Huo-Luo-Xiao-Ling (HLXL)-Dan, a Traditional Chinese Medicine, for patients with osteoarthritis of the knee: a multi-site, randomized, double-blind, placebo-controlled phase II clinical trial.

OBJECTIVE: To examine the efficacy and safety of Huo-Luo-Xiao-Ling (HLXL)-Dan, a Traditional Chinese Medicine (TCM), in patients with knee osteoarthritis (OA). DESIGN: A multi-site, randomized, double-blind, placebo-controlled phase II dose-escalation clinical trial was conducted. Eligible patients who fulfilled American College of Rheumatology criteria were randomized to receive either HLXL or placebo. Clinical assessments included measurement of knee pain and function with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), patient global assessment (PGA), and knee pain scores every 2 weeks. A Data and Safety Monitoring Board (DSMB) was established to review the data for ensuring the quality of the trial. RESULTS: In the first stage, 28 participants were randomized to receive either low-dose HLXL-Dan (2400 mg/day) or placebo for 6 weeks. The results showed no statistical difference between the two groups. The study was then re-designed following the recommendation of DSMB. Ninety-two patients were enrolled in the second stage and were randomized to receive either high-dose HLXL-Dan (4000 mg/day for week 1-2, and 5600 mg/day for week 3-8) or placebo for 8 weeks. All outcome assessments showed significant improvements for both groups after 8 weeks but no significant between-group differences. The change (mean ± SD) of WOMAC pain and WOMAC function scores of HLXL and placebo group after 8 weeks were -1.2 ± 1.7 vs -1.4 ± 1.5, and -1.1 ± 1.6 vs -1.3 ± 1.5 respectively. No serious adverse events were reported. CONCLUSION: Although safe to use, an 8-week treatment of HLXL-Dan was not superior to placebo for reduction in pain or functional improvement in patients with knee OA. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT00755326).

Platinum coat color in red fox (Vulpes vulpes) is caused by a mutation in an autosomal copy of KIT.

The red fox (Vulpes vulpes) demonstrates a variety of coat colors including platinum, a common phenotype maintained in farm-bred fox populations. Foxes heterozygous for the platinum allele have a light silver coat and extensive white spotting, whereas homozygosity is embryonic lethal. Two KIT transcripts were identified in skin cDNA from platinum foxes. The long transcript was identical to the KIT transcript of silver foxes, whereas the short transcript, which lacks exon 17, was specific to platinum. The KIT gene has several copies in the fox genome: an autosomal copy on chromosome 2 and additional copies on the B chromosomes. To identify the platinum-specific KIT sequence, the genomes of one platinum and one silver fox were sequenced. A single nucleotide polymorphism (SNP) was identified at the first nucleotide of KIT intron 17 in the platinum fox. In platinum foxes, the A allele of the SNP disrupts the donor splice site and causes exon 17, which is part of a segment that encodes a conserved tyrosine kinase domain, to be skipped. Complete cosegregation of the A allele with the platinum phenotype was confirmed by linkage mapping (LOD 25.59). All genotyped farm-bred platinum foxes from Russia and the US were heterozygous for the SNP (A/G), whereas foxes with different coat colors were homozygous for the G allele. Identification of the platinum mutation suggests that other fox white-spotting phenotypes, which are allelic to platinum, would also be caused by mutations in the KIT gene.

Defining migration and its health impact in China.

The scale and rapid expansion of urbanization resulting from socio-economic transformation in China at the beginning of the 21st century has accelerated rural-urban migration. Public health concerns from this increasing internal population mobility are now receiving attention from researchers. The health problems from internal migration pose particular demands on healthcare systems and relate to its demographic characteristics, with many younger and older people being left behind in the rural countryside. A review of literature, census, policy reports, government documents and media was undertaken to look at the classification system and health characteristics of China's internal migrants. It suggests that public health bears the consequences of political and economic decisions made elsewhere in society.

Estimating the incidence reporting rates of new influenza pandemics at an early stage using travel data from the source country.

During the surveillance of influenza pandemics, underreported data are a public health challenge that complicates the understanding of pandemic threats and can undermine mitigation efforts. We propose a method to estimate incidence reporting rates at early stages of new influenza pandemics using 2009 pandemic H1N1 as an example. Routine surveillance data and statistics of travellers arriving from Mexico were used. Our method incorporates changes in reporting rates such as linearly increasing trends due to the enhanced surveillance. From our results, the reporting rate was estimated at 0·46% during early stages of the pandemic in Mexico. We estimated cumulative incidence in the Mexican population to be 0·7% compared to 0·003% reported by officials in Mexico at the end of April. This method could be useful in estimation of actual cases during new influenza pandemics for policy makers to better determine appropriate control measures.

Nutritional Considerations in Hip and Knee Arthroplasty: A Critical Analysis of Current Evidence.

¼ Initial screening for malnutrition can be initiated with a fibrinogen-albumin ratio threshold <11.7.¼ Protein supplementation to goal (1.2-1.9 g/kg), along with essential amino acid augmented with beta-hydroxy-beta-methylbutyrate and resistance training have shown benefit, especially in sarcopenic patients.¼ Omega-3 and omega-6 polyunsaturated fatty acid supplementation has a strong antioxidant role and gain of muscle mass.¼ Supplementation with adenosine triphosphate and magnesium sulfate provides an avenue to decrease postoperative pain and opioid consumption.¼ Motivational interviewing and multidisciplinary teams to achieve preoperative weight loss >20 lbs in morbidly obese patients can decrease complication rates.

Bibliometric analysis of machine learning trends and hotspots in arthroplasty literature over 31 years.

Background: Artificial intelligence has demonstrated utility in orthopedic research. Algorithmic models derived from machine learning have demonstrated adaptive learning with predictive application towards outcomes, leading to increased traction in the literature. This study aims to identify machine learning arthroplasty research trends and anticipate emerging key terms. Methods: Published literature focused on machine learning in arthroplasty from 1992 to 2023 was selected through the Web of Science Core Collection of Clarivate Analytics. Following that, bibliometric indicators were attained and brought in to perform an additional examination using Bibliometrix and VOSviewer to identify historical and present patterns within the literature. Results: A total of 235 documents were obtained through bibliometric sourcing based on machine learning applications within the arthroplasty literature. Thirty-four countries published articles on the topic, and the United States was demonstrated to be the largest global contributor. Four hundred-five institutions internationally contributed articles, with Harvard Medical School and the University of California system as the most relevant institutes, with 75 and 44 articles produced, respectively. Kwon YM was the most productive author, while Haeberle HS and Ramkumar PN were the most impactful based on h-index. The Thematic map and Co-occurrence visualization helped identify both major and niche themes present in the scientific databases. Conclusions: Machine learning in arthroplasty research continues to gain traction with a growing annual production rate and contributions from international authors and institutions. Institutions and authors based in the United States are the leading contributors to machine learning applications within arthroplasty research. This research discerns trends that have occurred, are presently ongoing, and are emerging within this field, aiming to inform future hotspot development.

The Impact of Financial Education on Stress Among Orthopaedic Surgeons.

BACKGROUND: Financial stress has been an increasing area of concern for residents and attendings. The primary goal of this study was to determine the financial education level and differentiate financial outcome measures of orthopaedic surgery residents and attendings. METHODS: A survey of all residents and attendings of the 201 Accreditation Council for Graduate Medical Education (ACGME)-accredited orthopaedic surgery programs in the United States. RESULTS: Total participation in the study was 118 residents (postgraduate year (PGY) 1-5), three fellows (PGY 6), and 57 attending orthopaedic surgeons. A significant difference existed between average current financial stress scores between residents versus attending (2.32 vs 1.17), but not Doctor of Medicine (MD) versus Doctor of Osteopathic Medicine (DO) attendings (0.96 vs 1.67) and MD versus DO residents (2.25 vs 2.50). There was a significant difference in average future financial stress scores between residents and attendings (1.85 vs 1.44) and MD vs DO residents (1.61 vs 2.25) but no difference between MD vs DO attending (1.31 vs 1.63). Residents' confidence in financial knowledge compared to college graduates had a significantly negative Pearson coefficient with current financial stress score, while the attending group was not significant. CONCLUSIONS: Orthopaedic residents and attending physicians' financial stress levels are positively correlated with the amount of student debt they hold. Most residents who currently have no personal finance education offered in their residency would likely attend a personal finance course if offered. Decreasing the amount of debt held by residents, increasing their financial knowledge, and helping them develop good financial habits would likely lead to a decrease in financial stress.

Race and ethnic disparities arthroplasty trends and hotspots: Bibliometric analysis.

Introduction: Despite continual advancements in total joint arthroplasty and perioperative optimization, there remains national variability in outcomes. These outcome variabilities have been in part attributed to racial and ethnic disparities in healthcare quality and access to care. This study aims to identify arthroplasty racial and ethnic disparities research and to predict future hotspots. Methods: Ethnic and racial disparities articles between 1992 and 2022 were queried from the Web of Science Core Collection of Clarivate Analytics. Bibliometric indicators in excel format were extracted and subsequently imported for further analysis. Bibliometrix and VOSviewer analyzed current and previous research. Results: Database search yielded 234 total articles assessing racial and ethnic disparities between 1992 and 2022. Twenty-six countries published manuscripts with the United States producing the majority of publications. The Veterans Health Administration and University of Pittsburgh were the most relevant institutions. Ibrahim SA was the most relevant and influential author within this field. Visuals of thematic map and co-occurrences identified the basic, motor, and niche themes within the literature. Conclusions: Racial and ethnic disparity within arthroplasty literature demonstrate growing traction with global contributions. United States authors and institutions are the largest contributors within this field. This bibliometric analysis identified previous, current, and future trends for prediction of future hotspots.

Perioperative Nutritional, Functional, and Bone Health Optimization in Spine Surgery: A National Investigation of Spine Surgeons' Perceptions and Practices.

INTRODUCTION: While perioperative nutritional, functional, and bone health status optimization in spine surgery is supported with ample evidence, the implementation and surgeon perception regarding such efforts in clinical practice remain largely unexplored. This study sought to assess the current perception of spine surgeons and implementation regarding the nutritional, functional status, and bone health perioperative optimization. METHODS: An anonymous 30-question survey was distributed to orthopaedic spine fellowship and neurosurgery program directors identified through the North American Spine Society and American Association of Neurological Surgeons contact databases. RESULTS: The questionnaire was completed by 51 surgeon survey respondents. Among those, 62% reported no current formal nutritional optimization protocols with 14% not recommending an optimization plan, despite only 10% doubting benefits of nutritional optimization. While 5% of respondents perceived functional status optimization as nonbeneficial, 68% of respondents reported no protocol in place and 46% noted a functional status assessment relying on patient dependency. Among the respondents, 85% routinely ordered DEXA scan if there was suspicion of osteoporosis and 85% usually rescheduled surgery if bone health optimization goals were not achieved while 6% reported being suspicious of benefit from such interventions. CONCLUSION: While most responding spine surgeons believe in the benefit of perioperative nutritional and functional optimization, logistical and patient compliance challenges were noted as critical barriers toward optimization. Understanding surgeon perception and current practices may guide future efforts toward advancement of optimization protocols.

A photic visual cycle of rhodopsin regeneration is dependent on Rgr.

During visual excitation, rhodopsin undergoes photoactivation and bleaches to opsin and all-trans-retinal. To regenerate rhodopsin and maintain normal visual sensitivity, the all-trans isomer must be metabolized and reisomerized to produce the chromophore 11-cis-retinal in biochemical steps that constitute the visual cycle and involve the retinal pigment epithelium (RPE; refs. 3-8). A key step in the visual cycle is isomerization of an all-trans retinoid to 11-cis-retinol in the RPE (refs. 9-11). It could be that the retinochrome-like opsins, peropsin, or the retinal G protein-coupled receptor (RGR) opsin12-16 are isomerases in the RPE. In contrast to visual pigments, RGR is bound predominantly to endogenous all-trans-retinal, and irradiation of RGR in vitro results in stereospecific conversion of the bound all-trans isomer to 11-cis-retinal. Here we show that RGR is involved in the formation of 11-cis-retinal in mice and functions in a light-dependent pathway of the rod visual cycle. Mutations in the human gene encoding RGR are associated with retinitis pigmentosa.

The utilization of US-based large data in arthroplasty research: Bibiliometric analysis of trends and hotspots.

Background: The accessibility of digital information has expanded orthopaedic surgery with expanded role of Big Databases. The increasing interest have led to creation of large databases with increasing utilization in retrospective studies. The aim of this study is to identify Big Database research and predict future hotspots. Methods: Big Database publications between 1982 and 2022 were identified from the Web of Science Core Collection of Clarivate Analytics. Bibliometric indicators were obtained and imported for further analysis with VOSviewer and Bibliometrix to identify previous and ongoing trends within this field. Results: Bibliometric sourcing identified 811 total articles that was associated with major databases. Twenty-eight countries published manuscript in the field with the United States as the largest contributor. The most relevant institutions were Cleveland Clinic and Harvard University. Mont MA was the most productive and influential author. Co-occurrence visualization and thematic map identified niche and major themes within the literature. Conclusions: Large Database research continue to show an increasing trend since 2011 with contributions globally. United States institutions and authors are the leading contributors in big database research. This study identifies previous, current, and developing trends within this field for future hotspot development.

Epidemiology of primary and revision total knee arthroplasty: analysis of demographics, comorbidities and outcomes from the national inpatient sample.

INTRODUCTION: Primary total knee arthroplasty (TKA) is a preferred treatment for end-stage knee osteoarthritis. In the setting of a failed TKA, revision total knee arthroplasty (rTKA) acts as a salvage procedure and carries a higher risk compared to primary TKA. Given increased interest in postoperative outcomes from these procedures, a thorough understanding of the demographics, comorbidities, and inpatient outcomes is warranted. This study aimed to report the epidemiological data of demographics, comorbidity profiles and outcomes of patients undergoing TKA and rTKA. METHODS: A retrospective review of NIS registry discharge data from 2006 to 2015 third quarter was performed. This study included adults aged 40 and older who underwent TKA or rTKA. A total of 5,901,057 TKA patients and 465,968 rTKA patients were included in this study. Simple descriptive statistics were used to present variables on demographics, medical comorbidities, and postoperative complications. RESULTS: A total of 5,901,057 TKA and 465,968 rTKA discharges were included in this study, with an average age of 66.30 and 66.56 years, and the major payor being Medicare, accounting for 55.34% and 59.88% of TKA and rTKA cases, respectively. Infection (24.62%) was the most frequent reason for rTKA, and was followed by mechanical complications (18.62%) and dislocation (7.67%). The most common medical comorbidities for both groups were hypertension, obesity, and diabetes. All types of inpatient complications were reported in 22.21% TKA and 28.78% of rTKA cases. Postoperative anemia was the most common complication in both groups (20.34% vs. 25.05%). CONCLUSIONS: Our data demonstrated a 41.9% increase in patients receiving TKA and 28.8% increase in rTKA from the years 2006 to 2014. The data showed a 22.21% and a 28.78% "complication" rate with TKA and rTKA, with postoperative anemia being the most common complication. The top 3 medical comorbidities were hypertension, obesity, and diabetes for both groups and with increased focus on perioperative optimization, future analyses into preoperative medical optimization, and improved primary arthroplasty protocol may result in improved postoperative outcomes.

Assessing the predictive capacity of machine learning models using patient-specific variables in determining in-hospital outcomes after THA.

Background: Machine learning is a subset of artificial intelligence using algorithmic modeling to progressively learn and create predictive models. Clinical application of machine learning can aid physicians through identification of risk factors and implications of predicted patient outcomes. Aims: The aim of this study was to compare patient-specific and situation perioperative variables through optimized machine learning models to predict postoperative outcomes. Methods: Data from 2016 to 2017 from the National Inpatient Sample was used to identify 177,442 discharges undergoing primary total hip arthroplasty, which were included in the training, testing, and validation of 10 machine learning models. 15 predictive variables consisting of 8 patient-specific and 7 situational specific variables were utilized to predict 3 outcome variables: length of stay, discharge, and mortality. The machine learning models were assessed in responsiveness via area under the curve and reliability. Results: For all outcomes, Linear Support Vector Machine had the highest responsiveness among all models when using all variables. When utilizing patient-specific variables only, responsiveness of the top 3 models ranged between 0.639 and 0.717 for length of stay, 0.703-0.786 for discharge disposition, and 0.887-0.952 for mortality. The top 3 models utilizing situational variables only produced responsiveness of 0.552-0.589 for length of stay, 0.543-0.574 for discharge disposition, and 0.469-0.536 for mortality. Conclusions: Linear Support Vector Machine was the most responsive machine learning model of the 10 algorithms trained, while decision list was most reliable. Responsiveness was observed to be consistently higher with patient-specific variables than situational variables, emphasizing the predictive capacity and value of patient-specific variables. The current practice in machine learning literature generally deploys a single model, it is suboptimal to develop optimized models for application into clinical practice. The limitation of other algorithms may prohibit potential more reliable and responsive models.Level of Evidence III.

The progressive ankylosis protein regulates cementum apposition and extracellular matrix composition.

BACKGROUND/AIMS: Tooth root cementum is sensitive to modulation of inorganic pyrophosphate (PP(i)), an inhibitor of hydroxyapatite precipitation. Factors increasing PP(i) include progressive ankylosis protein (ANK) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) while tissue nonspecific alkaline phosphatase hydrolyzes PP(i). Studies here aimed to define the role of ANK in root and cementum by analyzing tooth development in Ank knock-out (KO) mice versus wild type. MATERIALS AND METHODS: Periodontal development in KO versus control mice was analyzed by histology, histomorphometry, immunohistochemistry, in situ hybridization, electron microscopy, and nanoindentation. Cementoblast cultures were used in vitro to provide mechanistic underpinnings for PP(i) modulation of cell function. RESULTS: Over the course of root development, Ank KO cervical cementum became 8- to 12-fold thicker than control cervical cementum. Periodontal ligament width was maintained and other dentoalveolar tissues, including apical cementum, were unaltered. Cervical cementum uncharacteristically included numerous cells, from rapid cementogenesis. Ank KO increased osteopontin and dentin matrix protein 1 gene and protein expression, and markedly increased NPP1 protein expression in cementoblasts but not in other cell types. Conditional ablation of Ank in joints and periodontia confirmed a local role for ANK in cementogenesis. In vitro studies employing cementoblasts indicated that Ank and Enpp1 mRNA levels increased in step with mineral nodule formation, supporting a role for these factors in regulation of cementum matrix mineralization. CONCLUSION: ANK, by modulating local PP(i), controls cervical cementum apposition and extracellular matrix. Loss of ANK created a local environment conducive to rapid cementogenesis; therefore, approaches modulating PP(i) in periodontal tissues have potential to promote cementum regeneration.

Rotenoids mediate potent cancer chemopreventive activity through transcriptional regulation of ornithine decarboxylase.

For the discovery of new cancer chemopreventive agents, we have studied the potential of plant extracts to inhibit phorbol ester-induced ornithine decarboxylase (ODC) activity in cell culture. Four active rotenoids were obtained from the African plant Mundulea sericea (Leguminosae). These isolates were highly potent when evaluated for inhibition of chemically induced preneoplastic lesions in mammary organ culture and inhibition of papillomas in the two-stage mouse skin model, and they appear to function by a unique mechanism at the level of ODC messenger RNA expression. Based on our findings, rotenoids can be regarded as promising new chemopreventive or anticancer agents.

Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis.

As a result of bioassay-guided fractionation, betulinic acid, a pentacyclic triterpene, was identified as a melanoma-specific cytotoxic agent. In follow-up studies conducted with athymic mice carrying human melanomas, tumour growth was completely inhibited without toxicity. As judged by a variety of cellular responses, antitumour activity was mediated by the induction of apoptosis. Betulinic acid is inexpensive and available in abundant supply from common natural sources, notably the bark of white birch trees. The compound is currently undergoing preclinical development for the treatment or prevention of malignant melanoma.

Dentoalveolar Defects in the Hyp Mouse Model of X-linked Hypophosphatemia.

Mutations in PHEX cause X-linked hypophosphatemia (XLH), a form of hypophosphatemic rickets. Hyp (Phex mutant) mice recapitulate the XLH phenotype. Dental disorders are prevalent in individuals with XLH; however, underlying dentoalveolar defects remain incompletely understood. We analyzed Hyp mouse dentoalveolar defects at 42 and 90 d postnatal to comparatively define effects of XLH on dental formation and function. Phex mRNA was expressed by odontoblasts (dentin), osteocytes (bone), and cementocytes (cellular cementum) in wild-type (WT) mice. Enamel density was unaffected, though enamel volume was significantly reduced in Hyp mice. Dentin defects in Hyp molars were indicated histologically by wide predentin, thin dentin, and extensive interglobular dentin, confirming micro-computed tomography (micro-CT) findings of reduced dentin volume and density. Acellular cementum was thin and showed periodontal ligament detachment. Mechanical testing indicated dramatically altered periodontal mechanical properties in Hyp versus WT mice. Hyp mandibles demonstrated expanded alveolar bone with accumulation of osteoid, and micro-CT confirmed decreased bone volume fraction and alveolar bone density. Cellular cementum area was significantly increased in Hyp versus WT molars owing to accumulation of hypomineralized cementoid. Histology, scanning electron microscopy, and nanoindentation revealed hypomineralized "halos" surrounding Hyp cementocyte and osteocyte lacunae. Three-dimensional micro-CT analyses confirmed larger cementocyte/osteocyte lacunae and significantly reduced perilacunar mineral density. While long bone and alveolar bone osteocytes in Hyp mice overexpressed fibroblast growth factor 23 (Fgf23), its expression in molars was much lower, with cementocyte Fgf23 expression particularly low. Expression and distribution of other selected markers were disturbed in Hyp versus WT long bone, alveolar bone, and cementum, including osteocyte/cementocyte marker dentin matrix protein 1 (Dmp1). This study reports for the first time a quantitative analysis of the Hyp mouse dentoalveolar phenotype, including all mineralized tissues. Novel insights into cellular cementum provide evidence for a role for cementocytes in perilacunar mineralization and cementum biology.

Primary structure and functional activity of a phosphatidylinositol-glycan-specific phospholipase D.

A phosphatidylinositol-glycan-specific phospholipase D (PI-G PLD) that specifically hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol-glycans (PI-Gs) has recently been purified from human and bovine sera. The primary structure of bovine PI-G PLD has now been determined and the functional activity of the enzyme has been studied. Expression of PI-G PLD complementary DNA in COS cells produced a protein that specifically hydrolyzed the inositol phosphate linkage of the PI-G anchor. Cotransfection of PI-G PLD with a PI-G-anchored protein resulted in the secretion of the PI-G-anchored protein. The results suggest that the expression of PI-G PLD may influence the expression and location of PI-G-anchored proteins.

Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.

Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.

Aberrant cementum phenotype associated with the hypophosphatemic hyp mouse.

BACKGROUND: Cementogenesis is sensitive to altered local phosphate levels; thus, we hypothesized a cementum phenotype, likely of decreased formation, would be present in the teeth of X-linked hypophosphatemic (Hyp) mice. Mutations in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (Phex) cause X-linked hypophosphatemia, characterized by rickets, osteomalacia, and hypomineralized dentin formation, a phenotype recapitulated in the Hyp mouse homolog. Here, we report a developmental study of tooth root formation in Hyp mouse molars, focusing on dentin and cementum. METHODS: Light and transmission electron microscopy were used to study molar tissues from wild-type (WT) and Hyp mice. Demineralized and hematoxylin and eosin-stained tissues at developmental stages 23 to 96 days postcoital (dpc) were examined by light microscopy. Immunohistochemistry methods were used to detect bone sialoprotein (BSP) distribution in Hyp and WT mouse molar tissues, and transmission electron microscopy was used to study similar molar tissues in the non-demineralized state. RESULTS: Dentin in Hyp mice exhibited mineralization defects by 33 dpc, as expected, but this defect was partially corrected by 96 dpc. In support of our hypothesis, a cementum phenotype was detected using a combination of immunohistochemistry and transmission electron microscopy, which included thinner BSP-positive staining within the cementum, discontinuous mineralization, and a globular appearance compared to WT controls. CONCLUSION: Mutations in the phosphate-regulating Phex gene of the Hyp mouse resulted in defective cementum development.