Intradiscal administration of osteogenic protein-1 increases intervertebral disc height and proteoglycan content in the nucleus pulposus in normal adolescent rabbits.

STUDY DESIGN: A study of the disc height and biochemical changes in the rabbit intervertebral disc after injection of osteogenic protein-1 into the nucleus pulposus. OBJECTIVES: To evaluate the in vivo effects of osteogenic protein-1 administered intradiscally to the intervertebral disc of rabbits. SUMMARY OF BACKGROUND DATA: Growth factors, such as osteogenic protein-1 and transforming growth factor-beta, have the ability to stimulate synthesis of proteoglycan and collagen in vitro. No attempts have yet been made to determine the effects of these growth factors in an in vivo model. METHODS: Twenty-four New Zealand adolescent white rabbits were divided evenly into two subject groups. In one group, three consecutive intervertebral discs were injected with saline; whereas in the other group, they were injected with osteogenic protein-1 in saline. At 2, 4, and 8 weeks after the injection, the intervertebral disc heights of the injected specimens were measured by lateral plain radiographs and compared with preinjection measurements. The change in disc height was expressed as the percent disc height index compared with the preinjection value. After the radiographic measurements were obtained, the intervertebral discs were removed and analyzed for DNA, proteoglycan, and collagen contents. RESULTS: At 2 weeks after the injections, the mean disc height index of the osteogenic protein-1-injected discs was 15% greater than that of the saline group. The increase in disc height with osteogenic protein-1 injection was still statistically significant at the 4- and 8-week time points. The proteoglycan content of the nucleus pulposus in discs injected with osteogenic protein-1 was higher than that in the saline group at the 2-week time point. The osteogenic protein-1-induced effect on the proteoglycan content was also present at the 4- and 8- week time intervals; however, these increases were not statistically significant. There were no significant differences in the DNA content, normalized to noninjected control, of the nucleus pulposus between the saline and osteogenic protein-1 groups. However, a significant increase in the DNA content of the anulus fibrosus in the osteogenic protein-1 group, compared with that of the anulus fibrosus in the saline group, was observed after 4 weeks. CONCLUSION: To date, no study has demonstrated the potential in vivo effects of growth factors on the intervertebral disc. The present study reports that the intradiscal administration of osteogenic protein-1 in vivo results in an increased disc height present at 2, 4, and 8 weeks and an increase in PG content of the nucleus pulposus at the 2-week time point. Therefore, osteogenic protein-1 may act to stimulate metabolic activity in the nucleus pulposus. Continued research is needed to evaluate the potential of growth factor-induced reversal of age-related disc degeneration in an appropriate animal model. In addition, studies in a nonhuman primate animal model will be essential before considering intradiscal injection of growth factors in humans.

Influence of pre-, intra- and post-operative parameters of donor liver on the outcome of isolated human hepatocytes.

The aim of the present study was to analyse, retrospectively on a large panel of patients (149), the influence of the donor liver characteristics on the outcome of human hepatocyte isolation obtained from resected liver biopsies from surgical waste after hepatectomy. Among the pre-operative parameters, the type of disease, age and sex of the patient, previous chemotherapy, alcohol or tobacco consumption did not affect the yield, viability, attachment rate and function of the isolated human hepatocytes. Pre-operative biological and anatomopathological data indicated that, while mild steatosis (10% steatotic hepatocytes) tended to decrease hepatocyte yield. Cholestasis, as assessed by gamma-glutamyl transferase serum values, significantly negatively correlated with the percentage of digested liver and the yield of viable cells. Intra-operative clamping time, that is, warm ischaemia, longer than 30 min was found to decrease both the percentage of digested liver and cell yield. Among the post-operative parameters, the percentage of digested liver decreased when biopsy weights were higher than 100 g, the use of glue tended to increase both the percentage of digested tissue and the yield of viable cells.In conclusion, human diseased livers appear to be a valuable source of isolated functional human hepatocytes. We recommend, for an optimal isolation, to use liver biopsies weighing less than 100 g, to glue the section surfaces of the biopsies and to avoid the use of moderate steatotic livers (>10% steatotic hepatocytes) and cholestatic livers, as well as livers undergoing warm ischaemia or clamping during resection due to the decrease in cell yield.

Long-term follow-up of Greenfield inferior vena cava filter placement in children.

OBJECTIVE: The long-term results of Greenfield inferior vena cava (IVC) filter placement have been well documented in adults; however, similar data do not exist for pediatric patients. The potential for growth and the increased life expectancy in younger patients may contribute to a difference in the natural history of filters placed in children. The objective of this study was to evaluate the long-term outcome of pediatric patients with IVC filters. METHODS: At the University of Massachusetts Memorial Medical Center, medical records and radiographs of patients 18 years old or younger at the time of IVC filter placement were reviewed. Follow-up data were obtained by interview, physical examination, and venous duplex ultrasound scanning. RESULTS: A total of 15 IVC filters were placed in children 18 years old or younger between 1983 and 1999. In 10 patients the indications for IVC filter placement were lower-extremity deep venous thrombosis (DVT) and/or pulmonary embolism. In five patients, prophylactic filters were placed in the absence of DVT because of a high risk for the development of pulmonary embolism. Surgical exposure of the right internal jugular vein was used to place the first eight filters. The remainder were inserted percutaneously through the right internal jugular vein or the right common femoral vein. There were no complications or mortality related to filter insertion. Follow-up of the surviving 14 patients ranged from 19 months to 16 years. During long-term follow-up, no patient had a pulmonary embolus. Of the nine patients who had lower-extremity DVT, three developed mild common femoral venous reflux documented by duplex scan. Of the five patients who had prophylactic filters, four had no symptoms or duplex evidence of reflux. The other patient, who was paraplegic, had bilateral leg edema but no venous varicosities and no reflux on duplex scan 11 years after filter placement. No patient in either group had chronic venous obstruction. CONCLUSION: In long-term follow-up there were no instances of pulmonary embolism, IVC thrombosis, significant postphlebitic symptoms, or significant filter migration among 14 pediatric patients with Greenfield IVC filters. This suggests a safety profile and efficacy similar to that seen in adults.

Recombinant thrombomodulin inhibits arterial smooth muscle cell proliferation induced by thrombin.

PURPOSE: Restenosis after angioplasty or bypass grafting to restore circulation to ischemic organs is still an unsolved problem. Thrombin generated in high concentrations at the sites of vascular injury plays a central role in thrombosis and hemostasis. alpha-Thrombin has also been implicated as a mitogen for smooth muscle cell (SMC) proliferation that contributes to arterial restenosis. Thrombomodulin has a high affinity of binding with thrombin and converts thrombin from a procoagulant to an anticoagulant. This study was designed to examine whether thrombomodulin could also moderate the thrombin-mediated SMC proliferative response. METHODS: Porcine carotid artery SMCs (passages 4-7) were plated onto 96-well plates and incubated for 3 days. After growth arrest in a defined serum-free medium for 2 to 3 days, SMCs were subjected to the reagents as follows: (1) human alpha-thrombin, (2) recombinant human soluble thrombomodulin containing a chondroitin sulfate moiety, (3) thrombin receptor agonist peptide (SFLLRNPNDKYEPF), and (4) alpha-thrombin or thrombin receptor agonist peptide combined with recombinant thrombomodulin (rTM). The viability and proliferation status of SMCs were quantified with MTT (thiazolyl blue) mitochondrial function and bromodeoxyuridine (BrdU)-DNA incorporation assays. RESULTS: Human alpha-thrombin increased SMC proliferation in a dose dependent manner by more than 25% and 30% with thrombin 1 U/mL to 3 U/mL compared with control groups on day 7 (P <.006). rTM concentrations from 0.5 microg/mL to 3 microg/mL have no significant effect on SMC growth. The stimulation of SMC proliferation induced by alpha-thrombin at 0.5 U/mL, 1 U/mL, and 2 U/mL was significantly inhibited with rTM at 2 microg/mL and 3 microg/mL on days 3, 7, and 10 as evaluated with MTT assay (P <.01 to <.05) and BrdU-DNA incorporation assay on day 3 (P <.008). Thrombin receptor agonist peptide increased SMC BrdU-DNA incorporation at 48 hours (P <.007), and its effect was not altered by rTM. CONCLUSION: rTM containing all of the extracellular domains of thrombomodulin inhibits the effect of thrombin on SMC proliferation in vitro. Because thrombin is a mitogenic mediator of SMC in vascular injury, inhibition of its function in vivo could help to prevent SMC hyperplasia. The success of further studies in vivo may lead to use of rTM for decreasing or preventing arterial restenosis.

Powerful connections for public health: the National Library of Medicine and the National Network of Libraries of Medicine.

As incorporated in Healthy People 2010 objectives, data and information systems and a skilled workforce are 2 of the critical components of the public health infrastructure. The National Library of Medicine (NLM) and the National Network of Libraries of Medicine (NN/LM) are important resources for improving Internet access and providing related training to the public health workforce and to those in training for public health careers. The NLM and the NN/LM have joined forces with the Centers for Disease Control and Prevention, the Health Resources and Services Administration, the Association of State and Territorial Health Officials, the National Association of County and City Health Officials, and the Public Health Foundation. The goal of this collaboration is to improve electronic resources useful in public health practice and increase awareness of them, to train public health professionals to use electronic information services, and to help public health agencies obtain the equipment and Internet connections needed to use these services effectively. The databases, outreach programs, and connection grants available to public health professionals from the NLM, and the training and ongoing support available from the NN/LM for accessing these programs and services, are described.

Web-based resources for retrieving health policy information: NLM and beyond.

This paper identifies Web-based resources of interest to the health policy community. Both information useful for developing health policy and information about existing health policy are included. Resources described are classified into three major categories: traditional and grey literature, statistical and epidemiological data, and legal and legislative material. National Library of Medicine (NLM) resources include MEDLINE, DIRLINE, HealthSTAR, HSRProj, and HSTAT. In addition, NLM's National Information Center on Health Services Research and Health Care Technology (NICHSR) has a Web page (http:/(/)www.nlm.nih.gov/nichsr/nichsr.++ +html) that provides an extensive listing of health-policy-related Web sites. Some of the other resources highlighted include those available from the Health Care Financing Administration (HCFA), the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC), the National Committee for Vital and Health Statistics (NCVHS), and the Library of Congress.

Suppression of fibroblast growth factor receptor signaling inhibits pancreatic cancer growth in vitro and in vivo.

BACKGROUND & AIMS: Fibroblast growth factors (FGFs) are mitogenic polypeptides that activate specific cell surface FGF receptors (FGFRs). Pancreatic cancers overexpress basic FGF (bFGF) and the type I FGF receptor (FGFR-1), and overexpression of bFGF has been correlated with decreased patient survival. The aim of this study was to examine the effects of abrogation of FGFR-1-dependent signaling on pancreatic cancer cell growth. METHODS: PANC-1 human pancreatic cancer cells were transfected with a truncated FGFR-1 complementary DNA (FGFR405), resulting in the expression of a kinase-deficient receptor. Activation of endogenous FGFR-1 was assessed in immunoblot studies with antiphosphotyrosine and anti-active mitogen-activated protein (MAP) kinase antibodies. Effects on cell growth were determined in vitro and in nude mice. RESULTS: PANC-1 clones expressing the truncated receptor showed attenuated receptor tyrosine phosphorylation and MAP kinase activation in response to bFGF, decreased basal cell growth, and a marked decrease in tumor-forming potential in vivo. Confirmatory experiments with MIA PaCa-2 pancreatic cancer cells indicated that FGFR405 also attenuated FGF-dependent MAP kinase activation in this cell line. CONCLUSIONS: The findings suggest that FGFR-dependent signaling is crucial for pancreatic cancer growth and raise the possibility that inhibition of FGFR signaling may ultimately prove useful as a therapeutic option in patients with pancreatic cancer.

Hormone replacement therapy and the risk of breast lesions that predispose to cancer.

To determine whether postmenopausal individuals being treated with hormone replacement therapy (HRT) have an increased risk for lesions that predispose to breast cancer, 156 women with benign breast lesions were retrospectively studied. Their ages ranged from 43 to 88. Each patient underwent a breast biopsy from 1991 to 1995. It was determined from chart review whether each of these patients had been treated with HRT. Fifty-seven of these patients had a biopsy finding that predisposed the patient to future breast cancer. The predisposing lesions included sclerosing adenosis, intraductal papilloma, and epithelial hyperplasia with atypia. Of these 57 patients, 36 (63%) were being treated with HRT. Only 30 of the 99 patients (30%) with nonproliferative lesions were treated with HRT (odds ratio, 3.9; P < 0.0005). On the basis of the results of this study, we believe that the use of HRT may promote lesions that predispose to cancer. This suggests that patients treated with HRT require vigilant surveillance by way of examination and mammography.

Non-invasive measurements of breast tissue optical properties using frequency-domain photon migration.

A multiwavelength, high bandwidth (1 GHz) frequency-domain photon migration (FDPM) instrument has been developed for quantitative, non-invasive measurements of tissue optical and physiological properties. The instrument produces 300 kHz to 1 GHz photon density waves (PDWs) in optically turbid media using a network analyser, an avalanche photodiode detector and four amplitude-modulated diode lasers (674 nm, 811 nm, 849 nm, and 956 nm). The frequency of PDW phase and amplitude is measured and compared to analytically derived model functions in order to calculate absorption, mu a, and reduced scattering, mu s, parameters. The wavelength-dependence of absorption is used to determine tissue haemoglobin concentration (total, oxy- and deoxy- forms), oxygen saturation and water concentration. We present preliminary results of non-invasive FDPM measurements obtained from normal and tumour-containing human breast tissue. Our data clearly demonstrate that physiological changes caused by the presence of small (about 1 cm diameter) palpable lesions can be detected using a handheld FDPM probe.

Impact of endoscopic ultrasound with fine-needle aspiration on the surgical management of pancreatic cancer.

BACKGROUND: Endoscopic ultrasound (EUS) with EUS-guided fine-needle aspiration (EUS-FNA) enables one to visualize the pancreas and surrounding structures and can provide access for FNA of those structures that appear suspicious for tumor. PATIENTS AND METHODS: From 1993 to 1995, 50 patients suspected of having pancreatic cancer underwent EUS/EUS-FNA and abdominal computed tomography (CT). Malignancy was found in 30 (60%) cases, which included 24 (48%) pancreatic adenocarcinomas. RESULTS: Endoscopic ultrasound/EUS-FNA identified 26 of the 30 malignancies (85%) and 21 of the 24 pancreatic adenocarcinomas (88%), with no false positives. Thirteen of the 24 pancreatic cancer patients had lymph nodes that were sampled with EUS/EUS-FNA. Seven of these 13 patients (62%) were found to have metastatic spread to lymph nodes. Operations were performed on 11 of the pancreatic cancer patients. Of these 11, the 5 that were predicted to be resectable by EUS/EUS-FNA underwent successful resection. Of the 6 predicted to be unresectable, 5 had palliative biliary bypasses, and 1 had a grossly positive margin of resection. CONCLUSIONS: Endoscopic ultrasound/EUS-FNA can identify patients for curative surgical resection. It can also preoperatively identify patients with regional nodal disease for inclusion in appropriately designed clinical trials.

Practice guidelines: a piece of the quality puzzle.

The National Library of Medicine (NLM) librarians provided support to the first thirteen panels sponsored by the Agency for Health Care Policy and Research by conducting literature searches, providing document delivery, and preparing bibliographic databases. Since then, NLM has moved into a consulting role, helping panels link up with local members of the National Network of Libraries of Medicine. NLM staff members have also prepared several documents useful to the development and dissemination of practice guidelines.

Price of dialysis, unit staffing, and length of dialysis treatments.

We analyzed the impact of the Medicare price for outpatient maintenance dialysis on the level and composition of staffing of dialysis units, and on the length (duration) of the average hemodialysis treatment for the period 1982 to 1987. With higher prices, dialysis units employ more total staff hours per patient per week (P less than 0.01) and use a higher proportion of registered nurses (RN) compared with other staff such as technicians and licensed practical nurses (LPN). Higher Medicare prices are also associated with longer average hemodialysis treatment duration for freestanding units (P less than 0.02), but there was no statistically significant association for hospital units. The impact of the Medicare price on both staffing and average treatment duration takes into account the calendar time trend, ie, 1987 versus 1982, which has a separate impact from the price effect. For example, to avoid the complication of technology changes over calendar time, we considered the impact of the price change at one point in time. Freestanding units that had a price cut of more than +15 in 1983, reported twice the reduction in the average dialysis treatment duration (-0.38 hours) compared with -0.20 hours (P = 0.01) for units that had a cut of less than +15. An analysis of the impact of average treatment duration on patient mortality provided some evidence that shorter treatment duration in freestanding units is associated with higher mortality. This result needs further analysis. There was no statistically significant relationship between the level of staffing in the dialysis unit or the percent of staff who were RNs and 3-year patient survival. The analysis in this report was based on 1,213 and 1,058 data forms filed with Medicare by freestanding and hospital units, respectively, for 1982 and 1987. In addition, we used a Cox proportional hazards model (multivariate) for the analysis of the 3-year patient survival for 14,807 new hemodialysis patients who started dialysis in 1984.

Urinary incontinence in the elderly: etiology and treatment.

Urinary incontinence is a common, though often hidden, medical problem among the elderly. Urinary continence requires integrity of the neural, muscular, and hormonal systems. Five distinct types of urinary incontinence can be distinguished based on patient symptoms. A variety of factors can impair continence, including aging, environmental barriers, and medications. Both pharmacological and nonpharmacological measures are useful in the treatment of incontinence.