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Biomedical subjects

D Hurst

Publications and source records attributed to D Hurst.

At least 19 recordsLinked to original sources
PubMed2004

Endurance training increases LKB1 and MO25 protein but not AMP-activated protein kinase kinase activity in skeletal muscle.

LKB1 complexed with MO25 and STRAD has been identified as an AMP-activated protein kinase kinase (AMPKK). We measured relative LKB1 protein abundance and AMPKK activity in liver (LV), heart (HT), soleus (SO), red quadriceps (RQ), and white quadriceps (WQ) from sedentary and endurance-trained rats. We examined trained RQ for altered levels of MO25 protein and LKB1, STRAD, and MO25 mRNA. LKB1 protein levels normalized to HT (1 +/- 0.03) were LV (0.50 +/- 0.03), SO (0.28 +/- 0.02), RQ (0.32 +/- 0.01), and WQ (0.12 +/- 0.03). AMPKK activities in nanomoles per gram per minute were HT (79 +/- 6), LV (220 +/- 9), SO (22 +/- 2), RQ (29 +/- 2), and WQ (42 +/- 4). Training increased LKB1 protein in SO, RQ, and WQ (P < 0.05). LKB1 protein levels after training (%controls) were SO (158 +/- 17), RQ (316 +/- 17), WQ (191 +/- 27), HT (106 +/- 2), and LV (104 +/- 7). MO25 protein after training (%controls) was 595 +/- 71. Training did not affect AMPKK activity. MO25 but not LKB1 or STRAD mRNA increased with training (P < 0.05). Trained values (%controls) were MO25 (164 +/- 22), LKB1 (120 +/- 16), and STRAD (112 +/- 17). LKB1 protein content strongly correlated (r = 0.93) with citrate synthase activity in skeletal muscle (P < 0.05). In conclusion, endurance training markedly increased skeletal muscle LKB1 and MO25 protein without increasing AMPKK activity. LKB1 may be playing multiple roles in skeletal muscle adaptation to endurance training.

AMP-Activated Protein Kinase Kinases↗
PubMed2004

Human recombinant DNA-derived antihemophilic factor in the treatment of previously untreated patients with hemophilia A: final report on a hallmark clinical investigation.

BACKGROUND: Development of recombinant factor VIII (rFVIII) replacement therapy represents a milestone in the treatment of hemophilia A. OBJECTIVE: The objective of this long-term, multicenter study was to assess the safety, efficacy and rate of inhibitor formation of rFVIII (Kogenate) in the treatment of hemophilia A in a group of previously untreated patients (PUPs). PATIENTS AND METHODS: Between January 1989 and October 1997, 102 evaluable patients (mean age 3.9 years) were treated with rFVIII as sole therapy for prophylaxis against bleeding or for hemorrhage. Patients with mild hemophilia were treated for > or =2 years, while those with moderate or severe hemophilia were treated for > or =5 years or 100 exposure days. RESULTS: All patients responded well to therapy, so that 82% of bleeding episodes required a single infusion for treatment. Only four mild drug-related adverse events were recorded during the study for an overall rate of 0.03% (4/13 464 infusions). No viral seroconversions were observed. The inhibitor incidence in PUPs with severe hemophilia was 29% (19/65). Overall, inhibitory antibodies developed in 21 patients (20.6%). Inhibitor titers were low (<10 Bethesda Units) in nine of the 21 patients despite continued episodic treatment with rFVIII and transient in eight patients receiving episodic treatment (seven low titer, one high titer). Eight high-titer inhibitor patients were treated with immune-tolerance induction therapy; five had successful outcomes. CONCLUSIONS: The observed incidence of inhibitor formation is similar to studies of PUPs receiving plasma-derived FVIII. These results demonstrate the safety and efficacy of rFVIII in long-term treatment of hemophilia A.

Adolescent↗
PubMed2001

Orthodontic outcomes assessment using the peer assessment rating index.

The purpose of the present study was to gain more information on the assessment of orthodontic treatment using the PAR Index. The PAR Index was used to assess the study casts of 54 cases treated by 5 orthodontists who successfully completed Phase III of the American Board of Orthodontics. These peer-reviewed cases were considered to represent a subjective opinion of an excellent treatment standard. The PAR scores for the Board-accepted cases were then compared with the PAR scores of 51 cases consecutively treated by orthodontic graduate students. The pretreatment, posttreatment, and percent changes in PAR scores for the Board cases and the graduate student-treated cases were compared. The PAR Index scores and treatment duration were analyzed for the entire sample using general linear models techniques. Results of the study showed no statistically significant difference between the Board-accepted cases and the graduate student-treated cases for any single component of the PAR Index at either the pretreatment or posttreatment times. However, the percent reduction in the mean PAR score for the Board-accepted cases was significantly more than the reduction for the graduate student-treated cases (87.9%+/-9.5% vs 81.7%+/-15.3%). Analysis of treatment duration showed that a higher pretreatment PAR score and a greater percent reduction in PAR score were significantly associated with longer treatment durations.

Episode of Care↗
PubMed2000

Safety and efficacy of solvent/detergent-treated antihaemophilic factor with an added 80 degrees C terminal dry heat treatment in patients with haemophilia A.

Plasma-derived factor VIII concentrates remain an important resource for haemophilia A patients. To improve the safety of these preparations, various methods of viral removal and inactivation have been used that are designed to eliminate both enveloped and non-enveloped viruses. There have been rare reports that some viral inactivation processes altered the immunogenicity of some concentrates, leading to the development of factor VIII inhibitors in previously treated haemophilia A patients. This study evaluated the safety, efficacy and lack of neo-antigenicity of a highly purified factor VIII preparation which undergoes both solvent/detergent treatment and final dry heat treatment at 80 degrees C for 72 h. The study included: (i) a single blind, single-dose crossover pharmacokinetic study in 18 previously treated patients, comparing sibling lots of the unheated preparation (Koate(R)-HP) and the heat-treated preparation (Koate(R)-DVI), and (ii) an extended home treatment programme for 36 patients at two haemophilia treatment centres primarily to assess immunogenicity. Clinical parameters were assessed at regular intervals. The results confirm that Koate(R)-HP and Koate(R)-DVI are bioequivalent, and that Koate(R)-DVI is safe and efficacious for treatment of acute bleeding episodes and for surgery. Furthermore, the heat-treated preparation is not associated with the development of inhibitors in previously treated patients.

Adolescent↗
PubMed2000

Increased expression of major basic protein (MBP) and interleukin-5(IL-5) in middle ear biopsy specimens from atopic patients with persistent otitis media with effusion.

BACKGROUND: Molecular biologic evidence to support an etiologic role for allergy in the pathogenesis of persistent otitis media with effusion (OME) is lacking. OBJECTIVE: The goal of this article was to document expression of allergy-associated Th-2-type cytokines and inflammatory cells in the middle ear mucosa of children with persistent OME. METHODS: With immunocytochemistry (CD3, major basic protein) and in situ hybridization (interleukin-5 mRNA), middle ear biopsy specimens from 7 children with persistent OME were stained. Nonatopic stapedectomy patients with no history of otitis media served as controls (n = 7). RESULTS: There was a statistically significant (P< 0.05) difference in expression of CD3, major basic protein, and interleukin-5 between experimental and control subjects. All 8 OME patients proved to be atopic by ELISA testing. CONCLUSIONS: Type I allergy involving a Th-2-type cytokine and cellular profile may be a contributing factor in the persistence of OME in atopic children. SIGNIFICANCE: The middle ear may serve as a target organ for allergic inflammation, suggesting that appropriate allergy management may be a useful adjunct to the management of OME.

Biopsy↗
PubMed1999

Human recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5-year study of home therapy. The KOGENATE Study Group.

Fifty-eight previously treated haemophilic subjects were treated exclusively with the recombinant FVIII (rFVIII-KOGENATE) produced by Bayer Corporation (Berkeley, CA) in an international multicentre prospective study of more than 5 years duration. Fifty-four of the 58 had severe haemophilia (< 2% FVIII) and four had moderate haemophilia (2-5% FVIII); 23/58 (40%) were seropositive for HIV, while 35/58 (60%) were HIV seronegative. Patients were monitored for safety and efficacy over a median period of 4.7 years (range 0.9-5.9 years) and received 17 922 infusions totalling 25.7 million units of rFVIII. Of 7107 bleeding episodes reported in home diaries, 5831 (82%) required only one treatment with rVIII. Twenty-five invasive surgical procedures in 17 patients, including eight joint replacements, were successfully accomplished and 13 serious bleeding episodes in eight patients were successfully treated. FVIII recovery performed on 885 occasions using 39 different lots of rFVIII showed mean incremental recovery of 2.48% IU-1 kg-1 (+/- 0.64). Adverse events were associated with 42 infusions (0.2%); none caused discontinuation of therapy. Immunological parameters remained stable in HIV-seronegative subjects treated with rFVIII; a small decrease in CD4 counts was noted in HIV-seropositive individuals (mean - 37.2 cells mm-3 yr-1). No de novo formation of inhibitors to FVIII was noted; and no clinical allergic reactions occurred to murine or hamster proteins. These conclusions from the longest monitored safety study ever performed for a haemophilia treatment product (with more than 5 years of observation) confirm previous interim study reports that rFVIII is well tolerated over the long-term, has biological activity comparable to that of plasma-derived FVIII, and is safe and efficacious for the treatment of haemophilia A.

Adolescent↗
PubMed1998

Evaluation of recombinant factor VIII (Kogenate) stability for continuous infusion using a minipump infusion device.

Continuous infusion of recombinant factor VIII (rFVIII) is desirable in clinical settings in order to maintain haemostatic levels in a cost-effective manner. This study was designed to determine rFVIII stability over time using a minipump set-up, which has been employed by clinicians for continuous infusion of rFVIII. Vials from three lots of Kogenate (Bayer Corporation) were reconstituted in sterile water for injection, pooled and transferred to minipump infusion sets composed of either polyvinylchloride (Medex # IPR86/tube volume 0.5 mL) or polyethylene (McGraw S5904-52, tube and adapter volume 2.1 mL), and held in temperature-controlled rooms at 5 degrees C, 25 degrees C and 30 degrees C. Additional bags of rFVII were prepared with heparin (4 U mL-1), and maintained at 30 degrees C. rFVIII was infused at a rate of 1.0 mL h-1. Samples were analysed for rFVIII activity over a 7-day period at 0, 1, 15, 24, 78 and 168 h. Prior to the start of the timed study, rFVIII activity was measured in the lot pools and in the polyvinylchloride or polyethylene bags, and in the first flush volumes through the tubing. There was no difference in rFVIII activity measured in the pools compared to the bags. rFVIII levels in the initial 3-mL infusion through the tubing showed a slight decrease in activity compared to the initial level which amounted to an insignificant loss of activity for the polyvinylchloride tubing but a significant loss in the polyethylene tubing (approximately 10 IU absolute loss in polyvinylchloride vs. 100 IU loss in polyethylene). After an initial flush of 1.0 mL for polyvinylchloride and 5.0 mL for polyethylene, activity returned to baseline and subsequently remained stable for all time points and temperatures from 5-30 degrees C over the 7-day period. We conclude that the standard polyvinylchloride in polyethylene minipump bags and tubing provide excellent delivery and stability of rFVIII for continuous infusion with or without heparin, and can be used in hospital and ambulatory settings.

Drug Evaluation↗
PubMed1998

In vivo recovery with products of very high purity--assay discrepancies.

In view of reports of FVIII assay discrepancies in post-infusion plasma samples depending on methods used, we compared FVIII results run by each of four different methods following infusion of rFVIII (Kogenate). Nine persons with haemophilia A were infused with each of two lots of product. Plasma samples were obtained at baseline, and at 10 min, 30 min, 1, 2, 4, 8, 12, 14, 30 and 48 h post-infusion for measurement of FVIII. FVIII assay methods were chromogenic, and one-stage APTT using three different types of activators: micronized, silica, ellagic acid, and kaolin. The same reference plasma standard was used throughout. Results demonstrated a consistent difference in FVIII values, with chromogenic assays being considerably higher than those run by one-stage assays. The discrepancy was greatest when kaolin was the activator. These results point out the problems in attempting to determine the "correct" FVIII level in patient plasma samples following infusion of high purity FVIII preparations. Potential "pitfalls" include the standard used for defining product potency, the methods, reagents, instrumentation and standards used in assaying plasma samples and, in some instances, the characteristics of the product itself. This situation has considerable cost implications, potential impact on patient care, and makes it difficult to compare results between laboratories.

Adolescent↗
PubMed1997

The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies. Recombinate and Kogenate Study Groups.

Approximately 25% of hemophilia A patients infused with factor VIII (fVIII) mount an immune response, which leads to its inactivation. Anti-fVIII autoantibodies are also seen rarely in individuals with normal fVIII. We have previously demonstrated that some anti-A2 and anti-C2 domain antibodies are fVIII inhibitors and that many patients have additional inhibitors with a fVIII light chain (LCh) epitope outside C2. Because the contribution of the different antibodies to the plasma inhibitor titer had been examined in a limited number of patients (14), we report in this study a more extensive analysis of 55 plasmas. The dominant inhibitors in 62% (13 of 21) of autoantibody plasmas were directed only against C2 or A2, but not both, whereas this pattern was found in only 15% (5 of 34) of hemophilic plasmas. In addition, anti-A2 inhibitors were present in 71% (24 of 34) of hemophilic plasmas, but only 33% (7 of 21) of autoantibody plasmas. These results demonstrated that the inhibitor response in hemophiliacs was more complex and the epitope specificity was somewhat different. A comparison of hemophiliacs treated only with plasma fVIII or recombinant fVIII showed no significant differences in the complexity of the inhibitor response, as > or = 2 different inhibitor antibodies were present in 78% (18 of 23) of the former and 82% (9 of 11) of the latter. In contrast, the major inhibitors in 35% (8 of 23) of hemophiliacs treated with plasma fVIII were directed against C2 and another LCh epitope within residues 1649-2137, but not A2, while none (0 of 11) treated with recombinant fVIII had this pattern.

Antibody Specificity↗
PubMed1996

Fetal polycystic kidney disease associated with glutaric aciduria type II: an inborn error of energy metabolism.

The findings of hyperechoic and enlarged fetal kidneys on routine antenatal ultrasonography is a non-specific finding that alerts the physician to a differential diagnosis of various genetic and non-genetic disorders, including fetal polycystic disease and Beckwith-Wiedeman syndrome. Detection of fetal or neonatal polycystic kidneys should alert the physician to the possibility of an associated lethal autosomal recessive inborn error of fatty acid metabolism known as multiple acyl-CoA-dehydrogenase defect (MADD). We report a case of fetal nephromegaly associated with rare inborn error of MADD. This case highlights the need for appropriate laboratory investigation of hyperechoic, enlarged fetal kidneys, and neonatal polycystic disease. The association of MADD with postnatally diagnosed polycystic disease of the kidney has been reported. The antenatal detection of nephromegaly followed by the subsequent postnatal diagnosis of MADD has not been previously reported. MADD should be considered in the differential diagnosis of this antenatal finding. Appropriate diagnostic procedures should be conducted, either pre- or postnatally, in order that appropriate genetic counseling may be provided for this autosomal recessively inherited disorder.

Acyl-CoA Dehydrogenases↗
PubMed1994

Immune status of human immunodeficiency virus seropositive and seronegative hemophiliacs infused for 3.5 years with recombinant factor VIII. The Kogenate Study Group.

Recent studies suggest that treatment of hemophiliacs with highly purified factor VIII concentrates may preserve immune function. To test this hypothesis, we prospectively studied 51 hemophilic patients (21 human immunodeficiency virus [HIV] seropositive and 30 seronegative) who were on home therapy exclusively with recombinant factor VIII (Kogenate, Miles Laboratory, Berkeley, CA) for 3.5 years. Patients, all of whom had been previously treated with plasma-derived factor VIII concentrates, were monitored every 6 months with T-lymphocyte subsets and beta 2-microglobulin levels. Mean rate of change in absolute CD4 cell counts, calculated from regression slopes for individual patients, showed a small but statistically significant decrease over the 3.5-year study period for HIV seropositive hemophiliacs. No decrease in CD4 cell counts was seen in HIV seronegative hemophiliacs when the data for children under age 6 years were excluded from the analysis. beta 2-microglobulin levels and CD8 cell counts remained unchanged. These data show stability of immunologic parameters in HIV seronegative hemophiliacs, and a small decrease in CD4 cell counts in HIV seropositive hemophiliacs treated with recombinant factor VIII.

CD4-Positive T-Lymphocytes↗
PubMed1993

Recombinant human GM-CSF treatment of neutropenia in glycogen storage disease-1b.

PURPOSE: Recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) was administered to two patients with glycogen storage disease, type 1b (GSD-1b), with chronic neutropenia, neutrophil dysfunction, and recurrent infections in an effort to increase neutrophil counts and increase resistance to infections. PATIENTS AND METHODS: The patients' baseline absolute neutrophil counts (ANC) ranged from 56 to 480 cells/mm3 despite increased granulocyte precursors in the bone marrow. GM-CSF was given s.c. at starting doses of 500 micrograms/m2/day divided into two doses. RESULTS: After 48 h, ANC rose to 2,025 cells/mm3 and 3,132 cells/mm3, respectively. Absolute eosinophil counts also rose to 1,048 cells/mm3 (24%) and 4,820 cells/mm3 (33%) on days 10 and 9 in the two patients. Although an initial 10-day course of GM-CSF was tolerated in one patient without significant reactions, subsequent s.c. injections of GM-CSF were complicated by increasingly painful local reactions that necessitated discontinuation after 7 to 8 days. Intravenous infusion was associated with a febrile systemic reaction. Despite lack of improvement in neutrophil superoxide anion generation measured in one, both patients demonstrated unusually rapid healing of cutaneous infections on GM-CSF. CONCLUSION: Our experience suggests that GM-CSF may be useful for short-term treatment of serious infections in GSD-1b. However, alternate dosage schedules or different preparations of GM-CSF to diminish local reactions would be required for long-term maintenance therapy. Granulocyte colony stimulating factor (G-CSF) has also been shown to increase neutrophils in this disease and has not been associated with allergic reactions.

Adolescent↗
PubMed1992

A structural model for human dihydrolipoamide dehydrogenase.

The hypothesis that dihydrolipoamide dehydrogenases (E3s) have tertiary structures very similar to that of human glutathione reductase (GR) was tested in detail by three separate criteria: (1) by analyzing each putative secondary structural element for conservation of appropriate polar/nonpolar regions, (2) by detailed comparison of putative active site residues in E3s with their authentic counterparts in human GR, and (3) by comparison of residues at the putative dimeric interface of the E3s with the authentic residues in GR. All three criteria are satisfied in a convincing way for the 7 E3s that were considered, supporting the conclusion that the structural scaffolding and the overall tertiary structure (which determines the location of functional sites and residues) are remarkably similar for the E3s and for GR. These analyses together with the crystal structures of human erythrocyte GR formed the basis for construction of a molecular model for human E3. The cofactor FAD and the substrates NAD and lipoic acid were also included in the model. Unexpectedly, the surface residues in the cleft that holds the lipoamide were found to be highly charged and predominantly acidic, allowing us to predict that the region around the lipoamide in the subunit should be basic in nature. The molecular model can be tested by site-directed mutagenesis of residues predicted to be in the dihydrolipoamide acetyltransferase subunit binding cleft.

Amino Acid Sequence↗
PubMed1992

Differentiation of homozygous hemoglobin E from compound heterozygous hemoglobin E-beta O-thalassemia by hemoglobin E mutation analysis.

OBJECTIVES: To facilitate the differential diagnosis of hemoglobin FE in newborn infants (homozygous hemoglobin E vs hemoglobin E-beta O-thalassemia). METHODS: The beta-globin gene in DNA from infants found to have hemoglobin FE in the California newborn screening program was amplified by the polymerase chain reaction, and the product was digested with Mnl I, which fails to cut the product when the hemoglobin E mutation is present. When both amplified alleles fail to be cut, homozygous EE is diagnosed. If only one allele is cut, a beta-globin allele without the E mutation is present (non-E), which is most likely a gene with a beta O-thalassemia mutation. RESULTS: Samples from 18 infants revealed an EE genotype, and from two samples a non-E/E genotype was determined. Clinical examination of these two patients confirmed a diagnosis of hemoglobin E-beta O-thalassemia. An independent clinical diagnosis agreed with DNA analysis for all 17 of the 20 infants for whom follow-up and family studies were available. The DNA results were obtained within a week, but the clinical diagnoses often could not be resolved unequivocally for months. CONCLUSIONS: The direct analysis of patient DNA samples for the hemoglobin E mutation allowed rapid and accurate diagnosis in this sample of infants with hemoglobin FE on the newborn screen. This rapid discriminatory test should reduce cost and simplify the diagnostic approach for these patients, which currently consists of expensive and lengthy follow-up until clinical data and family studies result in a diagnosis.

Asian↗
PubMed1989

Transfusion of infants with activation of erythrocyte T antigen.

A protocol for transfusion of infants with erythrocyte T-antigen activation was evaluated for safety and effectiveness in a prospective, 3-year, sequential series of 1672 infants admitted for intensive care. Erythrocyte T antigens are activated by enzymes produced by clostridia or other bacteria in infants with sepsis, often in association with necrotizing enterocolitis. Transfusion of these infants with blood products containing plasma carries the risk of causing intravascular hemolysis. Our transfusion protocol included testing for T-antigen activation, restricting transfusion of patients with activated T antigens to washed erythrocytes or washed platelets whenever possible, and selecting donors with low-titer anti-T when plasma-containing blood products were required. In this series, 10 patients had T-antigen activation, including four with clostridial infections. Severe hemolysis occurred in one patient who received plasma before T-antigen activation developed. Of five patients who received low-titer anti-T plasma, mild hemolysis occurred in three and no hemolysis in two. Four patients who received no plasma-containing blood products experienced no hemolysis. Used cautiously, this protocol allows a full range of transfusion therapy to infants with T-antigen activation.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1989

Sodium butyrate enhances fetal globin gene expression in erythroid progenitors of patients with Hb SS and beta thalassemia.

Increasing the expression of the gamma globin genes is considered a useful therapeutic approach to the beta globin diseases. Because butyrate and alpha-amino-n-butyric acid (ABA) augment gamma globin expression in normal neonatal and adult erythroid progenitors, we investigated the effects of sodium butyrate and ABA on erythroid progenitors of patients with beta thalassemia and sickle cell anemia who might benefit from such an effect. Both substances increased fetal hemoglobin (Hb F) expression in Bfu-e from 7% to 30% above levels found in control cultures from the same subjects with sickle cell anemia. The fraction of cultured erythroblasts producing Hb F increased more than 20% with sodium butyrate treatment in 70% of cultures. In most cultures, this produced greater than 20% total Hb F and greater than 70% F cells, levels which have been considered beneficial in ameliorating clinical symptoms. Alpha: non-alpha (alpha-non-alpha) imbalance was decreased by 36% in erythroid progenitors of patients with beta thalassemia cultured in the presence of butyrate compared with control cultures from the same subjects. These data suggest that sodium butyrate may have therapeutic potential for increasing gamma globin expression in the beta globin diseases.

Anemia, Sickle Cell↗