nAChR subtypes.

Methods: Xenopus laevis oocytes were injected with messenger RNA encoding for the subunits included in the human [alpha]1[beta]1[varepsilon][delta], [alpha]3[beta]2, [alpha]3[beta]4, [alpha]4[beta]2, and [alpha]7 nAChR subtypes. The interactions between each of these nAChR subtypes and atracurium, cisatracurium, d-tubocurarine, mivacurium, pancuronium, rocuronium, and vecuronium were studied using an eight-channel two-electrode voltage clamp setup. Responses were measured as peak current and net charge.

Results: All nondepolarizing NMBAs inhibited both muscle and neuronal nAChRs. The neuronal nAChRs were reversibly and concentration-dependently inhibited in the low micromolar range. The mechanism (i.e., competitive vs. noncompetitive) of the block at the neuronal nAChRs was dependent both on subtype and the NMBA tested. The authors did not observe activation of the nAChR subtypes by any of the NMBAs tested.     

Ethanol-induced inhibition of testosterone biosynthesis in rat Leydig cells: role of mitochondrial substrate shuttles and citrate

The mechanisms by which ethanol inhibits testicular testosterone synthesis in rats were studied in vitro using isolated rat Leydig cells. The ethanol-induced inhibition was reversed by 4-methylpyrazole, an alcohol dehydrogenase inhibitor, suggesting that ethanol metabolism was responsible for this inhibition. L-glutamate and pyruvate, when added to the Krebs-Ringer incubation medium, reversed the inhibition by ethanol. The membrane glutamate receptor agonists kainic acid and quisqualic acid had no effects, indicating metabolic mechanisms for the L-glutamate action. This was verified also by observations that the metabolic transaminase inhibitors aminooxyacetate and cycloserine inhibited testosterone synthesis. In the amino acid supplemented Krebs-Ringer, pyruvate could not fully prevent inhibition by ethanol alone, but addition of L-glutamate to this medium abolished ethanol-induced inhibition. Experiments performed using a new inhibitor of testosterone biosynthesis in intact Leydig cells, triethylcitrate, indicated that active citrate metabolism, and/or efflux from mitochondria, was essential for the steroidogenic pathway from pregnenolone to testosterone in the smooth endoplasmic reticulum. The early steps of hCG stimulation before pregnenolone formation were most sensitive to its effect. Our results indicate that the inhibition of steroidogenesis by ethanol results from decreased availability of the metabolites involved in the substrate shuttles maintaining the NAD(P)H redox states between the mitochondrial and the smooth endoplasmic reticulum compartments, and that the inhibition can be overcome by a proper selection of exogenous sources for these metabolites.     

Development of the histaminergic neurons and expression of histidine decarboxylase mRNA in the zebrafish brain in the absence of all peripheral histaminergic systems

The histamine-storing neural system in adult and developing zebrafish (Danio rerio) was studied with immunocytochemical and chromatographical methods. Furthermore, the gene for histidine decarboxylase was partially cloned and its expression mapped with in situ hybridization. The histamine-storing neurons were only seen in the caudal hypothalamus, around the posterior recess of the diencephalic ventricle. Almost all parts of the brain, except the cerebellum, contained at least some histamine-immunoreactive fibres. The ascending projections had the rostral part of the dorsal telencephalon as a major target. Descending projections terminated in the torus semicircularis, central grey and inferior olive. A prominent innervation of the optic tectum, which has not been reported in other fish, was seen. The in situ hybridization gave a strong signal in cells with the same anatomical position as the histamine-immunoreactive neurons. The first histamine-immunoreactive neurons appeared in the ventral hypothalamus at about 85 h post-fertilization, and at 90 h, immunoreactive fibres terminated in the dorsal telencephalon. The embryonic histamine production described in mammals was lacking in this species. Both immunocytochemical and chromatographical studies indicated that histamine is absent in all other parts of the zebrafish body, and no specific hybridization was seen in any other part of the fish than the hypothalamus. The zebrafish could therefore be a very useful model for pharmacological in vivo studies of the histaminergic system of the brain, since the powerful peripheral actions of histamine should be lacking in this species.