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Biomedical subjects

M Brady

Publications and source records attributed to M Brady.

At least 37 records · Page 2Linked to original sources
PubMed2001

Three-dimensional reconstruction of microcalcification clusters from two mammographic views.

Classification of benign/malignant microcalcification clusters is a major diagnostic challenge for radiologists. Clinical studies have revealed that the shape of the cluster, and the spatial distribution of individual microcalcifications within it, are important indicators of its malignancy. However, mammographic images of clustered microcalcifications confound their three-dimensional (3-D) distribution with image projection and breast compression. This paper presents a novel model-based method for reconstructing microcalcification clusters in 3-D from two mammographic views (cranio-caudal and medio-lateral oblique--"shoulder to the opposite hip" or lateral-medio). We develop a 3-D breast representation and a parameterised breast compression model which constraints geometrically the possible 3-D positions of a calcification in a two-dimensional image. Corresponding calcifications in the two views are matched using an estimate of the calcification volume. Both the geometric constraint and the matching criterion are utilized in the final reconstruction step to build the 3-D reconstructed clusters. Validation experiments are described using 30 clusters to verify the individual steps of the model, and results consistent with known ground truth are obtained. Some of the approximations in the model and future work are discussed in the concluding section.

Algorithms↗
PubMed2000

Inflammatory mediators in acute pancreatitis.

Inflammatory mediators play a key role in acute pancreatitis and the resultant multiple organ dysfunction syndrome, which is the primary cause of death in this condition. Recent studies have confirmed the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, PAF, IL-10, C5a, ICAM-1, and substance P. The systemic effects of acute pancreatitis have many similarities to those of other conditions such as septicaemia, severe burns, and trauma. The delay between the onset of inflammation in the pancreas and the development of the systemic response makes acute pancreatitis an ideal experimental and clinical model with which to study the role of inflammatory mediators and to test novel therapies. Elucidation of the key mediators involved in the pathogenesis of acute pancreatitis will facilitate the development of clinically effective anti-inflammatory therapy.

Acute Disease↗
PubMed2000

Segmentation and measurement of brain structures in MRI including confidence bounds.

The advent of new and improved imaging devices has allowed an impressive increase in the accuracy and precision of MRI acquisitions. However, the volumetric nature of the image formation process implies an inherent uncertainty, known as the partial volume effect, which can be further affected by artifacts such as magnetic inhomogeneities and noise. These degradations seriously challenge the application to MRI of any segmentation method, especially on data sets where the size of the object or effect to be studied is small relative to the voxel size, as is the case in multiple sclerosis and schizophrenia. We develop an approach to this problem by estimating a set of bounds on the spatial location of each organ to be segmented. First, we describe a method for 3D segmentation from voxel data which combines statistical classification and geometry-driven segmentation; then we discuss how the partial volume effect is estimated and object measurements are obtained. A comprehensive validation study and a set of results on clinical applications are also described.

Algorithms↗
PubMed2000

Treatment with neutralising antibody against cytokine induced neutrophil chemoattractant (CINC) protects rats against acute pancreatitis associated lung injury.

BACKGROUND: Lung injury manifest clinically as adult respiratory distress syndrome (ARDS) is a common cause of morbidity and mortality following acute pancreatitis (AP). Neutrophils play a critical role in the progression of AP to ARDS. C-x-C chemokines are potent neutrophil chemoattractants and activators and have been implicated in AP. AIMS: To evaluate the effect of blocking the C-x-C chemokine, cytokine induced neutrophil chemoattractant (CINC), in AP on pancreatic inflammation and the associated lung injury in rats. METHODS: AP was induced by hourly intraperitoneal injections of caerulein. Goat anti-CINC antibody was administered either before or after starting caerulein injections to evaluate the prophylactic and therapeutic effects, respectively. Severity of AP was determined by measuring plasma amylase, pancreatic water content, and pancreatic myeloperoxidase (MPO) activity as a measure of neutrophil sequestration in the pancreas. Lung injury was determined by measurement of pulmonary microvascular permeability and lung MPO activity. RESULTS: Treatment with anti-CINC antibody had little effect on caerulein induced pancreatic damage. However, it reduced the caerulein mediated increase in lung MPO activity as well as lung microvascular permeability when administered either prophylactically (lung MPO (fold increase over control): 1.53 (0.21) v. 3.30 (0.46), p<0.05; microvascular permeability (L/P%): 0.42 (0.07) v. 0.77 (0.11), p<0.05) or therapeutically (lung MPO (fold increase over control): 2.13 (0.10) v 4.42 (0.65), p<0.05; microvascular permeability (L/P%): 0.31 (0.05) v 0.79 (0.13), p<0.05). CONCLUSION: Treatment with anti-CINC antibody afforded significant protection against pancreatitis associated lung injury. These results suggest that CINC plays an important role in the systemic inflammatory response in AP.

Acute Disease↗
PubMed2000

Development of prediction models for three in vitro embryotoxicity tests in an ECVAM validation study.

Since 1997 the National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments, ZEBET, in Berlin, has been coordinating a validation study aimed at prevalidation and validation of three in vitro embryotoxicity tests, funded by the European Center for the Validation of Alternative Methods (ECVAM) at the Joint Research Center (JRC, Ispra, Italy). The tests use the cultivation of postimplantation rat whole embryos (WEC test), cultures of primary limb bud cells of rat embryos (micromass or, MM, test), and cultures of a pluripotent mouse embryonic stem cell line (embryonic stem cell test or EST). Each of the tests was performed in four laboratories under blind conditions. In the preliminary phase of the validation study 6 out of 20 test chemicals comprising different embryotoxic potential (non, weakly, and strongly embryotoxic) were tested. The results were used to define biostatistically based prediction models (PMs) to identify the embryotoxic potential of test chemicals for the WEC test and the MM test. The PMs developed with the results of the preliminary phase of the validation study (training set) will be evaluated with the results of the remaining 14 test chemicals (definitive phase) by the end of the study. In addition, the existing, improved PM (iPM) for the EST, which had been defined previously, was evaluated using the results of the preliminary phase of this study. Applying the iPM of the EST to the results of this study, in 79% of the experiments, chemicals were classified correctly according to the embryotoxic potential defined by in vivo testing. For the MM and the WEC test, the PMs developed during the preliminary phase of this validation study provided 81% (MM test) and 72% (WEC test) correct classifications. Because the PM of the WEC test took into account only parameters of growth and development, but not cytotoxicity data, a second PM (PM2) was developed for the WEC test by incorporating cytotoxicity data of the differentiated mouse fibroblast cell line 3T3, which was derived from the EST. This approach, which has previously never been used, resulted in an increase to 84% correct classifications in the WEC test.

3T3 Cells↗
PubMed1999

Sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) gene products are regulated post-transcriptionally during rat cardiac development.

OBJECTIVE: The Sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) plays a major role in the contraction-relaxation cycle and is responsible for transporting calcium into the lumen of the sarcoplasmic reticulum. This study was performed to determine if the increase in SERCA2 messenger RNA (mRNA) abundance during the perinatal period is regulated transcriptionally. METHODS: Transcriptional activity was determined by nuclear run-on assays and mRNA and protein abundances were determined during late fetal and early neonatal cardiac development in rat. RESULTS: From nuclear run-on assays, SERCA2 gene transcription at 17/18 embryonic days (139 +/- 41 parts per million (ppm), n = 7) did not differ from that at 20 neonatal days (139 +/- 37 ppm, n = 6) after birth. No increase in transcriptional activity could be demonstrated during the time frame examined. In contrast, both alpha and beta myosin heavy chains showed significant changes in measured transcriptional activity. SERCA2 mRNA normalized to 18S RNA levels are very low in the fetus (9.8 +/- 1.9 to 13.4 +/- 4.9 arbitrary units (A.U.) from 17/18 to 19/20 embryonic days) and significantly increase from birth (15 +/- 3.8 A.U.) to reach a maximum at 20 days of age (29.1 +/- 9.5 to 48.3 +/- 7.0 in 15 to 20 neonatal days rats respectively). Similarly, SR Ca(2+)-ATPase protein levels are less abundant in the fetus (0.82 +/- 0.08 to 1.13 +/- 0.13 A.U./microgram total protein) and reach a maximum at 15-20 neonatal days (3.08 +/- 0.58 to 2.98 +/- 0.17). Ca2+ uptake in the fetal heart is about one sixth the level seen in the adult, reaches the highest observed value at 5 days after birth (6.05 +/- 0.77 pmole Ca2+ per microgram/min) and remains relatively constant over the next 15 days. The activity increases even though phospholamban protein increases in abundance. CONCLUSIONS: Since the transcriptional activity of this gene is unchanged whereas the mRNA, protein abundance and activity increase, we conclude that the abundance of SERCA2 gene products is regulated primarily through post-transcriptional mechanisms during the perinatal period.

Animals↗
PubMed1999

Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams.

CONTEXT: With the success of zidovudine chemoprophylaxis for prevention of perinatal transmission of the human immunodeficiency virus (HIV), an increasing number of HIV-exposed but uninfected children will have in utero exposure to zidovudine and other antiretroviral drugs. OBJECTIVE: To evaluate the long-term effects of in utero exposure to zidovudine vs placebo among a randomized cohort of uninfected children. DESIGN: Prospective cohort study based on data collected during Pediatric AIDS Clinical Trials Group Protocol 076, a perinatal zidovudine HIV prevention trial, and Protocol 219, a long-term observational protocol. SETTING: Pediatric research clinics in the United States. PATIENTS: Two hundred thirty-four uninfected children born to 230 HIV-infected women enrolled in Protocol 076 and followed up through February 28, 1997, in Protocol 219 (122 in the zidovudine group and 112 in the placebo group). MAIN OUTCOME MEASURES: Physical growth measurements, immunologic parameters, cognitive/developmental function, occurrence of neoplasms, and mortality data assessed every 6 months for children younger than 24 months and yearly thereafter or as clinically indicated. Baseline echocardiogram and funduscopic evaluations were collected before 36 months of age. RESULTS: Median age of children at time of last follow-up visit was 4.2 years (range, 3.2-5.6 years). There were no significant differences between children exposed to zidovudine and those who received placebo in terms of sequential data on lymphocyte subsets; weight, height, and head circumference z scores; and cognitive/developmental function. No deaths or malignancies occurred. Two children (both exposed to zidovudine) are being followed up for abnormal, unexplained ophthalmic findings. One child exposed to zidovudine had a mild cardiomyopathy on echocardiogram at the age of 48 months; the child is clinically asymptomatic. CONCLUSIONS: No adverse effects were observed in HIV-uninfected children with in utero and neonatal exposure to zidovudine followed up for as long as 5.6 years. Continued prospective evaluations of children born to HIV-infected women who are exposed to antiretroviral or immunotherapeutic agents are critical to assess the long-term safety of interventions that prevent perinatal HIV transmission.

Anti-HIV Agents↗
PubMed1999

Cytokines and acute pancreatitis.

Cytokines have been shown to play a pivotal role in multiple organ dysfunction, a major cause of death in severe acute pancreatitis. Moreover, the two-hit hypothesis of the cytokine-induced systemic inflammatory response syndrome explains the variable individual response to severe acute pancreatitis and the impact of secondary events such as sepsis or therapeutic intervention. Many experimental anti-cytokine therapies have been administered following induction of experimental pancreatitis, and have proved to be therapeutic. Patients with severe pancreatitis present early because of pain. Clearly then a window for therapeutic intervention is available between onset of symptoms and peak pro-inflammatory cytokine expression. It is this fundamental observation that convinces many in the field that the treatment of AP will be one of the first clinical successes for novel drugs or therapy that seek to modulate the inflammatory response.

Acute Disease↗
PubMed1999

Female genital mutilation: complications and risk of HIV transmission.

There are over 100 million girls and women who have undergone female genital mutilation (FGM). The World Health Organization (WHO) estimates that another 2 million are subject to it every year. FGM is practiced in many countries, especially Africa and parts of the Middle East. Various degrees of FGM are prevalent, the most mutilating one being infibulation (pharaonic). With infibulation there are numerous life-long health problems such as hemorrhage, infection, dyspareunia, genital ulcers, and gynecological and obstetrical complications. It has been postulated that FGM may also play a significant role in facilitating the transmission of HIV infection through numerous mechanisms. In this article several of the most common complications are discussed and helpful suggestions for management during pregnancy and delivery are explored. Included are the legal and ethical ramifications.

Adolescent↗
PubMed1999

Detecting film-screen artifacts in mammography using a model-based approach.

Microcalcifications can be one of the earliest signs of breast cancer. Unfortunately, their appearance in mammograms can be mimicked by dust and dirt entering the imaging process and this has been shown previously to lead to false positives. We use a model of the imaging process and, in particular, the blurring functions inherent within it to detect the film-screen artifacts caused by dust and dirt and, thus, reduce false-positives. A crucial facet of the work is the choice of the correct image representation upon which to perform the image processing. After extensive testing, our algorithm has identified no microcalcifications as being artifacts and has an artifact detection rate of approaching 96%.

Algorithms↗
PubMed1999

[Development of prediction models for three in vitro embryotoxicity tests which are evaluated in an ECVAM validation study]

In 1997 ZEBET started the co-ordination of a study funded by the European Centre for the Validation of Alternative Methods (ECVAM) with the aim of pre-validation and validation of three in vitro embryotoxicity tests. These tests employ the cultivation of post-implantation whole rat embryos (WEC test), cultures of primary limb bud cells of rat embryos (micromass test, MM-Test), and cultures of a pluripotent mouse embryonic stem cell line (embryonic stem cell test, EST). In the current Validation Study each of the tests is evaluated in four laboratories under blind conditions. In an initial phase of the validation study six out of 20 test chemicals comprising different embryotoxic potential (non, weak and strong embryotoxic) were tested. The results were used to improve the prediction models (PM) for the WEC test and the MM-Test in order to identify the embryotoxic potential of test chemicals. In addition, the existing PM for the EST was evaluated using the results from testing of the initial six chemicals. The PM for the EST was developed using the results of a previous pre-validation study (Scholz et al.,1999), in which 94% of the learning sample were classified correctly. Applying this PM to the results of the initial phase of the current validation study, 80% of the experiments were classified correctly according to the embryotoxic potential of the tested chemicals in vivo. Applying the PM for the MM-Test and the WEC test that were developed during the current validation study in both tests, 79% correct classifications were achieved. Since the PM of the WEC-Test took into account only parameters of growth and development, but not cytotoxicity data, a second PM (PM2) for the WEC was developed that was improved by incorporating cytotoxicity data of the differentiated mouse fibroblast cell line 3T3 derived from the EST. This approach, which has previously never been used as an adjunct to the WEC test, resulted in an increase of correct classifications to 96%.

Journal Article↗
PubMed1998

EB1089, a synthetic analogue of vitamin D, induces apoptosis in breast cancer cells in vivo and in vitro.

1. Effects of the synthetic vitamin D analogue EB1089 on indices of apoptosis in cultured human breast cancer cells and in nitrosomethylurea-induced rat mammary tumours in vivo were investigated. 2. At a dose of 0.5 microg kg(-1) body weight, EB1089 caused significant inhibition of tumour progression over the 28 day treatment period in the absence of a significant increase in serum calcium concentration. Higher doses of EB1089 (1 and 2.5 microg kg(-1)) produced substantial regression of the experimental tumours which was accompanied by a striking change in the histological appearance of tumours consistent with induction of tumour cell death. 3. Fragmentation of genomic DNA is a characteristic feature of apoptosis. With the terminal transferase (TdT) assay, 3' DNA breaks indicative of DNA fragmentation were detected histochemically in mammary tumour cells from animals treated with EB1089 (2.5 microg kg(-1)) for 14 days. 4. Effects of the vitamin D analogue on induction of apoptosis were examined in vitro using the MCF-7 human breast cancer cell line. Using the TUNEL method, positive nuclear staining indicative of DNA fragmentation was detected in cells treated for 4 days with 10 nM EB1089. Apoptosis was also quantitated using a cell death ELISA which revealed a time and dose dependent induction of apoptosis by EB1089. 5. The effects of EB1089 on the expression of two oncoproteins which may regulate apoptosis, bcl-2 and bax were examined by Western analysis. In MCF-7 cell cultures treated with 1,25(OH)2D3 or EB1089 (1 x 10(-8) M), bcl-2 protein levels were decreased in a time-dependent manner relative to control levels. In contrast bax protein was not markedly regulated by these compounds. Densitometric analyses indicate that the vitamin D compounds lower the bcl-2/bax ratio favouring increased susceptibility of MCF-7 cells to undergo apoptosis. 6. These results suggest that the synthetic vitamin D analogue EB1089 may promote tumour regression by inducing active cell death.

Animals↗
PubMed1998

Expanding knowledge among Aboriginal service providers on treatment options for excessive alcohol use.

Approaches to the prevention of alcohol problems among Aboriginal people in Australia have tended to emphasize primary and tertiary prevention, while neglecting secondary prevention or early intervention. In contrast, members of the wider Australian community can now access a variety of early interventions through general practice, in hospital settings and through drug and alcohol treatment agencies. As part of a survey of the use of brief interventions, 178 agencies throughout Australia were interviewed, and findings are presented from the 29 agencies in this sample which provided services primarily for Aboriginal people. Approximately half offered a variety of approaches including brief interventions, with goals of moderation; the other half were entirely abstinence-orientated. These findings are discussed in the context of expanding the options that might be offered by Aboriginal-run agencies.

Journal Article↗
PubMed1998

Fur therapy: a home visitation program for children.

Dogs and kids--it's a natural match. One home care agency has started a "fur therapy" home visitation program that helps keep children with special needs at home as they receive the painful and potentially frightening treatment.

Animals↗