Preparedness and competency of New Zealand graduates for general dental practice - perceptions from the workforce.

BACKGROUND: Dental graduates need to demonstrate clinical competency. This mixed-methods study explored the perceptions of clinicians who employ or work with new graduates from the University of Otago, New Zealand, and identified themes reflecting graduates' preparedness for independent practice. METHODS: An online survey using a semantic differential scale and open-ended questions collected opinions and experiences from the workforce. Quantitative data were analysed using SPSS software, and qualitative data were analysed thematically. RESULTS: A representative sample of the workforce was obtained with a response rate of 35% (N = 83). Most clinicians engage new graduates to support the profession and/or rural communities. They perceived that graduates were well prepared in most areas, could translate theory to clinical practice and demonstrate professionalism. Graduates were reportedly stronger in basic dentistry, communication, ethics, and record keeping however were less strong in complex treatment planning, molar endodontics, fixed prosthodontics and exodontia. Clinical exposure during dental training was perceived as more limited, and mentoring and guidance in the transition to practice were deemed to be important. CONCLUSIONS: New Zealand dental graduates appear prepared for independent practice; however, maximising clinical opportunities during training, mentoring and early professional development in advanced areas of practice is essential to enhance competency and confidence.

Storage-related stability and antimicrobial efficacy of bottled, neutral-pH Electrolysed Oxidising Water.

OBJECTIVES: Denture stomatitis is prevalent in older people and poses serious health risks. Ready-to-use (RTU) neutral-pH Electrolysed Oxidizing Water (EOW) is an effective environmental disinfectant used in residential care settings and geriatric wards. However, the influence of storage on stability and effectiveness for denture disinfection has not been established. This research investigated the storage-related stability and antimicrobial activity of RTU EOW, and its efficacy against Candida albicans biofilms formed on denture resin. METHODS: The pH, oxidation/reduction potential (mV), available chlorine content (mg/L) and [HOCl] (mM) of RTU EOW (Envirolyte, New Zealand) solutions (n = 22) were measured from bottle opening to 28 days following storage at 4 °C, room temperature (RT) or 37 °C. Staphylococcus aureus and C. albicans cells were incubated in 80% EOW for contact times (CTs) up to 15 min and colony-forming units (cfu) determined. Minimum inhibitory concentrations (MIC90 EOW-HOCl) after CTs up to five minutes were determined for S. aureus and C. albicans reference strains and clinical isolates. C. albicans-denture resin disc biofilms were assessed after a five-minute CT with undiluted EOW by XTT-metabolic activity assay. RESULTS: [HOCl] remained stable when RTU EOW was stored at 4 °C or RT for five months after manufacture. One-minute CT resulted in log10 cfu reductions of >6 for S. aureus and >5 for C. albicans. Mean MIC90 for five-minute CT was 37 µM (S. aureus) and 54 µM (C. albicans). Undiluted EOW reduced C. albicans biofilm metabolic activity by 86%. CONCLUSIONS: RTU neutral-pH EOW is stable over five-months storage and is an effective denture disinfectant. CLINICAL SIGNIFICANCE: The efficacy of the RTU neutral EOW against C. albicans isolates and biofilms formed on denture resin surfaces supports its use as a denture disinfectant and can inform future research to assess its potential for preventing denture-related oral Candida infections in the older population, especially in resource-limited communities.

Examining the relationship between measures of autistic traits and neural synchrony during movies in children with and without autism.

Children who have been diagnosed with autism spectrum disorder (ASD) often show a marked deficit in measures of social cognition. In autistic adults, measures of social cognition have been shown to relate to differences in brain synchronization (as measured by fMRI) when individuals are processing naturalistic stimuli, such as movies. However, whether children who differ in their degree of autistic traits, with or without a diagnosis of ASD, differ in their neural responses to movies has not yet been investigated. In the current study, neural synchrony, measured using fMRI, was examined in three groups of children aged 7 to 12, who differed with respect to scores on a measure of autistic traits associated with social impairment and whether or not they had been diagnosed with ASD. While watching the movie 'Despicable Me', those diagnosed with ASD had significantly less neural synchrony in areas that have been previously shown to be associated with social cognition (e.g. areas related to 'theory of mind'), and plot following (e.g. the lateral prefrontal cortex), than those who did not have an ASD diagnosis. In contrast, two groups who differed in their degree of autistic traits, but did not have a diagnosis of ASD, showed no significant differences in neural synchrony across the whole brain. These results shed some light on how autistic traits may contribute to an individual's conscious experience of the world, and how, for children with ASD, that experience may differ markedly from that of those without ASD.

Antimicrobial Activity of a Colloidal AgNP Suspension Demonstrated In Vitro against Monoculture Biofilms: Toward a Novel Tooth Disinfectant for Treating Dental Caries.

A novel silver nanoparticle (AgNP) formulation was developed as a targeted application for the disinfection of carious dentine. Silver nitrate (AgNO3) was chemically reduced using sodium borohydrate (NaBH4) in the presence of sodium dodecyl sulfate (SDS) to form micelle aggregate structures containing monodisperse 6.7- to 9.2-nm stabilized AgNPs. AgNPs were characterized by measurement of electrical conductivity and dynamic light scattering, scanning electron microscopy, transmission electron microscopy, and inductively coupled plasma mass spectrometry. Antimicrobial activity of AgNPs was tested against planktonic cultures of representative gram-positive and gram-negative oral bacteria using well diffusion assays on tryptic soy broth media and monoculture biofilms grown with brain heart infusion ± sucrose anaerobically at 37°C on microtiter plates. Biofilm mass was measured by crystal violet assay. Effects were compared to silver diamine fluoride and chlorhexidine (negative controls) and 70% isopropanol (positive control) exposed cultures. In the presence of AgNPs, triplicate testing against Streptococcus gordonii DL1, C219, G102, and ATCC10558 strains; Streptococcus mutans UA159; Streptococcus mitis I18; and Enterococcus faecalis JH22 for planktonic bacteria, the minimum inhibitory concentrations were as low as 7.6 µg mL-1 and the minimum bacteriocidal concentrations as low as 19.2 µg mL-1 silver concentration. Microplate readings detecting crystal violet light absorption at 590 nm showed statistically significant differences between AgNP-exposed biofilms and where no antimicrobial agents were used. The presence of sucrose did not influence the sensitivity of any of the bacteria. By preventing in vitro biofilm formation for several Streptococcus spp. and E. faecalis, this AgNP formulation demonstrates potential for clinical application inhibiting biofilms.

Performance of the Index of Dental Anxiety and Fear in a population-based sample of adults.

BACKGROUND: The Index of Dental Anxiety and Fear (IDAF-4C) was introduced to overcome the theoretical and practical shortcomings of previously developed dental fear measures. This new scale has not been tested on population samples other than in its country of origin, Australia. The aim of this study was to validate the IDAF-4C in a different cultural setting and to determine the prevalence and sociodemographic associations of dental anxiety. METHODS: A cross sectional study of a representative New Zealand adult population sample was undertaken. The questionnaire was mailed to 523 randomly-selected participants. Data were collected on sociodemographic characteristics, oral and general health care, and dental anxiety using both the IDAF-4C and the Dental Anxiety Scale (DAS). RESULTS: The response rate was 51.8%. The factor structure of the IDAF-4C was confirmed. The prevalence estimates for high dental anxiety and fear were 18.6% using the DAS and 13.0% using the IDAF-4C. Mean scores for the IDAF-4C and DAS were higher among episodic dental visitors and those without a recent dental visit. CONCLUSIONS: The performance of the IDAF-4C in this New Zealand community sample supports its use for dental anxiety measurement.

Low-intensity pulsed ultrasound (LIPUS) treatment of cultured chondrocytes stimulates production of CCN family protein 2 (CCN2), a protein involved in the regeneration of articular cartilage: mechanism underlying this stimulation.

OBJECTIVE: CCN family protein 2/connective tissue growth factor (CCN2/CTGF) promotes cartilage regeneration in experimental osteoarthritis (OA) models. However, CCN2 production is very low in articular cartilage. The aim of this study was to investigate whether or not CCN2 was promoted by cultured chondrocytes treated with low-intensity pulsed ultrasound (LIPUS) and to clarify its mechanism. METHODS: Human chondrocytic cell line (HCS)-2/8, rat primary epiphyseal and articular cartilage cells, and Ccn2-deficient chondrocytes that impaired chondrocyte differentiation, were treated with LIPUS for 20 min at 3.0 MHz frequency and 60 mW/cm2 power. Expressions of chondrocyte differentiation marker mRNAs were examined by real-time PCR (RT-PCR) analysis from HCS-2/8 cells and Ccn2-deficient chondrocytes at 30 min and 1 h after LIPUS treatment, respectively. CCN2 production was examined by Western blotting after 5 h of LIPUS treatment. Moreover, Ca2+ influx was measured by using a Fluo-4 probe. RESULTS: The gene expression of chondrocyte differentiation markers and CCN2 production were increased in cultured chondrocytes treated with LIPUS. In addition, Ca2+ influx and phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)1/2 were increased by LIPUS treatment, and the stability of TRPV4 and BKca channel mRNAs was decreased by siRNA against CCN2. Consistent with those findings, the LIPUS-induced the gene expressions of type II collagen (COL2a1) and Aggrecan (ACAN) observed in wild-type cells were not observed in the Ccn2-deficient chondrocytes. CONCLUSION: These data indicate that chondrocyte differentiation represented by CCN2 production was mediated via MAPK pathways activated by LIPUS-stimulated Ca2+ influx, which in turn was supported by the induced CCN2 molecules in articular chondrocytes.

Connective tissue growth factor (CTGF/CCN2) in haemophilic arthropathy and arthrofibrosis: a histological analysis.

INTRODUCTION: Joint haemorrhage is the principal clinical manifestation of haemophilia frequently leading to advanced arthropathy and arthrofibrosis, resulting in severe disability. The degree and prevalence of arthrofibrosis in hemophilic arthropathy is more severe than in other forms of arthropathy. Expression of connective tissue growth factor (CTGF) has been linked to many fibrotic diseases, but has not been studied in the context of haemophilic arthropathy. AIM: We aim to compare synovial tissues histologically from haemophilia and osteoarthritis patients with advanced arthropathy in order to compare expression of proteins that are possibly aetiologic in the development of arthrofibrosis. METHODS: Human synovial tissues were obtained from 10 haemophilia and 10 osteoarthritis patients undergoing joint surgery and processed for histology and immunohistochemistry. RESULTS: All samples from haemophilia patients had synovitis with hypertrophy and hyperplasia of synovial villi. Histologically, synovial tissues contained hyperplastic villi with increased cellularity and abundant haemosiderin- and ferritin-pigmented macrophage-like cells (HMCs), with a perivascular localization in the sub-surface layer. CTGF staining was observed in the surface layer and sub-surface layer in all haemophilia patients, exclusively co-localizing with HMCs. Quantification showed that the extent of CTGF-positive areas was correlated with the degree of detection of HMCs. CTGF was not observed in any of the samples from osteoarthritis patients. CONCLUSION: Using histological analysis, we showed that CTGF expression is elevated in haemophilia patients with arthrofibrosis and absent in patients with osteoarthritis. Additionally, we found that CTGF is always associated with haemosiderin-pigmented macrophage-like cells, which suggests that CTGF is produced by synovial A cells following the uptake of blood breakdown products.

Intraoral pH and temperature during sleep with and without mouth breathing.

To measure and compare the intraoral pH and temperature of individuals during sleep with and without mouth breathing. Ten healthy participants [mean age = 25·8 (± 4·3)] wore a custom-made appliance fitted with a pH probe and thermocouple for two sets of 48 h. Continuous pH and temperature measurements were taken from the palatal aspect of the upper central incisors. To simulate mouth breathing during sleep, participants wore a nose clip for two nights of the four, with the first group (n = 5) wearing the nose clip during the first night and the rest (n = 5) wearing the nose clip during the second night of sleep to balance any potential bias from the wearing sequence. Both qualitative and quantitative analyses were conducted. The mean intraoral pH during daytime was 7·3 (± 0·4) and during sleep was 7·0 (± 0·5). The mean intraoral pH during sleep with mouth breathing was 6·6 (± 0·5), which was statistically significant compared with the normal sleep condition (P < 0·01). The intraoral pH decreased slowly over the hours of sleep in all participants. When sleeping with forced mouth breathing, intraoral pH showed a greater fall over a longer period of time. The mean intraoral temperature was 33·1 °C (± 5·2) during daytime and 33·3 °C (± 6·1) during sleep, with no statistical significance between sleep with and without mouth breathing (P > 0·05). The results suggest that mouth breathing during sleep is related to a decrease in intraoral pH compared with normal breathing during sleep, and this has been proposed as a causal factor for dental erosion and caries.

Continuous measurement of intra-oral pH and temperature: development, validation of an appliance and a pilot study.

To describe a novel approach for continuous measurement of intra-oral pH and temperature in individuals carrying out normal daily activities over 24 h. We designed, validated and constructed a custom-made appliance fitted with a pH probe and a thermocouple. Six subjects wore the appliance over a 24-h period for two non-consecutive days, while the intra-oral pH and temperature were measured continuously and recorded. Intra-oral pH and temperature were very similar across different recording days, the difference being not statistically significant (P ≥ 0.14). There was a noticeable difference in the pattern of variation of pH between day and night. During the day, the mean pH was 7.3 (±0.4) and dropped markedly only after consumption of acidic food and drinks. The intra-oral pH decreased slowly during sleep with an average pH of 6.6 (±0.4) being recorded. The difference between day and night was statistically significant (P = 0.002). The mean intra-oral temperature was 33.9 °C (±0.9) during daytime and 35·9 °C (±0·5) during sleep (P = 0.013) with minor fluctuations occurring over 24 h. The continuous and simultaneous intra-oral pH and temperature measurement system described in this report is reliable, easy to construct, able to measure variables over a sustained period and may serve as a future diagnostic tool in a number of applications.

Adherence of Candida albicans to silicone is promoted by the human salivary protein SPLUNC2/PSP/BPIFA2.

Interactions between Candida albicans, saliva and saliva-coated oral surfaces are initial events in the colonization of the oral cavity by this commensal yeast, which can cause oral diseases such as candidiasis and denture stomatitis. Candida albicans also colonizes silicone voice prostheses, and the microbial biofilm formed can impair valve function, necessitating frequent prosthesis replacement. We have previously shown that saliva promoted binding of C. albicans cells to silicone in vitro, and that the selective binding of specific salivary proteins to voice prosthesis silicone mediated attachment of C. albicans cells. The C. albicans cells adhered to a polypeptide (or polypeptides) of ~36 kDa eluted from saliva-treated silicone. We show here that a protein of similar size was identified in replicate blots of the eluate from saliva-treated silicone when the blots were probed with antibodies to human SPLUNC2, a salivary protein with reported microbial agglutination properties. In addition, SPLUNC2 was depleted from saliva that had been incubated with silicone coupons. To determine whether SPLUNC2 is a yeast-binding protein, SPLUNC2 cDNA was expressed in Escherichia coli. Purified recombinant His-tagged protein (SPLUNC2r) bound to silicone as demonstrated by immunoblot analysis of an eluate from SPLUNC2r-treated silicone coupons and (35) S-radiolabelled C. albicans cells adhered in a dose-dependent manner to SPLUNC2r-coated silicone. We conclude that SPLUNC2 binds to silicone and acts as a receptor for C. albicans adherence to, and subsequent colonization of, voice prosthesis silicone.

Abutment load transfer by removable partial denture obturator frameworks in different acquired maxillary defects.

STATEMENT OF PROBLEM: Excessive stress on abutment teeth adjacent to a maxillary resection defect during loading of partial denture obturator frameworks may shorten the life of the teeth. PURPOSE: The aim of this study was to photoelastically compare the forces exerted on the supporting structures of abutment teeth in 3 differently sized surgical resections with removable partial denture designs used to restore such maxillectomy defects. MATERIAL AND METHODS: Composite photoelastic models were constructed of a human maxilla that had undergone each of 3 maxillectomies: partial, radical, and radical involving the contralateral premaxilla. The abutment teeth included all remaining anterior teeth, the first premolar, and second molar, except the radical maxillectomy, which included the contralateral premaxilla where all remaining teeth were used as abutment teeth. All abutment teeth were restored with complete metal crowns, and removable partial denture frameworks were fabricated. Loading zones were selected according to the resection, and a 10-lb load was applied at each load point. The resulting stresses were observed and recorded photographically in a circular polariscope. The 2 teeth adjacent to the resection were then splinted, and the loading regimens were repeated. RESULTS: Without splinting, loads closer to the defect produced lingual tipping of the teeth adjacent to the resection and a mesial tipping tendency of the second molar. The tipping effects were greatest in the model with the largest resection. Splinting reduced tipping of the teeth adjacent to the resection and produced more uniform stress around these 2 abutment tooth roots for all of the models. CONCLUSION: The results of this in vitro study suggest that splinting the 2 teeth adjacent to a resection defect improves stress distribution around the roots during loading. This could increase the clinical life of the abutment teeth.

An in-vitro investigation of the antibacterial effect of nisin in root canals and canal wall radicular dentine.

AIM: To determine whether nisin, a bacteriocin, would be effective at killing Enterococcus faecalis and Streptococcus gordonii cells in solution and within the root canal system. METHODOLOGY: Bacterial isolates of E. faecalis and S. gordonii were grown from glycerol stocks in closed tubes containing BHY broth at 37 degrees C. The minimum bactericidal concentration (MBC) of nisin for both bacterial species was determined by a microdilution method. Extracted human teeth were decoronated to produce roots of equal length with a single canal and divided into six groups of 10 roots. The canals were prepared to a master apical size 30 file using 0.04 taper Ni-Ti rotary instruments. Bacterial samples of each species were inoculated into three groups of prepared roots and incubated in closed tubes at 37 degrees C for 21 days. The root canals in each group were then medicated with water (control), calcium hydroxide powder mixed with sterile water [Ca(OH)2], or nisin and incubated for a further 7 days. Rotary Ni-Ti files were used to take radicular dentine samples from the walls of each canal which were then incubated in BHY broth for 24 h. Optical density (OD600) readings were taken as a measure of bacterial growth. RESULTS: The MBC of nisin for E. faecalis and S. gordonii was 70 and 20 mg mL(-1) respectively. Calcium hydroxide and nisin medication eradicated infection within the root canal while cells remained viable in the control group. Mean optical density (OD600) readings from canal wall dentine shavings infected with E. faecalis were 1.32 +/- 0.98, 0.73 +/- 0.27 and 0.69 +/- 0.38 for the control, Ca(OH)2 and nisin samples respectively. Corresponding mean readings for S. gordonii were 1.19 +/- 0.18, 0.73 +/- 0.15 and 0.60 +/- 0.29. The Ca(OH)2 and nisin group readings were significantly (P < 0.01) lower than the control for each species as tested by Student's t-test and Mann-Whitney U statistical analysis. Values for Ca(OH)2 and nisin were not significantly (P > 0.01) different. CONCLUSION: Nisin was effective at eradicating E. faecalis and S. gordonii cells in pure culture and was comparable with Ca(OH)2 in the elimination of these species from within the root canal system.

Vocal fold mucosal tears: maintaining a high clinical index of suspicion.

Vocal fold mucosal tears have been discussed in the literature rarely, although they are not uncommon clinically. Disruptions in the epithelium usually follow trauma that may result from voice abuse and/or misuse, coughing, and other causes. A high index of suspicion is necessary to avoid missing vocal fold mucosal tears, and strobovideolaryngoscopy is indispensable in making the diagnosis. A brief period of complete voice rest is the standard of care and appears to be helpful in avoiding adverse sequelae and advancing the healing process, but there are no scientific studies to confirm its efficacy. Mucosal tears may heal completely or may be followed by the development of vocal fold masses, scar, and permanent dysphonia.

The type I BMP receptor BmprIB is essential for female reproductive function.

Maintenance of female reproductive competence depends on the actions of several hormones and signaling factors. Recent reports suggest roles for bone morphogenetic proteins (BMPs) in early stages of folliculogenesis. A role for the type I BMP receptor BmprIB as a regulator of ovulation rates in sheep has been described recently, but little is known about the roles of BMP signaling pathways in other aspects of reproductive function. We report here that BMPRIB is essential for multiple aspects of female fertility. Mice deficient in BmprIB exhibit irregular estrous cycles and an impaired pseudopregnancy response. BmprIB mutants produce oocytes that can be fertilized in vitro, but defects in cumulus expansion prevent fertilization in vivo. This defect is associated with decreased levels of aromatase production in granulosa cells. Unexpectedly, levels of mRNA for cyclooxygenase 2, an enzyme required for cumulus expansion, are increased. BmprIB mutants also exhibit a failure in endometrial gland formation. The expression of BmprIB in uterine linings suggests that these defects are a direct consequence of loss of BMP signaling in this tissue. In summary, these studies demonstrate the importance of BMP signaling pathways for estrus cyclicity, estradiol biosynthesis, and cumulus cell expansion in vivo and reveal sites of action for BMP signaling pathways in reproductive tissues.

Müllerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces SMAD6 expression.

Signal reception of Müllerian inhibiting substance (MIS) in the mesenchyme around the embryonic Müllerian duct in the male is essential for regression of the duct. Deficiency of MIS or of the MIS type II receptor, MISRII, results in abnormal reproductive development in the male due to the maintenance of the duct. MIS is a member of the transforming growth factor-beta (TGFbeta) superfamily of secreted protein hormones that signal through receptor complexes of type I and type II serine/threonine kinase receptors. To investigate candidate MIS type I receptors, we examined reporter construct activation by MIS. The bone morphogenetic protein (BMP)-responsive Tlx2 and Xvent2 promoter-driven reporter constructs were stimulated by MIS but the TGFbeta/activin-induced p3TP-lux or CAGA-luc reporter constructs were not. The induction of Tlx2-luc was dependent upon the kinase activity of MISRII and was blocked by a dominant negative truncated ALK2 (tALK2) receptor but not by truncated forms of the other BMP type I receptors ALK1, ALK3, or ALK6. MIS induced activation of a Gal4DBD-Smad1 but not a Gal4DBD-Smad2 fusion protein. This activation could also be blocked by tALK2. The BMP-induced inhibitory Smad, Smad6, was up-regulated by MIS endogenously in Leydig cell-derived lines and is expressed in male but not female Müllerian duct mesenchyme. ALK6 has been shown to function as an MIS type I receptor. Investigation of the pattern of ALK2, MISRII, and ALK6 in the developing urogenital system demonstrated overlapping expression of ALK2 and MISRII in the mesenchyme surrounding the duct while ALK6 was observed only in the epithelium. Examination of ALK6 -/- male animals revealed no defect in duct regression. The reporter construct analysis, pattern of expression of the receptors, and analysis of ALK6-deficient animals suggest that ALK2 is the MIS type I receptor involved in Müllerian duct regression.

BMP3: to be or not to be a BMP.

BACKGROUND: Bone morphogenetic proteins (BMPs) are osteogenic but also have diverse functions during development. BMP3 is a major component of osteogenin, which has osteogenic activity. However, recombinant BMP3 (rhBMP3) has no apparent osteogenic function, raising the possibility that BMP3 has no bone-inducing activity or that the recombinant material is not properly processed. To resolve this apparent discrepancy, we utilized a retroviral system to study the effects of BMP3 in vitro. In addition, we generated Bmp3-deficient mice to elucidate the function of BMP3 in vivo. METHODS: Retroviral as well as mammalian expression constructs were utilized to express BMP3 and to create BMP3 conditioned medium. Alkaline phosphatase (ALP) activity and transcriptional response assays were used to monitor the ability of BMP3 to elicit either a BMP-like or a transforming growth factor beta (TGF-beta)/activin-like response in osteoblastic cell lines. Finally, mice deficient in BMP3 were generated to investigate BMP3 function in vivo. RESULTS: BMP3 was unable to induce an osteogenic response in W-20-17, MC3T3-E1, or C3H10T1/2 cells, although all three cell lines were responsive to BMP2. However, BMP3 inhibited responsiveness to BMP2 in these assays, suggesting that BMP3 antagonizes BMP2 signaling. This inhibition did not occur through inhibition of binding of BMP2 to its receptors. BMP3 activated the TGF-beta/activin-pathway in these cells, suggesting that BMP3 exerts its inhibiting effects by activating a signaling pathway that antagonizes the BMP pathway. To examine the potential functional consequences of BMP3 action, Bmp3-/- mice, which lack BMP3, were generated. On an outbred genetic background, Bmp3-/- mice are viable and show no obvious skeletal phenotype as embryos or neonates. However, adult mice exhibit twice as much trabecular bone as do their wild-type littermates. This observation is consistent with our in vitro observations suggesting that BMP3 is an inhibitor of osteogenesis in vitro and of bone formation in vivo. CONCLUSIONS: BMP3 is an inhibitor of osteogenic BMPs and can signal through a TGF-beta/activin pathway. The ability of BMP3 to antagonize BMP2 activity may thus be a consequence of competition for signaling components common to TGF-beta/activin and BMP pathways. BMP3, the most abundant BMP in demineralized bone, may therefore play an essential role as a modulator of the activity of osteogenic BMPs in vivo. CLINICAL RELEVANCE: Therapies to accelerate bone healing usually utilize administration of exogenous BMP either in recombinant form or by gene therapy approaches. It is conceivable that the potency of osteogenic BMPs would be increased by inhibiting the activation of antagonistic signaling pathways or by increasing levels of rate-limiting signaling components shared by both BMP and TGF-beta/activin pathways.

The molecular control of upper extremity development: implications for congenital hand anomalies.

As the molecular aspects of limb development are being unraveled, more of the congenital anomalies seen by hand surgeons in the clinical setting will have an identifiable molecular basis. The majority of the data available regarding the molecular development of the upper extremity have come from experimental animal studies, specifically the mouse and chicken. These findings are being discovered by either direct surgical and molecular manipulation of the developing limb or by production of mice deficient in specific genes. Relatively few specific human mutations that cause limb abnormalities have been identified. Hand surgeons should be aware of the basic molecular pathways controlling limb development because they are in a unique position to be able to identify patients with such deformities. In turn, detailed clinical descriptions of congenital anomalies affecting the upper extremity will advance the understanding of the cellular events controlled by the molecular pathways of limb development. This review describes the general molecular basis of limb development and correlates it with disease processes affecting the upper extremity.

Bone morphogenetic protein-3 is a negative regulator of bone density.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) superfamily. Many BMPs are produced in bone and show osteogenic activity, suggesting that they may be determinants of bone mass. BMP3 was originally purified from bone as osteogenin, which induces osteogenic differentiation. Recombinant BMP3 (rhBMP3) has no biological activity, however, leaving its role in skeletal growth unclear. Here we show that BMP3 is an antagonist of osteogenic BMPs: BMP3 dorsalizes Xenopus laevis embryos, inhibits BMP2-mediated induction of Msx2 and blocks BMP2-mediated differentiation of osteoprogenitor cells into osteoblasts. These effects appear to be mediated through activin receptors. Finally, Bmp3(-/-) mice have twice as much trabecular bone as wild-type littermates, indicating that BMP3, the most abundant BMP in adult bone, is a negative determinant of bone density.

Autoimmune inner ear disease: steroid and cytotoxic drug therapy.

The goal of this study was to assess the effects of immunosuppressive therapy on hearing in patients with presumed autoimmune sensorineural hearing loss (AISNHL) and a Western blot assay positive for a 68 kD inner ear antigen. To achieve this objective, we conducted a retrospective review of 39 such patients who were treated with either a steroid alone or with a steroid followed by a cytotoxic agent. Pure-tone average (PTA) at 500 Hz, 1 kHz, 2 kHz, and 3 kHz, and speech discrimination scores (SDS) were used as objective measures of outcome. At the completion of treatment, 23 of the 39 patients (59.0%) exhibited a positive response to therapy. The steroid-only responders (n = 6) tended to demonstrate a greater improvement in PTA (14.8 vs 4.5 dB), while the cytotoxic-agent responders (n = 17) had a significantly greater improvement in SDS (26.2 vs 6.9%; p < 0.01). We conclude that most patients with AISNHL benefit from immunosuppressive therapy and that cytotoxic medications appear to improve SDS, even in some patients who have not responded to corticosteroid therapy.