Impact of Establishing Dental Access for Preventable Infectious Dental Diseases (PIDD) in Medical Settings: Case Study from Rural Wisconsin.

OBJECTIVE: The frequency of Preventable Infectious Dental Disease (PIDD) visits in medical centers was examined pre and post establishment of expanded dental access and adoption of an integrated medical-dental care delivery model. METHODS: A retrospective observational study of patient attributes and frequency of unscheduled PIDD visits between January 1, 1990 and February 29, 2020. Chi-squared tests compared (a) the number of PIDD visits (pre/post dental center establishment), (b) age at first diagnosis, (c) gender, (d) race, (e) primary insurance at the time of PIDD visits and (f) healthcare setting where visit occurred. RESULTS: System-wide, 21,957 unique patients were documented with a total of 34,892 PIDD visits as the primary diagnosis. Patients between 18-30 years and patients with Medicaid had the highest frequency of PIDD visits in medical settings. Following the establishment of dental centers, reduced relative risk of PIDD visits was observed for patients with no health insurance or self-pay/other coverage. PIDD visits in primary care settings was 0.87 times as likely as PIDD visits at ED/UCs after dental centers opened. CONCLUSIONS: The number of PIDD visits to medical centers increased before the dental infrastructure was established, followed by a decline afterwards, inclusive of disparity populations. Some residual persistence of PIDD visits to primary care settings was identified. This study reinforced importance of dental healthcare access for achieving appropriate PIDD management while reducing PIDD visits to medical settings.

Oral and Craniofacial Anomalies of Bardet-Biedl Syndrome: Dental Management in the Context of a Rare Disease.

Standardized guidelines for the oral health management of patients with rare diseases exhibiting morphologic anomalies are currently lacking. This review considers Bardet-Biedl syndrome (BBS), a monogenic autosomal recessive nonmotile ciliopathy, as an archetypal condition. Dental anomalies are present in a majority of individuals affected by BBS due to abnormal embryonic orofacial and tooth development. Genetically encoded intrinsic oral structural anomalies and heterogeneous BBS clinical phenotypes and consequent oral comorbidities confound oral health management. Since the comorbid spectrum of BBS phenotypes spans diabetes, renal disease, obesity, sleep apnea, cardiovascular disease, and cognitive disorders, a broad spectrum of collateral oral disease may be encountered. The genetic impact of BBS on the anatomic development of oral components and oral pathology encountered in the context of various BBS phenotypes and their associated comorbidities are reviewed herein. Challenges encountered in managing patients with BBS are highlighted, emphasizing the spectrum of oral pathology associated with heterogeneous clinical phenotypic expression. Guidelines for provision of care across the spectrum of BBS clinical phenotypes are considered. Establishment of integrated medical-dental delivery models of oral care in the context of rare diseases is emphasized, including involvement of caregivers in the context of managing these patients with special needs.

Long-term cardiac and vascular disease outcomes following adjuvant tamoxifen therapy: current understanding of impact on physiology and overall survival.

The relative impact of tamoxifen therapy in women with breast cancer on overall survival, especially as it pertains to cardiac and cardiovascular outcomes, remains under debate in the literature. This review focuses specifically on outcomes of studies that examined large clinical trials with longest duration in patient follow-up relative to these parameters in which compliance with therapy could be documented. Over time, evidence supports potential cardioprotective effects and capacity of adjuvant therapy to improve lipid profiles in women treated with tamoxifen. While some benefit to cardiac health is supported, outcomes related to cardiovascular events remain variable across studies and challenging to interpret. In summary, overall survival in women treated with tamoxifen over time has increasingly shown a trend towards positive outcomes in the context of evaluation of post-treatment cardiac and vascular health. Potential mechanisms underlying the cardioprotective effects of tamoxifen are briefly discussed.

The oral-systemic personalized medicine model at Marshfield Clinic.

Periodontal disease and diabetes, two diseases that have achieved epidemic status, share a bidirectional relationship driven by micro-inflammatory processes. The present review frames the current understanding of the pathological processes that appear to link these diseases and advances the hypothesis that reversal of the epidemic is possible through application of interdisciplinary intervention and advancement of oral-systemic personalized medicine. An overview of how Marshfield Clinic's unique clinical, informatics and bio-repository resources and infrastructures are being aligned to advance oral-systemic personalized medicine is presented as an interventional model with the potential to reverse the epidemic trends seen for these two chronic diseases over the past several decades. The overall vision is to engineer a transformational shift in paradigm from 'personalized medicine' to 'personalized health'.

Recurrent venous thromboembolism in patients with and without anticoagulation after inferior vena caval filter placement.

AIM: The aim of this study was to compare the rate of recurrent venothromboembolic (VTE) events and factors contributing to VTE events in patients with inferior vena caval (IVC) filters on chronic anticoagulation to those in whom anticoagulation was discontinued. METHODS: Retrospective cohort study of 353 patients who received IVC filters between 1986 and 2002. RESULTS: Anticoagulation status was available for 304 patients (132 on coumadin anticoagulation therapy and 172 who did not receive any anticoagulation therapy) whose IVC filters were placed within 30 days of their qualifying thromboembolic event. Two-year event-free survival for the anticoagulated group was 80.6% (95% confidence interval--CI--76.9, 84.3] and was 67.8% (95% CI 63.2, 72.3) for the non-anticoagulated group. Patients who had Greenfield filter had a higher, but not statistically significant different, rate of recurrence compared to those with other types of filters (hazard ratio 1.4; 95% CI 0.9, 2). The rate of recurrent VTE events was independent of age, gender, smoking status, or underlying medical condition. CONCLUSIONS: Among those with IVC filters, long-term anticoagulation therapy prolonged event-free survival for up to 2 years but did not prevent recurrent VTE events.

An analysis of PAX1 in the development of vertebral malformations.

An analysis of PAX1 in the development of vertebral malformations. Due to the sporadic occurrence of congenital vertebral malformations, traditional linkage approaches to identify genes associated with human vertebral development are not possible. We therefore identified PAX1 as a candidate gene in vertebral malformations and congenital scoliosis due to its mutation in the undulated mouse. We performed DNA sequence analysis of the PAX1 gene in a series of 48 patients with congenital vertebral malformations, collectively spanning the entire vertebral column length. DNA sequence coding variants were identified in the heterozygous state in exon 4 in two male patients with thoracic vertebral malformations. One patient had T9 hypoplasia, T12 hemivertebrae and absent T10 pedicle, incomplete fusion of T7 posterior elements, ventricular septal defect, and polydactyly. This patient had a CCC (Pro)-->CTC (Leu) change at amino acid 410. This variant was not observed in 180 chromosomes tested in the National Institute of Environmental Health Sciences (NIEHS) single nucleotide polymorphism (SNP) database and occurred at a frequency of 0.3% in a diversity panel of 1066 human samples. The second patient had a T11 wedge vertebra and a missense mutation at amino acid 413 corresponding to CCA (Pro)-->CTA (Leu). This particular variant has been reported to occur in one of 164 chromosomes in the NIEHS SNP database and was found to occur with a similar frequency of 0.8% in a diversity panel of 1066 human samples. Although each patient's mother was clinically asymptomatic and heterozygous for the respective variant allele, the possibility that these sequence variants have clinical significance is not excluded.

Risk assessment model for venothromboembolism in post-hospitalized patients.

AIM: Venothromboembolism (VTE) is an important condition in hospitalized patients accounting for significant morbidity and mortality, and the risk of VTE often continues post-hospitalization. Although risk assessment models have been developed to predict the risk of deep venous thrombosis (DVT) in hospitalized patients, no models have been developed that determine the risk of DVT during the post-hospitalization period. The objective of this study was to create a risk profile using risk factor assessment that could be used to predict which patients are at highest risk of developing DVT within 60 days following hospital discharge. METHODS: The computerized medical records of 380 patients (190 with DVT and 190 without DVT) who received care from 1995-2002 and were subsequently re-hospitalized within 60 days of discharge were retrospectively reviewed. Univariate and multivariate logistic regression analyses were conducted to identify risk variables related to VTE. A novel risk assessment model was created using risk factors from the logistic regression analyses. RESULTS: The prevalence of VTE was found to be 93.2% (69/74) in the high-risk category, 52.9% (109/206) in the moderate-risk category, and 12% (12/100) in the low-risk category. CONCLUSIONS: Once validated, this risk assessment model may be applied to identify patients who may be at increased risk of developing VTE post-hospitalization. Those at high risk should be considered for anticoagulation therapy during the post-hospitalization period. Availability of a risk profile using risk factor assessment to guide decisions related to anticoagulation therapy will have important ramifications relative to patient outcomes including morbidity, mortality, and reductions in VTE-associated cost.

Overview of risk factors for periodontal disease and implications for diabetes and cardiovascular disease.

Recent studies have shown that there is a definite relationship between diseases of the oral cavity, especially periodontal infections, and systematic diseases. Periodontal disease may also produce systemic effects in the body, including an association with cardiovascular disease. This article discusses the risk factors for periodontal disease, the pathogenesis and risk factors for cardiovascular disease, the relationship between periodontal infection and cardiovascular disease, and the need for future studies to further define the relationship between periodontal disease and cardiovascular disease.

Cloning, expression, and sequencing of a cell surface antigen containing a leucine-rich repeat motif from Bacteroides forsythus ATCC 43037.

Bacteroides forsythus is a recently recognized human periodontopathogen associated with advanced, as well as recurrent, periodontitis. However, very little is known about the mechanism of pathogenesis of this organism. The present study was undertaken to identify the surface molecules of this bacterium that may play roles in its adherence to oral tissues or triggering of a host immune response(s). The gene (bspA) encoding a cell surface-associated protein of B. forsythus with an apparent molecular mass of 98 kDa was isolated by immunoscreening of a B. forsythus gene library constructed in a lambda ZAP II vector. The encoded 98-kDa protein (BspA) contains 14 complete repeats of 23 amino acid residues that show partial homology to leucine-rich repeat motifs. A recombinant protein containing the repeat region was expressed in Escherichia coli, purified, and utilized for antibody production, as well as in vitro binding studies. The purified recombinant protein bound strongly to fibronectin and fibrinogen in a dose-dependent manner and further inhibited the binding of B. forsythus cells to these extracellular matrix (ECM) components. In addition, adult patients with B. forsythus-associated periodontitis expressed specific antibodies against the BspA protein. We report here the cloning and expression of an immunogenic cell surface-associated protein (BspA) of B. forsythus and speculate that it mediates the binding of bacteria to ECM components and clotting factors (fibronectin and fibrinogen, respectively), which may be important in the colonization of the oral cavity by this bacterium and is also a target for the host immune response.

Streptococcus-mutans-induced nephritis in rabbits: rheumatoid factors and nephritogenicity.

The pathogenesis of streptococcus-induced nephritides (SIN) involves immune complex-mediated inflammation; however, specific mechanisms are still poorly understood. Using preparations of two strains of Streptococcus mutans (SM) in attempts to induce SIN in rabbits, one preparation was strongly and the other virtually not nephritogenic. The non-nephritogenic preparation provided a negative control for our studies. Streptococcal components were present in circulating immune complexes (CIC) as well as in tissue-bound immune complexes (TIC), especially early in the disease. CIC and TIC also contained rheumatoid factors (RF), which tended to predominate in late stages of the disease. The nephritogenic and the non-nephritogenic preparations of SM shared the same major tissue-binding components and induced similar titers of antimicrobial antibodies, but differed significantly in their ability to induce CIC and RF. It is proposed that kidney-binding microbial components, antimicrobial antibodies and high serum concentration of RF are necessary and sufficient determinants for the pathogenesis of SIN in this rabbit model.

Identification of Streptococcus pyogenes proteins that bind to rabbit kidney in vitro and in vivo.

Proteins were extracted from the surface of a nephritogenic strain of Streptococcus pyogenes M12 and tested for binding to rabbit kidney using indirect immunofluorescence and enzyme-linked immunoassays. Streptococcal antigens bound in vitro in a fine linear pattern to basal laminae of glomeruli, Bowman's capsule, and tubules. Perfusion of rabbit kidney in vivo with streptococcal components resulted in focal and segmental fine granular staining of glomerular capillaries. Three streptococcal proteins (43, 31 and 9 kDa) were recovered from renal tissue that was pretreated in vitro with S. pyogenes extract. Streptococcal components bound in vitro to heparan sulfate, heparin, laminin and collagen IV but only weakly or not at all to fibronectin, bovine serum albumin or dextran sulfate. Affinity chromatography of bacterial extracts on heparin-agarose produced a 9 kDa streptococcal protein (pI 9.5) which bound to kidney basement membranes in vitro and in isolated perfused kidneys. Several additional strains of group A streptococci were found to contain the 9 kDa cationic protein. This bacterial protein, when released into the blood by the bacterium during infection, may contribute to the pathogenesis of streptococcus-associated nephritides in man.

Induction by transforming growth factor beta of pemphigus vulgaris antigen activity in mouse papilloma cells.

Induction of a marker of epidermal spinous cells, pemphigus antigen activity, was detected by indirect immunofluorescence in murine papilloma cells exposed to human transforming growth factor beta (TGF-beta). Detection of pemphigus antigen activity required exposure of cells to 1.4 mM Ca2+ for 3 h just prior to immunoassay. The brief exposure to Ca2+ may be necessary for translocation of intracellular pemphigus antigen to the cell surface, where it is accessible to antibody. Cells grown in medium containing 0.02-0.04 mM Ca2+ were shown previously to be primarily basal cells characterized by pemphigoid antigen activity. Following treatment with 0.25-25 pg/ml TGF-beta for 44 h under 0.02-0.04 mM Ca2+ conditions, 63 +/- 9% (SD) of cells were pemphigus positive. This percentage was comparable to that of positive control cultures exposed to 1.4 mM Ca2+ for 44 h (70 +/- 10%) and was up to 2-fold that of solvent control cultures. Pemphigus antigen activity was significantly induced by 0.1-25 pg/ml TGF-beta, out of a tested range of 10(-5)-10(3) pg/ml. The total number of papilloma cell colonies was unaffected by treatment with 0.1-25 pg/ml TGF-beta but was reduced greater than 90% by treatment with 10(3)-5 x 10(3) pg/ml TGF-beta. The described immunofluorescence assay for pemphigus antigen activity may be useful for preliminary evaluation of differentiation-inducing agents in anticarcinoma therapy.

Pemphigoid, pemphigus and desmoplakin as antigenic markers of differentiation in normal and tumorigenic mouse keratinocyte lines.

The expression of differentiation stages in a murine epidermal cell transformation model has been investigated as a basis for studies of chemically-induced differentiation. Antibodies in sera of patients with the autoimmune diseases bullous pemphigoid and pemphigus vulgaris exhibit specific reactivity to antigenic determinants of basal and spinous cells, respectively, in sections of mouse and human epidermis. In addition, spinous cells in epidermis are reactive with a mouse monoclonal antibody to desmoplakin, a desmosomal component immunologically distinct from pemphigus. These antibodies were used to identify and attempt to quantify keratinocyte subpopulations in culture based on differentiation stage. Epidermal cell lines were cultured under conditions which favour proliferation (0.02 to 0.04 mM extracellular Ca2+, i.e. low Ca2+ conditions) or differentiation (0.1 mM to 1.4 mM Ca2+), as previously shown using primary cultures of mouse keratinocytes. Two independently-derived normal keratinocyte lines demonstrated Ca2(+)-dependent reactivity with pemphigoid and pemphigus antiserum, like that which has been observed in primary cultures. Furthermore, a Ca2+ and time-dependent reactivity with the three antisera was also observed in a papilloma cell line (derived from one of the normal cell lines after treatment in vitro with 7,12-dimethylbenz[alpha]anthracene). Papilloma cells cultured under conditions of low extracellular Ca2+ were comprised of three subpopulations: cells reactive only with pemphigoid anti-serum, cells reactive only with desmoplakin antibody. However, like the normal cell lines, papilloma cells underwent a transition to predominantly a spinous cell population (i.e. reactive with pemphigus and desmoplakin antibody) in response to extracellular Ca2+. A slower loss of pemphigoid antibody reactivity was noted in papilloma cells, consistent with an abnormal regulation of differentiation. The attempt to characterize these dynamic transitions from basal to spinous cell subpopulations in culture was considered to be prerequisite for the use of the model to investigate differentiation-inducing agents in carcinoma therapy.

Streptococcus mutans-induced nephritis in rabbits.

Intravenous administration of disrupted Streptococcus mutans into rabbits over 23-76 weeks led to severe nephritis involving glomeruli, tubules, and interstitium. Light-microscopic observation of glomeruli documented diffuse endocapillary proliferative glomerulonephritis accompanied often (65%) by epithelial crescents. Electron-microscopic observation revealed humps in glomeruli of 70% of kidney specimens. In the glomeruli of some rabbits, extensive fibrin deposits and sclerosis were evident. Immunofluorescence showed linear, granular, often ribbonlike or patchy immune deposits encompassing, in order of decreasing frequency, C3, IgG, streptococcal antigen, IgA, and IgM. The histopathologic and immunohistologic features of the nephritis seen in rabbits given S mutans thus shows many features of Streptococcus-associated nephritides in man, in particular, the diffuse glomerular nephritis encountered in subacute bacterial endocarditis. Further, analysis of nephritis induced by administration of S mutans may have implications for the evaluation and purification of dental caries vaccines.

Dissociation of immune complexes in tissue sections by excess of antigen.

Immune complexes (IC) present in the glomeruli of rabbits with chronic serum sickness (CSS) and in patients with systemic lupus erythematosus (SLE), idiopathic membranous nephropathy (IMN), and acute poststreptococcal glomerulonephritis (PSGN) were analyzed by incubation with antigenic preparations. The efficacy of these preparations to dissolve IC was assayed by comparison of results of direct immunofluorescence tests performed with the kidney tissues before and after incubation with antigenic preparations. The FITC-conjugated antisera used in these tests were specific for IgG, C3, and-in the case of CSS-for the eliciting antigen, bovine serum albumin (BSA). During the acute proteinuric phase of CSS in rabbits, incubation of tissue sections with BSA alone led to complete dissolution of IC. In many rabbits with late phase proteinuria, however, tissues had to be incubated with both BSA and aggregated fraction II of rabbit serum. In all biopsy specimens from patients with IMN, and in some specimens from patients with PSGN and SLE, aggregated fraction II of human serum resulted in complete or incomplete dissolution of IC. On the other hand, incubation of tissues with excess DNA in SLE or with streptococcal antigens PSGN did not lead to dissolution of IC. These studies suggest significant participation of antibodies to aggregated immunoglobulins (i.e., rheumatoid factors or rheumatoid-like factors) in IC found in the above-mentioned diseases. Other antigen -antibody systems, however, may also contribute to the deposits in the glomerulonephritides studied.