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Biomedical subjects

C J Burke

Publications and source records attributed to C J Burke.

At least 19 recordsLinked to original sources
PubMed2006

Seizures, ataxia, developmental delay and the general paediatrician: glucose transporter 1 deficiency syndrome.

AIM: Glucose transporter 1 deficiency syndrome (GLUT1-DS) is an important condition for the general paediatrician's differential armamentarium. We describe a case series of eight patients in order to raise awareness of this treatable neurometabolic condition. The diagnosis of GLUT1-DS is suggested by a decreased absolute cerebrospinal fluid (CSF) glucose value (<2.2 mmol/L) or lowered CSF: plasma glucose ratio (<0.4). METHODS: This is a review of eight Queensland patients with GLUT1-DS. The clinical presentation, clinical course, laboratory investigations and treatment outcomes are discussed. RESULTS: The clinical features noted in our patient cohort include combinations of ataxia, developmental delay and a severe seizure disorder that is refractory to anticonvulsant medications. Seizures are the most common clinical manifestation and may be exacerbated by phenobarbitone. The paired CSF: plasma glucose results ranged from 0.2 to 0.39 (normal <0.6) with an average of 0.33. 3-O-Methyl-D-Glucose uptake and GLUT1 Genotyping analysis have been performed on five patients thus far. Rapid and impressive seizure control was observed in 100% of our patients once the ketogenic diet was instituted, with half of the cohort being able to wean completely from anticonvulsants. CONCLUSION: Children presenting with a clinical phenotype consisting of a refractory seizure disorder, ataxia and developmental delay should prompt the consideration of Glucose transporter 1 deficiency syndrome. While the diagnostic test of lumbar puncture is an invasive manoeuvre, the diagnosis provides a viable treatment option, the ketogenic diet. GLUT1-DS displays clinical heterogeneity, but the value of early diagnosis and treatment is demonstrated by our patient cohort.

3-O-Methylglucose↗
PubMed1999

Placental pathology and neurodevelopment of the infant with intrauterine growth restriction.

The placentas of 68 infants with intrauterine growth restriction (IUGR) were examined for evidence of impaired uteroplacental circulation and compared with those of 65 appropriately grown infants. Infarcts and/or accelerated villous maturation were present in the placentas in 27 (40%) of the infants with IUGR compared with seven (11%) of the infants without IUGR (P<0.001). The infants were followed-up at 4 and 12 months of age and growth parameters recorded. Medical and developmental assessments and neuromotor developmental examinations were also performed. The 23 infants in the IUGR group with placentas with evidence of impaired uteroplacental circulation were compared with the 31 infants with IUGR with normal placentas. There was no difference between the groups in growth, cognitive development, or neuromotor abnormality. It was concluded that IUGR is strongly associated with placental markers of impaired uteroplacental blood flow while it would appear that there is no association between placental pathology and growth or neurodevelopment in the first year.

Child Development↗
PubMed1999

Formulation, stability, and delivery of live attenuated vaccines for human use.

The successful use of live attenuated viral and bacterial vaccines depends not only on the proper choice and delivery of the microorganisms, but also on maintaining the sufficient potency required for an immune response. The inherent lability of live organisms presents a particular formulation challenge in terms of stabilizing and preserving vaccine viability during manufacturing, storage, and administration. This review examines pharmaceutical approaches to the stabilization, formulation, and lyophilization of biological macromolecules in general, as well as the specific applicability of these principles to live attenuated viral and bacterial vaccines. Several formulation development case studies with live vaccines are presented. In addition, comparative stability data are summarized for many other live viral and bacterial preparations. Various pharmaceutical issues with conventional and novel delivery systems for administration of parenteral and oral live vaccines are also discussed.

Bacterial Vaccines↗
PubMed1998

Regional development of glutamate-N-methyl-D-aspartate receptor sites in asphyxiated newborn infants.

The N-methyl-D-aspartate (NMDA) subclass of glutamate receptors was examined in newborn infants dying between 25 weeks' gestation and term, either from acute cerebral hypoxia, or from other noncerebral conditions incompatible with life. Frontal, occipital, temporal, and motor cortex tissue samples were obtained at autopsy (post mortem delay: median, 45.9 hr; range, 24-96 hr) and frozen for subsequent [3H]MK801 homogenate binding assays. Whereas no significant variation was observed in ligand affinity (KD), in all cases receptor density (BMAX) increased with gestational age, in occipital cortex (27 weeks, BMAX = 222 +/- 44 fmol x mg protein(-1); 39 weeks, 439 +/- 42 fmol x mg protein[-1]), but not in motor or temporal cortex. The gestational-age increase also occurred in control frontal cortex (27 weeks, 284 +/- 80; 39 weeks, 567 +/- 40 fmol x mg protein[-1]), but was significantly less marked in frontal cortex in hypoxia cases (27 weeks, 226 +/- 90; 39 weeks, 326 +/- 47 fmol x mg protein[-1]). In all cortical areas except temporal, the maximal response to glutamate did not vary across case groups. Hypoxia cases showed an increased response to glutamate enhancement selectively in temporal cortex. Binding site density did not correlate with degree of hypoxia as assessed pathologically, suggesting that receptor differences preceded the hypoxic episode. Regional differences in glutamate-NMDA receptor sites may underlie increased vulnerability to hypoxia at birth.

Autopsy↗
PubMed1997

Size and conformational stability of the hepatitis A virus used to prepare VAQTA, a highly purified inactivated vaccine.

A variety of biophysical techniques have been employed to examine the size and conformational integrity of highly purified hepatitis A virus (HAV) in solution (purified HAV particles are subsequently formalin-inactivated and adsorbed to aluminum salts for use as the vaccine VAQTA). The size of HAV particles was assessed by a combination of electron microscopy, sedimentation velocity, and dynamic light scattering. The effect of ionic strength and temperature on the overall conformational stability of HAV was determined by a combination of intrinsic HAV protein fluorescence, fluorescent probes of both RNA and protein, and UV-visible spectroscopy. A major structural change in HAV occurs near 60 degrees C with the addition of 0.2 M magnesium chloride enhancing the thermal stability of HAV by approximately 10 degrees C. Salt concentrations above 0.2 M, however, decrease the solubility of HAV. The effect of pH on the physical properties of HAV particles was monitored by dynamic light scattering, analytical size exclusion HPLC, and interaction with fluorescent dyes. HAV particles undergo a substantially reversible association/aggregation at pH values below 6 with the concomitant exposure of previously buried hydrophobic surfaces below pH 4. These results are in good agreement with previous studies of HAV thermal stability under extreme conditions in which the irreversible inactivation of the viral particles was measured primarily by the loss of viral infectivity. The wide variety of biophysical measurements described in this work, however, directly monitor structural changes as they occur, thus providing a molecular basis with which to monitor HAV stability during purification and storage.

Chromatography, High Pressure Liquid↗
PubMed1997

Ischaemic cerebral injury, intrauterine growth retardation, and placental infarction.

Two hundred and twenty-five consecutive autopsies performed on fetuses >20 weeks' gestation were reviewed, and 37 growth-retarded stillborn fetuses without multiple congenital abnormalities or evidence of intrauterine infection were identified. Histological evidence of ischaemic cerebral injury was found in 31 of the 37 cases and placental infarction was seen in 26 of 36 placentas. Of the 31 cases with cerebral ischaemia, 24 had placental infarcts. Twenty-six of 27 stillborn fetuses >26 weeks' gestation showed histological evidence of cerebral ischaemia. It was concluded that in the group of growth-retarded fetuses studied, there was a high incidence of both cerebral and placental ischaemic abnormality.

Anthropometry↗
PubMed1996

Biochemical and biophysical comparison of native and chemically synthesized phospholamban and a monomeric phospholamban analog.

Phospholamban (PLB) was rapidly isolated from canine cardiac sarcoplasmic reticulum using immunoaffinity chromatography and prepared by solid phase peptide synthesis. The two proteins are indistinguishable when analyzed by SDS-polyacrylamide gel electrophoresis and exhibit pentameric oligomeric states. They are similarly detected on Western blots, are phosphorylation substrates, have identical amino acid compositions that directly reflect their predicted values, yield the same internal amino acid sequences upon CNBr digestion, and have molecular mass values agreeing with the expected value (approximately 6123 Da). Native and synthetic PLB reduced the calcium sensitivity of Ca2+ATPase, which is reversed by anti-PLB antibody. A Cys-to-Ser PLB analog, where the cysteines (36, 41, and 46) were substituted by serines, is monomeric on SDS-polyacrylamide gel electrophoresis, can be phosphorylated, and is recognized by polyclonal antisera. PLB migrates with a sedimentation coefficient of 4.8 S in sedimentation velocity ultracentrifugation experiments, whereas Cys-to-Ser PLB does not sediment, consistent with a monomeric state. Circular dichroism spectral analysis of PLB indicates about 70% alpha-helical structure, whereas Cys-to-Ser PLB manifests only about 30%. Because the physiochemical properties of native and synthetic PLB appear identical, the more readily available synthetic protein should be suitable for more extensive structural studies.

Adenosine Triphosphatases↗
PubMed1996

Tibial diaphyseal nonunions after external fixation treated with nonreamed solid core nails.

Twenty-nine patients with tibial diaphyseal fractures had external fixators applied to treat their initial fractures and underwent nonreamed solid core nailing for nonunion (> 22 weeks). Fifteen Alta, 11 Lottes, and 3 Rush nails were used. The original fracture grades were: 1 closed, 1 grade I, 7 grade II, 3 grade IIIA, and 17 grade IIIB. The duration of nonunion was 51 weeks (average: 22 to 173). The average duration of external fixation was 19 weeks (range: 9 to 47). The average interval from fixator removal to nail was 32 weeks (range: 0 to 156). Twenty-eight patients were seen at > 12 months' follow up (average: 35; range: 10 to 58) and completion of treatment. Twenty-seven patients' fractures united at an average of 14 weeks (range: 6 to 40). One patient required a reamed exchange nailing at 39 weeks and united 58 weeks post-exchange nailing. One patient had a persistent asymptomatic nonunion. One patient developed a stress fracture 49 months post nail requiring an exchange nailing. Eleven fractures had a pre-nail deformity of 10 degrees or more; 9 were corrected. Eight patients had pre-nail wound and five had pre-nail pin tract infections. Except for two cases, all of these infections were treated successfully with surgical debridement and/or antibiotics prior to nail insertion. Two patients had their nail inserted through active infections that could not be controlled with an unstable fracture. One patient healed uneventfully in 6 weeks. One required two subsequent debridements. There were no other infections. The authors conclude that nonreamed solid core nailing is an acceptable treatment for tibial diaphyseal nonunions following external fixation.

Adult↗
PubMed1996

Pilon fractures treated with an articulated external fixator: a preliminary report.

Nine high-energy pilon fractures with severe soft tissue injuries were treated by a medial external fixator with an articulated ankle-hinge and limited internal fixation (1.7 screws per case). A 100% union rate was achieved; however, there was a 100% complication rate associated with the fixator. Both B3 fractures required a vertical transarticular pin to maintain reduction. Seven C2 fractures suffered calcaneal screw loosening and drainage, necessitating removal of the fixator prior to union. Due to these complications, the articulated ankle hinge could not be utilized. At a minimum of 6 months follow up, eight of nine fractures had acceptable radiographic and early clinical results.

Adult↗
PubMed1996

Pelvic ring injuries. A long term functional outcome study.

Eighty patients with pelvic fractures, without hip, spine injuries with neurologic deficits, or traumatic cognitive deficits, 61% treated with external fixators, were reviewed with greater than 5 years of followup. The Short Form-36 General Health Survey, the Iowa pelvic scores, and additional questionnaires concerning return to previous sexual function, occupation, and recreation, and a perception of the worst sequelae of their pelvic trauma were administered. Fractures were classified according to Tile as 25 undisplaced Class A, 31 rotationally displaced Class B, and 24 vertically displaced Class C fractures. Injury severity scores, associated injuries, and mechanisms of injuries were similar across Tile classes. Statistical analysis compared Tile Classes A with B with C and Classes A with B and C. Variations by Tile class among the Short Form-36 survey, Iowa pelvic score, or questionnaire result's were not seen. Approximately 75% of patients returned to their previous sexual function and 80% to their previous occupation. Similarities comparing undisplaced with displaced pelvic fractures question whether reduction of pelvic ring injuries can alter patient long term functional outcomes.

Adolescent↗
PubMed1996

Analysis of vaccine stability.

The complexity of vaccines creates a unique formulation challenge. Vaccines may consist of one or more types of antigenic component including live attenuated or killed viral or bacterial particles, polysaccharides, proteins, polynucleotides and particle conjugates. In addition, other excipients such as adjuvants may be present. Not only must the chemical and structural integrity of the various components be maintained, but immunogenicity must be ensured. The inherent lability of vaccines can critically limit their distribution, administration, and efficacy in parts of world where it is difficult to maintain a cold chain. Combination with other vaccines and oral administration may also compromise vaccine stability. Successful vaccine stabilization strategies include both empirical efforts to screen and identify appropriate stabilizers and environmental conditions and more rational approaches toward developing an understanding of the causes and mechanisms of vaccine inactivation. In principle, by elucidating the conformational and chemical pathways of macromolecular inactivation, more rational strategies to minimize their occurrence can be adopted. This presentation will review the application of classical techniques such as viral plaque assays to identify vaccine stabilizers by empirical testing. The potential of using various biophysical techniques (both hydrodynamic and spectroscopic methods) to characterize the physicochemical stability of purified vaccine preparations (Hepatitis A and B) is also explored.

Antigens, Viral↗
PubMed1995

Developmental rearrangements of cortical glutamate-NMDA receptor binding sites in late human gestation.

NMDA-preferring glutamate receptor biding sites were characterized using the site-selective ligand [3H]MK801, in synaptic membranes prepared from cerebral cortex tissue obtained postmortem from human infants who had died with minimal neurological and neuropathological impairment between 22 and 42 weeks' gestation. It proved necessary to modify the assay protocol used with adult tissue before reliable data could be obtained. In the four cortical region studied (prefrontal, motor, occipital, temporal), [3H]MK801 bound to a single class of sites which showed significant variations in affinity only in motor cortex. The density of [3H]MK801 binding sites (calculated at constant affinity) showed marked increases in all cortical regions over this period. The extent to which glutamate could enhance [3H]MK801 binding became significantly lower in prefrontal and motor cortex as gestation progressed, so that at term, little activation was apparent. In occipital and temporal cortex, this parameter was low throughout late gestation. The evidence suggests that Glutamate-NMDA binding sites may undergo structural rearrangements which alter their ability to interact with ligands during the later stages of human gestation, and that such changes are regionally variable.

Binding Sites↗
PubMed1995

Solution structure of the cytoplasmic domain of phopholamban: phosphorylation leads to a local perturbation in secondary structure.

Peptides representing the N-terminal domain (Ia) of the cardiac sarcoplasmic reticulum protein phospholamban (residues 1-25 [PLB(1-25)] and a phosphorylated form [pPLB(1-25)]) were synthesized and their conformations examined using circular dichroism and nuclear magnetic resonance spectroscopy. In aqueous solution, both PLB(1-25) and pPLB(1-25) adopt a primarily disordered conformation. In 30% trifluoroethanol/10 mM phosphate, PLB(1-25) exhibits a CD spectrum consistent with 60% helical structure. This value decreases to 27% for the phosphorylated peptide. CD spectra in 2% SDS indicate 40% alpha-helix for PLB(1-25) and 20% for pPLB(1-25). Full chemical shift assignments were obtained by conventional homonuclear NMR methodologies for both PLB(1-25) and pPLB(1-25) in 30% trifluoroethanol/water and 300 mM SDS. The solution structure of PLB(1-25) in 30% TFE/water was determined from distance geometry calculations using 54 NOE distance constraints and 17 torsion angle constraints. In the family of 20 calculated conformers, the root mean square deviation from the mean structure is 0.79 A for backbone heavy atoms of residues 1-17. The structure comprises a regular alpha-helix extending from M1 to S16 with the remaining C-terminal residues disordered. The calculated structure is supported by analysis of C alpha H secondary shifts which are significantly negative for residues 1-16. Chemical shift degeneracy is substantially more extensive in the phospho form and precludes a direct comparison of calculated structures. However, the magnitudes of upfield secondary shifts are decreased by 20% in residues 1-11 and are not significantly helical for residues 12-16 according to the criteria of Wishart et al. [(1992) Biochemistry 31, 1647-1651]. 3JHN alpha coupling constants measured for I12, R13, A15, and S16 also suggest that residues 12-16 undergo a local unwinding of the helix upon phosphorylation. Similar results are obtained for PLB(1-25) and pPLB(1-25) in 300 mM perdeuterated sodium dodecyl sulfate except that differences in backbone dynamics for the helical and nonhelical regions of the peptide are evident in the DQF-COSY line shapes for fingerprint cross-peaks. This disruption of structure at the C-terminus of the helix suggests a model for phosphorylation-induced dissociation of the PLB/Ca(2+)-ATPase complex.

Amino Acid Sequence↗
PubMed1995

Enhancing the avidity of a human recombinant anti-HIV-1 monoclonal antibody through oligomerization.

The oligomerization by chemical cross-linking of a recombinant human antiviral monoclonal antibody (MAb), r447-1, and its characterization are described. This MAb binds to an epitope residing in the hypervariable V3 region of the envelope protein (gp120/160) of HIV-1. A dimeric form of this MAb displays enhanced avidity and was found to be capable of neutralizing a greater variety of lymphoid cell culture-adapted HIV-1 variants and HIV-1 primary isolates than its monomeric form. The superior binding and breadth of reactivity of this antibody suggests it may have utility as a therapeutic and/or prophylactic agent, if it possesses an appropriate safety and immunogenicity profile.

Antibodies, Monoclonal↗
PubMed1995

The development and cross-validation of methods based on radioimmunoassay and LC/MS-MS for the quantification of the class III antiarrhythmic agent, MK-0499, in human plasma and urine.

An analytical method based on radioimmunoassay (RIA) has been developed for the determination of the antiarrhythmic agent, MK-0499, in plasma and urine. Owing to the potency of the drug, the specificity of this assay in human plasma could not be adequately determined using conventional RIA procedures. A highly specific procedure, based on LC/MS-MS, was developed to cross-validate the RIA. The lower quantifiable limits of the RIA and LC/MS-MS-based methods were 0.05 and 0.013 ng ml-1, respectively. Cross-validation data, compared using paired student's t-test regression analysis, showed excellent correlation between methods. The mass spectrometric assay was also used to simultaneously measure plasma concentrations of unlabeled and 14C-labeled MK-0499 following administration of the drug at high specific activity to volunteers.

Animals↗
PubMed1995

Nonreamed nailing of tibial diaphyseal fractures in blunt polytrauma patients.

The efficacy of nonreamed nailing as the treatment of choice of unstable blunt tibial diaphyseal fractures was studied. From March 1, 1990, through August 31, 1991, 72 patients with 74 fractures that required fixation were treated. One patient died and six were lost to follow-up, leaving 65 patients with 67 fractures. Follow-up averaged 21 months (range 5-43). Fisher's exact and logistic regression analyses were used to compare grades of open fractures, comminution as classified by Winquist, and dynamic and static nailings. The failure rates of 51 titanium and 16 stainless steel nails were compared. Times to union were compared by the log rank statistic method. The average time to union was 32 weeks with 26 (39%) additional operations required to achieve union; 13 dynamizations (12 successful), 12 exchange nailings (11 successful), and one plate and bone graft. The rate of reconstructive procedures to achieve union was a more sensitive indicator of difficulties achieving union than was time to union. Reoperation rates were 33% for closed or grade I and II fractures compared with 46% for grade III fractures (NS). Among closed grade I and II static versus dynamic nailing, times to union were 36 versus 25 weeks (p < 0.01), and the reoperation rates were 44% versus 13% (p < 0.04). Winquist I and II fractures required a 24% reoperation rate versus 53% for grade III and IV and segmental fractures (p < 0.01). Static locked fractures required a 48% reoperation rate versus 12% for dynamic locked fractures (p < 0.01). A logistic regression analysis demonstrated that locking mode was the most important factor in determining reoperation rates. Fifteen additional reoperations for infection, broken or painful implants, or to remodel bones that united with an incomplete circumference of cortex were performed. With an additional 12 elective nail removals, the total reoperations numbered 53 (79%). Titanium alloy nails had a 2% failure rate versus 25% for stainless steel nails (p < 0.01). Two of 28 (7%) grade III fractures became infected. All fractures united within 10 degrees of normal alignment and 1 cm of length. Nine (13%) united with an incomplete cortical circumference, refractory to dynamization and full weight bearing. Thirteen of the 58 (22%) fractures available for an evaluation of ankle motion were symptomatic, with < 10 degrees of dorsiflexion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1995

Prenatal brain damage and placental infarction--an autopsy study.

The histopathological abnormalities seen at autopsy in the brains and corresponding placentas of a consecutive four-year series of stillborn infants are presented. After excluding stillbirths with major cerebral malformations, the brains of 175 cases and the corresponding placentas in 165 cases were available for assessment. 70 of the 175 brains (40 per cent) showed microscopic evidence of ischaemic cerebral injury, using a combination of haematoxylin-eosin and glial fibrillary acid protein stains. In 62 of these 70 brains, the periventricular white matter was the main site of damage. 46 (28 per cent) of the corresponding 165 placentas showed macroscopic and microscopic evidence of infarction, 39 of which were associated with ischaemic cerebral lesions. It was concluded that placental infarcts are commonly associated with prenatal cerebral ischaemic lesions.

Astrocytes↗