Lesions and characteristic injury patterns caused by high-voltage fault arcs.

Exposure to high-voltage electric arcs as a result of an accident or by means to commit suicide can affect people's health and cause death. There are characteristic external findings that can be found on external examination. These include extensive skin burns, periorbital recesses or "crow's feet," vapor deposition of conductor material, known as metallization, and tightly spaced, roundish, crocodile skin like burns. The Institute of Legal Medicine of the Rostock University Medical Center recorded 16 deaths caused by exposure to electricity between 1990 and 2018. Six of these deaths were caused by exposure to high-voltage electric arcs and five of these deaths (83 %) showed crocodile skin like burns and one had periorbital recesses burns on the face as a result of a fault arc. To our knowledge, the present paper is the first report describing the frequent occurrence of crocodile skin like burns due to high-voltage fault arcs.

Refining the continuum of CFTR-associated disorders in the era of newborn screening.

Clinical heterogeneity in cystic fibrosis (CF) often causes diagnostic uncertainty in infants without symptoms and in older patients with milder phenotypes. We performed a cross-sectional evaluation of a comprehensive set of clinical and laboratory descriptors in a physician-defined cohort (N = 376; Children's Hospital of Wisconsin and the American Family Children's Hospital CF centers in Milwaukee and Madison, WI, USA) to determine the robustness of categorizing CF (N = 300), cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (N = 19), and CFTR-related (CRMS) metabolic syndrome (N = 57) according to current consensus guidelines. Outcome measures included patient demographics, clinical measures, sweat chloride levels, CFTR genotype, age at diagnosis, airway microbiology, pancreatic function, infection, and nutritional status. The CF cohort had a significantly higher median sweat chloride level (105 mmol/l) than CFTR-related disorder patients (43 mmol/l) and CFTR-related metabolic syndrome patients (35 mmol/l; p ≤ 0.001). Patient groups significantly differed in pancreatic sufficiency, immunoreactive trypsinogen levels, sweat chloride values, genotype, and positive Pseudomonas aeruginosa cultures (p ≤ 0.001). An automated classification algorithm using recursive partitioning demonstrated concordance between physician diagnoses and consensus guidelines. Our analysis suggests that integrating clinical information with sweat chloride levels, CFTR genotype, and pancreatic sufficiency provides a context for continued longitudinal monitoring of patients for personalized and effective treatment.

Urban park-related risks for Giardia spp. infection in dogs.

Giardia spp. is a common gastrointestinal (GI) parasite of multiple host species, including dogs and humans, with the potential for zoonotic transmission. The risk of GI parasitism in dogs (including Giardia spp.) may increase with park use in urban areas. This study aimed to (1) determine whether park attendance is a risk factor for Giardia spp. infection in dogs and (2) characterize the behavioural and demographic risk factors for Giardia spp. infection in park-attending and non-park-attending dogs. From August to September 2012, a total of 1293 dog owners completed a survey and 860 corresponding dog faecal samples were collected. Dog faeces were screened for Giardia spp. using a direct immunofluorescence assay and associations assessed among behaviours, demographics, and Giardia spp. infection. Main results included off-leash and swimming frequencies within parks as significantly positively associated with Giardia spp. infection in dogs. Dog-owner age was negatively associated with off-leash and swimming frequencies in parks. The results suggest some recreational behaviours in parks and certain demographics are risk factors for parasitism in pet dogs.

The association of pre-operative physical fitness and physical activity with outcome after scheduled major abdominal surgery.

We studied whether reported physical activity and measurements of fitness (hand, leg and inspiration) were associated with postoperative in-hospital mortality, length of stay and discharge destination in 169 patients after major oncological abdominal surgery. In multivariate analysis, adequate activity level (OR 5.5, 95% CI 1.4-21.9) and inspiratory muscle endurance (OR 5.2, 95% CI 1.4-19.1) were independently associated with short-term mortality, whereas conventional factors, such as age and heart disease, were not. Adequate activity level (OR 6.7, 95% CI 1.4-3.0) was also independently associated with discharge destination. The factors that were independently associated with a shorter length of hospital stay were as follows: absence of chronic obstructive pulmonary disease (HR 0.6, 95% CI 0.3-1.1); adequate activity level (HR 0.6, 95% CI 0.4-0.8); and inspiratory muscle strength (HR 0.6, 95% CI 0.5-0.9). For all postoperative outcomes physical activity and fitness significantly improved the predictive value compared with known risk factors, such as age and comorbidities. We conclude that pre-operative questionnaires of physical activity and measurements of fitness contribute to the prediction of postoperative outcomes.

Access to off-leash parks, street pattern and dog walking among adults.

We examined whether dog-walking among dog-owners correlated with street pattern and proximity to a park area designated for off-leash use. Dog-walking was associated with street pattern and with nearby off-leash areas, but these associations varied by the measure of dog-walking examined (participation versus frequency in a usual week). Interventions to increase dog-walking should be undertaken and evaluated. Demographic factors, urban design, and whether owners already walk their dogs should be taken into account in planning.

Marginal voices in the media coverage of controversial health interventions: how do they contribute to the public understanding of science?

While the media are a significant source of information for the public on science and technology, journalists are often accused of providing only a partial picture by neglecting the points of view of vulnerable stakeholders. This paper analyzes the press coverage of four controversial health interventions in order to uncover what voices are treated marginally in the media and what the relative contributions of these voices are to the stories being told. Our empirical study shows that: 1) patterns of source utilization vary depending on the health intervention and less dominant stakeholders are in fact represented; and 2) the use of marginal voices fills certain information gaps but the overall contribution of such voices to the controversies remains limited. In order to strengthen the media coverage of science and technology issues, we suggest that further research on journalistic practices: 1) move beyond the dichotomy between journalists and scientists, and 2) explore how different categories of readers appraise the meaning and relevance of media content.

Integrated analysis of genetic and proteomic data identifies biomarkers associated with adverse events following smallpox vaccination.

Complex clinical outcomes, such as adverse reaction to vaccination, arise from the concerted interactions among the myriad components of a biological system. Therefore, comprehensive etiological models can be developed only through the integrated study of multiple types of experimental data. In this study, we apply this paradigm to high-dimensional genetic and proteomic data collected to elucidate the mechanisms underlying the development of adverse events (AEs) in patients after smallpox vaccination. As vaccination was successful in all of the patients under study, the AE outcomes reported likely represent the result of interactions among immune system components that result in excessive or prolonged immune stimulation. In this study, we examined 1442 genetic variables (single nucleotide polymorphisms) and 108 proteomic variables (serum cytokine concentrations) to model AE risk. To accomplish this daunting analytical task, we employed the Random Forests (RF) method to filter the most important attributes, then we used the selected attributes to build a final decision tree model. This strategy is well suited to integrated analysis, as relevant attributes may be selected from categorical or continuous data. Importantly, RF is a natural approach for studying the type of gene-gene, gene-protein and protein-protein interactions we hypothesize to be involved in the development of clinical AEs. RF importance scores for particular attributes take interactions into account, and there may be interactions across data types. Combining information from previous studies on AEs related to smallpox vaccination with the genetic and proteomic attributes identified by RF, we built a comprehensive model of AE development that includes the cytokines intercellular adhesion molecule-1 (ICAM-1 or CD54), interleukin-10 (IL-10), and colony stimulating factor-3 (CSF-3 or G-CSF) and a genetic polymorphism in the cytokine gene interleukin-4 (IL4). The biological factors included in the model support our hypothesized mechanism for the development of AEs involving prolonged stimulation of inflammatory pathways and an imbalance of normal tissue damage repair pathways. This study shows the utility of RF for such analytical tasks, while both enhancing and reinforcing our working model of AE development after smallpox vaccination.

The supramolecular organization of fibrillin-rich microfibrils.

We propose a new model for the alignment of fibrillin molecules within fibrillin microfibrils. Automated electron tomography was used to generate three-dimensional microfibril reconstructions to 18.6-A resolution, which revealed many new organizational details of untensioned microfibrils, including heart-shaped beads from which two arms emerge, and interbead diameter variation. Antibody epitope mapping of untensioned microfibrils revealed the juxtaposition of epitopes at the COOH terminus and near the proline-rich region, and of two internal epitopes that would be 42-nm apart in unfolded molecules, which infers intramolecular folding. Colloidal gold binds microfibrils in the absence of antibody. Comparison of colloidal gold and antibody binding sites in untensioned microfibrils and those extended in vitro, and immunofluorescence studies of fibrillin deposition in cell layers, indicate conformation changes and intramolecular folding. Mass mapping shows that, in solution, microfibrils with periodicities of <70 and >140 nm are stable, but periodicities of approximately 100 nm are rare. Microfibrils comprise two in-register filaments with a longitudinal symmetry axis, with eight fibrillin molecules in cross section. We present a model of fibrillin alignment that fits all the data and indicates that microfibril extensibility follows conformation-dependent maturation from an initial head-to-tail alignment to a stable approximately one-third staggered arrangement.

'When the dog bites': What can we learn about health geography from newspaper coverage in a 'model city' for dog-bite prevention?

Despite calls for the adoption of 'One-Health' approaches, dog-bite injuries remain neglected in healthcare and public health, and our study may help to understand why. Media coverage can influence policy directions, including policies that address dogs. We collected articles (n = 65) published in two local newspapers, 2012-2017, then carried out an ethnographically-informed discourse analysis of the dog-bite reports. The newspapers portrayed dog-bites mainly as matters of public disorder, as opposed to priorities for healthcare and public health. Even as our study took place in a city that has shown dog-bite reductions without recourse to 'breed bans' or restrictions (i.e., breed-specific legislation), journalists still tended to emphasize dog breed as a narrative element in explaining dog-bite incidents. Nonetheless, the news coverage did not reproduce a 'nature versus nurture' dichotomy. Rather, the journalists presented dog breed, and presumably associated aggressive behaviour, as entanglements with social, economic, and cultural contexts. Meanwhile, the news stories reduced contextual complexity to geographic locations, as codes for community reputation, in attributing causality and morality.

Walking or vitamin B for cognition in older adults with mild cognitive impairment? A randomised controlled trial.

OBJECTIVE: To examine the effects of aerobic exercise or vitamin B supplementation on cognitive function in older adults with mild cognitive impairment (MCI). DESIGN: Randomised placebo-controlled trial. SETTING: General community. PARTICIPANTS: Community-dwelling adults aged 70-80 with MCI. Interventions : The 152 participants were randomly assigned to two INTERVENTIONS: (1) a twice-weekly, group-based, moderate-intensity walking programme (WP, n = 77) or a low-intensity placebo activity programme (n = 75) for one year; and (2) daily vitamin pill containing 5 mg folic acid, 0.4 mg vitamin B-12, 50 mg vitamin B-6 (FA/B12/B6, n = 78) or placebo pill (n = 74) for one year. OUTCOME MEASURES: Cognitive function, measured with neuropsychological tests at baseline and after six and 12 months. RESULTS: Median session attendance at the exercise programmes (25th-75th percentile) was 63% (2%-81%) and median compliance with taking pills (25th-75th percentile) was 100% (99%-100%). Gender was an effect modifier. Intention-to-treat analysis revealed no main intervention effect for either intervention. In women in the WP, attention (Stroop combination task) improved by 0.3 seconds (p = 0.04) and memory (auditory verbal learning test) by 0.04 words (p = 0.06) with each percentage increase in session attendance. In men attending at least 75% of the sessions, the WP improved memory (beta 1.5 (95% CI: 0.1 to 3.0) words). CONCLUSION: The walking programme and/or FA/B12/B6 supplementation were not effective in improving cognition within one year. The walking programme, however, was efficacious in improving memory in men and memory and attention in women with better adherence. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register, 19227688, http://www.controlled-trials.com/isrctn/

Analytical and biological variation in repeated sweat chloride concentrations in clinical trials for CFTR modulator therapy.

BACKGROUND: Using sweat chloride as a biomarker for CFTR modifying drugs requires knowledge of analytical and biological variation. METHODS: 979 sweat chloride concentrations from 128 subjects enrolled in the placebo arm of 2 multicenter, investigational drug trials were analyzed to determine coefficients of variation (CV) as well as reference change value (RCV) and index of individuality (II). RESULTS: For these populations, calculated values for the two studies were: analytical variation (3.9, 4.1%); within-subject variation (4.4, 6.0%); between-subject variation (8.9, 7.0%); RCV (13.7, 17.0%) and II (0.7, 1.0). Sweat chloride variation was not affected by sex, collection site or sample weight; but was slightly affected by age in one of the two studies. CONCLUSION: Through determination of analytical as well as between- and within-subject variation, and with a larger sample size, our data allows improved estimates of the RCV and II, and can contribute to future trials of CFTR modulators and inform the design and interpretation of n of 1 trials in both research and clinical settings.

Cost-consequence analysis of two different active flowable hemostatic matrices in spine surgery patients.

OBJECTIVES: A recently published retrospective analysis comparing two different active flowable hemostatic matrices (FLOSEAL and SURGIFLO Kit with Thrombin) showed significantly increased resource use and complications (surgery time, risk of blood product transfusion, and amount of matrix used) with SURGIFLO use compared to FLOSEAL in major spine surgery, and also significantly increased surgical time with SURGIFLO use in severe spine surgery. This analysis was developed as a follow-up to this prior analysis, to evaluate the cost-consequence of using FLOSEAL vs SURGIFLO in major and severe spine surgery. METHODS: A cost consequence model was constructed from a US hospital provider perspective. Model parameters combined clinical inputs from the published retrospective analysis with supplemental analyses on annual spine surgery volume using the 2012 National Inpatient Sample (NIS) database. Cost of hemostatic matrices, blood product transfusion, and operating room time were identified from published literature. Various one-way and probabilistic sensitivity analyses were performed. RESULTS: The base case for a medium volume hospital showed that, compared to SURGIFLO, patients receiving FLOSEAL required three fewer blood product transfusions and saved 27 h of OR time, resulting in annual savings of $151 per major and $574 per severe spine surgery. Additional scenarios for high and low volume hospitals supported cost savings in the base case. Probabilistic sensitivity analysis revealed FLOSEAL was cost-saving in 76% of simulations in major spine and 97% of iterations in severe spine surgery. CONCLUSIONS: This economic analysis indicates that use of FLOSEAL instead of SURGIFLO hemostatic matrices to induce hemostasis in both major and severe spine surgery could potentially lead to sizable cost savings in US hospitals, regardless of spinal surgery case-mix.

Cost-consequence analysis of different active flowable hemostatic matrices in cardiac surgical procedures.

BACKGROUND: A recent retrospective comparative effectiveness study found that use of the FLOSEAL Hemostatic Matrix in cardiac surgery was associated with significantly lower risks of complications, blood transfusions, surgical revisions, and shorter length of surgery than use of SURGIFLO Hemostatic Matrix. These outcome improvements in cardiac surgery procedures may translate to economic savings for hospitals and payers. OBJECTIVE: The objective of this study was to estimate the cost-consequence of two flowable hemostatic matrices (FLOSEAL or SURGIFLO) in cardiac surgeries for US hospitals. METHODS: A cost-consequence model was constructed using clinical outcomes from a previously published retrospective comparative effectiveness study of FLOSEAL vs SURGIFLO in adult cardiac surgeries. The model accounted for the reported differences between these products in length of surgery, rates of major and minor complications, surgical revisions, and blood product transfusions. Costs were derived from Healthcare Cost and Utilization Project's National Inpatient Sample (NIS) 2012 database and converted to 2015 US dollars. Savings were modeled for a hospital performing 245 cardiac surgeries annually, as identified as the average for hospitals in the NIS dataset. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to test model robustness. RESULTS: The results suggest that if FLOSEAL is utilized in a hospital that performs 245 mixed cardiac surgery procedures annually, 11 major complications, 31 minor complications, nine surgical revisions, 79 blood product transfusions, and 260.3 h of cumulative operating time could be avoided. These improved outcomes correspond to a net annualized saving of $1,532,896. Cost savings remained consistent between $1.3m and $1.8m and between $911k and $2.4m, even after accounting for the uncertainty around clinical and cost inputs, in a one-way and probabilistic sensitivity analysis, respectively. CONCLUSIONS: Outcome differences associated with FLOSEAL vs SURGIFLO that were previously reported in a comparative effectiveness study may result in substantial cost savings for US hospitals.

Changes in disability in older adults with generalized radiographic osteoarthritis: A complex relationship with physical activity.

OBJECTIVE: The aim of the present study was to report on factors associated with changes in disability after 5 years, with a focus on physical activity (PA) in community-dwelling older adults with generalized radiographic osteoarthritis (GROA). METHODS: Assessment of GROA (hand, knee, hip) and disability (Health Assessment Questionnaire) in the Rotterdam Study (cohort RS-1, N = 7,983; with GROA, n = 821). A good outcome at follow-up was defined as improved or mild disability, and a poor outcome as worsened or severe disability. Factors potentially associated with outcome were demographics, joint complaints, other chronic health problems or limitations (body mass index, number of chronic conditions, cognition), and level of different types of PA. Some of these assessments were repeated in between 1997 and 1999 (RS-3), and between 2002 and 2004 (RS-4). RESULTS: A total of 309 older adults with GROA and valid measures on RS-3 and RS-4 showed mild to moderate disability, with minor increases over 5 years (follow-up N = 287 RS-3 to RS-4). PA levels decreased with increasing disability, especially in sport and walking. PA was univariately associated with a better outcome at follow-up but when adjusted for other factors (higher age, having knee pain and stiffness, and having more than two other chronic conditions) was associated with negative changes in general and lower limb disability, although not with upper limb disability. CONCLUSIONS: This was the first study to report that community-dwelling older adults with GROA show moderate levels of disability, and that reduced levels of disability are associated with higher levels of PA, but when adjusted for other confounders this association is lost. Further research is needed to study the complex relationships between PA and other determinants of disability.

Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma.

PURPOSE: To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naive or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS: This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. RESULTS: An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naive and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. CONCLUSION: Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.

The social context of smoking: the next frontier in tobacco control?

A better understanding of the social context of smoking may help to enhance tobacco control research and practice.

[More exercise for seniors: report of program evaluation]. / Meer bewegen voor ouderen gymnastiek: verslag van een evaluatiestudie.

Since 1980, More Exercise for Seniors (MBvO in Dutch) has provided a number of special physical activities for the elderly. The aim is to improve social participation and integration, and to prevent a need for care. Despite the fact that MBvO has been active for more than 25 years, and weekly 300,000 people participate in gymnastics, swimming, dancing, etc, no effect on fitness and health has been proven to date. The study was carried out in two regions: Drenthe and Zuid-Holland. Using the GALM (Groningen Active Living Model) method, 4600 independently living people aged 65 years and older were asked to participate in a motor fitness test. Of the 721 people who participated, 386 (the least fit) were invited to take part in the study. They were than randomly divided into an experimental and a control group. The experimental group did gymnastics once or twice a week. The control group received a health educational program. Assessments were carried out at pretest and posttest (10 weeks). In the groups offered MBvO gymnastics once a week, no effects were found on subjective health, physical performance or quality of life and only minor effects on physical fitness. In the groups offered MBvO gymnastics twice a week, some beneficial quality of life effects were found in the least physically active people at baseline. It is recommended that the frequency and intensity of the regular MBvO gymnastics should be increased, to emphasize the importance of health education, and that relatively inactive and older individuals (70+) should be recruited.

Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) administered as a ninety-minute infusion every 3 weeks.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11; Irinotecan), a semisynthetic analogue of camptothecin (CPT) with broad preclinical antitumor activity, has demonstrated impressive activity in phase II trials in Japan in advanced small and non-small cell lung, colorectal, cervical, and ovarian carcinomas, as well as in refractory lymphomas and leukemias. In this phase I and pharmacological study, 90-min infusions of CPT-11 were administered every 3 weeks at doses ranging from 100 to 345 mg/m2 to patients with solid malignancies. Acute, severe, and refractory vomiting, diarrhea, and/or abdominal cramps associated with flushing, warmth, and diaphoresis occurred in the immediate posttreatment period at the 240-mg/m2 dose level in several patients who were not treated with premedications. The characteristics and temporal nature of these toxicities, the prompt resolution of symptoms following treatment with diphenhydramine, and the successful use of a premedication regimen consisting of ondansetron and diphenhydramine in preventing these acute effects suggest that vasoactive substances are involved in the mediation of these acute toxicities. With the routine use of these premedications, there was no single toxicity type that limited the escalation of CPT-11 doses. Instead, a constellation of severe hematological and gastrointestinal effects precluded the repetitive administration of CPT-11 at doses above 240 mg/m2, the maximum tolerated dose and recommended phase II dose on this schedule. Major responses were observed in patients with advanced colorectal, cervical, and renal cancers. The disposition of total CPT-11 in plasma was fit by a biexponential kinetic model with renal elimination accounting for 37 +/- 4% (SE) of total drug disposition. The Cmax for the active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38), was achieved at 2.2 +/- 0.1 h after treatment, and mean residence times for both CPT-11 and SN-38 were long, 9.1 and 10.0 h, respectively. Compared with topotecan, another CPT analogue under development, a larger proportion of total drug exposure was accounted for by the active lactone (closed-ring) forms of CPT-11 and SN-38; areas under the time-versus concentration curve for their respective lactone were 44 and 50% of areas under the time-versus-concentration curve for total CPT-11 and SN-38. Although intermittent dosing schedules appear to be superior to single dosing schedules for CPT and some CPT analogues in preclinical tumor models, the maintenance of biologically relevant concentrations of SN-38 for relatively long durations may negate the potential pharmacological benefits of intermittent and continuous administration schedules for CPT-11.(ABSTRACT TRUNCATED AT 400 WORDS)

MDR1 gene expression and outcome in osteosarcoma: a prospective, multicenter study.

PURPOSE: Increased expression of the multidrug resistance gene (MDR1) has been implicated in osteosarcoma prognosis. This study represents the first prospective assessment of the prognostic value of MDR1 mRNA expression in patients with newly diagnosed extremity osteosarcoma. PATIENTS AND METHODS: A series of patients with high-grade, nonmetastatic extremity osteosarcoma were enrolled from six tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 30 months). All patients were treated with (neo)adjuvant chemotherapy and surgery. Tumors from 123 patients were analyzed for MDR1 mRNA expression. The association of the level of MDR1 expression with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Using the highest MDR1 value for each patient, a dose-response relationship was not identified between the level of MDR1 expression and systemic relapse (relative risk, 1.15; P =.44). Analyses based on biopsy or resection values alone gave similar results (P =.11 and.41, respectively, log rank test). In multivariate analysis, large tumor size (> 9 cm) was the only significant independent predictor of systemic outcome (relative risk, 2.8; P =.002). CONCLUSION: We did not identify any correlation between MDR1 mRNA expression and disease progression in patients with osteosarcoma. It is likely that alterations in other genes are involved in resistance to chemotherapy in osteosarcoma and that they play a more critical role than MDR1 in this disease.

Fibrillin degradation by matrix metalloproteinases: identification of amino- and carboxy-terminal cleavage sites.

Fibrillin molecules form the structural framework of elastic fibrillin-rich microfibrils of the extracellular matrix. We have investigated the proteolysis of recombinant fibrillin molecules by five matrix metalloproteinases. Cleavage sites were defined at the carboxy-terminal end of the fibrillin-1 proline-rich region and the corresponding fibrillin-2 glycine-rich region (exon 10), and within exon 49 towards the carboxy-terminus of fibrillin-1. Cleavage at these sites is predicted to disrupt the structure and function of the fibrillin-rich microfibrils.