Mechanism-based inactivation of CYP2D6 by 5-fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine.

SCH 66712 [5-fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine] caused a time- and NADPH-dependent loss of CYP2D6 activity. The inactivation of human liver (HL) microsomal dextromethorphan O-demethylase activity, a prototype marker for CYP2D6, was characterized by a K(I) of 4.8 microM and a maximal rate constant of inactivation (k(inact)) of 0.14 min(-1). The inactivation of the recombinant CYP2D6 in Supersomes (r-CYP2D6) was characterized by a K(I) of 0.55 microM and a k(inact) of 0.32 min(-1). Extensive dialysis of the SCH 66712-inhibited enzyme failed to restore the activity to control levels (dialyzed reaction mixture lacking SCH 66712) for both HL microsomes and r-CYP2D6. Addition of glutathione, superoxide dismutase, or mannitol to the reaction mixture failed to protect CYP2D6 against SCH 66712-NADPH-catalyzed inactivation. Addition of quinidine, a reversible inhibitor of CYP2D6, to a preincubation mixture consisting of SCH 66712, HL microsomes, or Supersomes and NADPH partially protected CYP2D6 from inactivation. SCH 66712 also inhibited HL microsomal CYP3A4, CYP2C9, and CYP2C19; however, the concentrations required to inhibit those isoforms were 5- to 10-fold higher than those required to inhibit CYP2D6. These results demonstrate that SCH 66712 is a potent and fairly selective mechanism-based inhibitor of CYP2D6.

Nail involvement in pemphigus vulgaris.

Nail involvement in pemphigus vulgaris is relatively rare. We describe a case of severe pemphigus involving both the skin and oral mucosa in which an acute exacerbation was preceded by the onset of nail involvement of all 4 extremities. Nail involvement occurred in the form of hemorrhagic paronychia of multiple digits. Oral, cutaneous, and nail manifestations of the disease were all well controlled by systemic therapy. A review of the literature on nail involvement in pemphigus reveals that this involvement may be manifested in multiple ways, with chronic paronychia and onychomadesis being the most common. Involvement of the nail occurs most frequently either as part of the initial presentation, or just before or concurrent with a flare of pre-existing disease. Nail involvement, when it occurs, is usually present when the disease is severe. Topical therapy is insufficient, and systemic therapy is warranted. In the majority of cases, nail recovery is complete, with no residual damage.

A role for TNF in bone resorption of deciduous molars in human beings.

In this study, tumor necrosis-alpha was sampled from the gingival crevice of human deciduous molars; this was compared with values measured from the crevice of those deciduous molars missing a permanent successor, and from the crevice of deciduous ankylosed molars. Tumor necrosis-alpha was harvested from the gingival crevice with magnetic microspheres coated with tumor necrosis-alpha antibodies. The amount of bead-bound tumor necrosis-alpha was quantified with the use of an enzyme-linked immunosorbent assay. One hundred seven sites (from 41 patients) were sampled; for each patient, the normal value was compared with either the molars missing a permanent successor or ankylosed value. The tumor necrosis-alpha levels were 1.6 times higher from the crevice of ankylosed deciduous molars when compared with normal deciduous molars and 2.6 times higher from the crevice of sites with a molar missing a permanent successor. The mean and standard error mean distribution of tumor necrosis-alpha expressed as picograms was: normal molars 91 pg (standard error mean +/- 20), ankylosed molars 150 pg (standard error mean +/- 31), and missing permanent successor 236 pg (standard error mean +/- 67). Analysis of variance showed the difference among the 3 means was close to attaining significant difference (F [2.104] = 2.7905, P =.066). Multiple comparison procedures indicated that the mean for molars missing a permanent successor and the normal groups were significantly different, P =.05. The results of this study suggest tumor necrosis-alpha values are elevated in the gingival crevice of deciduous molars with ankylosis and where the permanent tooth bud is congenitally missing.

History of the Atlantic Dermatological Conference: the first 75 years.

On May 1, 1998, the 75th meeting of the Atlantic Dermatological Conference was held in New York City. The following presents the origin, development, and sustaining aspects of this treasured annual educational conference. The enthusiasm and participation of a record number of attendees is a testimony for the continued need for this type of postgraduate education with live patient presentation.

Orthodontic and temporomandibular joint considerations in treatment of patients with Ehlers-Danlos syndrome.

The gross clinical manifestations, the classifications of the syndrome, and a summary of the pathophysiology are presented. Dental manifestations are described with an emphasis on the orthodontic and temporomandibular joint problems found in the disease. Finally, there are short clinical reports of orthodontic and surgical temporomandibular joint treatments.

Continuous mechanical loading alters properties of mechanosensitive channels in G292 osteoblastic cells.

G292 osteoblastic cells were cultured in dishes made with a flexible base of polytetrafluoroethylene (PTFE) and stretched ( approximately 1% strain level) continuously for 48 hours. Patch-clamp recording techniques were then used to monitor single channel currents of mechanosensitive ion channels in these cells. To stimulate mechanosensitive channels, we applied suction to the membrane, expressed as -cm Hg, directly through the patch pipette. GigaOhm seals were obtained on a total of 33 osteoblasts that contained a high-conductance ( approximately 180 pS) mechanosensitive channel, all in the cell attached configuration. Of these, 18 were obtained from cells that had been stretched for either 1 (n = 6), 24 (n = 4), or 48 (n = 8) hours, and 15 were obtained in control (nonstretched) cells at either 1 (n = 2), 24 (n = 5), or 48 (n = 8) hours. For unstrained cells, applied pressures ranging from -1 to -5 cm Hg increased the probability of channel opening (Popen) from 0.05 +/- 0. 01 (mean + SEM) to 0.12 +/- 0.07. By contrast, for the same values of applied pressure in stretched cells, Popen ranged from 0.06 +/- 0. 01 to 0.49 +/- 0.15. Our results suggest that intrinsic properties of mechanosensitive ion channels in the G292 osteoblastic cell may be modulated by continuous mechanical loading of the cell itself.

Evaluation of the American Academy of Dermatology's National Skin Cancer Early Detection and Screening Program.

BACKGROUND: Increasing incidence and mortality rates from cutaneous melanoma are a major public health concern. As part of a national effort to enhance early detection of melanoma/skin cancer, the American Academy of Dermatology (AAD) has sponsored an annual education and early detection program that couples provision of skin cancer information to the general public with almost 750,000 free skin cancer examinations (1985-1994). OBJECTIVE: To begin to evaluate the impact of this effort, we determined the final pathology diagnosis of persons attending the 1992-1994 programs who had a suspected melanoma at the time of examination. METHODS: We directly contacted all such persons by telephone or mail and received pathology reports from those who had a subsequent biopsy. RESULTS: We contacted 96% of the 4458 persons with such lesions among the 282,555 screenings in the 1992-1994 programs. We obtained a final diagnosis for 72%, and the positive predictive value for melanoma was 17%. Three hundred seventy-one melanomas were found in 364 persons. More than 98% had localized disease. More than 90% of the confirmed melanomas with known histology were in situ or "thin" lesions (< or = 1.50 mm thick). The median thickness of all melanomas was 0.30 mm. The 8.3% of AAD cases with advanced melanoma (metastatic disease, regional disease, or lesions > or = 1.51 mm) is a lower proportion than that reported by the 1990 Surveillance, Epidemiology and End Result Registry. The rate of thickest lesions (> or = 4 mm) and late-stage melanomas among all participants was 2.83 per 100,000 population. Of persons with a confirmed melanoma, 39% indicated (before their examination) that without the free program, they would not have considered having a physician examine their skin. CONCLUSION: The 1992-1994 free AAD programs disseminated broad skin cancer educational messages, enabled thousands to obtain a free expert skin cancer examination, and found mostly thin, localized stage 1 melanomas (usually associated with a high projected 5-year survival rate). Because biases impose possible limitations, future studies with long-term follow-up and formal control groups should determine the impact of early detection programs on melanoma mortality.

Orthodontic forces increase tumor necrosis factor alpha in the human gingival sulcus.

The production of cytokines has been associated with the biology of tooth movement in animal populations. The purpose of this study was to measure tumor necrosis factor-alpha (TNF) directly in the human gingival sulcus before and after the application of an orthodontic force. To recover TNF from the sulcus, paramagnetic beads, coated with monoclonal antibodies for TNF, were introduced into the gingival sulcus of 50 teeth undergoing orthodontic tooth movement (by two force systems) in 20 patients. Retrieval was performed by a permanent magnetic device designed to fit the periodontal sulcus. The samples were taken before force application (controls), and at a fixed time after force application. The amount of immunoabsorbed TNF was quantified with an immunochemical assay. There was a greater than twofold increase in TNF recoverable from the gingival sulcus after application of orthodontic forces (mean of 12.9 ng vs 30.5 ng). A Student's t test for paired samples demonstrated statistical significance at p < 0.01. We conclude that the quantity of paradental TNF, found in human gingival sulcus, is elevated during tooth movement. The source may be from the adjacent gingiva, but more likely the compressed periodontal ligament and the resorbing bone adjacent to the root surface.

A methodical study of shape changes in human oral cells perturbed by a simulated orthodontic strain in vitro.

Cells are known to alter their shape as a response to physical and chemical changes. Mechanical loads applied to teeth produced cellular perturbations resulting in orthodontic movement. An in vitro model was developed to simulate the in vivo strain of orthodontic movement. Calibrated forces were applied to human periodontal ligament cells and buccal mucosal fibroblasts (controls). A biaxial strain-producing device was used to stretch vital cells growth on flexible polytetrafluorethylene membranes. In addition, a new cell adhesive, Cell Tak, was employed to examine the effect of an adhesive substrate on the cellular response to two known loads. The shape changes of unstrained (control) and strained cells were evaluated by time-lapse telemicroscopy, and plots of time-dependent alterations in area and shape were recorded. The fusiform cells became more rounded over a given time of up to 1400 s. The responses appeared to be independent of cell type, the strain employed, and the presence of cell adhesive. Scanning electron microscopy demonstrated, irrespective of cell type, that the surface of stressed cells produced a striking number of microvilli as compared with the relatively smooth-surfaced controls.

Uprighting impacted second molars with segmented springs.

Severe impaction of lower second molars often leads to their extraction to avoid potential damage to the first molar root. We present a case in which we used the clinical application of simple biomechanical principles to allow us to upright bilaterally impacted lower second molars into the desired location in a fairly short time.

The spectrum of nail disease in patients with human immunodeficiency virus infection.

There are no known pathognomonic nail signs of human immunodeficiency virus (HIV) infection. However, several presentations should increase the index of suspicion. (1) Proximal white subungual onychomycosis or superficial white onychomycosis, especially of the fingernails, is present. Trichophyton rubrum appears to cause both most commonly in HIV-infected patients. Periungual dermatophyte involvement and involvement of all 10 fingernails is unusual in non-HIV-infected persons. (2) Candida is a primary pathogen of the nail bed and nail plate especially if many nails are involved. (3) A destructive, almost granulomatous-like psoriatic involvement of the nails is present. (4) Squamous cell carcinoma of the nail bed in a young adult. There are no clinical trails to confirm the efficacy of therapy mentioned in this article. The treatment suggestions are empirical and are the personal views of the authors.

Orthodontic treatment and temporomandibular joint disorders.

The overall objective of this project was to study the relationship between orthodontic treatment and temporomandibular joint (TMJ) disorders. This relationship has been and remains an important and complex issue in orthodontics. The objectives of the study were to determine the incidence of TMJ pain and dysfunction in a group of orthodontic patients who were symptom-free on entering treatment, and to assess and characterize the level of pain and dysfunction in patients with symptoms, and track changes in these parameters during the course of orthodontic treatment. Standardized functional indices and physical measurements were used to describe and assess TMJ pain and dysfunction. The results of this study showed that of 451 patients without symptoms undergoing treatment at our university clinic during the 18-month project, no patient developed signs and symptoms of TMJ disorders during that time. In addition, for the 11 patients who presented with signs and symptoms of TMJ disorders at the time of their entry into the treatment program, no clear or consistent changes in levels of pain and dysfunction occurred longitudinally during the treatment period followed in this study. On the basis of these findings, a relationship between either the onset of TMJ pain and dysfunction and the course of orthodontic treatment or the change in TMJ pain and dysfunction and the course of orthodontic treatment could not be established in this particular patient population.

Common and uncommon reactions to formaldehyde-containing nail hardeners.

A spectrum of reactions to free formaldehyde containing nail hardeners is presented. These include inflammatory and noninflammatory onycholysis, paronychia, chromonychia, nail plate shedding, and pterygium inversum unguis as well as satellite reactions on the skin and mucous membranes. Primary irritants are more common than allergic reactions. Nail cosmetic products containing free formaldehyde are available to the consumer, but federal guidelines dictate their labeling, acceptable concentration, and usage.

A device for the application of known simulated orthodontic forces to human cells in vitro.

Connective tissues are responsive to mechanical forces. In orthodontic tooth movement it appears that the periodontal ligament (PDL) is the source of a pleuropotential cell population and extracellular matrix structure which translates mechanical perturbation information into a host of cellular events. These include proliferation, repair, differentiation, and shape change. We have designed, built, and tested a simple, adaptable machine which enables us to examine molecular changes or events in the cell nucleus, cell membrane, and the cytoskeleton of any eukasytic cell that will adhere to a membrane. These responses to clinically simulated forces applied to an in vitro system can be measured.

Attachment of epiphyseal cartilage cells and 17/28 rat osteosarcoma osteoblasts using mussel adhesive protein.

These experiments show that mussel adhesive protein (MAP) enhances the attachment of osteoblasts and epiphyseal cartilage cells to plastic culture dishes and Vitallium. When MAP was applied to culture plate surfaces, there were two- to fivefold increases in the numbers of cells attaching compared to control surfaces (no MAP). Results were confirmed using two different cell attachment assay techniques. Osteoblast replication and culture on MAP is possible, suggesting that MAP is not toxic to cells. MAP also holds applied cells to surfaces as initially attached.

Buccal mucosa fibroblasts and periodontal ligament cells perturbed by tensile stimuli in vitro.

Human buccal mucosa fibroblasts and periodontal ligament cells grown in tissue culture were subjected to tensile forces approximating those used for orthodontic bodily tooth movement. The cells were synchronized into pre S phase and positively tested for response to nonmechanical physical stimuli. Two-dimensional gel analysis and immunohistochemical analysis of the three cytoskeletal components showed a lack of response. Similar negative results were found when the cells were perturbed in the presence of substance P. We hypothesize that perhaps these cells respond more readily to injury, a secondary effect of the forces of tooth movement, than to tensile forces.

The effect of aging cellular mechanisms on tooth movement.

In summary, there appears to be indirect evidence that the dentoalveolar system undergoes a number of changes with age. These changes have the potential of affecting the biologic response of these tissues to the forces of tooth movement. They should not, however, create a barrier toward the successful completion of orthodontic therapy in most cases.

Calcium incorporation in cultured chondroblasts perturbed by an electromagnetic field.

We tested the hypothesis that electric perturbation influences 45Ca incorporation in extracellular matrix (ECM) of cartilage in vitro. Hypertrophic chondroblasts of tibial epiphyses (HC), sternum (SC), and skin fibroblasts (F) were cultured from chick embryos. HC, SC, and F cells were micromass seeded three times per week and maintained at 37.5 degrees C with 5% CO2 for two weeks. Cultures were randomly designated control (C) or exposed (E) to a pulsed electromagnetic field (PEMF). A time course experiment of calcium incorporation for all cultured groups showed that 24 h of exposure produced the largest biological response in chondroblasts. Calcium incorporation required supplemental phosphate. Autoradiography data indicated that the calcium incorporation into macromolecules largely occurred in the ECM. 45Ca steady-state perturbation was enhanced by Streptomyces hyaluronidase (SH) but not by testicular hyaluronidase (TH). 45Ca incorporation experiments tested the effects of phosphate, SH, TH, and PEMF alone and in various combinations on these cultures. Only PEMF or SH plus PEMF with phosphate enhanced 45Ca incorporation. Other experiments examined the effect of rotenone or freeze-thawing on cells exposed to PEMF. PEMF plus freeze-thaw enhanced calcium incorporation in HC only. PEMF appeared to cause disruption of the ECM, enhancing the probability of matrix calcification.