Biomedical subjects

S R Simon

Publications and source records attributed to S R Simon.

At least 19 recordsLinked to original sources

PubMed2001

Kinetics of the inhibition of proteinase 3 by elafin.

Excessive proteolytic activity of proteinase 3 (Pr3) has been suggested to be a factor contributing to the pathogenesis of emphysema and other inflammatory disorders. We report here on the kinetics of inhibition of Pr3 by one of its major endogenous inhibitors, the 6-kD inhibitory domain of elafin. The results are consistent with a reaction mechanism in which a single elafin molecule binds a single Pr3 molecule to form a fully reversible complex. The association and dissociation rate constants, and the inhibition constant were measured to be 4.0 x 10(6) M(-1) s(-1), 1.7 x 10(-3) s(-1), and 4.2 x 10(-10) M, respectively. Triton X-100 and dimethyl sulfoxide, which are frequently added in assay mixtures for enzymatic analysis of Pr3 activity, significantly reduced the association rate. A fraction of the total neutrophil content of Pr3 has been reported to be bound to the surface of the plasma membrane of activated and nonactivated neutrophils. In this study, we also measured the reaction rate constants of elafin with Pr3 that had been previously allowed to associate with phospholipid bilayer vesicles. Binding to the model membranes slowed down the association rate to 3.3 x 10(5) M(-1) s(-1), but the membrane-bound Pr3 and elafin formed a more stable complex, with a dissociation rate constant of 9.1 x 10(-4) s(-1). Based on the kinetic parameters determined here and the estimated elafin concentrations in vivo, it may be concluded that elafin plays a limited role in the regulation of proteolytic activity of Pr3 in lung secretions.

Detergents↗

PubMed2001

Inhibition of tumor cell invasiveness by chemically modified tetracyclines.

COLO 205 is a cell line derived from a human colon carcinoma with high degradative activity towards extracellular matrix (ECM). It has been shown that COLO 205 cells produce matrix metalloproteinases (MMPs). MMPs are a family of enzymes known to degrade components of the ECM and have been implicated in tumor invasion. In the present study, we have analyzed the multiple effects of chemically modified tetracyclines (CMTs) on the expression and activity of MMPs secreted by COLO 205 cells in vitro with the aim of evaluating these compounds for potential use in management of invasive tumors. Because COLO 205 cells can degrade an interstitial ECM in serum-free medium in vitro, we have been able to compare the effects of the tetracyclines on this measure of invasive activity with their effects on proteinase expression and activity. We demonstrate here that one of the chemically modified tetracyclines, 6-deoxy-6-demethyl-4-de(dimethylamino)tetracycline (CMT-3) can effectively inhibit ECM degradation mediated by COLO 205 cells or their conditioned medium. Gelatin zymography and immunoblots show that CMT-3 has the ability to inhibit release of MMP-2 into conditioned medium as well as to inhibit MMP-2 gelatinolytic activity, which correlates with the results from ECM degradation assays. On the basis of our findings with COLO 205 cells we have expanded our evaluation of the tetracyclines to include effects on a genetically engineered line of MDA-MB-231 breast tumor cells overexpressing MMP-9 at levels over tenfold those of the parent cell line, and on three human prostate tumor cell lines, LNCaP, DU-145, and PC-3. We show here that CMT-3 displays multiple modes of action: inhibiting MMP activity, reducing levels of MMP expression, and exhibiting selective cytotoxicity towards some of the tumor cell lines.

Antineoplastic Agents↗

PubMed2000

The effect of medical student teaching on patient satisfaction in a managed care setting.

OBJECTIVE: To measure the effect on patient satisfaction of medical student participation in care and the presence of medical student teaching. DESIGN: Prospective cohort study. SETTING: Eight outpatient internal medicine departments of a university-affiliated HMO in Massachusetts. PATIENTS: Two hundred seven patients seen on teaching days (81 patients who saw a medical student-preceptor dyad and 126 patients who saw the preceptor alone), and 360 patients who saw the preceptor on nonteaching days. Five hundred (88%) of 567 eligible patients responded. MEASUREMENTS AND MAIN RESULTS: Thirteen closed-response items on a written questionnaire, measuring satisfaction with specific dimensions of care and with care as a whole. Visit satisfaction was similar among patients on teaching and nonteaching days. Ninety-one percent of patients seeing a medical student, 93% of patients seeing the preceptor alone on teaching days, and 93% of patients on nonteaching days were satisfied or very satisfied with their visit; less than 2% of patients in each group were dissatisfied with their visit. Satisfaction on all measured dimensions of care was similar for patients seeing a medical student, patients seeing the preceptor alone on teaching days, and patients seeing the preceptor on nonteaching days. CONCLUSIONS: Medical student participation and the presence of medical student teaching had little effect on patient satisfaction. Concerns about patient satisfaction should not prevent managed care organizations from participating in primary care education.

Clinical Clerkship↗

PubMed2000

Biomechanical and metabolic effects of varying backpack loading on simulated marching.

Twelve healthy, male Army recruits performed three, 40-min treadmill marches at 6 km/h, under three load carriage conditions: 0%-body weight (BW) backpack load, 15%-BW load and 30%-BW load. Kinematic and kinetic data were obtained, immediately before and after each treadmill march, for computing ankle, knee and hip joint rotations and moments. Metabolic data (oxygen uptake (VO2), expired ventilation (VE), respiratory exchange ratio (RER)), heart rate (HR) and ratings of perceived exertion (RPE) were collected continuously during marching. Significant differences (p < or = 0.05) were observed between each load for VO2, HR and VE throughout the marches. At 40 min, relative energy costs for 0%-BW, 15%-BW and 30%-BW loads were 30, 36 and 41% VO2max, respectively. RPE responses during marching significantly differed for only the 30%-BW load and were greater than responses at 0%-BW and 15%-BW loads. During load carriage trials prior to treadmill marches (pre-march), peaks in internal, hip extension, knee extension and ankle plantar flexion moments increased with increasing backpack load. Relative to 0%-BW load, percentage increases in knee moments, due to 15%-BW and 30%-BW loads, pre-march, were substantially larger than the percentage increases for hip extension and plantar flexion moments, pre-march. Pre-march and post-march peaks in hip extension and ankle plantar flexion moments were similar with all loads, while notable pre-march to post-march declines were observed for knee extension moment peaks, at 15%-BW and 30%-BW load. Pre-march joint loading data suggests that the knee may be effecting substantial compensations during backpack loaded marching, perhaps to attenuate shock or reduce load elsewhere. Post-march kinetic data (particularly at 15%-BW and 30%-BW load), however, indicates that such knee mechanics were not sustained and suggests that excessive knee extensor fatigue may occur prior to march end, even though overall metabolic responses, at 15%-BW and 30%-BW load, remained within generally recommended limits to prevent fatigue during prolonged work.

Adolescent↗

PubMed2000

DNA from bronchial secretions modulates elastase inhibition by alpha(1)-proteinase inhibitor and oxidized secretory leukoprotease inhibitor.

Previously we reported that DNA from sputum promotes the inhibition of human leukocyte elastase (HLE) by native secretory leukoprotease inhibitor (SLPI). This study shows that sputum DNA also promotes the inhibition by oxidized SLPI, a form of SLPI that may occupy a large fraction of the inhibitor in the lungs under conditions of high oxidative stress. With sputum DNA at 5 microg/ml, a concentration much lower than those in vivo, the inhibition constant (K(i) ) of oxidized SLPI against HLE is reduced from 31 nM to 23 to 920 pM, as compared with the K(i) of native SLPI, 58 pM, under the same conditions. On the other hand, sputum DNA retards inhibition of HLE by alpha(1)-proteinase inhibitor (alpha(1)-PI). The association rate of alpha(1)-PI and HLE is decreased from 1 x 10(7) M(-1) s(-1) in the absence of DNA to 2 to 6 x 10(6) M(-1) s(-1) in the presence of sputum DNA at 100 microg/ml. On the basis of results with an elastase-specific oligonucleotide aptamer, it was found that the downregulation of alpha(1)-PI activity can be attributed to an interaction between sputum DNA and multiple DNA-binding sites on HLE. DNA-binding sites on HLE also participate in the upregulation of oxidized SLPI activity. Data from this and our previous studies demonstrate that sputum DNA facilitates the association of HLE with native and oxidized SLPI, whereas it delays the association of HLE with alpha(1)-PI. We conclude that by modulating the inhibition of HLE, sputum DNA directly affects the balance between proteases and antiproteases in the lungs.

Base Sequence↗

PubMed2000

Arthrodesis as an early alternative to nonoperative management of charcot arthropathy of the diabetic foot.

BACKGROUND: This study was performed to evaluate the use of arthrodesis of the tarsal-metatarsal area for the treatment of Eichenholtz stage-I Charcot arthropathy in patients with diabetes. Currently, the standard treatment of stage-I Charcot arthropathy is the application of a non-weight-bearing total-contact cast. Although this treatment can be effective for allowing a patient to walk without undergoing an operation, a nonunion or malunion may still result. The subsequent deformities may lead to complications, including ulceration of the foot and the need for operative intervention. Recently, a group of patients who had had early operative intervention for a variety of reasons provided us with the opportunity to objectively evaluate the effects of such treatment. This analysis provided valuable information about whether this treatment is a reasonable alternative to current nonoperative approaches. METHODS: Between January 1991 and December 1996, fourteen patients had an operation because of Eichenholtz stage-I diabetic neuropathy. The classification of the disease as Eichenholtz stage I (the developmental stage) was based on radiographic evidence of varying degrees of articular-surface and subchondral-bone resorption and fragmentation as well as joint subluxation or dislocation without evidence of coalescence or callus formation. The operative procedure consisted of extensive debridement, open reduction, and internal fixation of the tarsal-metatarsal region with autologous bone graft. Postoperative treatment consisted of immobilization of the limb in a non-weight-bearing cast for a minimum of six weeks. All of the patients returned for a final follow-up visit at a mean of forty-one months (range, 25.3 to 77.3 months) postoperatively, at which time clinical and radiographic evaluations as well as gait analysis (with measurement of plantar pressures) were performed. The gait-analysis data was compared with similar data from a group of fourteen patients with diabetic neuropathy who had had a below-the-knee amputation and with that from a group of fourteen patients with diabetic neuropathy who had no history of plantar ulceration. RESULTS: All of the arthrodesis procedures were successful. Clinically, none of the patients had immediate or long-term complications postoperatively. No patient reported ulceration after the operation. The mean time to assisted weight-bearing was 10 +/- 3.3 weeks (range, six to fifteen weeks), the mean time to unassisted weight-bearing was 15 +/- 8.8 weeks (range, eight to thirty-four weeks), and the mean time to return to the use of regular shoes was 27 +/- 14.4 weeks (range, twelve to sixty weeks). All of the patients regained the level of walking ability that they had had prior to the arthropathy. The calculated confidence intervals revealed no differences between the arthrodesis group and either of the two comparison groups with regard to the time-distance gait parameters of velocity, cadence, and stride length or with regard to the minimum, maximum, and total range of motion of each of the joints. In contrast to able-bodied subjects, all three groups showed a reduction in sagittal-plane ankle motion that was primarily related to loss of plantar flexion. The first metatarsal, great toe, and heel showed the highest peak plantar pressures, with little difference among the groups. CONCLUSIONS: To our knowledge, the present study is the first to demonstrate the potential for early operative treatment to restore anatomical alignment and improve function of diabetic patients with stage-I Charcot arthropathy.

Adult↗

PubMed1999

Moses Maimonides: medieval physician and scholar.

Moses Maimonides (1135-1204), physician and philosopher, was the greatest Jewish thinker of the Middle Ages. Faced with a life of persecution, exile, and tragedy, Maimonides overcame obstacles to become the leading physician in his era, a clinician whose skills were sought across continents. Despite long days caring for patients, Maimonides wrote extensively about both medicine and philosophy. His medical works span all topics of clinical medicine and reflect rational thinking and an understanding of the relationship between mind and body. Well known for his philosophical writings, such as The Guide for the Perplexed, Maimonides codified Jewish law and revolutionized Jewish thinking. This review of his life and achievements provides insight into the world of a remarkable 12th-century physician and may offer valuable lessons for physicians today.

Clinical Medicine↗

PubMed1999

Matrix metalloproteinase inhibitor prevents acute lung injury after cardiopulmonary bypass.

BACKGROUND: Acute lung injury (ALI) after cardiopulmonary bypass (CPB) results from sequential priming and activation of neutrophils. Activated neutrophils release neutral serine, elastase, and matrix metalloproteinases (MMPs) and oxygen radical species, which damage alveolar-capillary basement membranes and the extracellular matrix, resulting in an ALI clinically defined as adult respiratory distress syndrome (ARDS). We hypothesized that treatment with a potent MMP and elastase inhibitor, a chemically modified tetracycline (CMT-3), would prevent ALI in our sequential insult model of ALI after CPB. METHODS AND RESULTS: Anesthetized Yorkshire pigs were randomized to 1 of 5 groups: control (n=3); CPB (n=5), femoral-femoral hypothermic bypass for 1 hour; LPS (n=7), sham bypass followed by infusion of low-dose Escherichia coli lipopolysaccharide (LPS; 1 microgram/kg); CPB+LPS (n=6), both insults; and CPB+LPS+CMT-3 (n=5), both insults plus intravenous CMT-3 dosed to obtain a 25-micromol/L blood concentration. CPB+LPS caused severe lung injury, as demonstrated by a significant fall in PaO(2) and an increase in intrapulmonary shunt compared with all groups (P<0.05). These changes were associated with significant pulmonary infiltration of neutrophils and an increase in elastase and MMP-9 activity. CONCLUSIONS: All pathological changes typical of ALI after CPB were prevented by CMT-3. Prevention of lung dysfunction followed an attenuation of both elastase and MMP-2 activity. This study suggests that strategies to combat ARDS should target terminal neutrophil effectors.

Acute Disease↗

PubMed1999

Views of managed care--a survey of students, residents, faculty, and deans at medical schools in the United States.

BACKGROUND AND METHODS: Views of managed care among academic physicians and medical students in the United States are not well known. In 1997, we conducted a telephone survey of a national sample of medical students (506 respondents), residents (494), faculty members (728), department chairs (186), directors of residency training in internal medicine and pediatrics (143), and deans (105) at U.S. medical schools to determine their experiences in and perspectives on managed care. The overall rate of response was 80.1 percent. RESULTS: Respondents rated their attitudes toward managed care on a 0-to-10 scale, with 0 defined as "as negative as possible" and 10 as "as positive as possible." The expressed attitudes toward managed care were negative, ranging from a low mean (+/-SD) score of 3.9+/-1.7 for residents to a high of 5.0+/-1.3 for deans. When asked about specific aspects of care, fee-for-service medicine was rated better than managed care in terms of access (by 80.2 percent of respondents), minimizing ethical conflicts (74.8 percent), and the quality of the doctor-patient relationship (70.6 percent). With respect to the continuity of care, 52.0 percent of respondents preferred fee-for-service medicine, and 29.3 percent preferred managed care. For care at the end of life, 49.1 percent preferred fee-for-service medicine, and 20.5 percent preferred managed care. With respect to care for patients with chronic illness, 41.8 percent preferred fee-for-service care, and 30.8 percent preferred managed care. Faculty members, residency-training directors, and department chairs responded that managed care had reduced the time they had available for research (63.1 percent agreed) and teaching (58.9 percent) and had reduced their income (55.8 percent). Overall, 46.6 percent of faculty members, 26.7 percent of residency-training directors, and 42.7 percent of department chairs reported that the message they delivered to students about managed care was negative. CONCLUSIONS: Negative views of managed care are widespread among medical students, residents, faculty members, and medical school deans.

Administrative Personnel↗

PubMed1999

Improved pulmonary distribution of recombinant human Cu/Zn superoxide dismutase, using a modified ultrasonic nebulizer.

Prophylactic, intratracheal instillation of recombinant human Cu/Zn superoxide dismutase (rhSOD) has been shown to lessen lung injury produced by 48 h of hyperoxia and mechanical ventilation in neonatal piglets. However, instillation of small volumes of rhSOD intratracheally would not be expected to result in uniform pulmonary distribution. Aerosolization is a technique that may improve pulmonary distribution of drugs, but is limited by the poor efficiency of most nebulizers. A newly modified ultrasonic nebulizer was tested to assess pulmonary distribution of rhSOD compared to that achieved by intratracheal instillation. rhSOD was dual-labeled with technetium-99m (99mTc) and a fluorescent analog (permitting quantitative and qualitative assessments of pulmonary distribution), and administered to neonatal piglets by intratracheal instillation or by aerosolization. Intratracheal instillation of rhSOD to piglets when supine resulted in nonuniform distribution, with most of the drug being found in the right caudal lobe, and localized in airways. Placing animals in 30 degrees of Trendelenburg and administering half the dose in the left and half in the right lateral decubitus positions improved distribution, but alveolar deposition remained patchy. Aerosolization using a modified ultrasonic nebulizer uniformly delivered 45.8 +/- 3.8% of the rhSOD to the lungs that had been placed in the nebulizer. The rhSOD was still active and present in airways and alveoli in a homogeneous fashion. We conclude that intratracheal instillation of rhSOD in small volumes results in nonuniform pulmonary distribution, while aerosolization enhances rhSOD distribution and alveolar deposition. This has important implications for ongoing clinical trials of rhSOD for the prevention of acute and chronic lung injury in premature neonates.

Aerosols↗

PubMed1999