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Background: The success of a restoration largely depends on the quality of its fit. This study aimed to investigate the fit quality of monolithic zirconia veneers (MZVs) produced through traditional and digital workflows., Methods: A typodont maxillary right central incisor was prepared. The maxillary arch with the prepared tooth was scanned with Trios 3 Pod intra-oral scanner (IOS), which served as a pattern to create thirty 3D resin models through printing. Additionally, thirty conventional impressions of the maxillary with the prepared tooth were taken using polyvinyl siloxane (PVS) impression material. These impressions were cast using dental gypsum products to create thirty stone dies, which were then scanned externally. Sixty MZVs were milled from multi-layered zirconia disks. The marginal and internal gaps of restorations were assessed using the silicone replica technique., Results: The highest marginal accuracy for both the conventional and digital impression groups was observed in the cervical area, with values of 74.6 μm and 61.9 μm, respectively. The smallest internal gaps for both groups were also recorded in the cervical area, at 109.9 μm for the conventional group and 109.7 μm for the digital group. The digital group exhibited better marginal fit, particularly in the incisal and mesial areas (79.3 μm and 75.7 μm, respectively), compared to the conventional group (88.1 μm and 90.8 μm). No statistically significant differences in internal fit were observed., Conclusion: MZVs fabricated using the digital workflow exhibited superior marginal fit compared to those fabricated using the conventional workflow, though both techniques yielded clinically acceptable results., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Surgical drainage for chronic pancreatitis patients with a normal-sized pancreatic head remains controversial. Both Frey and extended Partington procedures could be used, but the level of evidence is weak., Method: The object of this prospective cohort study was to assess the mid-term results concerning pain, quality of life, and pancreatic function of surgical drainage (Frey or extended Partington procedure) in patients with painful chronic pancreatitis and a normal-sized pancreatic head., Results: Fifty-nine patients (Frey procedure: 14 cases; extended Partington procedure: 45 cases) were enrolled in the study with a median length of follow-up of 16 months. The effective and complete pain relief rate was 85% and 58%, respectively. The Izbicki score decreased from 53.4 preoperatively to 8.8 postoperatively. The general 12-Item Short Form Health Survey (SF-12) score increased from 45.2 to 75.4. The pancreatic insufficiency did not change significantly postoperatively. At three months after surgery, the complete pain relief and Izbicki score were more favorable in the Frey group than in the extended Partington group., Conclusion: Both Frey and extended Partington procedures resulted in excellent pain relief and quality of life improvement and did not worsen pancreatic function. The Frey procedure could yield a more favorable result in the early postoperative period., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Mai et al.)

As a country with one of the highest per capita gambling losses per year in the world, and an evolving multicultural profile, Australia has become an important setting in which to examine the harms and benefits related to gambling. The Australian population includes people from East Asian cultural backgrounds who are a key demographic of interest for gambling operators planning to grow revenue. However, Australian gambling research has concentrated primarily on those belonging to the dominant cultural group. Most of the previous and limited number of studies to examine gambling among culturally and linguistically diverse (CALD) residents have focused on people of Chinese descent, and much of the literature is now becoming relatively old. This review examines the current evidence around cultural variations in gambling prevalence, motivations, beliefs, behaviours, and help service utilisation, focusing on gamblers with an East Asian cultural background. Numerous domains in which gambling motivations and behaviours vary across cultural groups are identified, and methodological considerations related to ethnographic gambling research are discussed. This review found that while barriers and predictors to help-seeking for CALD gamblers have been studied extensively, contemporary evidence of help service utilisation and effectiveness in Australia is lacking. Further research providing an accurate assessment of the impacts of gambling for CALD gamblers is needed to ensure that harm minimisation resources are effective for those most vulnerable to harm., (© 2023. The Author(s).)

Bellevue Hospital is known as the oldest public hospital in the United States of America. Although its historical beginnings date back to the 1600s, it was officially founded on the second floor of the New York City Almshouse in 1736, 40 years before the American Revolution. It has since been at the forefront of administering comprehensive patient care and medical education. Moreover, Bellevue has built a reputation for serving homeless, immigrant, or minority populations while also delivering care to United States presidents. This tradition of treating patients regardless of socioeconomic or racial status has made Bellevue one of the most historically renowned hospitals in the country. Today, Bellevue hospital represents a significant branch of the New York City health system and a public health leader. Moreover, it has housed pioneers in neurosurgery, including the father of functional ultrasonic neurosurgery, Dr. Russel Meyers, as well as Dr. Dorothy Klenke Nash, the only active female neurosurgeon in the United States from 1928 to 1960. Herein, we will explore Bellevue's historical and medical significance, from its humble beginnings to its current status as a public health leader., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To assess the safety of the subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human choroideremia (CHM)-encoding cDNA in CHM., Design: Prospective, open-label, nonrandomized, dose-escalation, phase I/II clinical trial., Participants: Fifteen CHM patients (ages 20-57 years at dosing)., Methods: Patients received uniocular subfoveal injections of low-dose (up to 5 × 10 10 vector genome [vg] per eye, n = 5) or high-dose (up to 1 × 10 11 vg per eye, n = 10) of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human CHM-encoding cDNA (AAV2-hCHM). Patients were evaluated preoperatively and postoperatively for 2 years with ophthalmic examinations, multimodal retinal imaging, and psychophysical testing., Main Outcome Measures: Visual acuity, perimetry (10-2 protocol), spectral-domain OCT (SD-OCT), and short-wavelength fundus autofluorescence (SW-FAF)., Results: We detected no vector-related or systemic toxicities. Visual acuity returned to within 15 letters of baseline in all but 2 patients (1 developed acute foveal thinning, and 1 developed a macular hole); the rest showed no gross changes in foveal structure at 2 years. There were no significant differences between intervention and control eyes in mean light-adapted sensitivity by perimetry or in the lateral extent of retinal pigment epithelium relative preservation by SD-OCT and SW-FAF. Microperimetry showed nonsignificant (< 3 standard deviations of the intervisit variability) gains in sensitivity in some locations and participants in the intervention eye. There were no obvious dose-dependent relationships., Conclusions: Visual acuity was within 15 letters of baseline after the subfoveal AAV2-hCHM injections in 13 of 15 patients. Acute foveal thinning with unchanged perifoveal function in 1 patient and macular hole in 1 patient suggest foveal vulnerability to the subretinal injections. Longer observation intervals will help establish the significance of the minor differences in sensitivities and rate of disease progression observed between intervention and control eyes., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Beyond providing critical information to biologists, species distributions are useful for naturalists, curious citizens, and applied disciplines including conservation planning and medical intervention. Venomous snakes are one group that highlight the importance of having accurate information given their cosmopolitan distribution and medical significance. Envenomation by snakebite is considered a neglected tropical disease by the World Health Organization and venomous snake distributions are used to assess vulnerability to snakebite based on species occurrence and antivenom/healthcare accessibility. However, recent studies highlighted the need for updated fine-scale distributions of venomous snakes. Pitvipers (Viperidae: Crotalinae) are responsible for >98% of snakebites in the New World. Therefore, to begin to address the need for updated fine-scale distributions, we created VenomMaps, a database and web application containing updated distribution maps and species distribution models for all species of New World pitvipers. With these distributions, biologists can better understand the biogeography and conservation status of this group, researchers can better assess vulnerability to snakebite, and medical professionals can easily discern species found in their area., (© 2022. The Author(s).)

Highly methylated Long Interspersed Nucleotide Elements 1 (LINE-1) constitute approximately 20% of the human genome, thus serving as a surrogate marker of global genomic DNA methylation. To date, there is still lacking a consensus about the precise location in LINE-1 promoter and its methylation threshold value, making challenging the use of LINE-1 methylation as a diagnostic, prognostic markers in cancer. This study reports on a technical standardization of bisulfite-based DNA methylation analysis, which ensures the complete bisulfite conversion of repeated LINE-1 sequences, thus allowing accurate LINE-1 methylation value. In addition, the study also indicated the precise location in LINE-1 promoter of which significant variance in methylation level makes LINE-1 methylation as a potential diagnostic biomarker for lung cancer. A serial concentration of 5-50-500 ng of DNA from 275 formalin-fixed paraffin-embedded lung tissues were converted by bisulfite; methylation level of two local regions (at nucleotide position 300-368 as LINE-1.1 and 368-460 as LINE-1.2) in LINE-1 promoter was measured by real time PCR. The use of 5 ng of genomic DNA but no more allowed to detect LINE-1 hypomethylation in lung cancer tissue (14.34% versus 16.69% in non-cancerous lung diseases for LINE-1.1, p < 0.0001, and 30.28% versus 32.35% for LINE-1.2, p < 0.05). Our study thus highlighted the optimal and primordial concentration less than 5 ng of genomic DNA guarantees the complete LINE-1 bisulfite conversion, and significant variance in methylation level of the LINE-1 sequence position from 300 to 368 allowed to discriminate lung cancer from non-cancer samples., Competing Interests: The authors have declared that no competing interests exist.

Heat shock protein 90 (Hsp90) is one of the most potential targets in cancer therapy. We have demonstrated using a combination of molecular docking and fast pulling of ligand (FPL) simulations that marine fungi derivatives can be possible inhibitors, preventing the biological activity of Hsp90. The computational approaches were validated and compared with previous experiments. Based on the benchmark of available inhibitors of Hsp90, the GOLD docking package using the ChemPLP scoring function was found to be superior over both Autodock Vina and Autodock4 in the preliminary estimation of the ligand-binding affinity and binding pose with the Pearson correlation, R = -0.62. Moreover, FPL calculations were also indicated as a suitable approach to refine docking simulations with a correlation coefficient with the experimental data of R = -0.81. Therefore, the binding affinity of marine fungi derivatives to Hsp90 was evaluated. Docking and FPL calculations suggest that five compounds including 23, 40, 46, 48, and 52 are highly potent inhibitors for Hsp90. The obtained results enhance cancer therapy research., Competing Interests: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (This journal is © The Royal Society of Chemistry.)

In this Article originally published, owing to a technical error, the author 'Laurent Chirio' was mistakenly designated as a corresponding author in the HTML version, the PDF was correct. This error has now been corrected in the HTML version. Further, in Supplementary Table 3, the authors misspelt the surname of 'Danny Meirte'; this file has now been replaced.

The distributions of amphibians, birds and mammals have underpinned global and local conservation priorities, and have been fundamental to our understanding of the determinants of global biodiversity. In contrast, the global distributions of reptiles, representing a third of terrestrial vertebrate diversity, have been unavailable. This prevented the incorporation of reptiles into conservation planning and biased our understanding of the underlying processes governing global vertebrate biodiversity. Here, we present and analyse the global distribution of 10,064 reptile species (99% of extant terrestrial species). We show that richness patterns of the other three tetrapod classes are good spatial surrogates for species richness of all reptiles combined and of snakes, but characterize diversity patterns of lizards and turtles poorly. Hotspots of total and endemic lizard richness overlap very little with those of other taxa. Moreover, existing protected areas, sites of biodiversity significance and global conservation schemes represent birds and mammals better than reptiles. We show that additional conservation actions are needed to effectively protect reptiles, particularly lizards and turtles. Adding reptile knowledge to a global complementarity conservation priority scheme identifies many locations that consequently become important. Notably, investing resources in some of the world's arid, grassland and savannah habitats might be necessary to represent all terrestrial vertebrates efficiently.

We assessed the appropriate geographic scale to apply an area deprivation index (ADI), which reflects a geographic area's level of socioeconomic deprivation and is associated with health outcomes, to identify and screen patients for social determinants of health. We estimated the relative strength of the association between the ADI at various geographic levels and a range of hospitalization rates by using age-adjusted odds ratios in an 8-county region of New York State. The 10-km local ADI estimates had the strongest associations with all hospitalization rates (higher odds ratios) followed by estimates at 20 km, 30 km, and the regional scale. A locally sensitive ADI is an ideal measure to identify and screen for the health care and social services needs and to advance the integration of social determinants of health with clinical treatment and disease prevention.

Middle America is one of the most biodiverse regions in the world, harboring an exceptional number of rare and endemic species. This is especially true of Middle American cloud forests, where montane specialists occupy restricted, high-elevation ranges making them attractive candidates for investigating historical biogeography and speciation. One such highland-restricted species, the black speckled palm-pitviper (Bothriechis nigroviridis), occupies the Central, Tilarán, and Talamanca Cordilleras in Costa Rica and Panama. In this study, we investigate the genetic and morphological variation among populations of B. nigroviridis by inferring a multilocus phylogeny (21 individuals) and analyzing meristic scale characters with a principal component analysis (64 individuals). We find B. nigroviridis sensu stricto to be composed of two deeply divergent lineages, one with a restricted range in the northern and central Cordillera Talamanca and the other ranging throughout the Central, Tilarán, and Talamanca Cordilleras. Furthermore, these two lineages are morphologically distinct, with previously unrecognized differences in several characters allowing us to name and diagnose a new species B. nubestris sp. nov. We also examine the genetic and morphological variation within B. nigroviridis and discuss biogeographic hypotheses that may have led to the diversification of Bothriechis lineages.

Adrenal glands are zonated endocrine organs that are essential in controlling body homeostasis. How zonation is induced and maintained and how renewal of the adrenal cortex is ensured remain a mystery. Here we show that capsular RSPO3 signals to the underlying steroidogenic compartment to induce β-catenin signaling and imprint glomerulosa cell fate. Deletion of RSPO3 leads to loss of SHH signaling and impaired organ growth. Importantly, Rspo3 function remains essential in adult life to ensure replenishment of lost cells and maintain the properties of the zona glomerulosa. Thus, the adrenal capsule acts as a central signaling center that ensures replacement of damaged cells and is required to maintain zonation throughout life., (© 2016 Vidal et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Female patients with atrial fibrillation (AF) experience increased risk of thromboembolism compared to males, an observation that is reflected by its inclusion in the CHA2DS2VASc score. New onset AF (often associated with tachycardia) also confers upon patients increased thromboembolic risk. The mechanisms underlying this risk are uncertain, but new onset AF is associated with profound impairment of platelet nitric oxide (NO) signalling. Given that cardiovascular responses to catecholamines are gender-dependent, and that the presence of tachycardia in new onset AF may represent a response to catecholaminergic stimulation, we explored the potential impact of gender and tachycardia on platelet aggregation and NO signalling., Methods: Interactions were sought in 87 AF patients between the extent of adenosine diphosphate (ADP)-induced platelet aggregation, the anti-aggregatory effects of the NO donor, sodium nitroprusside, gender, and admission heart rate. The potential impact of platelet expression of thioredoxin-interacting protein (Txnip) was also evaluated., Results: Analysis of covariance confirmed the presence of physiological antagonism between platelet ADP and NO responses [F (1, 74) = 12.212, P < 0.01], while female sex correlated with impaired NO responses independent of platelet aggregability [F (2, 74) = 8.313, P < 0.01]. Admission heart rate correlated directly with platelet aggregation (r = 0.235, P < 0.05), and inversely with NO response (r = -0.331, P < 0.01). Txnip expression varied neither with gender nor with heart rate., Conclusions: These results indicate that gender and heart rate are independent determinants of platelet function. Prospective studies of the putative benefit of reversal of tachycardia on restoration of normal platelet function are therefore a priority.

Purpose: To evaluate the host β-globin gene fragment lengths in the cell-free peri-implant crevicular fluid (PICF) during the wound healing process., Materials and Methods: Nineteen patients (25 implants) were recruited into this study. As part of the control group, gingival crevicular fluids (GCF) from healthy teeth were collected before implant placement. PICF specimens from each implant were collected during weeks 2 to 12 after implant placement. All GCF and PICF specimens were centrifuged to collect the supernatant as cell-free DNA. Five primer pairs specific to the β-globin gene for amplifying 110-base pair (bp), 325-bp, 408-bp, 536-bp, and 2-kilo-base pair (kb) amplicons were used to evaluate DNA fragment lengths with conventional polymerase chain reaction (PCR). The longest PCR amplicon of each specimen was recorded., Results: The number of 536-bp amplicons (10 of 25 implant specimens) and 2-kb amplicons (8 of 25 implant specimens) in week 2 was higher than at the other visits. In the study, the mucositis group showed the highest number of 536-bp amplicons (22 of 34 implant specimens) and 2-kb amplicons (12 of 34 implant specimens), whereas the healthy implant group showed a low number of 536-bp amplicons (3 of 66 implant specimens), and the cell-free PICF specimens had no 2-kb amplicons. Furthermore, 325-bp and 110-bp amplicons were similar in number in the control teeth and healthy implants., Conclusion: There was a difference in the number of the longest amplicons of cell-free PICF specimens between the mucositis and healthy implant groups. This pilot study suggests that the PCR amplicon lengths of β-globin gene fragments in cell-free PICF specimens might be used as a biomarker to monitor soft tissue inflammation around implants.

The South American gymnophthalmid genus Euspondylus is distributed from Venezuela through Peru, with its highest diversity occurring in Peru. Euspondylus paxcorpus sp. nov. is a new species from Junín, Peru possessing prefrontal scales and represented by 60 specimens. The new species differs from all other species by the combination of four supraoculars with supraocular/supraciliary fusion, 5-7 occipitals, a single palpebral scale, five supralabials and infralabials, quadrangular dorsal scales with low keels arranged in transverse series only, 40-45 in a longitudinal count and 22-28 in a transverse count, 12 rows of ventrals in a transverse count and 23-25 in a longitudinal count, and no sexual dimorphism in coloration. The discovery of E. paxcorpus increases the known number of Euspondylus species to 13. Because the coloration patterns of the specimens were greatly different after preservation in alcohol, caution should be used when identifying Euspondylus species from museum specimens.

Background: Risk of substantial haemorrhage represents a critically important limitation to effective anti-thrombotic treatment in patients with atrial fibrillation (AF). While it is known that this risk is increased in anticoagulated patients either in the presence of anti-aggregatory drugs or concomitant renal insufficiency, there are currently few data on the potential interactions between endogenous platelet aggregability and bleeding risk., Objective: We therefore evaluated in a cohort of AF patients: (1), the putative relationship between platelet aggregability and HAS-BLED score; (2), the potential biochemical bases for such a relationship., Methods: Patients were included as part of SAFETY, a randomised controlled trial evaluating outpatient management of AF patients. Platelet response to ADP was evaluated via whole blood impedance aggregometry; clinical and biochemical correlates of platelet aggregation were sought via univariate and multivariate analysis., Results: Platelet aggregation correlated inversely (r=-0.220, p<0.05) with HAS-BLED score. Univariate biochemical correlates of decreased platelet aggregation were plasma concentrations of symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). On multivariate analyses, plasma SDMA concentration (β=-0.318, p<0.01), platelet content of thioredoxin-interacting protein (Txnip, β=0.261, p<0.05) and plasma thrombospondin-1 (TSP-1, β=0.249, p<0.05) concentration were predictive of platelet ADP response. Consistent with previous reports, plasma SDMA concentrations were strongly and inversely correlated with estimated glomerular filtration rate (eGFR, r=-0.780, p<0.001)., Conclusions: These data therefore suggest that (1), physiologically impaired, like pharmacologically impaired, platelet aggregability may increase bleeding risk in anticoagulated AF patients; (2), the biochemical basis for this may include impaired effects of nitric oxide (via Txnip, TSP-1) but also concomitant renal dysfunction.

Aortic sclerosis (ASc) represents the earliest stage of development of aortic valve thickening, and may eventually progress to aortic valve stenosis (AS). ASc is associated with intra-valvular inflammatory activation, and potentially with attenuation of the anti-inflammatory effect of nitric oxide (NO). We have shown that ASc occurs less frequently in obese individuals, in whom systemic inflammatory activity is generally increased. We explored these relationships further by stratifying a population of 253 ageing individuals according to BMI. Increasing BMI was associated with increased hs-CRP concentrations (r=0.43; p<0.001). However, presence/absence of ASc did not significantly modify this relationship. Furthermore, increasing BMI was independent of tissue responsiveness to NO, as measured via inhibition of platelet aggregation by the NO donor sodium nitroprusside. Therefore the association of low BMI with increased risk of ASc appears to interact neither with systemic inflammatory activation in such individuals, nor with any "paradoxical" occurrence of NO resistance.

Aortic valve stenosis (AS) is the commonest form of valvular heart disease in the Western world. Its prevalence increases exponentially with age and it is present in 2-7% of all patients over 65 years of age. In view of the considerable cardiovascular morbidity and mortality associated not only with AS, but even its earlier stage, aortic sclerosis, many investigations have been directed towards better understanding of its pathogenesis, with the ultimate objective of developing strategies to retard its progression. Although risk factors and downstream mediators appear similar for AS and atherosclerosis (older age, male sex, hypertension, smoking, hypercholesterolemia, and diabetes, as many as 50% of patients with AS do not have clinically significant atherosclerosis. On the basis both of recent experimental evidence and clinical trials, it appears that atherogenesis is not pivotal to the pathogenesis of AS. On the other hand, there is increasing evidence of active involvement of aortic valve fibroblasts with resultant increased production of reactive oxygen species, active pro-inflammatory and pro-fibrotic processes culminating in calcification. We also discuss the evidence of involvement of the nitric oxide system in the pathogenesis of AS. The renin-angiotensin system has also emerged as a major player in the pathogenesis of AS. Histologically, there is increased ACE expression and elevated angiotensin II levels in stenotic valves, while we have just demonstrated amelioration of AS with the use of ACE inhibitors in an animal model. We further discuss intervention studies aimed at retarding AS progression, including recent failures of statins to retard progression of AS in large randomized clinical studies. Finally, we discuss the special case of bicuspid aortic valve, including its genetics and unique associated features.

Phylogenetic studies incorporating multiple loci, and multiple genomes, are becoming increasingly common. Coincident with this trend in genetic sampling, model-based likelihood techniques including Bayesian phylogenetic methods continue to gain popularity. Few studies, however, have examined model fit and sensitivity to such potentially heterogeneous data partitions within combined data analyses using empirical data. Here we investigate the relative model fit and sensitivity of Bayesian phylogenetic methods when alternative site-specific partitions of among-site rate variation (with and without autocorrelated rates) are considered. Our primary goal in choosing a best-fit model was to employ the simplest model that was a good fit to the data while optimizing topology and/or Bayesian posterior probabilities. Thus, we were not interested in complex models that did not practically affect our interpretation of the topology under study. We applied these alternative models to a four-gene data set including one protein-coding nuclear gene (c-mos), one protein-coding mitochondrial gene (ND4), and two mitochondrial rRNA genes (12S and 16S) for the diverse yet poorly known lizard family Gymnophthalmidae. Our results suggest that the best-fit model partitioned among-site rate variation separately among the c-mos, ND4, and 12S + 16S gene regions. We found this model yielded identical topologies to those from analyses based on the GTR+I+G model, but significantly changed posterior probability estimates of clade support. This partitioned model also produced more precise (less variable) estimates of posterior probabilities across generations of long Bayesian runs, compared to runs employing a GTR+I+G model estimated for the combined data. We use this three-way gamma partitioning in Bayesian analyses to reconstruct a robust phylogenetic hypothesis for the relationships of genera within the lizard family Gymnophthalmidae. We then reevaluate the higher-level taxonomic arrangement of the Gymnophthalmidae. Based on our findings, we discuss the utility of nontraditional parameters for modeling among-site rate variation and the implications and future directions for complex model building and testing.

Formation of the cartilaginous otic capsule is directed by otic epithelial-periotic mesenchymal interactions. In response to induction by otic epithelium, condensations of mesenchyme appear in the periotic region and form a chondrified otic capsule that serves as the template for the subsequent formation of the endochondral bony labyrinth. Previous studies indicate that members of the transforming growth factor beta superfamily, including transforming growth factor beta(1), participate in guiding these tissue interactions. In this study, we report the localization of bone morphogenetic protein 4 (BMP4) to the mesenchymal and epithelial-derived tissues of the mouse inner ear between 10.5 and 14 days of embryonic development. We demonstrate modulation of chondrogenesis in cultured mouse periotic mesenchyme by exogenous BMP4 protein and investigate the function of endogenous BMP4 in otic capsule chondrogenesis. We show that in the presence of the BMP antagonist, Noggin, otic capsule chondrogenesis is suppressed in culture in a dose-dependent manner. Consistent with this finding, addition of BMP4-specific antisense oligonucleotide to cultures of mouse periotic mesenchyme containing otic epithelium decreases levels of endogenous BMP4 protein and suppresses the chondrogenic response of the cultured periotic mesenchyme, providing evidence of the necessity for BMP4 in mediating otic capsule chondrogenesis. Supplementation of either Noggin- or BMP4 antisense oligonucleotide-treated cultures with BMP4 protein can restore the extent of chondrogenesis to normal levels. Our findings support BMP4 as an essential mediator of chondrogenesis in the developing otic capsule in situ., (Copyright 2003 Wiley-Liss, Inc.)