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Biomedical subjects

L Brady

Publications and source records attributed to L Brady.

At least 19 recordsLinked to original sources
PubMed2006

NGF receptor TrkAd5: therapeutic agent and drug design target.

Biochemical studies have shown that domain 5 of the TrkA (tropomyosin receptor kinase A) receptor is involved in the binding of NGF (nerve growth factor). Crystallographic studies have confirmed this, demonstrating that one homodimer of NGF binds to two TrkAd5 molecules. TrkAd5 has been made recombinantly in Escherichia coli, purified and shown to bind NGF with picomolar affinity. We have used the co-ordinates of the crystal structure of the NGF-TrkAd5 complex to screen approximately two million compounds in silico for the identification of small molecule agonists/antagonists. Selected hits were shown to be active in an in vitro ligand-binding assay; structure-activity relationships are now being investigated. In addition, TrkAd5 has been shown to be efficacious in preclinical models of inflammatory pain and asthma by the sequestration of excess levels of endogenous NGF, and therefore represents a novel therapeutic agent.

Alzheimer Disease↗
PubMed2004

Surface analysis and depth profiling of corrosion products formed in lead pipes used to supply low alkalinity drinking water.

Modern analytical techniques have been applied to investigate the nature of lead pipe corrosion products formed in pH adjusted, orthophosphate-treated, low alkalinity water, under supply conditions. Depth profiling and surface analysis have been carried out on pipe samples obtained from the water distribution system in Glasgow, Scotland, UK. X-ray diffraction spectrometry identified basic lead carbonate, lead oxide and lead phosphate as the principal components. Scanning electron microscopy/energy-dispersive x-ray spectrometry revealed the crystalline structure within the corrosion product and also showed spatial correlations existed between calcium, iron, lead, oxygen and phosphorus. Elemental profiling, conducted by means of secondary ion mass spectrometry (SIMS) and secondary neutrals mass spectrometry (SNMS) indicated that the corrosion product was not uniform with depth. However, no clear stratification was apparent. Indeed, counts obtained for carbonate, phosphate and oxide were well correlated within the depth range probed by SIMS. SNMS showed relationships existed between carbon, calcium, iron, and phosphorus within the bulk of the scale, as well as at the surface. SIMS imaging confirmed the relationship between calcium and lead and suggested there might also be an association between chloride and phosphorus.

Corrosion↗
PubMed2002

Variable response to exogenous Lactobacillus acidophilus NCFM consumed in different delivery vehicles.

AIMS: To study the effects of the delivery vehicle for Lactobacillus acidophilus on the human faecal microbiota. Our hypotheses were that (i) the delivery vehicle would influence faecal lactobacilli numbers and (ii) consumption of Lact. acidophilus would influence the populations of Bifidobacterium and hydrogen sulphide-producing bacteria. METHODS AND RESULTS: Ten subjects each received Lact. acidophilus with skim milk or water. Lactobacillus, Bifidobacterium and hydrogen sulphide-producing bacterial populations were analysed before, during and after each treatment. Regardless of the vehicle, faecal lactobacilli populations changed during treatment. Bifidobacteria and the hydrogen sulphide-producing bacteria underwent no statistically significant population changes. Intra- and intersubject variability was observed. CONCLUSIONS: The vehicle in which Lact. acidophilus was delivered did not influence faecal lactobacilli numbers. Consumption of Lact. acidophilus did not influence the populations of Bifidobacterium and hydrogen sulphide-producing bacteria. The lactobacilli populations of subjects were variable. The fed lactobacilli did not appear to colonize the gastrointestinal tract. SIGNIFICANCE AND IMPACT OF THE STUDY: We provide evidence that (i) there was no collective advantage to using skim milk as a delivery vehicle vs water; (ii) exogenous Lact. acidophilus did not affect endogenous bifidobacteria or hydrogen sulphide-producing bacteria; (iii) data should be carefully examined before pooling for analysis and (iv) continuous feeding was required to maintain an elevated lactobacilli population.

Adult↗
PubMed2002

16S ribosomal DNA analysis of the faecal lactobacilli composition of human subjects consuming a probiotic strain Lactobacillus acidophilus NCFM.

AIMS: The aims of this study were to evaluate the ability of exogenous Lactobacillus acidophilus strain NCFM to survive through the human gastro-intestinal (GI) tract, and to evaluate the selectivity of Rogosa SL medium for faecal lactobacilli. METHODS AND RESULTS: The composition of the faecal lactobacilli of 10 healthy subjects was monitored for two weeks prior to, two weeks during and two weeks after the administration of the Lact. acidophilus strain NCFM consumed with skim milk (daily dose 10(10) viable cells). Fresh faecal samples were collected, processed and cultured on Rogosa SL selective medium for lactobacilli enumeration. Colonies demonstrating various morphologies were identified and purified for 16S ribosomal DNA sequence analysis for speciation of colonial genotype. The species composition of cultivable faecal lactobacilli changed considerably during consumption of the strain NCFM. CONCLUSIONS: The probiotic Lact. acidophilus strain NCFM can survive through the human GI tract, but cannot colonize itself during the two-week consumption. Rogosa SL medium is selective for faecal lactobacilli. However, genetic analysis is required for colony speciation. SIGNIFICANCE AND IMPACT OF THE STUDY: It is demonstrated that continuous consumption is necessary to maintain a high population of the probiotic strain, and that the Rogosa SL medium is reliable.

Adult↗
PubMed2001

Risk factors for chronic rejection after pediatric liver transplantation.

BACKGROUND: Chronic rejection is a major cause of graft failure and a frequent reason for retransplantation after pediatric liver transplantation. Identification of risk factors for chronic rejection in pediatric transplant recipients is vital to understanding the pathogenesis of chronic rejection and may help prevent further graft loss. METHODS: The study population consisted of 285 children with 385 liver transplants performed at University of Chicago between 1991 and 1999. Logistic regression analysis was used to evaluate risk factors for chronic rejection, including age, sex, race, type of graft (living related vs. cadaveric), native liver disease, acute rejection episodes, cytomegalovirus (CMV) infection, and posttransplant lymphoproliferative disease (PTLD). RESULTS: The chronic rejection rate was significantly lower in recipients of living-related grafts than in recipients of cadaveric grafts (4% vs. 16%, P=0.001). African-American recipients had a significantly higher rate of chronic rejection than did Caucasian recipients (26% vs. 8%, P<0.001). Numbers of acute rejection episodes, transplantation for autoimmune disease, occurrence of PTLD, and CMV infection were also significant risk factors for chronic rejection. However, recipient age, gender, donor-recipient gender mismatch, and donor-recipient ethnicity mismatch were not associated with higher incidence of chronic rejection CONCLUSION: We have identified a number of risk factors for chronic rejection in a large group of pediatric liver allograft recipients. We believe that donor-recipient matching for gender or race is not likely to reduce the incidence of chronic rejection. The elucidation of the mechanisms by which living-related liver transplantation affords protection against chronic rejection may provide insight into the immunogenetics of chronic rejection and help prevent further graft loss.

Black or African American↗
PubMed2001

De novo hepatitis with autoimmune antibodies and atypical histology: a rare cause of late graft dysfunction after pediatric liver transplantation.

BACKGROUND: Late graft dysfunction after orthotopic liver transplantation is commonly due to chronic rejection, recurrence of primary disease, sepsis, lympho-proliferative disease, or vascular or biliary complications. Herein we describe a subset of pediatric liver transplant patients in whom late graft dysfunction was associated with autoimmune markers, bile ductular proliferation, and portal infiltrates, which progress to fibrosis. This subset of patients has not been previously described. METHODS: Six of the 115 children followed for greater than 5 years after transplantation developed this unusual form of graft dysfunction. All children were on a low-dose single immunosuppressive therapy (mean trough cyclosporine concentration 89 microg/L) and had been tapered off steroids for a median duration of 1.5 year. Liver biopsies were performed in all children to evaluate the graft dysfunction, and the histologic findings were interpreted by an experienced hepato-pathologist. All patients were tested for antibodies to hepatitis C virus, hepatitis B surface antigen, and IgM antibodies to hepatitis A. Smooth muscle antibody, antinuclear antibody, and antibody to liver/kidney microsome type 1 were sought by indirect immunofluorescence. International Autoimmune Hepatitis Group scores were calculated. All patients underwent ultrasonography with doppler studies at the onset of graft dysfunction. Three patients with marked bile duct proliferation on histology had cholangiograms. RESULTS: Histology in all patients showed mononuclear cell infiltrates in the portal area with interface hepatitis, portal fibrosis, and ductular proliferation without duct damage or loss. All six patients had positive antinuclear antibody or smooth muscle antibody titers. Viral studies for hepatitis A, B, and C were negative in all patients. On the International Autoimmune Hepatitis Group scoring system, five patients had probable autoimmune hepatitis (score of 10-15) and one had definite autoimmune hepatitis (score > 15) at the onset of graft dysfunction. All were treated with azathioprine and prednisone similar to treatment for autoimmune hepatitis. However, despite aggressive treatment, four patients developed bridging portal fibrosis resulting in graft loss in two patients. CONCLUSION: This clinical constellation is associated with worse outcome then that previously described for pediatric patients with posttransplantation de novo autoimmune hepatitis. Further studies are needed to find an optimal treatment regimen for these patients.

Adolescent↗
PubMed2001

Neuroimaging consortium workshop: development of novel PET and SPECT ligands for brain imaging.

It was clear from the levels of participation in this panel discussion and from the levels of interest expressed in the upcoming NIMH tracer Consortium Workshop that there is a great deal of potential benefit to public health from the development of new PET and SPECT (and, perhaps, MRI?) tracers. For extramural NIH programs, the tool guidelines for grantees are in fact only that--guidelines--but they could become specific regulations if unacceptable threats to basic research are perceived. This is because the benefits of collaboration among basic scientists are considered essential for the success of research programs. On the other hand, intramural programs at NIH are considered by some to be the "beta test site" for emerging issues and policies, regardless of the specific scientific topic. This may well be true for research tools and presents an opportunity to find new ways of working. As for the industry, threats to intellectual property arise from myriad sources. The magnitude of these threats can only be appreciated from the perspective of long-term investment in research-based industries with significant regulation. In particular, the pharmaceutical industry enjoys only a relatively short period of time during which investments in the last medicament can be recouped to support the development of the next. A great deal of commitment and sophistication will be required if the United States shall succeed in finding new ways of translating basic into applied science for the practical benefit of currently underserved patient populations.

Brain↗
PubMed2001

What does receiving the care programme approach mean for service users?

OBJECTIVE: To explore what receiving the Care Programme Approach means for service users. DESIGN: A qualitative study based on peer group discussion, the transcript being subjected to issues analysis to generate key themes. SETTING: Ayrshire and Arran, West of Scotland. SUBJECTS: Six people with severe and enduring mental illness who were receiving the Care Programme Approach. The size of the group was restricted to allow service users time to express their views. (A representative response was not being sought.) RESULTS: Four major themes emerged from the service users: the power of user involvement, how receiving CPA can help to avert potential problems, the rights of service users, and the benefits of advocacy. These service users felt that CPA had made a real difference to their lives. CONCLUSION: As user involvement is an integral part of CPA, it is important that we develop strategies that allow their views to shape, in a genuine way, the services being put in place to meet their needs. In Ayrshire they seem to have learned that their participation mattered.

Female↗
PubMed2000

Combined liver and kidney transplantation in children.

BACKGROUND: Preexisting renal dysfunction has been reported to significantly increase the morbidity and mortality associated with orthotopic liver transplantation (OLT). OLT alone has been recommended for adults and children with end-stage liver disease and reversible causes of renal failure (i.e., hepatorenal syndrome), whereas combined liver and kidney transplantation (LKT) has been shown to be an effective treatment for adults with combined end-stage liver and kidney disease. The purpose of this study was to examine the role of LKT in children. METHODS: Between October of 1984 and 1997, 385 children less than 18 years of age underwent OLT at the University of Chicago. During this same time period 12 patients underwent LKT. Data were gathered by retrospective review of the patients medical records and by interviews conducted with the patients' families. RESULTS: Actuarial patient survival was comparable for children who underwent OLT alone and LKT (69% versus 67% at 5 years). All allograft losses in the LKT group were the result of patient death and occurred within the first 90 postoperative days. Factors associated with decreased patient survival included severity of illness as reflected by United Network of Organ Sharing status and LKT after failed OLT or cadaveric renal transplant. CONCLUSIONS: In children with concomitant endstage liver and kidney disease, LKT can be considered an effective therapeutic option in selected patients. Long-term patient survival in patients undergoing LKT is comparable to that of patients with normal renal function undergoing OLT alone.

Child↗
PubMed2000

Plaque radiotherapy for management of ciliary body and choroidal melanoma with extraocular extension.

PURPOSE: To report the results of plaque radiotherapy of ciliary body and choroidal melanoma with extraocular extension. METHODS: This retrospective study of 17 eyes of 17 patients with ciliary body and choroidal melanoma demonstrated extraocular extension that was clinically evident but less than 3 mm in thickness. In 14 eyes, the extraocular extension was located anteriorly and in three posteriorly. The outcome of plaque radiotherapy in terms of intraocular and extraocular tumor responses and the development of metastasis were analyzed. RESULTS: At a median follow-up of 63 months (range, 23 to 164 months) after plaque radiotherapy, all patients showed control of both the intraocular and extraocular components of ciliary body and choroidal melanoma. In no case did the intraocular or extraocular portion of the tumor relapse. The initial median thickness of the intraocular component was 4.9 mm, and the final median thickness was 2.4 mm. The initial median thickness of the extraocular component was 2.0 mm, and the final median thickness was 1.0 mm. The initial median basal diameter of the extraocular component was 3.5 mm, and the final median basal diameter was 2.0 mm. Of 17 patients, 11 (10 with anterior and one with posterior extraocular extension) showed partial regression in base and thickness of the extraocular extension, and in six there was little or no change. In those with anterior extrascleral extension, the sclera remained intact without clinically observable necrosis, and the scleral fibers were gradually more visible as the tumor regressed. Three patients (18%) died of metastatic melanoma at a median interval of 38 months after plaque radiotherapy. CONCLUSIONS: Plaque radiotherapy appears to be a reasonable treatment option for selected cases of ciliary body and choroidal melanoma with clinically visible extraocular extension less than 3 mm in thickness.

Adult↗
PubMed2000

Modern immunosuppression.

The current treatment of posttransplant lymphoproliferative disease (PTLD) includes prophylaxis at the time of transplant, decreasing or stopping immunosuppresion and initiation of antiviral therapy in patients with polymerase chain reaction or clinical evidence of PTLD, and judicial reintroduction of immunosuppression in patients who have cleared their PTLD and have begun to have rejection. The pharmacology, pharmacokinetics, notable side effects, and toxicities of the immunosuppressive agents are described in this article. At the conclusion of each section the author's current practice with these agents and treatment strategies are described.

Antibodies↗
PubMed2000

Percutaneous treatment of portal venous stenosis in children and adolescents with segmental hepatic transplants: long-term results.

PURPOSE: To evaluate the long-term effectiveness of the percutaneous treatment of portal venous stenoses in children and adolescents with reduced-size hepatic transplants. MATERIALS AND METHODS: During the past 5 years, percutaneous transhepatic balloon venoplasty was attempted in 25 children and adolescents with anastomotic portal venous stenoses that occurred after reduced-size hepatic transplantation. All procedures were performed with direct puncture of the intrahepatic portal vein and with subsequent balloon dilation. Intravascular stents were deployed in patients with suboptimal results after dilation or with recurrent stenoses. RESULTS: Percutaneous venoplasty was technically successful in 19 of 25 patients. In the remaining six patients, portal venous occlusion precluded access to the extrahepatic portal vein. Intravascular stents were deployed in 12 patients for "elastic" (n = 5) or recurrent (n = 7) stenoses. Seven patients who underwent successful venoplasty without stent placement have required no further intervention. All stents have remained patent without further intervention. Portal venous patency has been maintained for 5-61 months (mean time, 46 months) in all 19 patients. CONCLUSION: Percutaneous treatment of portal venous stenoses is effective and long lasting in children with reduced-size hepatic transplants. In patients with elastic or recurrent lesions, portal venous stents have excellent long-term primary patency despite continued patient growth. Successful, percutaneous transhepatic venoplasty eliminates the need for surgical revision, portacaval shunting, or repeat transplantation.

Adolescent↗
PubMed1999

Unsuspected bile duct paucity in donors for living-related liver transplantation: two case reports.

Alagille's syndrome is a common cause of liver disease in children and may lead to the need for orthotopic liver transplantation. Alagille's syndrome is inherited in an autosomal dominant manner, with variable penetration, and may also be present in patients' parents, who may be considered potential donors for living-related transplantation. We report here on two cases in which the living-related donors for children with Alagille's syndrome had no liver function abnormalities or characteristic features of Alagille's syndrome. In both cases, the operation for living-related donation had to be aborted because of a paucity of bile ducts discovered intraoperatively. Given the variable presentation of Alagille's syndrome, we believe that it is necessary preoperatively to evaluate the biliary system of family members who are potential living-related donors for patients with this condition.

Adult↗
PubMed1999

A new minimally invasive technique to show nerve ischaemia in diabetic neuropathy.

AIMS/HYPOTHESIS: Experimental studies have shown that abnormalities of nerve microcirculation are important factors in the pathogenesis of diabetic neuropathy but there have been few clinical studies. We have applied microlightguide spectrophotometry to measure intravascular oxygen saturation (HbO2%) and blood flow in human sural nerve. METHODS: We studied ten patients with mild-moderate sensory motor diabetic neuropathy, nine patients without neuropathy and nine control subjects. We took 300 measurements of oxygen saturation under direct visual control through a 1.9 mm rigid endoscope over three regions of the nerve. Spectrophotometric measurements of nerve fluorescence were taken after an intravenous injection of sodium fluorescein and the rate of increase in nerve fluorescence (rise time) was used as an indicator of nerve blood flow. RESULTS: Nerve oxygen saturation was reduced in patients with neuropathy compared with control subjects (67.1 +/- 2.2% vs 76.7 +/- 2.1%, p = 0.006). Fluorescein rise time was prolonged in patients with neuropathy compared with the control group (48.5 +/- 7.0 s vs 14.0 +/- 3.1 s, p = 0.001) suggesting impaired nerve blood flow. There was a correlation between rise time, nerve oxygen saturation, glycaemic control and sural nerve sensory conduction velocity (p < 0.01). CONCLUSION/INTERPRETATION: The combination of microlight-guide spectrophotometry and micro-endoscopy provides a valuable minimally invasive technique for clinical investigation of nerve microcirculation. We have shown reduced nerve oxygenation and impaired blood flow in diabetic neuropathy and these findings strongly support a central role of microvascular disease in the pathogenesis of diabetic neuropathy.

Diabetic Neuropathies↗
PubMed1999

Liver transplantation at the University of Chicago.

Since our 1995 report, improvements in patient survival after liver transplantation have widened indications for liver transplantation and led to a greater imbalance between donor supply and need. The organ shortage is the major barrier to liver transplantation at this time. Despite expanded donor criteria, there has been only a marginal increase in the number of liver transplants performed nationally. We have used several approaches to decrease the demand for organs in both adults and children. Our center was one of the first institutions to use reduced-size, living-donor, and split liver transplants routinely. The use of reduced-size liver transplants has decreased as the use of split liver transplantation has increased. Both split liver transplantation and living donor transplantation play an important role in caring for pediatric and adult patients with end-stage and fulminant liver disease. We have concentrated our recent efforts to optimizing the technical aspects of living donor transplantation in order to decrease the need for retransplantation and further organ use. These efforts have dramatically increased graft survival. We have also focused attention on treating patients prior to transplantation in an attempt to eventually abrogate the need for traditional transplantation in some disease processes. With the use of hepatocytes and liver assist devices, we have demonstrated that we can provide a level of metabolic support not achieved with traditional medical therapy for patients with fulminant hepatic failure. As further advances in these therapies are made over the next several years, a concerted effort to bridge patients to recovery will be made. As liver transplantation has become more standardized, it has opened the door to more challenges. We have used liver transplantation in combination with cardiac transplantation to care for selected patients with end stage disease of both organs. This has been remarkably successful for the 3 patients transplanted at the University of Chicago. The immunologic benefit of this combination appears to be a decreased incidence of cardiac rejection. We have standardized the technical components of this combined operation to allow for optimal organ function and patient survival.

Adult↗