Modulation of matrix metalloproteinase activities in periodontitis as a treatment strategy.
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Alveolar Bone Loss↗
Biomedical subjects
M E Ryan
Publications and source records attributed to M E Ryan.
A chemically modified nonantimicrobial tetracycline (CMT-8) inhibits gingival matrix metalloproteinases, periodontal breakdown, and extra-oral bone loss in ovariectomized rats.
Estrogen deficiency in the postmenopausal (PM) female is the major cause of osteoporosis and may contribute to increased periodontal disease, including alveolar bone loss, seen in these women. In the current study, an animal model of PM osteoporosis, the OVX adult female rat, was studied to determine: (i) the relationship between periodontal breakdown and skeletal bone loss, and (ii) the effect of CMT-8 on gingival collagenase and bone loss. OVX rats were daily gavaged with CMT-8 (1, 2, or 5 mg/rat) for 28 or 90 days; non-OVX rats and those gavaged with vehicle alone served as controls. Elevated collagenase activity, assessed using [3H-methyl] collagen as substrate in the presence or absence of APMA, was seen in the gingiva of the OVX rats, and CMT-8 therapy suppressed this effect. Western blot revealed a similar pattern for MMP-8 and MMP-13 concentrations. The changes in the gingival collagenase activity paralleled changes in periodontal bone loss, which, in turn, reflected trabecular bone density changes. Preliminary studies on PM humans administered sub-antimicrobial tetracycline as a matrix metalloproteinase inhibitor are under way.
Alveolar Bone Loss↗
MMP-mediated events in diabetes.
Both Type I and Type II diabetes mellitus (DM) have been associated with unusually aggressive periodontitis. Accordingly, rat models of both types of DM were used to study (i) mechanisms mediating this systemic/local interaction and (ii) new pharmacologic approaches involving a series of chemically modified tetracyclines (CMTs) that have lost their antimicrobial but retained their host-modulating (e.g., MMP-inhibitory) properties. In vitro experiments on tissues from Type I DM rats demonstrated that several of these CMTs were better matrix metalloproteinase (MMP) inhibitors than was antibacterial doxycycline (doxy), except for CMT-5, which, unlike the other MMP inhibitors, was found not to react with zinc. Data from in vivo studies on the same rat model generally supported the relative efficacy of these compounds: the CMTs and doxy were found to inhibit MMP activity, enzyme expression, and alveolar bone loss. To examine other long-term complications such as nephropathy and retinopathy, a Type II (ZDF) model of DM was studied. Treatment of these DM rats with CMT-8 produced a 37% (p < 0.05), 93% (p < 0.001), and 50% (p < 0.01) reduction in the incidence of cataract development, proteinuria, and tooth loss, respectively; whereas the doxy-treated ZDF rats showed little or no effect on these parameters. CMT treatment decreased mortality of the Type II ZDF diabetic animals, clearly indicating that CMTs, but not commercially available antibiotic tetracyclines (TCs), may have therapeutic applications for the long-term management of diabetes.
Alveolar Bone Loss↗
CMT-8/clodronate combination therapy synergistically inhibits alveolar bone loss in LPS-induced periodontitis.
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Alveolar Bone Loss↗
Same-day discharge after endoscopic biliary sphincterotomy: observations from a prospective multicenter complication study. The Multicenter Endoscopic Sphincterotomy (MESH) Study Group.
BACKGROUND: Same-day discharge after endoscopic biliary sphincterotomy (ES) is a common clinical practice, but there have been few data to guide appropriate selection of patients. Using a prospective, multicenter database of complications, we examined outcomes after same-day discharge as it was practiced by a variety of endoscopists and evaluated the ability of a multivariate risk factor analysis to predict which patients would require readmission for complications. METHODS: A 150-variable database was prospectively collected at time of ES, before discharge and again at 30 days in consecutive patients undergoing ES at 17 centers. Complications were defined by consensus criteria and included all specific adverse events directly or indirectly related to ES requiring more than 1 night of hospitalization. RESULTS: Six hundred fourteen (26%) of 2347 patients undergoing ES were discharged on the same day as the procedure, ranging from none at 6 centers to about 50% at 2 centers. After initial observation and release, readmission to the hospital for complications occurred in 35 (5.7%) of 614 same-day discharge patients (20 pancreatitis and 15 other complications, 3 severe). Of the same-day discharge patients, readmission was required for 14 (12.2%) of 115 who had at least one independently significant multivariate risk factor for overall complications (suspected sphincter of Oddi dysfunction, cirrhosis, difficult bile duct cannulation, precut sphincterotomy, or combined percutaneous-endoscopic procedure) versus 21 (4.2%) of 499 without a risk factor (odds ratio 3.1: 95% confidence interval [1.6, 6.3], p < 0.001). Of complications presenting within 24 hours after ES, only 44% presented within the first 2 hours, but 79% presented within 6 hours. CONCLUSIONS: Same-day discharge is widely utilized and relatively safe but results in a significant number of readmissions for complications. For patients at higher risk of complications, as indicated by the presence of at least one of five independent predictors, observation for 6 hours or overnight may reduce the need for readmission.
Adult↗
RSV infection in infants and young children. What's new in diagnosis, treatment, and prevention?
RSV is the most important respiratory pathogen in infants and young children. About 1% of primary RSV infections result in hospitalization. The virus is spread by large droplets of secretions or contact with contaminated secretions. Infants infected with RSV may demonstrate poor feeding, rhinorrhea, apnea, lethargy, wheezing, and respiratory distress. Diagnosis may be made by clinical signs and symptoms (especially those observed during epidemics), by chest radiographs showing hyperinflation, or by rapid antigen detection with immunofluorescence of nasopharyngeal aspirates. Risk factors for severe disease accompanied by complications include chronic heart disease, chronic lung disease, immunodeficiency, HIV, and prematurity. Immunity is incomplete and of short duration, and reinfection is common. Treatment remains supportive and consists of oxygen administration, hydration, and diligent monitoring. Use of corticosteroids, bronchodilators, antibiotics, and ribavirin is controversial and is dependent largely on physician preference. Use of ribavirin should be reserved for patients who have severe underlying conditions associated with increased mortality rates. Intravenous RSV Ig has been replaced by palivizumab, which is generally recommended for infants at high risk for severe RSV, including those with a history of prematurity and those with chronic lung disease.
Anti-Bacterial Agents↗
Endoscopic intervention for biliary leaks after laparoscopic cholecystectomy: a multicenter review.
BACKGROUND: Endoscopic therapy of biliary tract leaks was uncommon before laparoscopic cholecystectomy. Studies have demonstrated the efficacy of endoscopic drainage by endoscopic sphincterotomy or stent placement. Various endoscopic therapeutic modalities and long-term follow-up of this problem were studied. METHODS: Members of the Midwest Pancreaticobiliary Group reviewed all patients referred for endoscopic therapy of biliary leaks after laparoscopic cholecystectomy from 1990 to 1994. Long-term follow-up was by direct patient contact. RESULTS: Fifty patients were referred for endoscopic therapy of biliary leaks. Abdominal pain was present in 94%. The mean time from laparoscopic cholecystectomy to referral was 6.9 days. Therapy consisted of sphincterotomy only in 6 patients, stent only in 13, and sphincterotomy with stent in 31. Biliary leaks were healed in 44 patients at a mean of 5.4 weeks. A second or third endoscopic procedure was necessary to achieve healing in five patients. Two stent-related complications were noted. Percutaneous or surgical drainage of biliary fluid collections was required in 16 patients. The mean hospital stay for treatment of the leak was 11.1 days after endoscopic therapy. On follow-up (mean 17.5 months), all patients were well except two with mild abdominal discomfort. CONCLUSIONS: Endoscopic sphincterotomy, stent placement, or sphincterotomy with stent are effective in healing biliary leaks after laparoscopic cholecystectomy. Despite prolonged treatment for the leak, patients did well on long-term follow-up.
Bile↗
Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms.
A seminal experiment involving a germ-free rat model of connective tissue breakdown (followed soon thereafter by a series of in vitro studies) identified an unexpected non-antimicrobial property of tetracyclines (TCs). This ability of TCs to inhibit matrix metalloproteinases (MMPs) such as collagenase was found to reflect multiple direct and indirect mechanisms of action, and to be therapeutically useful in a variety of dental (e.g., adult periodontitis) and medical (e.g., arthritis, osteoporosis, cancer) diseases. The site on the TC molecule responsible for its MMP-inhibitory activity was identified which led to the development of a series of chemically modified non-antimicrobial analogs, called CMTs, which also have therapeutic potential but do not appear to induce antibiotic side-effects. Longitudinal double-blind studies on humans with adult periodontitis have demonstrated that a sub-antimicrobial dose of doxycycline (previously reported to suppress collagenase activity in the periodontal pocket) is safe and effective and has recently been approved by the FDA as an adjunct to scaling and root planing.
Animals↗
How do tetracyclines work?
This paper is a summary of a panel discussion by the following panelists: L. Golub, J. te Koppele, G. Nieman, M. Nelson, R. Ashley, T. Sorsa, and S. Simon. The panel discussed the mechanisms by which the tetracyclines and their non-antimicrobial counterparts may provide therapeutic efficacy in a variety of chronic and acute diseases.
Adult↗
Tetracyclines inhibit protein glycation in experimental diabetes.
Glycation of proteins, which is accelerated in the diabetic state, has been implicated in many of the long-term complications of diabetes. This process can be inhibited by members of the tetracycline family of compounds. This novel finding is supported by studies conducted on drug (streptozotocin)induced Type I and genetic (ZDF/Gmi-fa/fa) Type II diabetic rats. These animals were orally gavaged daily with 5 mg of doxycycline and a variety of non-antimicrobial chemically modified tetracycline derivatives for time periods of 3 weeks to 11 months, while control untreated diabetic and nondiabetic animals were gavaged with vehicle alone (2% CMC). Blood and tissue samples were collected and analyzed for glucose and glycated proteins. None of the treatments had any effect on the severity of hyperglycemia or the intracellular glycation of hemoglobin of either Type I or II diabetic animals. However, the tetracycline analogues did affect the extracellular glycation of several proteins such as those found in the serum as well as skin collagen. In the Type II (ZDF) animals, initial mortality (3-5 months) was seen only in the doxycycline-treated animals, associated with infection by tetracycline-resistant micro-organisms, which was eventually surpassed by mortality rates in the untreated diabetics (6-9 months). CMT treatment not only decreased mortality but also increased longevity in the Type II diabetic animals, most likely by preventing the development of a number of long-term complications of uncontrolled diabetes, including glycation of proteins, that eventually lead to the demise of untreated diabetic animals.
Analysis of Variance↗
Modulation of the host response in the treatment of periodontitis.
Periodontitis has two distinct but interconnected etiologic components: periodontopathic bacteria adjacent to the periodontal tissues, and host-mediated connective tissue-destructive responses to the specific causative bacteria and their metabolic products. Although past and existing therapies have focused primarily on the causative microbial challenge, the host component of periodontal destruction has recently been intensely studied. New treatment strategies that focus on attenuating destructive host responses are emerging. Host modulatory agents, when used adjunctively, may enhance clinical therapeutic responses and make these responses more predictable in the susceptible host. The ongoing development of safe, effective pharmacotherapies that specifically target host response mechanisms, and the introduction of such pharmacotherapies as adjuncts to traditional, antimicrobial interventions may represent a new, integrated approach in the long-term treatment and management of this chronic disease.
Anti-Inflammatory Agents, Non-Steroidal↗
A matrix metalloproteinase inhibitor reduces bone-type collagen degradation fragments and specific collagenases in gingival crevicular fluid during adult periodontitis.
OBJECTIVE AND DESIGN: To determine whether an inhibitor of matrix metalloproteinases (MMPs), administered to human subjects in a dental school research clinic, can reduce bone-type collagen degradation fragments in oral inflammatory exudates containing excessive levels of collagenase. MATERIALS AND SUBJECTS: Gingival crevicular fluid (GCF) was collected from 18 subjects with adult periodontitis whose clinical findings (gingival inflammation, pocket depth, and bone loss on radiographs) predicted excessive MMP activity in their periodontal pockets. TREATMENT: One month before the baseline appointment, plaque and calculus were removed from the teeth by supra- and subgingival scaling. After collection of GCF from 8-12 pocket sites per subject and recording of clinical indices, 12 of the 18 subjects were treated with doxycycline at a low dosage (20 mg b.i.d.) known via an extensive literature to suppress mammalian MMP activity by a non-antimicrobial mechanism. The remaining 6 subjects were followed without drug treatment. METHODS: At the baseline, 1 and 2-month appointments, GCF samples were analyzed for ICTP. (carboxyterminal peptide, a pyridinoline-containing fragment of Type I collagen) and osteocalcin by radioimmunoassay, as well as collagenolytic enzyme activity and MMP species (Western blot). Statistical analyses were determined by ANOVA. RESULTS: GCF ICTP and functional collagenase activity (but not osteocalcin levels) were significantly reduced (p < 0.05) in the doxycycline-treated subjects at both 1 and 2 month evaluations: there was no such change in the non-treated subjects. Western blots revealed that neutrophil-type collagenase (MMP-8) was the predominant MMP; MMP-13, which has been associated with pathologic collagenolysis including bone resorption, was detected in human GCF for the first time and was more substantially reduced than MMP-8. CONCLUSION: This is the first demonstration in human subjects of the simultaneous reduction of excessive MMP activity with concomitant reduction in levels of collagen degradation fragments. The findings are potentially applicable to a wide variety of human diseases characterized by excessive collagenase activity.
Adult↗
Pitfalls in diagnosis of Lyme disease. What you need to know about serologic testing.
Lyme disease can be difficult to recognize because not all patients have erythema migrans or other classic symptoms. Therefore, laboratory testing has become an important aid to clinical diagnosis. But the story doesn't end there-serologic testing presents another set of problems and concerns. Drs. Still and Ryan explain how aspects of the disease itself and various factors inherent in the available tests can affect laboratory results.
Antibodies, Bacterial↗
Cost-effective management of group A streptococcal pharyngitis.
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Child↗
Complications of endoscopic biliary sphincterotomy.
BACKGROUND: Endoscopic sphincterotomy is commonly used to remove bile-duct stones and to treat other problems. We prospectively investigated risk factors for complications of this procedure and their outcomes. METHODS: We studied complications that occurred within 30 days of endoscopic biliary sphincterotomy in consecutive patients treated at 17 institutions in the United States and Canada from 1992 through 1994. RESULTS: Of 2347 patients, 229 (9.8 percent) had a complication, including pancreatitis in 127 (5.4 percent) and hemorrhage in 48 (2.0 Percent). There were 55 deaths from all causes within 30 days; death was directly or indirectly related to the procedure in 10 cases. Of five significant risk factors for complications identified in a multivariate analysis, two were characteristics of the patients (suspected dysfunction of the sphincter of Oddi as an indication for the procedure and the presence of cirrhosis) and three were related to the endoscopic technique (difficulty in cannulating the bile duct achievement of access to the bile duct by "precut" sphincterotomy, and use of a combined percutaneous-endoscopic procedure). The overall risk of complications was not related to the patient's age, the number of coexisting illnesses, or the diameter of the bile duct. The rate of complications was highest when the indication for the procedure was suspected dysfunction of the sphincter of Oddi (21.7 percent) and lowest when the indication was removal of bile-duct stones within 30 days of laparoscopic cholecystectomy (4.9 percent). As compared with those who performed fewer procedures, endoscopists who performed more than one sphincterotomy per week had lower rates of all complications (8.4 percent vs. 11.1 percent, P=0.03) and severe complications (0.9 percent vs. 2.3 percent, P=0.01). CONCLUSIONS: The rate of complications after endoscopic biliary sphincterotomy can vary widely in different circumstances and is primarily related to the indication for the procedure and to endoscopic technique, rather than to the age or general medical condition of the patients.
Age Factors↗
Elucidation of homeoprotein Cart-1 function during in vitro chondrogenesis of C3H10T1/2 micromass cultures.
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Animals↗
Potential of tetracyclines to modify cartilage breakdown in osteoarthritis.
For several decades, it has been recognized that an imbalance between activated matrix metalloproteinases, generated locally by both infiltrating and resident cells, and their endogenous inhibitors may play a role in the pathologic breakdown of the joint extracellular matrix in osteoarthritis. This understanding has stimulated the search for a number of synthetic matrix metalloproteinase inhibitors that could serve as potential therapeutic agents. Tetracycline analogues are currently on the threshold of approval as anti-matrix metalloproteinases for another extracellular matrix-destructive disease, periodontitis, and this application could be extended to osteoarthritis and rheumatoid arthritis therapy. In this regard, specially formulated low-dose regimens of a commercially available tetracycline, doxycycline, have been used in long-term clinical trials and were found to reduce extracellular matrix breakdown, including bone loss, in adult periodontitis. Matrix metalloproteinase inhibition by tetracycline analogues is now recognized as complex, and multiple mechanisms have been proposed. A series of recently discovered nonantimicrobial chemically modified tetracyclines are potent inhibitors of several classes of matrix metalloproteinases, preventing collagen breakdown and bone loss in a variety of animal models, although these analogues have not yet been approved for human use. Various tetracyclines have reduced the severity of osteoarthritis in animal models, indicating therapeutic potential for this class of compounds in the future.
Animals↗
Oxygen consumption calculated from the Fick equation has limited utility.
OBJECTIVE: To determine if oxygen consumption (VO2) calculated using the Fick relationship (calculated VO2) determines total body VO2 accurately and precisely enough to employ this method during clinical assessment of oxygen transport. DESIGN: Methods comparison, using repeated measures during four physiologic states: normal heart/normal lungs, heart failure/normal lungs, normal heart/acute lung injury, heart failure/acute lung injury. SETTING: University research laboratory. SUBJECTS: Thirteen adult Yucatan pigs. INTERVENTIONS: Oleic acid-induced acute lung injury; heart failure was induced with a continuous infusion of esmolol. MEASUREMENTS AND MAIN RESULTS: Calculated VO2 was determined by multiplying thermodilution cardiac output by the arterialvenous oxygen content difference in anesthetized, spontaneously breathing animals. Conditions were tightly controlled so that calculated VO2 would be as accurate as possible. "True" VO2 was measured simultaneously with a water-sealed spirometer (spirometry VO2). Calculated VO2 and spirometry VO2 were determined and analyzed during the four physiologic states listed above. Pooled data also were evaluated. Mean spirometry VO2 and calculated VO2 differed significantly during all four physiologic states and when data were pooled (spirometry VO2 273 +/- 70, calculated VO2 178 +/- 58 mL/min; p < .01). Calculated VO2 consistently underestimated spirometry VO2, as demonstrated by the large, positive bias in pooled data (95 +/- 59 mL of oxygen/min) and in the four physiologic states. Linear regression of data from all four states yielded slopes that were indistinguishable from 1, but y intercepts that varied from -152 to +182. For pooled data, the following equation was used: calculated VO2 = 0.5 x (spirometry VO2 + 46); r2 = .35. Precision in pooled data was 22% of the mean spirometry VO2. Data analysis for the four physiologic states demonstrated results similar to those results obtained when data were pooled. CONCLUSIONS: Even in a tightly controlled, clinical simulation in the laboratory, calculated VO2 from the Fick relationship systematically underestimated VO2 measured with a water-sealed spirometer. If true VO2 changes, the magnitude and direction of change will be reflected by calculated VO2 but with approximately 20% error in the absolute value. Heart failure, acute lung injury, and their combination did not affect the accuracy of calculated VO2. Therefore, calculating VO2 using the Fick relationship is too inaccurate to be used for research purposes. Because assessment of the directional change of VO2 may be clinically useful, calculated VO2 can be employed with discretion during clinical oxygen transport evaluation, bearing in mind the calculation's inherent imprecision.
Animals↗