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Biomedical subjects

R Meyers

Publications and source records attributed to R Meyers.

At least 19 recordsLinked to original sources
PubMed2003

Comparative pharmacokinetic study of high-dose etoposide and etoposide phosphate in patients with lymphoid malignancy receiving autologous stem cell transplantation.

The pharmacokinetics of two etoposide (E) formulations were evaluated in patients with refractory hematologic malignancies receiving high-dose conditioning with autologous stem cell transplantation. Patients were randomized to either E at 800 mg/m(2) (containing polysorbate 80 and polyethylene glycol) or etoposide phosphate (EP) at 910 mg/m(2) on days -7 and -5, prior to melphalan, 80 mg/m(2) on day -5. On day -3, EP was repeated. Plasma E was analyzed after each formulation on days -7 and -5 to compare intrapatient pharmacokinetics. In total, 10 patients were treated: four each with multiple myeloma or Hodgkin's disease and two with non-Hodgkin's lymphoma. Mucositis was the major toxicity with seven patients. EP first produced grade 3 mucositis. There was no procedure-related mortality and eight patients remained alive 1 year post-transplant. Cumulative etoposide exposure (AUC) was slightly greater with EP (P=0.056). Conversely, the volume of distribution was slightly, 33%, larger (P=0.052) and clearance was increased with the E infusion (P=0.14). As none of the differences reached statistical significance, both E formulations appear to be pharmacokinetically equivalent in the high-dose transplant setting. The combination of high-dose EP with melphalan is an active preparative regimen prior to ABMT for hematologic malignancies.

Adult↗
PubMed1999

Thrombin peptide, TP508, induces differential gene expression in fibroblasts through a nonproteolytic activation pathway.

Prior studies have shown that synthetic peptides representing the domain of thrombin responsible for high-affinity binding to fibroblasts stimulate chemotactic and cell proliferative signals through a nonproteolytic mechanism. One of these peptides, TP508, has recently been shown to be chemotactic for neutrophils, to enhance collagen accumulation in wounds, to enhance revascularization of wounds, and to accelerate the healing of incisional and open wounds in normal animals and in animals with impaired healing. To determine whether TP508 activates the proteolytically activated receptor for thrombin (PAR1), or the signals that are activated by PAR1, we treated human fibroblasts with TP508 and the PAR1-activating peptide, SFLLRNP, and analyzed the effects of these peptides on gene expression using differential display reverse transcriptase polymerase chain reaction. TP508 induces expression of a number of specific message fragments with short tyrosine kinase-like domains that are not induced by SFLLRNP. Sequencing full-length clones prepared by Marathon extension of TP508-induced fragments revealed that among the induced transcripts, there was a sequence with 88% homology to human annexin V. Northern analysis with authentic annexin V cDNA confirms that TP508, but not SFLLRNP, induces expression of annexin V in human fibroblasts. These results demonstrate that TP508 activates a cellular response separate from that activated through PAR1 and supports the hypothesis that TP508 acts through a separate nonproteolytically activated thrombin receptor that may be responsible for high-affinity thrombin binding and for nonproteolytic signals that are required for thrombin stimulation of cell proliferation.

Annexin A5↗
PubMed1999

ARF mediates recruitment of PtdIns-4-OH kinase-beta and stimulates synthesis of PtdIns(4,5)P2 on the Golgi complex.

The small GTPase ADP-ribosylation factor (ARF) regulates the structure and function of the Golgi complex through mechanisms that are understood only in part, and which include an ability to control the assembly of coat complexes and phospholipase D (PLD). Here we describe a new property of ARF, the ability to recruit phosphatidylinositol-4-OH kinase-beta and a still unidentified phosphatidylinositol-4-phosphate-5-OH kinase to the Golgi complex, resulting in a potent stimulation of synthesis of phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate; this ability is independent of its activities on coat proteins and PLD. Phosphatidylinositol-4-OH kinase-beta is required for the structural integrity of the Golgi complex: transfection of a dominant-negative mutant of the kinase markedly alters the organization of the organelle.

1-Phosphatidylinositol 4-Kinase↗
PubMed1998

In vivo phosphocreatine and ATP in piglet cerebral gray and white matter during seizures.

The creatine kinase (CK) reaction is thought to be important in coupling ATP metabolism and regulating ADP concentration in tissues with high and variable ATP turnover, including cerebral gray matter (GM). There is low phosphocreatine (PCr), low CK reaction rates, and high mitochondrial CK (MiCK) isoenzyme activity in GM compared to white matter (WM). To compare the CK reaction in GM and WM when ATP metabolism is high, CK reactants and reaction rates were measured in predominantly GM and WM slices in vivo in 2 and 14-day old piglets during pentylenetetrazole (PTZ) seizures using 31P nuclear magnetic resonance (NMR) 1-dimensional chemical shift imaging (CSI). Arterial pressure, temperature, and blood gasses were stable at both ages. Before seizures, the PCr/nucleoside triphosphate (NTP) ratio was higher in WM than GM at both ages with a developmental increase seen in WM. The CK reaction rate constant increased in both regions between 2 and 14 days. During seizures, PCr/NTP increased in GM at 14 days due to increased PCr while the ratio and PCr decreased in WM. The NTP was more stable in WM and GM at both ages. The CK reaction rate decreased in both regions more at 2 than at 14 days. Thus, brain ATP, deduced from NTP, is stable during seizures in the piglet. In GM stable ATP is associated with a unique increase in PCR concentration.

Adenosine Triphosphate↗
PubMed1998

Analytical and biological inequivalence of two commercial formulations of the antitumor agent bleomycin.

Bleomycin is an antitumor agent which is a mixture of glycopeptides containing at least 55-75% bleomycin A2 and 25-32% bleomycin B2 fractional composition. Two bleomycin formulations, bleomycin sulfate, USP (Blenoxane, Bristol-Myers Squibb Oncology, Princeton, N.J.) and bleomycin HCI (Tianjin Hebei Pharmaceutical, Tianjin, China) were compared analytically and biologically. Reverse-phase high-performance liquid chromatography (HPLC) analyses using the USP methodology showed that Blenoxane contained primarily (69%) bleomycin A2 and 29.3% bleomycin B2. In contrast, Tianjin-supplied bleomycin HCI contained 97% bleomycin A5 fraction. In vitro tumor cell growth inhibition assays showed equivalent activity in human OVCAR-3 ovarian cancer cells and slightly greater potency in murine L-1210 leukemia cells for the Tianjin formulation. In C57/B1 mice bearing B-16 melanoma tumors, Tianjin-supplied bleomycin produced slightly greater tumor growth inhibition at the expense of greater drug-induced lethality at higher dose levels. These studies show there are significant differences in two international bleomycin formulations. These compositional differences lead to altered biologic effects.

Analysis of Variance↗
PubMed1998

A contextually relevant assessment of the impact of child maltreatment on the social competencies of low-income urban children.

OBJECTIVE: A developmental-ecological model was used to explore the psychological adjustment and peer social competencies of maltreated preschool children. METHOD: Enhanced research methods were used that included verification of maltreatment status, multiple-variable matching of comparison children, and contextually relevant assessment. One hundred eight Head Start children, of whom 54 were maltreated, participated. Assessment of social functioning included measurement of peer play interactions, global social skills, peer sociometrics, and teacher and parent ratings of behavior problems. RESULTS: Findings indicated that maltreated children were significantly less interactive in peer play and overall exhibited less self-control and interpersonal skill in social interactions than nonmaltreated children. In addition, maltreated children were more likely than their nonmaltreated peers to receive low sociometric ratings and were found by both teachers and parents to display more internalizing behavior problems than comparison children. CONCLUSIONS: These findings indicate the importance of using developmentally sensitive research methods to inform contextually relevant interventions.

Case-Control Studies↗
PubMed1997

Cloning and characterization of a wortmannin-sensitive human phosphatidylinositol 4-kinase.

Phosphatidylinositol (PtdIns) 4-kinases catalyze the synthesis of PtdIns-4-P, the immediate precursor of PtdIns-4,5-P2. Here we report the cloning of a novel, ubiquitously expressed PtdIns 4-kinase (PI4Kbeta). The 2.4-kilobase pair cDNA encodes a putative translation product of 801 amino acids which shows greatest homology to the yeast PIK1 gene. The recombinant protein exhibits lipid kinase activity when expressed in Escherichia coli, and specific antibodies recognize a 110-kDa PtdIns 4-kinase in cell lysates. The biochemical properties of PI4Kbeta are characteristic of a type III enzyme. Interestingly, both recombinant PI4Kbeta and the endogenous protein are inhibited by 150 nM wortmannin, suggesting that we have cloned the previously described PtdIns 4-kinase that is responsible for regulating the synthesis of agonist-sensitive pools of polyphosphoinositides (Nakanishi, S., Catt, J. K., and Balla, T. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 5317-5321).

1-Phosphatidylinositol 4-Kinase↗
PubMed1997

Nutrition management of congenital glucose-galactose malabsorption: a case study.

In this article we describe the clinical history, diagnostic evaluation, and management of an infant who had congenital glucose-galactose malabsorption (CGGM)--a rare disorder thought to be inherited as an autosomal recessive trait. Because of defective sodium-coupled cotransport of glucose and galactose in the intestinal mucosa, infants with CGGM suffer from chronic, profuse, watery diarrhea that often leads to hypertonic dehydration. This infant experienced persistent diarrhea and hypernatremic dehydration during the first 3 months of life. Despite management with elemental formulas and continuous nasogastric feedings during initial hospitalizations, worsening diarrhea and dehydration persisted and malnutrition occurred. Diagnostic evaluations ruled out cystic fibrosis and bacterial or viral gastroenteritis. Diagnostic tests also revealed normal pancreatic exocrine function and normal villus architecture. The persistence of glucose-positive, watery diarrhea, even when the infant was fed an oral electrolyte solution, led to the diagnosis of CGGM. The infant was treated successfully with a carbohydrate-free infant formula to which fructose was added incrementally to meet energy requirements. Parental education about dietary management of CGGM with specialized formula supplemented with fructose and solid food feedings was an important component of this infant's nutrition therapy. Aggressive nutrition intervention for the infants and judicious dietary counseling for parents can lead to normal growth and neurological development for an infant with CGGM.

Absorption↗
PubMed1997

Brain creatine kinase reaction rates and reactant concentrations during seizures in developing rats.

Brain creatine kinase (CK) catalyzed phosphorus fluxes between phosphocreatine (PCr) and ATP and changes in reactant concentrations were measured using [31P] nuclear magnetic resonance spectroscopy ([31P]NMR) before and during pentylenetetrazole-induced seizures in 7 and 21 day old rats. The CK rate constants measured before seizures were three times higher in the older than in the younger rats. The rate constants increased 60% during seizures in the older rats but did not change or decreased in the younger. Small decreases in PCr were seen during seizures at both ages. A small decrease in ATP was seen at 7 days but not at 21 days.

Adenosine Triphosphate↗
PubMed1997

Development and testing of a process measure of nursing home quality of care.

OBJECTIVE: To develop and test quality of care process measures for three medical conditions of nursing home patients: fever, shortness of breath, and chest pain. DESIGN: Flowsheets designed to capture the critical elements of care for the above conditions were developed by an expert panel. Nursing home residents charts were reviewed retrospectively using the flow sheets. The reviews were translated into clinical scenarios, and the quality of care the scenarios represented was rated by an expert panel. SETTING: All nursing homes in Hennepin County, MN, that care for Medicaid patients. PATIENTS: A random sample of 1405 Medicaid nursing home residents from 1984 and 1988. MEASURES: Measures of quality of physician assessment and intervention, quality of nurse assessment and intervention, and global quality were developed and the intra- and interrater reliability were tested. The measures' validity was assessed by their ability to predict resident death. RESULTS: Intrarater reliability was measured as the correlation of the ratings of blinded duplicates. The correlation for the global scale and the four subscales ranged from .74 to .88 (P < .001 for all). Interrater reliability was tested by examining what percentage of the quality ratings were within one unit (1-5 scale) for all three raters. All three raters were within one unit for more than 72% scenarios for all scales. The subscale of quality of physician assessment was able to predict resident death when the worst episode of care (OR = .47, 95% CI(.31-.74)) or the mean episode of care (OR .54, 95% CI(.30-.99)) was used. None of the other subscales or the global measure predicted death. CONCLUSIONS: Through the use of an expert panel, measures of nursing home quality of care were developed for shortness of breath, fever, and chest pain. These measures have reasonable reliability and significant face validity. Their validity is supported further by the ability of one of the measures to predict resident death.

Aged↗
PubMed1997

In vivo brain phosphocreatine and ATP regulation in mice fed a creatine analog.

Mitochondrial and cytosolic creatine kinase (CK) isozymes are active in cells with high and variable ATP metabolic rates. beta-Guanidinopropionic acid (GPA), a competitive inhibitor of creatine transport, was used to study the hypothesis that the creatine-CK-phosphocreatine (PCr) system is important in regulating brain ATP metabolism. The CK-catalyzed reaction rate and reactant concentrations were measured in vivo with 31P nuclear magnetic resonance spectroscopy during energy deficit (hypoxia) or high-energy turnover (seizures) states in urethane-anesthetized mice fed GPA, creatine, or standard chow (controls). Brain phosphagen (i.e., cellular energy reserves) or PCr plus phosphorylated GPA (GPAP) concentrations were equal. The phosphagen-to-NTP ratio was lower than in controls. In vivo CK reaction rate decreased fourfold, whereas ex vivo CK activity that was biochemically measured was doubled. During seizures, CK-catalyzed fluxes increased only in GPA-fed mice. Phosphagen increased in GPA-fed mice, whereas PCr decreased in controls. Survival was higher and brain phosphagen and ATP losses were less for hypoxic GPA-fed mice than for controls. In contrast to mice fed GPA, hypoxic survival and CK reactant concentrations during hypoxia and seizures were the same in creatine-fed mice and controls. Thus GPA, GPAP, or adaptive changes in ATP metabolism stabilize brain ATP and enhance survival during hypoxia in mice.

Adenosine Triphosphate↗
PubMed1996

Community-based resilient peer treatment of withdrawn maltreated preschool children.

The purpose of the present study was to evaluate differences in the social play of maltreated and nonmaltreated preschool children and the effectiveness of a resilient peer treatment (RPT) for socially withdrawn victims of physical abuse and neglect. RPT is a peer-mediated classroom intervention based on a developmental-ecological model. It involves pairing withdrawn children with resilient peers in the natural classroom under the supervision of a parent assistant. Forty-six Head Start children, of whom 22 were maltreated, were randomly assigned to RPT and control conditions. Outcome variables were observational categories of social play and standardized teacher ratings. Before treatment, maltreated children were significantly more isolated and less interactive in peer play than nonmaltreated children. RPT resulted in a significant increase in positive interactive peer play and a decrease in solitary play for maltreated and nonmaltreated, socially withdrawn children. Moreover, treatment gains in social interactions were validated 2 months following treatment. Findings are discussed in terms of a developmental-ecological model.

Child Abuse↗
PubMed1996

Phosphocreatine and creatine kinase in piglet cerebral gray and white matter in situ.

Rates of adenosine triphosphate (ATP) metabolism are higher in cerebral gray matter than in white matter. Like other excitable tissues, brain contains a phosphocreatine (PCr)/creatine kinase (CK)/ATP system including cytosolic (B-CK) and mitochondrial (Mi-CK) isozymes. High B-CK activity is present in white and gray matter while Mi-CK is mostly in gray matter. An in situ localizing 31P-NMR technique, one-dimensional chemical shift imaging (1D-CSI), has been used to study the PCr/CK/ATP system in these regions. In the metabolically mature 4-week-old piglet, the PCr/nucleoside triphosphate (NTP) ratio measured by the 1D-CSI technique is at least 50% higher in white than gray matter. Total creatine (Cr), ATP, and total NTP concentrations are the same in rapidly frozen rat white and gray matter, suggesting that PCr/Cr ratio is much higher in white matter. The PCr increases more in gray than white matter between 4 days and 4 weeks of age in piglet brain. The CK catalyzed reaction rate constant, measured by combining the saturation transfer experiment with the 1D-CSI, is also much higher in white than gray matter at both ages. The postnatal maturational increase in the CK rate constant is greater in gray matter. In summary, these differences in PCr concentration and CK reaction rates and isozymes characterize two physiologically different PCr/CK/ATP systems in gray and white matter.

Animals↗
PubMed1996

Safety of autotransplants with high-dose melphalan in renal failure: a pharmacokinetic and toxicity study.

Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response effect. It can be escalated without excessive toxicity to 200 mg/m2, a myeloablative dose requiring hematopoietic stem cell support. Patients with marked renal insufficiency, not an infrequent finding in MM, have either received reduced doses or have been excluded from therapy with high-dose MEL. A prospective study was performed to evaluate the relationship between MEL pharmacokinetics and renal function in 20 patients with MM. Six patients had severe renal insufficiency (creatinine clearance, <40 ml/min), including five on chronic hemodialysis. Three patients with severe renal impairment first received a low test dose of MEL (16 mg/m2) for pharmacokinetic studies. All patients received 200 mg/m2 MEL divided into two equal doses of 100 mg/m2 i.v. on 2 consecutive days, followed by the administration of peripheral blood stem cells. MEL pharmacokinetics, performed after the first dose of 100 mg/m2, was not adversely affected by impaired renal function. The median half-life (t1/2), area under the concentration curve, and clearance of MEL were 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients with a creatinine clearance of <40 ml/min compared to 1.9, 7.9, and 23.6 for the others. Renal insufficiency also had no apparent negative impact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment, transfusion requirements, incidence of severe mucositis, or overall survival. However, it was associated with longer durations of fever (P = 0. 0005) and hospitalization (P = 0.004). No transplant-related deaths were observed. Plasma t1/2 and area under the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the lowest and highest values. These large variations in MEL elimination could not be explained by patient or disease characteristics. We conclude that renal failure does not require dose reduction of MEL in autologous transplant. Due to marked interindividual variation in MEL elimination, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in achieving a more uniform antitumor effect.

Adult↗
PubMed1994

Monotherapy with cyclosporine for chronic immunosuppression in pediatric liver transplant recipients.

Children who survive liver transplantation (LT) suffer the adverse effects of life-long immunosuppression. In an attempt to minimize these effects, we have instituted a program of tapering immunosuppression, resulting in chronic monotherapy for children after LT. Seventy-three children ages 4 months to 19 years received LT between January 1987 and December 1992. Patient survival was 85% (62/73), with graft survival of 73%, at one year. Triple therapy with prednisone, cyclosporine, and azathioprine begun at transplant was tapered as follows: 1-2 mg/kg prednisone at discharge was reduced by .2 mg/kg every 2 months until a .2 mg/kg total was reached. Alternate-day steroids (.2 mg/kg) were begun at 1 year and discontinued at 1.5 years. AZA (1 mg/kg) was begun posttransplant and discontinued after any serious viral illness or by 1 year. Currently 37 survivors are > 18 months post-LT and were considered candidates for monotherapy. Monotherapy was attempted in 28 (76%), and 25 of these remain on monotherapy an average of 2 years later. All have normal liver function. After monotherapy and alternate-day steroids were achieved, 66% of children < 5th percentile for height at the time of transplant improved to greater than the 5th percentile. There were 3 (11%) patients who rejected while on monotherapy an average of 1.15 years after it was started. These patients had the following predisposing factors that decreased cyclosporine levels and led to rejection: common bile duct stricture, chronic and intermittent antibiotic administration for urinary tract infection, and noncompliance. In the 9 potential candidates not tapered to monotherapy, 6 have had recurrent acute or chronic rejection; 2 of these now receive FK506. We conclude that the majority of stable pediatric LT recipients may be safely tapered to chronic cyclosporine monotherapy. Increased growth is a major benefit of decreased steroid dosing in these children. Cyclosporine absorption and adequate levels are crucial for success of this approach.

Azathioprine↗
PubMed1994

Cartilage chondrolysis by fibronectin fragments is associated with release of several proteinases: stromelysin plays a major role in chondrolysis.

We have reported that three different Fn fragments (Fn-f) added to bovine articular cartilage cultured in serum-free DMEM cause marked elevation of proteoglycan (PG) degradation and release into the culture media. We report here that the PG release required the continual presence of Fn-f, that PG release still occurred when serum-free cultures were switched to bovine synovial fluid media, and that addition of recombinant IGF-1, TGF-beta, and recombinant interferon gamma to cultures did not affect Fn-f-mediated PG release. The Fn-f caused a 25-fold enhanced release of stromelysin-1 protein from cartilage by Day 1 and up to 120-fold by Day 3. The stromelysin form released was 43 kDa, the activated form of pro-stromelysin-1. This stromelysin form apparently played a major role in Fn-f-mediated PG release, since addition of Sepharose-bound anti-stromelysin-1 to cartilage cultures greatly slowed rates of PG release. Potential activators of pro-stromelysin-1, plasmin, and u-PA (urinary plasminogen activator), were also detected in conditioned media of Fn-f-treated cartilage. u-PA levels were increased in the presence of the Fn-f but by only a few fold. Addition of alpha-1-antiproteinase inhibitor, which can block enzymatic activity of u-PA, was found to inhibit about half the PG-releasing activity of the Fn-f. Levels of TIMP-1, the 30-kDa tissue inhibitor of metalloproteinases, which can inhibit stromelysin, doubled within 24 h when a Fn-f was added to culture. These data suggest that stromelysin-1 may be a major mediator of Fn-f-mediated PG release from cartilage.

Animals↗
PubMed1994

Issues in the development of subject recruitment strategies and eligibility criteria in multisite trials of matching.

Decision-making in selecting and recruiting subjects for treatment matching research is a complex process involving conceptual, methodological and practical considerations. In selecting clients, concerns arise about whether the criteria will produce a subject population that is (1) relevant to the dimensions associated with the treatment matching, (2) representative of persons typically seen in alcohol treatment settings and, for practical purposes, (3) able or willing to comply with the requirements of the study protocol. Also, in order to fulfill sampling requirements, it may be necessary to employ a variety of creative outreach methods. However, these recruitment mechanisms can pose additional logistical and methodological problems for the research. This article focuses on various issues arising in the selection and recruitment of subjects in matching research. Project MATCH serves to highlight issues related to client eligibility and recruitment and to discuss effective strategies for resolving these matters.

Adult↗