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Biomedical subjects

J Cunningham

Publications and source records attributed to J Cunningham.

At least 19 recordsLinked to original sources
PubMed2001

Treatment of steroid-refractory acute graft-versus-host disease with anti-CD147 monoclonal antibody ABX-CBL.

ABX-CBL, an immunoglobulin M murine monoclonal antibody, recognizes CD147 and initiates cell killing through complement-mediated lysis. In a dose-finding trial, 27 patients with steroid-refractory acute graft-versus-host disease (GVHD) received ABX-CBL at 0.01 (presumed no effect dose), 0.1, 0.2, or 0.3 mg/kg per day, and an additional 32 patients were given ABX-CBL at 0.2 or 0.15 mg/kg per day. All patients had undergone allogeneic transplantation for malignant or nonmalignant disorders and received GVHD prophylaxis, generally with methotrexate- and cyclosporine-containing regimens. None responded to methylprednisolone, given for a minimum of 3 days. ABX-CBL was started 20 to 236 (median, 47) days after transplantation; it was given for 7 consecutive days and was followed by 2 infusions per week for 2 more weeks. Among 51 patients evaluable for efficacy, 26 (51%) responded, including 13 with complete responses (CR) and 13 with partial responses (PR). CR lasting 14 days or longer or PR lasting 7 days or longer occurred in 21 (41%; 8 CR, 13 PR) patients, including 19 of 43 (44%) patients who received 0.1 to 0.3 mg/kg ABX-CBL and 2 of 8 (25%) patients given 0.01 mg/kg per day. Myalgias at doses 0.2 mg/kg or greater were dose limiting and resolved without sequelae. Causes of death included organ failure, progressive GVHD, and infection. No death was attributed to ABX-CBL. At 6 months after the initiation of ABX-CBL therapy, 26 (44%) patients were surviving. These results are encouraging. Further studies on the use of ABX-CBL in the management of GVHD are warranted.

Acute Disease↗
PubMed2001

Characterization of glycated hemoglobin in diabetic patients: usefulness of electrospray mass spectrometry in monitoring the extent and distribution of glycation.

A combination of chromatographic and mass spectrometric techniques was used to evaluate the extent and distribution of glycation within the glycated hemoglobin (GHb) molecule. Studies on quantification of hemoglobin (Hb) glycation by electrospray ionization mass spectrometry (ES-MS) of intact globins employed specimens from 10 diabetic individuals and five normal controls. Detailed structural analysis of the phenylboronate affinity chromatography/ion-exchange (IE) HPLC-separated sub-populations of GHb was performed on a specimen carrying 13.7% GHb. An efficient protocol for mapping glycation sites within alpha and beta globins was developed, e.g., Glu-C/Asp-N proteolytic digestion followed by LC-ES-MS. Relative site occupancy within discrete components of GHb was evaluated. A correlation between the degree of glycation measured at Hb level (by affinity chromatography) and at globin level (measured by ES-MS) was carried out. The above studies led us to conclude that during the process of phenylboronate chromatography GHb dimers, rather than tetramers, are bound to the affinity resin so a fraction of glycated dimers rather than tetramers is measured. This finding implies that a process of glycation affects a much higher number of native Hb tetramers than was previously contemplated. No glycation sites appear to be missed by phenylboronate affinity chromatography. We have found no evidence of the presence of multiple glycations within a single globin chain. While glycation of both globins within a dimer cannot be excluded, it is unlikely to be a significant phenomenon. According to ES-MS data, an equivalent of about one globin per alphabeta dimer of the affinity chromatography-isolated GHb carried glycation.

Amino Acid Sequence↗
PubMed2001

Convection-enhanced delivery of AAV-2 combined with heparin increases TK gene transfer in the rat brain.

Adeno-associated virus type2 (AAV-2) binds to heparan-sulfate proteoglycans on the cell surface. In vivo, attachment of viral particles to cells adjacent to the injection tract limits the distribution of AAV-2 when infused into the CNS parenchyma and heparin co-infusion might decrease the binding of AAV-2 particles to cells in the vicinity of the infusion tract. We have previously shown that heparin co-infusion combined with convection enhanced delivery enhances distribution of the GDNF family trophic factors (heparin-binding proteins) in the rat brain. In this work we show that heparin co-infusion significantly increases the volume of distribution of AAV-2 as demonstrated by immunoreactivity to the transgene product 6 days after infusion into the rat striatum.

Animals↗
PubMed2001

Regional variation in the incidence of end-stage renal disease in Indigenous Australians.

OBJECTIVE: To evaluate regional variation in the incidence of end-stage renal disease (ESRD) in Indigenous Australians, and to examine the proximity to ESRD treatment facilities of Indigenous patients. DESIGN: Secondary data review, with collection of primary data regarding patients' place of residence before beginning ESRD treatment. PARTICIPANTS: Indigenous ESRD patients who commenced treatment in Australia during 1993-1998. METHODS: We obtained data from the Australian and New Zealand Dialysis and Transplant Registry regarding 719 Indigenous patients who started ESRD treatment between 1 January 1993 and 31 December 1998. We obtained primary data from the treating renal units to determine the place of residence before beginning renal replacement therapy. We calculated the average annual incidence of ESRD for each of the 36 Aboriginal and Torres Strait Islander Commission regions using population estimates based on the 1996 Census, and calculated standardised incidence ratios with 95% confidence intervals for each region. We compared the number of cases with the treatment facilities available in each region. MAIN OUTCOME MEASURE: Regional standardised ESRD incidence for Indigenous Australians referenced to the total resident population of Australia. RESULTS: Standardised ESRD incidence among Indigenous Australians is highest in remote regions, where it is up to 30 times the national incidence for all Australians. In urban regions the standardised incidence is much lower, but remains significantly higher than the national incidence. Forty-eight per cent of Indigenous ESRD patients come from regions without dialysis or transplant facilities and 16.3% from regions with only satellite dialysis facilities. CONCLUSIONS: There is marked regional variation in the incidence of ESRD among Indigenous Australians. Because of the location of treatment centres, there is inequitable access to ESRD treatment services for a significant proportion of Indigenous patients.

Australia↗
PubMed2001

Erythroid Kruppel-like factor (EKLF) coordinates erythroid cell proliferation and hemoglobinization in cell lines derived from EKLF null mice.

Erythroid Kruppel-like factor (EKLF) is a transcription factor of the C2H2 zinc-finger class that is essential for definitive erythropoiesis. We generated immortal erythroid cell lines from EKLF(-/-) fetal liver progenitor cells that harbor a single copy of the entire human beta-globin locus and then reintroduced EKLF as a tamoxifen-inducible, EKLF-mutant estrogen receptor (EKLF-ER) fusion protein. Addition of tamoxifen resulted in enhanced differentiation and hemoglobinization, coupled with reduced proliferation. Human beta-globin gene expression increased significantly, whereas gamma-globin transcripts remained elevated at levels close to endogenous mouse alpha-globin transcript levels. We conclude that EKLF plays a role in regulation of the cell cycle and hemoglobinization in addition to its role in beta-globin gene expression. The cell lines we used will facilitate structural and functional analyses of EKLF in these processes and provide useful tools for the elucidation of nonglobin EKLF target genes.

Active Transport, Cell Nucleus↗
PubMed2001

Functional effect of adeno-associated virus mediated gene transfer of aromatic L-amino acid decarboxylase into the striatum of 6-OHDA-lesioned rats.

In animal models of Parkinson's disease, gene transfer of aromatic L-amino acid decarboxylase (AADC) leads to an increase in the capacity of the striatum to decarboxylate exogenous L-DOPA. However, the functional effects of enhanced L-DOPA to dopamine conversion have not been explored. Here, we show that following adeno-associated virus (AAV)-AADC transduction, the transgenic AADC is able to decarboxylate exogenous L-DOPA more efficiently so that a dose of L-DOPA ineffective before gene transfer elicits a motor asymmetry (rotational behavior) following gene transfer. Furthermore, rotation scores showed a strong correlation with AADC activity in the lesioned striatum, thus allowing for behavioral screening of successful gene transfer in the brain. In animals receiving AAV2-AADC, dopamine production was restored to 50% of normal levels 12 weeks after the infusion. Microdialysis experiments demonstrated an in vivo enhanced conversion of L-DOPA to dopamine, but no storage capacity as dopamine was released to the extracellular space in a continuous, nonregulated fashion. In addition to the potential clinical benefit of improving decarboxylation efficiency in Parkinson's disease, our approach may be relevant for the treatment of AADC deficiency, a rare, autosomal recessive disorder causing a severe movement disorder and progressive cognitive impairment.

Animals↗
PubMed2001

Echoviruses 1 and 8 are closely related genetically, and bind to similar determinants within the VLA-2 I domain.

Echoviruses (EV) 1 and 8 were originally considered to be distinct serotypes, but more recently have been considered strains of the same virus. In experiments with chimeric recombinant fusion proteins, both viruses bound to the I domain of the integrin VLA-2, and both required the same receptor residues for attachment. A full-length, infectious cDNA clone encoding EV1 was obtained; its nucleotide sequence was determined, as were the sequences encoding the EV8 capsid. EV1 and 8 show 94% amino acid identity within the capsid region and are more similar to each other than to any other human picornavirus.

Amino Acid Sequence↗
PubMed2001

Neurobiologic responses to speech in noise in children with learning problems: deficits and strategies for improvement.

OBJECTIVES: Some children with learning problems (LP) experience speech-sound perception deficits that worsen in background noise. The first goal was to determine whether these impairments are associated with abnormal neurophysiologic representation of speech features in noise reflected at brain-stem and cortical levels. The second goal was to examine the perceptual and neurophysiological benefits provided to an impaired system by acoustic cue enhancements. METHODS: Behavioral speech perception measures (just noticeable difference scores), auditory brain-stem responses, frequency-following responses and cortical-evoked potentials (P1, N1, P1', N1') were studied in a group of LP children and compared to responses in normal children. RESULTS: We report abnormalities in the fundamental sensory representation of sound at brain-stem and cortical levels in the LP children when speech sounds were presented in noise, but not in quiet. Specifically, the neurophysiologic responses from these LP children displayed a different spectral pattern and lacked precision in the neural representation of key stimulus features. Cue enhancement benefited both behavioral and neurophysiological responses. CONCLUSIONS: Overall, these findings contribute to our understanding of the preconscious biological processes underlying perception deficits and may assist in the design of effective intervention strategies.

Adolescent↗
PubMed2001

Perceived vulnerability to alcohol-related harm in young adults: independent effects of risky alcohol use and drinking motives.

Perceived vulnerability to negative outcomes can motivate heavy drinkers to adopt health-protective behavior, but little is known about determinants of perceived vulnerability to alcohol-related harm. University students (N = 286) were assessed to determine epidemiological risk status on a standardized problem drinking measure, typical reasons for drinking and cutting down, and perceived risk of experiencing alcohol-related harm. Results showed a positive relationship between problem drinking status and perceived risk of experiencing harm. However, at-risk drinkers believed that they were less likely to personally experience harm than comparable peers (p < .001), whereas not-at-risk drinkers showed no self-other differences in perceived vulnerability. Drinking motives significantly improved the prediction of perceived vulnerability when epidemiological risk status was controlled. Perceived vulnerability to alcohol-related harm is affected by problem drinking status and (independently) by the psychological functions that drinking serves.

Adult↗
PubMed2001

Successful unrelated donor bone marrow transplantation for paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease of hematopoiesis due to a mutation in the PIG-A gene. Affected patients may demonstrate hemolysis or venous thrombosis, and may develop MDS or aplastic anemia. Successful results may be obtained after conditioning and transplantation from syngeneic or genotypically matched sibling donors. Experience with transplantation from matched unrelated donors (MUD) is limited to eight patients, with only one survivor. We report three patients who underwent successful MUD BMT for PNH. All three patients had severe aplastic anemia (SAA) and PNH at the time of BMT. Unrelated donors were six-antigen HLA-matched (n = 2) or HLA-A mismatched (n = 1). Conditioning consisted of cytarabine, cyclophosphamide, TBI, and ATG. Grafts were T cell-depleted by anti-CD6/CD8 antibodies + complement. Further GVHD prophylaxis consisted of cyclosporine. Patients received 0.7-1.1 x 10(8) nucleated cells/kg and 1.1-2.1 x 10(6) CD34(+) cells/kg. Neutrophil engraftment occurred at 16-21 days. One patient developed grade 1 acute GVHD. Although all three patients experienced significant transplant-related complications, they ultimately resolved and all patients are alive and well 30-62 months after BMT. T cell-depleted MUD BMT is an effective treatment option for PNH-related MDS and SAA.

Adolescent↗
PubMed2001

Bisphosphonates in renal osteodystrophy.

The present review considers the role that bisphosphonates might have in patients with renal failure. Although bisphosphonates are widely used to reduce fracture risk in patients with osteoporosis, few studies have documented their effect in patients with renal osteodystrophy. The pathogenesis of bone loss after renal transplantation and the role of the recently identified osteoprotegerin/receptor activating nuclear factor-kappaB system is described. Inhibition of bone resorption may prove beneficial when high bone turnover is present, but there are potential drawbacks to widespread use of bisphosphonates. These issues are discussed, with emphasis placed on reports published within the past 18 months.

Animals↗
PubMed2001

Social disadvantage and variation in the incidence of end-stage renal disease in Australian capital cities.

OBJECTIVE: To evaluate variation in the incidence of end-stage renal disease (ESRD) within Australian capital cities. To explore the relation between the incidence of ESRD and socioeconomic disadvantage. METHODS: We obtained data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) regarding 5,013 patients from capital cities who started ESRD treatment between 1 April 1993 and 31 December 1998. We used the postcode at the start of treatment to calculate the average annual incidence of ESRD for each of 51 capital city regions using 1996 Census counts based on place of usual residence. We calculated standardised incidence ratios with 95% confidence intervals for each region. The standardised incidence ratios were examined in relation to the SEIFA Index of Relative Socio-economic Disadvantage (IRSD), derived from the 1996 Census. Low IRSD values indicate more disadvantaged areas. RESULTS: There is significant variation in the standardised incidence of ESRD within capital cities. There was a significant correlation (r=-0.41, p=0.003) between the standardised incidence ratio for ESRD and the SEIFA IRSD. CONCLUSIONS AND IMPLICATIONS: Capital city areas that are more disadvantaged have a higher incidence of ESRD. Socioeconomic factors may be important determinants of the risk of developing ESRD.

Australia↗
PubMed2001

Psychosocial determinants of perceived vulnerability to harm among adult drinkers.

OBJECTIVE: Perceived vulnerability to harm is widely acknowledged as a determinant of behavior change, but little is known about why some drinkers believe that they are personally "at risk" for problems while others do not. This study examined perceived vulnerability to alcohol-related harm in relation to epidemiological risk status on a standardized problem-drinking measure and two psychosocial measures of drinking context: (1) typical reasons for drinking and cutting down and (2) social network influences related to alcohol use. We evaluated the general hypothesis that these psychosocial variables would independently affect perceived vulnerability to alcohol-related harm, over and above epidemiological risk status. METHOD: Adults between the ages of 18 and 79 (N = 430; 249 women, 173 men, 8 gender unknown) completed a questionnaire about drinking behavior and drinking-related social and motivational context. RESULTS: There was a positive relationship between problem-drinking status and perceived risk of experiencing harm, and no support for the idea that objectively "at-risk" drinkers believe that they are less likely to personally experience harm than comparable peers. Drinking motives and social network variables each significantly improved the prediction of perceived vulnerability when epidemiological risk status was controlled. CONCLUSIONS: Interventions designed to alter drinkers' risk perceptions should take into account the reasons that people have for drinking and the social network context of alcohol use, in addition to whether or not individuals are "problem drinkers."

Adolescent↗
PubMed2001

Nonresponse in a follow-up to a representative telephone survey of adult drinkers.

OBJECTIVE: Examined predictors of nonresponse among respondents who agreed to receive a follow-up questionnaire on alcohol use after participating in a representative telephone survey, and among respondents who did and did not return the follow-up questionnaire. METHOD: A total of 2,072 (52.2% female) respondents to a representative monthly telephone survey were assessed on sociodemographic variables and alcohol use. Respondents were asked whether they would be willing to fill out an additional mailed questionnaire on alcohol use and attitudes toward drinking. Almost half (n = 956; 46%) of respondents agreed to participate in the follow-up survey; 430 (45%) of those individuals completed and returned the questionnaire. RESULTS: Agreement to receive the follow-up questionnaire was unrelated to alcohol use. Regarding gender, men were 1.42 times more likely than women to exhibit nonresponse in returning the follow-up questionnaire (95% CI: 1.08-1.42). After adjusting for the impact of demographic factors, respondents who consumed alcohol at least once per week were 1.43 times more likely than respondents who drank less frequently to exhibit nonresponse in returning the questionnaire (95% CI: 1.05-1.93). Respondents who consumed five or more standard drinks at least once per week were 1.83 times more likely to exhibit nonresponse in returning the questionnaire, compared with respondents who engaged in heavy drinking less frequently (95% CI: 1.15-2.92). CONCLUSIONS: Mailout questionnaires following a representative telephone survey may bias samples toward obtaining fewer men, fewer weekly drinkers and fewer heavier drinkers. Although the magnitude of these biases were relatively small, epidemiological studies on alcohol use may wish to oversample men and heavier drinkers in follow-up studies recruiting from population surveys.

Adult↗
PubMed2001

Self-assessed health among indigenous Australians: how valid is a global question?

OBJECTIVES: This study assessed the validity of a global measure of self-assessed health among Indigenous Australians. METHODS: Logistic regression was used to identify factors associated with self-assessed health in a nationally representative sample. RESULTS: Among 8782 adult respondents, poorer self-assessed health was strongly associated with several factors, including age, number of health conditions, and recent health actions. The association with health conditions was attenuated when the respondent's primary language was not English. CONCLUSIONS: Self-assessed health may be a valid measure among indigenous Australians whose primary language is English. However, although the measure draws on common experiences of health and illness, it may obscure differences in how people incorporate these experiences into social actions.

Adolescent↗