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Biomedical subjects

S Emerson

Publications and source records attributed to S Emerson.

At least 19 recordsLinked to original sources
PubMed2001

Hepatocyte growth factor is secreted by osteoblasts and cooperatively permits the survival of haematopoietic progenitors.

Human osteoblasts (HOBs) support the growth of human haematopoietic progenitor cells, and support the survival and limited expansion of long-term culture-initiating cells. Using human CD34+ cells and the murine myelomonocytic cell line NFS-60 as targets, we previously found that one component of HOB-derived haematopoietic activity is cell-associated granulocyte colony-stimulating factor (G-CSF). However, antibody failed to neutralize all the activity, suggesting that more than one factor supports haematopoietic cells. In the present investigations, we asked whether the HOB-derived, non-G-CSF secreted activity was as a result of other known growth factors. We found that, among the cytokines expressed by HOBs, only hepatocyte growth factor (HGF) and G-CSF stimulated NFS-60 cell proliferation. HOB cells and osteosarcoma cells secreted biologically active HGF, although the levels varied considerably. Moreover, addition of neutralizing HGF antibody to CD34+ cell/HOB co-cultures resulted in a significant reduction ( approximately 50%) in the ability of the HOBs to support haematopoietic progenitor cells. These results suggest that a major component of osteoblast-derived haematopoietic activity is HGF. Secretion of HGF, in concert with cell-associated cytokines such as G-CSF, may account for the stem cell-stimulating activities of osteogenic cells and, thereby, the unique stem cell-supporting role of the osteoblasts within the bone marrow microenvironment.

Antibodies, Monoclonal↗
PubMed2000

Anthropometric measures and risk of death in children with end-stage renal disease.

We evaluated the association between anthropometric measurements and death among pediatric patients with end-stage renal disease (ESRD) using data from the Pediatric Growth and Development Special Study (PGDSS) from the US Renal Data System. Height, growth velocity, and body mass index (BMI) were used for the analysis of 1,949 patients in the PGDSS. To standardize these measurements, SD scores (SDSs) were calculated using population data from the Third National Health and Nutrition Examination Survey. Using Cox proportional hazards models, we assessed the association between anthropometric measures and death, controlling for demographic factors and stratifying by age. Multivariate analysis showed that each decrease by 1 SDS in height was associated with a 14% increase in risk for death (adjusted relative risk [aRR], 1.14; 95% confidence interval [CI], 1.02 to 1.27; P = 0.017). For each 1 SDS decrease in growth velocity among patients in our sample, the risk for death increased by 12% (aRR, 1.12; 95% CI, 1.00 to 1.25; P = 0.043). There was a statistically significant U-shaped association between BMI and death (P = 0.001), with relatively low and high BMIs associated with an increased risk for death. In children with ESRD, growth delay and extremes in BMI are associated with an increased risk for mortality.

Adolescent↗
PubMed1999

Screening plasma aluminum levels in relation to aluminum bone disease among asymptomatic dialysis patients.

Aluminum accumulation in plasma and tissues is a well-described complication among persons undergoing peritoneal dialysis or hemodialysis. Excess bone aluminum is associated with low bone formation rates and increased risk for fractures. Current recommendations for care of patients with end-stage renal disease include screening for aluminum toxicity with plasma aluminum levels; patients with levels below 40 microg/L are considered to be at low risk for aluminum bone disease (ABD). We examined data from the Toronto Renal Osteodystrophy Study to evaluate the performance of plasma aluminum levels in screening for ABD. Two hundred fifty-eight unselected patients undergoing peritoneal dialysis (n = 143) or hemodialysis (n = 115) underwent diagnostic bone biopsy and measurement of plasma aluminum level. Sixty-nine patients (26.7%) were identified as having ABD, defined as low or normal bone formation rates with 25% or more bone surface aluminum staining. Plasma aluminum level was strongly associated with the presence of ABD; the odds ratio was 1.4 for each increase of 10 microg/L (95%CI, 1.2, 1.6). However, only 50.1% of patients with a plasma aluminum level of 40 microg/L or greater had ABD, whereas 14.2% of patients with a level below this threshold also had ABD. Using this cutoff level of 40 microg/L, the sensitivity and specificity were 65.2% and 76.7%, respectively. We conclude that although there is a correlation between high aluminum levels and ABD, a patient's plasma aluminum level does not predict well the presence of ABD in spite of a relatively high prevalence of disease.

Adult↗
PubMed1999

Dose-response relationship of intrathecal morphine for postcesarean analgesia.

BACKGROUND: This series investigated the quality of analgesia and the incidence and severity of side effects of intrathecal morphine for post-cesarean analgesia administered over a dose range of 0.0-0.5 mg. METHODS: ONE hundred eight term parturients undergoing cesarean delivery at term and given spinal anesthesia were randomized to receive a single dose of intrathecal morphine (0.0, 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, 0.4, or 0.5 mg). A patient-controlled analgesia (PCA) device provided free access to additional analgesics. PCA morphine use, incidence and severity of side effects, and need for treatment interventions were recorded for 24 h. Data were analyzed with analysis of variance and linear regression analysis for trends among groups. RESULTS: Patient-controlled analgesia use differed significantly between groups; PCA use was higher in the control group than in groups receiving 0.075, 0.1, 0.3, 0.4, or 0.5 mg. Twenty-four-hour PCA morphine use was 45.7 mg lower (95% CI, 4.8-86.6 mg lower) in the 0.075-mg group than the control group. There was no difference in PCA morphine use between the 0.075- and 0.5-mg groups (95% CI, 36.8 mg lower to 45.0 mg higher); despite a fivefold increase in intrathecal morphine dose, PCA morphine use remained constant. There was no difference between control and treatment groups or among treatment groups with respect to nausea and vomiting. Pruritus and the need for treatment interventions increased in direct proportion to the dose of intrathecal morphine (linear regression, P = 0.001 and P = 0.0002, respectively). CONCLUSIONS: These data indicate there is little justification for use of more than 0.1 mg for post-cesarean analgesia. For optimal analgesia, augmentation [corrected] of intrathecal morphine with systemic opioids may be necessary.

Analgesics, Opioid↗
PubMed1999

Is greater continuity of care associated with less emergency department utilization?

BACKGROUND: The benefits of continuity of care (COC) have not been firmly established for pediatric patients. OBJECTIVE: To assess whether greater COC is associated with lower emergency department (ED) utilization. SETTING: Outpatient teaching clinic at Children's Hospital and Regional Medical Center, Seattle, WA. PATIENTS: All 785 Medicaid managed care children ages 0 to 19 years followed at Children's Hospital and Regional Medical Center between 1993 to 1997 who had at least four outpatient visits. METHODS: Retrospective claims-based analysis. COC was quantified based on the number of different care providers in relation to the number of clinic visits. RESULTS: Attending COC was significantly greater than resident COC. In a multiple event survival analysis, compared with those patients in the lowest tertile of attending COC, those in the middle tertile had 30% lower ED utilization (hazard ratio 0.70 [0.53-0.93]) and those in the highest tertile had 35% lower ED use (hazard ratio 0.65 [0.50-0.80]). Resident COC was not significantly associated with ED use. CONCLUSION: Greater COC with attending physicians in outpatient teaching clinics is associated with lower ED utilization.

Adolescent↗
PubMed1998

Effect of alpha-difluoromethylornithine on rectal mucosal levels of polyamines in a randomized, double-blinded trial for colon cancer prevention.

BACKGROUND: Polyamines (e.g., putrescine, spermidine, and spermine) are required for optimal cell growth. Inhibition of polyamine synthesis suppresses carcinogen-induced epithelial cancers, including colon cancer, in animal models. In a short-term phase IIa trial, we determined that low doses of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (an enzyme involved in polyamine synthesis), reduced the polyamine content of normal-appearing rectal mucosa of subjects with a prior history of resected colon polyps. In a follow-up study, we have attempted to determine the lowest dose of DFMO that can suppress the polyamine content of rectal mucosa over a course of 1 year with no or minimal side effects. METHODS: Participants were randomly assigned to daily oral treatment with a placebo or one of three doses (0.075, 0.20, or 0.40 g/m2) of DFMO. Baseline and serial determinations of polyamine levels in rectal mucosa and extensive symptom monitoring (including audiometric measurements, since DFMO causes some reversible hearing loss at higher doses) were performed over a 15-month period. RESULTS: DFMO treatment reduced putrescine levels in a dose-dependent manner. Following 6 months of treatment, doses of 0.20 and 0.40 g/m2 per day reduced putrescine levels to approximately 34% and 10%, respectively, of those observed in the placebo group. Smaller decreases were seen in spermidine levels and spermidine:spermine ratios. Polyamine levels increased toward baseline values after discontinuation of DFMO. Although there were no statistically significant differences among the dose groups with respect to clinically important shifts in audiometric thresholds and nonaudiologic side effects, statistically significant higher dropout and discontinuation rates were observed in the highest dose group. CONCLUSIONS: Polyamine levels in rectal mucosa can be continuously suppressed by daily oral doses of DFMO that produce few or no side effects. A dose of 0.20 g/m2 can be used safely in combination phase IIb or single-agent phase III chemoprevention trials.

Adult↗
PubMed1998

Risk of death among chronic dialysis patients infected with hepatitis C virus.

Hepatitis C virus (HCV) infection is highly prevalent among chronic dialysis patients (10% to 40%) and is the most common cause of chronic liver disease. However, there are no studies estimating the risk for death among dialysis patients infected with HCV compared with those not infected. We conducted a prospective cohort study to estimate the risk for death among chronic dialysis patients infected with HCV compared with those not infected. In 1992, 200 patients (91%) who had been undergoing dialysis therapy for at least 6 months consented to be screened for HCV infection by enzyme immunoblot assay and polymerase chain reaction (PCR). Information about potential confounders and potential risk factors for death and HCV infection was obtained from the dialysis center database. Patient outcomes collected included death, transplantation, and loss to follow-up. The Cox proportional hazards model was used to estimate the odds of death among dialysis patients who were positive for the HCV antibody and HCV RNA compared with negative patients. Forty-four patients (22%) were HCV antibody positive. Thirty-four patients (17%) were HCV RNA positive. Patients in the HCV RNA-positive group were more likely to be younger (51.8+/-12.6 v 57.2+/-17.3 years of age), men (77% v 54%), and black (65% v 37%). None of the home hemodialysis or peritoneal dialysis patients were HCV RNA positive, whereas one of the home hemodialysis and one of the peritoneal dialysis patients were HCV antibody positive. Two patients became infected with HCV during the follow-up period. Patients who were HCV RNA positive and those who were HCV antibody positive were at increased risk for death compared with patients who were negative (adjusted relative risk [aRR]=1.78; 95% confidence interval [CI], 1.01 to 3.14; P=0.045; and aRR=1.97; 95% CI, 1.16 to 3.33; P=0.012, respectively), after adjusting for time on dialysis, race, transplantation, and age. We conclude that HCV infection increased the risk for death during the study period compared with those not infected. Further studies should assess the measures used to prevent and treat HCV infection.

Adult↗
PubMed1997

Association of hepatitis C virus infection with mortality and graft survival in kidney-pancreas transplant recipients.

BACKGROUND: Although most studies have not demonstrated decreased patient or graft survival in kidney-alone allograft recipients infected with hepatitis C virus (HCV), the impact of HCV infection on patient and graft survival in HCV-infected kidney-pancreas recipients has not been studied. METHODS: We undertook a retrospective cohort analysis of 137 kidney-pancreas transplant recipients who were transplanted between January 1989 and May 1996. HCV infection was determined by a positive polymerase chain reaction. Relative risk of death and graft failure was calculated using the Cox proportional hazards model with time-dependent covariates. Relative risks were adjusted (aRR) to control for the number of OKT3-treated rejections and cytomegalovirus status of the recipient at the time of transplantation. RESULTS: Mean length of follow-up was 30.4 months in the HCV-infected patients compared with 31.7 months in noninfected patients. Seven (5.1%) patients were infected with HCV before transplant, one (1%) relapsed after transplantation, and four (2.9%) acquired the infection after transplantation. The HCV-infected group had a 3.7-fold (95% confidence interval [CI], 1.0-13.5) increased risk of death after transplant compared with the HCV-negative group, with an aRR of 5.5 (95% CI, 1.5-20.0). Death in the HCV-infected group (n=3) was generally the result of liver failure and sepsis, whereas death for those in the uninfected group (n=11) was primarily of cardiovascular origin. Patients infected with HCV were 3.4-fold (95% CI, 1.1-10.1) more likely to develop kidney graft failure than HCV-negative patients with an aRR of 5.1 (95% CI, 1.7-15.4). The risk of pancreatic allograft failure was not significantly increased. CONCLUSIONS: We conclude that HCV infection in kidney-pancreas transplant patients results in a significantly increased risk of kidney allograft failure and death.

Adult↗
PubMed1997

The effect of wheat bran fiber and calcium supplementation on rectal mucosal proliferation rates in patients with resected adenomatous colorectal polyps.

Colorectal cancers continue as the second most common cause of death from cancer in the United States. Only a few prospective, randomized clinical trials have been performed to evaluate the potential preventive effects of dietary fiber or calcium in patients with an increased risk for the development or recurrence of colorectal cancer. We designed and conducted a double-blinded, placebo-controlled randomized trial involving supplementation of fiber and calcium intake and measurements of [3H]thymidine labeling index (LI) percentages in rectal mucosal biopsies obtained from patients with resected colorectal adenomas to examine the potential mechanisms by which dietary interventions might reduce colorectal cancer risk. We performed a randomized, double-blinded, Phase II study, using a factorial design to measure the effects of supplemental dietary wheat bran fiber (2.0 or 13.5 g/day) and calcium carbonate (250 or 1500 mg/day elemental calcium) supplementation on [3H]thymidine LI percentages in rectal mucosal crypts and 24-h in vitro outgrowth cultures. Measurements were made at baseline randomization (i.e., after a 3-month placebo run-in period using 2.0 g of wheat bran fiber plus 250 mg of calcium carbonate) and after 3 and 9 months on treatment in 100 randomized participants who had a history of colon adenoma resection. Neither the wheat bran fiber nor the calcium carbonate supplements significantly reduced [3H]thymidine LI percentages in rectal mucosal crypts (total or compartmental analysis) or 24-h in vitro outgrowth cultures at either 3 or 9 months of daily supplementation in the 93 evaluable participants. We conclude that 9 months of high-dose wheat bran fiber and calcium carbonate supplementation in study participants with a history of recently resected colorectal adenomas does not have a significant effect on cellular proliferation rates in rectal mucosal biopsies, comparing 3- and 9-month results to baseline results. Ultimately, there is great need for the evaluation of these two different nutrient interventions in the setting of Phase III studies wherein adenomatous polyp recurrence, rather than a rectal mucosal biomarker, serves as the primary end point.

Adenomatous Polyps↗
PubMed1996

Serum can inhibit reversal of multidrug resistance by chemosensitisers.

The purpose of this study was to evaluate to what extent the ability of various chemosensitisers (CS) to reverse P-glycoprotein-associated multidrug resistance (MDR) is reduced when tested in physiological serum protein concentrations. Utilising drug sensitivity and accumulation assays, the CS were tested in medium containing 10% fetal bovine serum and in 100% horse or human serum. Two RPMI 8226 human myeloma sublines were used which express different levels of P-glycoprotein. The CS were tested at various concentrations, including clinically achievable blood levels. When using the CS at high doses, wide differences were observed in the extent CS activity was diminished by serum. Verapamil, cyclosporin A and quinine were not affected, quinidine and medroxyprogesterone acetate were moderately inhibited, and amiodarone and trifluoperazine were largely inactivated. When the CS were used at concentrations achievable in humans, the activity of all agents except quinine was markedly reduced by serum. With respect to the extent to which CS activity was diminished by serum, good statistical correlation (r > 0.90, P < 0.001) was found between the use of cytotoxicity and drug accumulation assays, horse and human serum or cell lines with high and low levels of P-glycoprotein, respectively. These studies demonstrated that physiological serum protein concentrations can profoundly diminish the MDR reversing activity of particular CS. Some drugs, such as amiodarone and trifluoperazine, are largely inactivated by serum when used at a wide range of concentrations. Other agents, such as verapamil and cyclosporin A, are essentially unaffected when used at high doses but markedly inhibited at concentrations achievable in humans. These data suggest that in vitro studies of CS in medium containing low serum protein concentrations can result in misleading conclusions regarding the potential clinical activity of such agents.

Animals↗
PubMed1996

A hydrophobic heptad repeat of the core protein of woodchuck hepatitis virus is required for capsid assembly.

The capsid particle of hepadnaviruses is assembled from its dimer precursors. However, the mechanism of the protein-protein interaction is still poorly understood. A small region in the capsid protein of woodchuck hepatitis virus (WHV) contains four hydrophobic residues, including leucine 101, leucine 108, valine 115, and phenylalanine 122, that are conserved and spaced every seventh residue in the primary sequence to form a hydrophobic heptad repeat (hhr). A hydrophobic force often plays an important role in the interaction of proteins. Therefore, to investigate the role of this region in capsid assembly, we individually changed the codons specifying these four hydrophobic amino acids to codons specifying alanine or proline. In addition, we examined the in vivo infectivity of a WHV genome bearing a naturally occurring single amino acid change (histidine 104-->proline) in the hhr region. The phenotype of each altered genome was determined in both eukaryotic and prokaryotic systems by a capsid protein assay and electron microscopic examination. We show that replacement of any one of the four hydrophobic residues with alanine did not prevent capsid assembly. However, assembled capsid particles were not detected if combinations of any two of the four residues were substituted with alanines or if the spacing of these four hydrophobic residues was changed. An individual introduction of a proline (which dramatically changes the secondary structure of proteins) into different positions of this small region also abolished capsid assembly in vitro or viral replication in vivo. These results suggested that the hhr region of the core protein of WHV was critical for capsid assembly.

Amino Acid Sequence↗
PubMed1995

Cytogenetics of 158 patients with regional or disseminated melanoma. Subset analysis of near-diploid and simple karyotypes.

We report on the cytogenetic analyses of 158 cases of metastatic malignant melanoma, comprised of 63 cases with regional disease (RD) and 95 cases with distant (metastatic) disease (DD). Clonal structural abnormalities were identified in 126 (80%) cases and were significantly increased ( < 0.01 after adjusting for multiple comparisons) on chromosomes (in order of frequency of involvement) 1, 6, 7, 11, 9, and 3. Clustering of breakpoints occurred at 1p36, 1p22-q21, 6p11-q21, 9p, 11q23-qter, 13p (especially for cases with DD), and 19q13. The most common clonal numerical abnormalities, in a subset of 49 near-diploid cases were -10, -22, -9, +7, -19, and -Y. Analysis of chromosome segment gains and losses (CSRP) showed frequent loss of chromosomes 6 and 10, followed by equal rates of involvement of chromosomes 1, 7, and 9. Whole or segmental losses of chromosome 9 (especially 9p) correlate well with recent molecular genetic studies identifying putative suppressor genes, and are also likely important genetic abnormalities. However, based on the frequency of abnormalities in this large series of metastatic melanomas, it is likely that structural abnormalities of 1 and 6, and 10 are important in the pathogenesis of sporadic advanced melanoma.

Adult↗
PubMed1995

Acute viral hepatitis in Saudi Arabia: seroepidemiological analysis, risk factors, clinical manifestations, and evidence for a sixth hepatitis agent.

We conducted a prospective, descriptive cohort study of all 217 cases of acute viral hepatitis (AVH) seen in adults during 1992 at the sole hospitals with infectious disease departments in the second and third largest cities in the Kingdom of Saudi Arabia. In addition, we undertook a nested case-control study. Our goals were (1) to determine the causes, demographics, risk factors, and clinical characteristics of AVH in the Kingdom; (2) to evaluate the reliability of diagnostic tests for acute hepatitis C and E; and (3) to assess the relative importance, characteristics, and risk factors of a sixth hepatitis agent, non-A-E. All cases and controls completed a questionnaire. Cases provided blood samples for studies of serum bilirubin, alanine and aspartate aminotransferases, and antibody to hepatitis viruses as well as genome detection studies. The results of serological and molecular tests were used to categorize each case as hepatitis A, B, C, D, E, or non-A-E. Historical, clinical, and laboratory determinants were statistically analyzed by comparisons between groups with different types of AVH and controls. Analysis of risk factors suggested that hepatitis C and D were parenterally transmitted, while hepatitis A, E, and non-A-E were not; the route of transmission of hepatitis B was unclear. Hepatitis E was strongly associated with living or traveling on the Indian subcontinent. The clinical disease caused by all six agents was indistinguishable. The putative sixth agent caused 13% of cases. The second-generation tests for antibody to HCV and HEV were relatively reliable for the diagnosis of AVH.

Acute Disease↗
PubMed1994

Epidemic hepatitis E in Pakistan: patterns of serologic response and evidence that antibody to hepatitis E virus protects against disease.

IgM and IgG anti-hepatitis E virus (HEV) patterns were determined in sera collected during a hepatitis outbreak in Pakistan. HEV infection was detected serologically in 122 patients. IgM anti-HEV was detected in specimens collected up to 2 weeks before and 5-7 weeks after hospitalization in 91% and 100%, respectively, of 122 HEV-infected patients. IgG followed a similar pattern. Peak antibody titers appeared 2-4 weeks after hospitalization. At 20 months after hospitalization, IgM anti-HEV was not detected in any of 33 patients; IgG was found in all. IgG anti-HEV appeared to be protective in contracts of patients. This study confirms HEV as the cause of the outbreak, quantifies IgM and IgG anti-HEV responses, provides evidence that IgG anti-HEV protects against hepatitis E, and demonstrates that IgG anti-HEV persists, but at diminished titer, after infection. Hepatitis E in young adults is the result of primary infection with HEV and, if reinfection occurs, it does not commonly cause serious illness.

Antibodies, Viral↗
PubMed1993

In vitro evaluation of chemosensitizers for clinical reversal of P-glycoprotein-associated Taxol resistance.

The purpose of this study was to estimate the potential usefulness of currently available chemosensitizers (CS) for clinical reversal of P-glycoprotein-mediated Taxol resistance. The 8226/DOX6 human myeloma cells were used to evaluate CS effects in serum-rich medium by means of the human tumor cloning assay. The 8226/DOX6 cells express low levels of P-glycoprotein as typically found in clinical cancer specimens and are approximately 40-fold resistant to Taxol when continuously exposed to the drug in serum-rich medium. The CS were used at maximum tolerated plasma levels (Cmax) and at the concentrations achieved in human plasma by oral administration (Coral). Of nine CS tested, cyclosporine A (CSA), verapamil (VER), quinidine (QD), and quinine (Q) were able to overcome Taxol resistance. QD and Q were effective at Coral, whereas CSA and VER required Cmax to significantly enhance Taxol cytotoxicity. The most potent agent was CSA, which increased sensitivity to Taxol by 8-, 12-, and 18-fold when used at concentrations of 1.0, 2.0, and 4.0 microM, respectively. At 5.0 microM, CSA was capable of fully normalizing Taxol sensitivity. On the basis of these data, infusional CSA might prove useful for clinical reversal of P-glycoprotein-associated Taxol resistance. It remains to be seen, however, whether the CSA concentrations needed to reverse Taxol resistance effectively can be safely achieved in human plasma when CSA is coadministered with Taxol.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Use of cytosine arabinoside and total body irradiation as conditioning for allogeneic marrow transplantation in patients with acute lymphoblastic leukemia: a multicenter survey.

We report the experience of 14 centers which have used the combination of cytosine arabinoside (ara-C; 24-36 g/m2) and total body irradiation (TBI) to prepare 213 patients with acute lymphoblastic leukemia (ALL) for allogeneic BMT. The overall 3-year disease-free survival (DFS) probability is 38% (95% CI: 31-45%); 75 patients died of complications and 51 relapsed. Multivariate analysis identified three factors independently associated with outcome: age, remission/relapse status and patient-donor relationship. The 3-year DFS probability is 52% (41-63%) for the 106 patients aged 0-11 and 25% (16-33%) for the 104 aged 11+ years; the DFS probability was 54% (34-74%), 41% (32-49%) and 19% (5-33%) for those in first remission, later remissions and relapse respectively. Older patients suffered both more toxic deaths and more relapses than young ones. No other covariate was found to predict for outcome. The results using ara-C-TBI are similar to those achieved using cyclophosphamide plus TBI to prepare ALL patients for BMT, perhaps because a seemingly lower relapse rate is offset by more toxic deaths particularly in older patients. Therapeutic trials should focus on reducing toxicity while maximizing antileukemic efficacy, and should stratify for patient and disease-related factors.

Adolescent↗