Molecular and Cellular Mechanisms of Delayed Fracture Healing in Mmp10 (Stromelysin 2) Knockout Mice

The remodeling of the extracellular matrix is a central function in endochondral ossification and bone homeostasis. During secondary fracture healing, vascular invasion and bone growth requires the removal of the cartilage intermediate and the coordinate action of the collagenase matrix metalloproteinase (MMP)-13, produced by hypertrophic chondrocytes, and the gelatinase MMP-9, produced by cells of hematopoietic lineage. Interfering with these MMP activities results in impaired fracture healing characterized by cartilage accumulation and delayed vascularization. MMP-10, Stromelysin 2, a matrix metalloproteinase with high homology to MMP-3 (Stromelysin 1), presents a wide range of putative substrates identified in vitro, but its targets and functions in vivo and especially during fracture healing and bone homeostasis are not well defined. Here, we investigated the role of MMP-10 through bone regeneration in C57BL/6 mice. During secondary fracture healing, MMP-10 is expressed by hematopoietic cells and its maximum expression peak is associated with cartilage resorption at 14 days post fracture (dpf). In accordance with this expression pattern, when Mmp10 is globally silenced, we observed an impaired fracture-healing phenotype at 14 dpf, characterized by delayed cartilage resorption and TRAP-positive cell accumulation. This phenotype can be rescued by a non-competitive transplant of wild-type bone marrow, indicating that MMP-10 functions are required only in cells of hematopoietic linage. In addition, we found that this phenotype is a consequence of reduced gelatinase activity and the lack of proMMP-9 processing in macrophages. Our data provide evidence of the in vivo function of MMP-10 during endochondral ossification and defines the macrophages as the lead cell population in cartilage removal and vascular invasion. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

A civil rights primer for healthcare organizations

"Diversity helps us build a better product for the diverse customers we're serving," says University of Michigan Hospitals' Ellen J. Gaucher. And several healthcare organizations stand out for their efforts to build a diverse workforce. Leaders agree that an atmosphere open to diversity starts at the top. They identify four major steps that board members and senior executives can take to ensure a system that welcomes all racial and ethnic groups into the fold.     

Benchmarks: investing in civil rights and diversity

HSL talks to leaders of four healthcare organizations in various states of developing programs for ensuring a workforce representative of the communities they serve. Programs range from internships for future leaders to creating diversity ambassadors among the workforce.     

Improving vaccination coverage in urban areas through a health communication campaign: the 1990 Philippine experience.

From March to September 1990 the Philippine Department of Health, with the assistance of the HEALTHCOM Project, carried out a national mass-media communication campaign to support routine vaccination services. The essential elements of the campaign strategy were as follows: focusing on measles as a way to get mothers to bring their children to the health centre; emphasizing logistic knowledge in the mass-media messages, in particular popularizing a single day of the week as "vaccination day" and giving clear information about the age for measles vaccination; and focusing on urban areas, which had lower vaccination rates than rural areas. Evaluation of the effects of the campaign indicates an increase in vaccination coverage and a substantial increase in the timeliness of vaccination that can be attributed to improvement in carers'' knowledge about vaccination. Furthermore, most of the observed increase in knowledge was related to exposure to the mass-media campaign. There was no evidence of any programmatic change that could account for the increase in vaccination or evidence that increased health education efforts at health centres could account for the change in knowledge. These results indicate that when countries meet certain conditions--a high level of access to the media, sufficient expertise and funds available to develop and produce high-quality radio and television advertisements, and a routine system that is able to serve the increased demand--a mass communication campaign can significantly improve vaccination coverage.     

Striatal grafts in a rat model of Huntington's disease: time course comparison of MRI and histology

Survival and integration into the host brain of grafted tissue are crucial factors in neurotransplantation approaches. The present study explored the feasibility of using a clinical MR scanner to study striatal graft development in a rat model of Huntington's disease. Rat fetal lateral ganglionic eminences grown as free-floating roller-tube cultures were grafted into the quinolinic acid-lesioned striatum, and T1- and T2-weighted sequences were acquired at 2, 7, 21, and 99 days posttransplantation. MR images were then compared with images of corresponding histological sections. The lesion-induced striatal degeneration caused a progressive ventricle enlargement, which was significantly different from controls at 21 days posttransplantation. Seven days posttransplantation, T1-weighted images revealed a defined liquid-isointense signal surrounded by a hyperintense rim at the site of graft placement, which was found unaltered for the first 21 days posttransplantation, whereas a hypointense graft signal was detected at 99 days posttransplantation. At 2 days posttransplantation, T2-weighted images showed the graft region as a hyperintense area surrounded by a rim of low signal intensity but at later time-points graft location could not be further verified. Measures for graft size and ventricle size obtained from MR images highly correlated with measures obtained from histologically processed sections (R = 0.8, P < 0.001). In conclusion, the present study shows that fetal rat lateral ganglionic eminences grown as free-floating roller-tube cultures can be successfully grafted in a rat Huntington model and that a clinical MR scanner offers a useful noninvasive tool for studying striatal graft development.     

Smoking among schoolchildren in metropolitan Manila

A total of 2000 school children aged 8-20 years from 3 sets of elementary and secondary schools in Metropolitan Manila (Philippines) were surveyed to determine the prevalence of smoking among them and to learn the factors affecting the acquisition of the habit. The students were chosen to represent each of the 3 socioeconomic classes of school children in Metropolitan Manila -- 500 each came from socioeconomic class 1 and socioeconomic class 2, and 1000 came from socioeconomic class 3. Cluster random sampling was used in the selection of study subjects. The necessary information was obtained by self-administered questionnaires. The students ranged in age from 8 years to over 20 years with a mean of 14 years for both males and females. The proportion of boys was the same as girls among the ever-smokers. Their mean age was likely comparable. The same result was noted among the nonsmokers. The mean age of ever-smokers was 15 + or - 1.75 years; the mean age of nonsmokers was 13 + or - 2.11. The age differences were significantly different, with ever-smokers being generally older than the nonsmokers. The prevalence of ever-smokers in the class 1 school was 34.4%. The proportion of boy ever-smokers was not significantly different from the girl ever-smokers. In class 2 school, the prevalence rate was 23.4%, and the proportion of boys and girls was not significantly different. Among class 3 school children, boy ever-smokers were significantly more prevalent than girl ever-smokers, and the combined prevalence of ever-smokers in this social class was 29.2%. A regular smoker among school children is defined as one who smokes at least 1 cigarette per week. The overall prevalence rate of regular smokers in the 3 schools was 6.6% for both sexes (11.6% for males and 1.7% for females). The proportion of boy ever-smokers was about the same or slightly higher than the girl ever-smokers except among the 15-year-olds where the proportion of girl ever-smokers was much higher than those of boy ever-smokers. The older the boy ever-smoker is, the higher the probability of him being a regular smoker. This trend was not observed among the girl ever-smokers and girl regular smokers. The male smokers were most prevalent in class 1 school (14.7%), followed by class 3 (11.0%) and class 2 (9.2%). For the female regular smokers, class 1 had a rate of 6.3% and class 3, 0.6%. Class 2 school did not have any regular female smokers. The most surprising observation was that the smoking habit of the school children, male or female, was not influenced at all by either parent, but the habit of the girl ever-smoker was affected by the brother.     

Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy.

PURPOSE: To assess the efficacy of the marine-derived alkaloid ecteinascidin 743 (ET-743) in patients with soft tissue sarcomas that progressed despite prior conventional chemotherapy and to characterize the pharmacokinetic profiles of ET-743 in this patient population. PATIENTS AND METHODS: Thirty-six previously treated soft tissue sarcoma patients from three institutions received ET-743 as a 24-hour continuous intravenous (IV) infusion at a dose of 1,500 microg/m(2) every 3 weeks. Pharmacokinetic studies were also performed. Patients were restaged every two cycles for response by objective criteria. RESULTS: Objective responses were observed in three patients, with one complete response and two partial responses, for an overall response rate of 8% (95% CI, 2% to 23%). Responses were durable for up to 20 months. Two minor responses (43% and 47% tumor reduction) were observed, for an overall clinical benefit rate of 14%. The predominant toxicities were neutropenia and self-limited transaminitis of grade 3 to 4 severity in 34% and 26% of patients, respectively. The estimated 1-year time to progression and overall survival rates were 9% (95% CI, 3% to 27%) and 53% (95% CI, 39% to 73%), respectively. The maximum observed plasma concentration and total plasma clearance of ET-743 (mean +/- standard deviation), 1.04 +/- 0.48 ng/mL and 35.6 +/- 16.2 L/h/m(2), respectively, were consistent with previously reported values from phase I studies of the drug given as a 24-hour IV infusion. CONCLUSION: ET-743 is a promising new option for the management of several histologic subtypes of sarcoma. Durable objective responses were obtained in a subset of sarcoma patients with disease progression despite prior chemotherapy. Additionally, the relatively high survival rate noted in this series of previously treated patients further justifies development of this agent.     

Infected endovascular graft secondary to coil embolization of endoleak: a demonstration of the importance of operative sterility

A 60-year-old male underwent endovascular repair of a 5.4-cm enlarging abdominal aortic aneurysm with intraoperative recognition of a type I endoleak. The endoleak was demonstrated to be arising from the left limb of the bifurcated prosthesis. An intravascular stent was placed in the limb near the origin of the common iliac artery and it appeared that the endoleak had sealed. However, 1 month after operation a CT scan demonstrated a persistent, substantial size endoleak without aneurysm enlargement. Coil embolization of the endoleak was undertaken in the interventional radiology suite with apparent satisfactory result. Four days after embolization the patient developed abdominal pain and after 8 days fever and leukocytosis developed. Two weeks after embolization an abdominal CT and indium scan revealed an infected endovascular graft. By CT, the posterior wall of the aneurysm was destroyed and a peri-graft fluid collection with gas was present at the location of the coils. The patient was treated with graft and coil excision and autologous vein reconstruction. Endoluminal prostheses can be contaminated at the time of operative placement. However, an additional source of endoluminal graft infection can arise from secondary endovascular procedures for endoleaks and other graft complications. Since we began placing endovascular grafts at our institution in 1993, most coil embolizations have been performed in the interventional radiology suite. This experience of coil-induced infection causes us to consider performing this type of secondary intervention in the operating room environment.     

Adverse cardiac remodeling due to maternal low protein diet is associated with alterations in expression of genes regulating glucose metabolism

Background and aimsWe have previously shown that a maternal low protein (LP) diet during pregnancy in the rat results in adverse ventricular remodeling and contractile deficiencies of the neonatal rat heart. Since pathological cardiac hypertrophy is associated with increased expression of genes involved in glucose handling, this study was undertaken to examine if maternal LP diet alters the expression of genes encoding for some key components of glucose metabolism and uptake, and of the insulin receptor (IR) signal transduction in the heart of male offspring.Methods and resultsWe determined the effect of maternal LP and normal diet (90 and 180 g/casein/kg respectively) on IR β-subunit, insulin receptor substrate (IRS)-1, phosphotyrosyl protein phosphatase (PTP) 1B, GLUT4 and phosphatidylinositol (PI) 3-kinase in male rat offspring at 24 h and at 1, 4 and 8 wks post-partum. Quantitative real-time RT-PCR revealed significant age-dependent increases in the expression of IR β-subunit, IRS-1, PTP1B, GLUT4 and PI3-kinase in the LP group with concomitant increases in corresponding protein abundance at 4 wks of age. These changes were associated with increases in left ventricular (LV) internal diameters as well as increases in LV wall thickness.ConclusionA maternal LP diet can induce increases in the gene expression and protein levels of key components of glucose metabolism and the IR signal transduction pathway in the neonatal rat heart, which may be related to accelerated energy supply, demand and utilization for ventricular remodeling due to compromised contractile performance during early life.