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Biomedical subjects

J Lipton

Publications and source records attributed to J Lipton.

At least 19 recordsLinked to original sources
PubMed2002

The effects of long-term cadmium exposure on the growth and survival of juvenile bull trout (Salvelinus confluentus).

Bull trout (Salvelinus confluentus) have been listed recently as threatened in the United States under the federal Endangered Species Act. This species currently resides, or historically resided, in several waterways that either are impacted or are under threat of impact from metals mining activities. We conducted a 55-day sub-chronic (i.e. sublethal) cadmium (Cd) exposure in water at 30 mg l(-1) (as CaCO(3)) hardness, pH 7.5, and 8 degrees C. Exposures were conducted using six replicate exposure tanks for each of the six treatments (five Cd concentrations and one control). Measured Cd concentrations were <0.013 (control), 0.052, 0.089, 0.197, 0.383, and 0.786 microg Cd l(-1). Exposure to 0.786 microg Cd l(-1) caused increased mortality (37%) and reduced growth (28% reduction in weight change) in fish exposed for 55 days. All Cd exposure concentrations caused significant whole body accumulation of Cd compared with controls. Our results indicate that even though fish are significantly accumulating Cd in each non-control treatment, growth reductions in bull trout occurred only at Cd concentrations that also caused significant mortality. The Cd concentration that reduced growth and survival in this long-term exposure (0.786 microg Cd l(-1)) is greater than the recently-revised US federal aquatic life criteria (ALC) value for the corresponding hardness concentration (ALC=0.62 microg Cd l(-1) for acute effects and 0.11 microg Cd l(-1) for chronic effects).

Animals↗
PubMed2002

Relationship between exposure duration, tissue residues, growth, and mortality in rainbow trout (Oncorhynchus mykiss) juveniles sub-chronically exposed to copper.

We conducted a 56-day sub-chronic test on the effects of Cu on rainbow trout (Oncorhynchus mykiss) fry at a nominal water hardness of 100 mg l(-1) (as CaCO(3)). Response measures were growth, whole body Cu concentrations, and mortality. Significant mortality was observed in fish exposed to 54.1 microg Cu l(-1) (47.8%) and 35.7 microg Cu l(-1) (11.7%). Growth was dose-dependent over the range of Cu treatments (0-54 microg Cu l(-1)), and was modeled as a function of Cu exposure concentration and exposure duration. Calculated inhibition concentrations (based on change in wet weight through a 56-day Cu exposure) were IC(50)=54.0 microg Cu l(-1), IC(20)=21.6 microg Cu l(-1), IC(10)=10.8 microg Cu l(-1), and IC(01)=1.1 microg Cu l(-1). Measured whole body Cu was also dose-dependent, and growth of trout fry was readily modeled as a function of tissue Cu and exposure duration. This model was virtually identical to a model previously developed for rainbow trout exposed to Cu at a hardness of 25 mg l(-1). Following the 56-day exposure period, we performed a 96-h acute challenge to Cu and Cd to evaluate the effects of Cu acclimation on acute Cu and Cd toxicity. Sensitivity to Cu was dependent on the 'acclimation dose'; trout previously held in control aquaria (i.e. not acclimated to Cu) suffered over 80% mortality, whereas trout previously exposed to 35.7 microg Cu l(-1) for 56 day suffered 20% mortality. These fish also showed somewhat reduced sensitivity to Cd, suggesting acclimation to Cu can enhance tolerance to other metals. Finally, the relationship between growth response and hardness (derived from several studies) appeared to have a different slope than the hardness relationship previously observed for lethality responses.

Adaptation, Physiological↗
PubMed2001

Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis.

BCR/ABL fluorescent in situ hybridization study of chronic myeloid leukemia (CML) and Philadelphia(+) (Ph(+)) acute lymphoid leukemia (ALL) indicated that approximately 9% of patients exhibited an atypical hybridization pattern consistent with a submicroscopic deletion of the 5' region of ABL and the 3' region of the BCR genes on the 9q(+) chromosome. The CML patients with deletions had a shorter survival time and a high relapse rate following bone marrow transplant. Since deletions are associated with both Ph(+) CML and ALL, it seemed probable that other leukemia-associated genomic rearrangements may also have submicroscopic deletions. This hypothesis was confirmed by the detection of deletions of the 3' regions of the CBFB and the MLL genes in AML M4 patients with inv(16) and in patients with ALL and AML associated with MLL gene translocations, respectively. In contrast, analysis of the AML M3 group of patients and AML M2 showed that similar large deletions were not frequently associated with the t(15;17) or t(8;21) translocations. Analysis of sequence data from each of the breakpoint regions suggested that large submicroscopic deletions occur in regions with a high overall density of Alu sequence repeats. These findings are the first to show that the process of deletion formation is not disease specific in leukemia and also implicate that the presence of repetitive DNA in the vicinity of breakpoint regions may facilitate the generation of submicroscopic deletions. Such deletions could lead to the loss of one or more genes, and the associated haploinsufficiency may result in the observed differences in clinical behavior. (Blood. 2001;97:3581-3588)

Adolescent↗
PubMed2001

A randomised trial comparing cytomegalovirus antigenemia assay vs screening bronchoscopy for the early detection and prevention of disease in allogeneic bone marrow and peripheral blood stem cell transplant recipients.

Preemptive antiviral therapy is often employed for CMV prevention following allogeneic BMT. Two common strategies are a screening bronchoscopy for CMV post-BMT or regular CMV antigenemia testing with ganciclovir administration for a positive result. In a randomised trial, we prospectively compared the efficacy of these two preemptive strategies. Consecutive patients were randomised to either a bronchoscopy for CMV on day 35 post BMT or weekly CMV antigenemia testing. If the bronchoscopy was positive for CMV, patients received preemptive ganciclovir for 8-10 weeks. If the antigenemia was positive for CMV, patients received a minimum of 2 weeks of preemptive ganciclovir. The primary endpoint was the development of active CMV disease. One hundred and eighteen allogeneic BMT patients were enrolled (60 in the antigenemia arm and 58 in the bronchoscopy arm). The two groups were comparable with respect to baseline demographic data, underlying disease, conditioning regimen, and immunosuppression. Active CMV disease developed in 7/58 (12.1%) patients in the bronchoscopy arm vs 1/60 patients (1.7%) in the CMV antigenemia arm (P = 0.022). Based on the screening test, 13.8% of patients received preemptive ganciclovir in the bronchoscopy arm vs 48.3% of patients in the antigenemia arm (P < 0.001). There was no significant difference in the rate of graft-versus-host disease, bacteremia, invasive fungal infections or mortality between the two groups. Preemptive therapy based on regular CMV antigenemia monitoring is superior to screening bronchoscopy for the prevention of CMV disease after allogeneic BMT.

Adult↗
PubMed2001

Training pathways for careers in dental, oral, and craniofacial research.

There are virtually unlimited opportunities for biomedical research training through either extramural or intramural training mechanisms, with programs designed for both the pre- and postdoctoral educational levels. The only difficulty is selecting from the vast array of research topic areas.

Career Choice↗
PubMed2000

Bone marrow mobilized with granulocyte colony-stimulating factor in related allogeneic transplant recipients: a study of 29 patients.

We studied whether a short course of granulocyte colony-stimulating factor (G-CSF) administered to normal donors immediately before bone marrow (BM) harvest would shorten time to neutrophil and platelet engraftment in matched related allogeneic BM recipients. Twenty-nine normal donors received 4 consecutive daily subcutaneous injections of G-CSF (median dose, 12.1 microg/kg per day; range, 9.6-15.7 microg/kg per day) immediately before BM harvest. Donors tolerated G-CSF well, with only mild myalgias and arthralgias, and BM was easy to aspirate. The BM harvest contained a median of 5.3 x 10(8) white blood cells (WBCs)/kg (range, 3.1-11.1 x 10(8) WBCs/kg) and 2.5 x 10(6) CD34+ cells per kg (range, 1.5-7.3 x 10(6) CD34+ cells per kg). Median times to neutrophil (18 days [range, 11-30 days] versus 22 days [range, 16-36 days]; P = .05) and platelet (22 days [range, 15-55 days] versus 27 days [range, 18-46 days]; P = .04) engraftment were statistically shorter than those of historical control subjects whose donors had not received G-CSF before BM harvest. However, secondary engraftment-dependent outcomes including red blood cell and platelet transfusions, febrile days, days on antibiotics, days from transplant to hospital discharge, and days in hospital during the first 60 days after transplant were not statistically different from historical control subjects. We conclude that G-CSF administered to normal donors immediately before harvest facilitates BM aspiration, increases the WBC content of the harvest, and hastens neutrophil and platelet engraftment compared with historical control subjects.

Adolescent↗
PubMed2000

Subretinal abscess due to Nocardia farcinica infection.

PURPOSE: Nocardia infection of the eye is uncommon. A case of choroidal abscess due to Nocardia farcinica infection is presented, and the literature is reviewed. METHODS: A 41-year-old immunocompromised man with chronic myeloid leukemia developed a unilateral choroidal abscess. N. farcinica was isolated from a simultaneous subcutaneous abscess and both infections responded to systemic sulfonamide therapy. RESULTS: Three weeks after discontinuation of the sulfonamides, the choroidal abscess recurred with involvement of the vitreous. The infection was brought under control after reinstitution of the same drug. CONCLUSIONS: Nocardiosis is a multisystem disease that has high mortality and ocular morbidity rates. The eyes of immunocompromised patients should be examined frequently as early detection and administration of the proper antibiotics may reduce the risk of this life-threatening infection.

Abscess↗
PubMed1999

Management of allogeneic bone marrow transplant recipients at risk for cytomegalovirus disease using a surveillance bronchoscopy and prolonged pre-emptive ganciclovir therapy.

BACKGROUND: Patients undergoing allogeneic bone marrow transplant (BMT) are considered to be at increased risk of cytomegalovirus (CMV) disease if they and/or their donor are CMV seropositive pre-transplant. Although several pre-emptive strategies have been shown to be effective in preventing early CMV disease, the ability of pre-emptive strategies using prolonged ganciclovir therapy to reduce the incidence of late-onset CMV infection, disease and mortality has not been fully evaluated. OBJECTIVE: To assess the efficacy of 18 weeks of pre-emptive ganciclovir therapy in preventing late-onset (> 100 days post-transplant) CMV disease when administered to asymptomatic BMT patients found to have CMV in bronchoalveolar lavage (BAL) fluid obtained during a surveillance bronchoscopy approximately 35 days post-transplant. To determine whether or not survival of BMT recipients is influenced by pre-transplant donor and recipient CMV serostatus in the context of this pre-emptive ganciclovir strategy. STUDY DESIGN: Consecutive patients undergoing allogeneic BMT were assessed for their risk of developing CMV disease based on their pre-transplant CMV serostatus and that of their donor. Patients who were CMV seropositive and/or received marrow from a CMV seropositive donor underwent a surveillance bronchoscopy and BAL approximately 35 days post-transplant. Patients with positive BAL fluid for CMV received pre-emptive ganciclovir therapy for 18 weeks at decreasing dose levels. Patients considered to be at low risk for the development of CMV disease (donor and recipient CMV seronegative) were followed without intervention. RESULTS: Of 98 consecutive patients, 55 were considered to be at risk for CMV disease and underwent a surveillance bronchoscopy. Sixteen (29%) patients had a positive BAL fluid for CMV and were started on pre-emptive ganciclovir therapy. Two patients progressed and died with CMV-related pneumonia. One additional patient developed CMV-related enteritis on day 42 post-transplant and recovered with continuing ganciclovir treatment. Of the 39 patients with a negative BAL fluid for CMV, one developed a fatal CMV pneumonia 150 days post-transplant and two additional patients developed gastrointestinal CMV disease 28 and 57 days post-BMT, respectively. None of the patients in the low risk group developed CMV disease. CONCLUSIONS: The strategy utilizing a surveillance bronchoscopy for CMV and initiating prolonged (18 weeks) pre-emptive ganciclovir therapy for patients with a positive BAL fluid for CMV resulted in a low incidence of CMV-related post-transplant complications. After a minimum follow-up of 16 months, late CMV reactivations (occurring > 100 days post-transplant) were not observed in the group of individuals pre-emptively treated with ganciclovir. This observation suggests that prolonged therapy with a reduced dose of ganciclovir may be important in the prevention of CMV reactivation. The CMV serostatus of donors and recipients prior to BMT did not correlate with survival.

Adult↗
PubMed1999

The clinical utility of CMV surveillance cultures and antigenemia following bone marrow transplantation.

At our institution, the cytomegalovirus (CMV) prophylaxis protocol for allogeneic bone marrow transplant (BMT) recipients who are CMV-seropositive or receive marrow from a CMV-seropositive donor consists of a surveillance bronchoscopy approximately 35 days posttransplant. Patients with a positive surveillance bronchoscopy for CMV receive pre-emptive ganciclovir. In order to determine the utility of other screening methods for CMV, we prospectively performed weekly CMV antigenemia, and blood, urine and throat cultures from time of engraftment to day 120 post-BMT in 126 consecutive patients. Pre-emptive ganciclovir was given to 11/81 patients (13.6%) because of a positive surveillance bronchoscopy for CMV. Results of CMV blood, urine and throat cultures and the antigenemia assay done prior to or at the time of the surveillance bronchoscopy were analyzed for their ability to predict the bronchoscopy result. The antigenemia test had the highest positive and negative predictive values (72% and 96%, respectively). The ability of these tests to predict CMV disease was evaluated in the 70 patients with a negative surveillance bronchoscopy who did not receive pre-emptive ganciclovir. Of 19 cases of active CMV disease, CMV antigenemia was positive in 15 patients (79%) a mean of 34 days preceding symptoms. Blood cultures were positive in 14/19 patients (74%) a mean of 31 days before onset of disease. CMV antigenemia is useful for predicting the surveillance bronchoscopy result, and also predicts the development of CMV disease in the majority of patients missed by the surveillance bronchoscopy.

Adolescent↗
PubMed1999

Phase I trial of sequential topotecan followed by etoposide in adults with myeloid leukemia: a National Cancer Institute of Canada Clinical Trials Group Study.

Prolonged exposure to a topoisomerase I inhibitor may increase expression of topoisomerase II, making cells more susceptible inhibitors of that enzyme. This study was undertaken to establish the maximum tolerated dose (MTD) of a topotecan/topoisomerase II inhibitor sequential combination that may be active in acute leukemia, and to evaluate the effects of in vivo exposure to topotecan on topoisomerase II levels in leukemic blast cells as measured by image cytometry. Patients who were eligible for this phase I study had relapsed or refractory acute myeloid leukemia (< or = 2 prior regimens) or CML blast crisis (0 or 1 prior regimen). Topotecan was given as a 5 day continuous i.v. infusion and was to be escalated through three levels (1.5, 1.75 and 2.0 mg/m2 day), followed by etoposide at two dose levels (100 and 150 mg/m2) i.v. bolus days 6, 7 and 8. Topoisomerase IIalpha levels in leukemic blasts from bone marrow were measured by image cytometry prior to starting treatment, on day 5 of topotecan infusion and on day 28; and daily during topotecan in peripheral blood blasts. Dose-limiting toxicity was seen in two of six patients at the first dose level (topotecan 1.5 mg/m2/day, etoposide 100 mg/m2/day; > or = grade 3 mucositis in both cases). This cohort was expanded to 10 patients; no further non-hematologic dose-limiting toxicity was observed, but given the extent of toxicity seen, further dose escalation was judged not to be feasible. Topo IIalpha levels increased in peripheral blood blasts during the first 72 h of topotecan infusion and returned to near baseline by day 5, whereas levels appeared to decrease in bone marrow blasts by day 5 compared to pretreatment. One complete hematologic and cytogenetic remission in a patient with CML blast crisis was observed in the 10 patients evaluable for response. The sequential administration of topotecan 1.5 mg/m2/day continuous infusion for 5 days followed by etoposide 100 mg/m2/day x 3 is the recommended phase II dose for this schedule. Topotecan increases topo IIalpha expression in vivo in leukemia cells, but levels of the enzyme are cell cycle dependent. Pharmacodynamic evaluation of the sequential or combination administration of novel antileukemic agents may help improve treatment strategies in acute leukemia.

Acute Disease↗
PubMed1999

Elevated serum cytokines are associated with cytomegalovirus infection and disease in bone marrow transplant recipients.

To assess the relationship between serum cytokines and cytomegalovirus (CMV) reactivation, 75 allogeneic bone marrow transplant patients underwent weekly measurements of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-alpha, CMV blood cultures, and antigenemia tests. Of the patients, 44 (58.7%) developed CMV infection, and 19 (25.3%) developed clinical CMV disease. The mean maximum levels of all three cytokines were significantly increased in patients with CMV infection compared with levels in those without. Maximum levels of IL-6 were significantly higher in patients with active CMV disease than in those who did not develop CMV disease (281.2+/-85.5 vs. 95.7+/-15.0 pg/mL; P=.034). Levels of IL-8 and TNF-alpha were also elevated in patients who developed active disease. In a multivariate logistic regression model, IL-6 levels were independently associated with CMV disease (odds ratio=1.70 per 100-pg/mL increase in IL-6; P=.009). Cytokines may play an important role in the pathogenesis of CMV after bone marrow transplantation and may be a useful predictor for CMV.

Adult↗
PubMed1998

Clinical and economic analysis of allogeneic peripheral blood progenitor cell transplants: a Canadian perspective.

Allogeneic peripheral blood progenitor cell (PBPC) transplants are an alternative to BMT, although G-CSF mobilization dose, timing of pheresis and risk of GVHD are not well defined. We compared harvest characteristics, donor and recipient outcomes and costs of two PBPC transplant strategies with historical controls who received BMT. Twenty donors mobilized with four daily s.c. G-CSF doses (5 microg/kg/day) (group 1) and 20 mobilized with 10 microg/kg/day G-CSF (group 2) were compared with 20 BM controls (group 3). G-CSF and phereses were well tolerated. Four of 40 PBPC donors required femoral catheter placement. At least 2.5 x 10(6) CD34+/kg recipient weight were collected with two phereses in 19/20 donors (group 1) and 18/20 donors (group 2). Time to neutrophil (18 vs 20 vs 22 days, P = 0.02) and platelet (21 vs 24 vs 27 days, P = 0.005) engraftment was shorter in the PBPC groups (group 2 vs group 1 vs group 3) but secondary engraftment outcomes were not different. The incidence of grade 2-4 aGVHD was higher in the low-dose G-CSF group (group 1) but there was no difference in cGVHD, 100-day or 1-year survival. The mean PBPC transplant cost (group 1) at first hospital discharge was less than BM (group 3) ($34,643 vs $37,354) but the mean overall cost for both groups was similar at 100 days ($46,334 vs $46,083). Allogeneic PBPC transplant with short course, low-dose G-CSF mobilization is safe, feasible and cost equivalent to allogeneic BMT.

Bone Marrow Transplantation↗
PubMed1998

Effect of cytomegalovirus infection on 1-year mortality rates among recipients of allogeneic bone marrow transplants.

The effect of cytomegalovirus (CMV) infection on 1-year mortality rates among allogeneic bone marrow transplant recipients who are receiving a standard protocol as prophylaxis for CMV infection is unclear. We determined the risk factors for death within 1 year among 103 bone marrow transplant recipients by performing a multivariate analysis. The results of donor and recipient CMV serologies did not predict 1-year mortality, although there was a trend towards higher mortality among CMV-seropositive recipients who received marrow from seronegative donors (P = .077). Multivariate analysis revealed that the factors independently associated with 1-year mortality were the development of CMV antigenemia (relative risk [RR] = 2.74; confidence interval [CI] = 1.28-5.86), bone marrow transplantation (BMT) from unrelated donors (RR = 3.20; CI = 1.30-7.92), and severe acute graft-versus-host disease (RR = 3.50; CI = 1.50-8.17). Although significant on univariate analysis, advanced underlying disease before BMT and the development of active CMV disease after BMT were not independent risk factors. In conclusion, the development of CMV antigenemia after BMT was associated with increased 1-year mortality, while the development of active CMV disease was not. Reactivation of CMV infection may represent a marker of poor immune reconstitution or may contribute to further immunosuppression after BMT.

Adolescent↗
PubMed1997

Evaluation of critical body residue QSARs for predicting organic chemical toxicity to aquatic organisms.

The critical body residue (CBR) is the concentration of chemical bioaccumulated in an aquatic organism that corresponds to a defined measure of toxicity (e.g., mortality). The CBR can provide an alternative measure of toxicity to traditional waterborne concentration measurements (e.g., concentration in water causing 50% mortality). The CBR has been suggested as a better estimator of dose than the external water concentration and has been postulated to be constant for chemicals with the same mode of action. CBR QSARs have both theoretical and experimental support, developed primarily from studies on the acute toxicity of narcotic chemicals to small fish. CBR QSARs are less well developed for the aquatic toxicity of non-narcotic chemicals. CBRs vary substantially with the mode of action and toxicity endpoint, and may be affected by genetic, hormonal or environmental variation. CBR QSARs may not be applicable to very hydrophobic chemicals, chemicals with specific modes of action, or those with toxicity controlled by kinetic processes such as biotransformation. CBRs models have not been developed or evaluated for sediment and dietary exposure routes. Application of CBR QSARs to contaminated site assessments will require further research and development.

Animals↗
PubMed1996

Alpha-melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation.

Alpha-Melanocyte-stimulating hormone (MSH) is a potent anti-inflammatory agent in many models of inflammation, suggesting that it inhibits a critical step common to different forms of inflammation. We showed previously that alpha-MSH inhibits nitric oxide (NO) production in cultured macro-phages. To determine how alpha-MSH acts in vivo, we induced acute hepatic inflammation by administering endotoxin (LPS) to mice pretreated with Corynebacterium parvum, alpha-MSH prevented liver inflammation even when given 30 min after LPS administration. To determine the mechanisms of action of alpha-MSH, we tested its influence on NO, infiltrating inflammatory cells, cytokines, and chemokines. Alpha-MSH inhibited systemic NO production, hepatic neutrophil infiltration, and increased hepatic mRNA abundance for TNF alpha, and the neutrophil and monocyte chemokines (KC/IL-8 and MCP-1). We conclude that alpha-MSH prevents LPS-induced hepatic inflammation by inhibiting production of chemoattractant chemokines which then modulate infiltration of inflammatory cells. Thus, alpha-MSH has an effect very early in the inflammatory cascade.

Animals↗
PubMed1996

Acute anterior uveitis in juvenile Reiter's syndrome.

We describe the case of an acute anterior uveitis (AAU) and reactive arthritis following a gastrointestinal infection of Salmonella typhimurium in a 9-year-old girl. Reiter's syndrome mainly affects men and is unusual in children especially in young females.

Acute Disease↗