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T R Hall

Publications and source records attributed to T R Hall.

At least 19 recordsLinked to original sources
PubMed2006

Longitudinal epitope analysis of insulin-binding antibodies in type 1 diabetes.

Autoantibodies to insulin (IAA) are one of the first markers of the autoimmune process leading to type 1 diabetes (T1D). While other autoantibodies in T1D have been studied extensively, relatively little is known about IAA and their binding specificities, especially after insulin treatment is initiated. We hypothesize that insulin antibodies (IA) that develop upon initiation of insulin treatment differ in their epitope specificities from IAA. We analysed insulin antibody binding specificities in longitudinal samples of T1D patients (n = 49). Samples were taken at clinical diagnosis of disease and after insulin treatment was initiated. The epitope specificities were analysed using recombinant Fab (rFab) derived from insulin-specific monoclonal antibodies AE9D6 and CG7C7. Binding of radiolabelled insulin by samples taken at onset of the disease was significantly reduced in the presence of rFab CG7C7 and AE9D6. rFab AE9D6 competed sera binding to insulin significantly better than rFab CG7C7 (P = 0.02). Binding to the AE9D6-defined epitope in the initial sample was correlated inversely with age at onset (P = 0.005). The binding to the AE9D6-defined epitope increased significantly (P < 0.0001) after 3 months of insulin treatment. Binding to the CG7C7-defined epitope did not change during the analysed period of 12 months. We conclude that epitopes recognized by insulin binding antibodies can be identified using monoclonal insulin-specific rFab as competitors. Using this approach we observed that insulin treatment is accompanied by a change in epitope specificities in the emerging IA.

Adolescent↗
PubMed2006

Identification and characterization of a novel isoform of the vesicular gamma-aminobutyric acid transporter with glucose-regulated expression in rat islets.

Pancreatic islets are unique outside the nervous system in that they contain high levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), synthesized by the enzyme glutamic acid decarboxylase (GAD). Since the role that GABA plays in the islet and the mechanisms whereby the two major GAD isoforms (GAD65 and GAD67) function as diabetes-associated autoantigens are unknown, continued characterization of the islet GAD-GABA system is important. We previously demonstrated that the GABA and glycine transporter vesicular inhibitory amino acid transporter (VIAAT also known as VGAT) is present in rat islets. Here we identify a novel 52 kDa variant of VIAAT in rat islets: VIAAT-52 (V52). V52 is an amino-terminally truncated form of VIAAT (V57) that likely results from utilization of a downstream start site of translation. V57 and V52 display different patterns of post-translational modification and cellular expression. Our results have indicated that islet content of V52, but not V57, is responsive to changes in glucose concentration and other extracellular conditions. VIAAT is expressed in the islet alpha cells, but there have been conflicting findings regarding the presence of VIAAT in the beta cells. Here we have also provided additional evidence for the presence of VIAAT in islet beta cells and show that the beta cell line INS-1 expresses V57. V52 may be better adapted than V57 to the unique rat alpha cell GAD-GABA system, which lacks GAD65 and in which VIAAT traffics to secretory granules rather than just to synaptic microvesicles.

Animals↗
PubMed2005

Epitope analysis of insulin autoantibodies using recombinant Fab.

Autoantibodies to insulin are often the first autoantibodies detected in young children with type 1 diabetes and can be present before the onset of clinical diabetes. These autoantibodies and their epitopes are, however, not well characterized. We explored the use of monoclonal antibodies and their recombinant Fab as reagents for epitope analysis. In this study we cloned and characterized the recombinant Fab of the insulin-specific monoclonal antibody CG7C7. We found the epitope of this antibody to be located predominantly at the A-chain loop of the insulin molecule. The recombinant Fab was then used to compete for insulin binding against insulin autoantibodies present in sera from patients with type 1 or type 1.5 diabetes. In competition experiments with sera positive for autoantibodies to insulin the recombinant Fab significantly reduced the binding to [125I]-insulin by sera of type 1 (n = 35) and type 1.5 diabetes [latent autoimmune diabetes in adults (LADA)] (n = 14) patients (P < 0.0001). We conclude that competition between insulin-specific monoclonal antibodies or their recombinant Fab and insulin autoantibodies should prove useful in the epitope analysis of autoantibodies to insulin.

Adolescent↗
PubMed2000

Mycotic aneurysm of the thoracic aorta due to Aspergillus terreus: case report and review.

Mycotic aneurysms of the aorta caused by fungi are uncommon. We describe an unusual case of aortic aneurysm infection caused by Aspergillus terreus, which most likely spread from an adjacent pulmonary focus. Successful treatment included partial pneumonectomy, resection of the aneurysm with graft repair, and prolonged sequential administration of amphotericin B and itraconazole. A review of the published experience with aortic aneurysms caused by Aspergillus species is also presented. When invasive aspergillosis is suspected in proximity to areas with major vascular structures in immunocompromised patients, further investigation to rule out vascular invasion may be warranted. If the diagnosis is confirmed, aggressive and prompt treatment with antifungal agents combined with surgical debridement is essential to improve outcome.

Aneurysm, Infected↗
PubMed1999

Variable morbidity in alagille syndrome: a review of 43 cases.

BACKGROUND: Alagille syndrome is one of the most common inherited disorders that cause chronic liver disease in children. Early reports suggested a benign course in these patients. Subsequent reports showed significant morbidity and mortality. This study was designed to analyze the long-term clinical course in Alagille syndrome. METHODS: The records of children with Alagille syndrome seen during a 20-year period were reviewed. RESULTS: Forty-three patients were identified. Liver disease was diagnosed before 12 months of age in 95%. The frequencies of renal anomalies (50%) and intracranial hemorrhage (12%) were significant. The high incidence of chronic otitis media (35%) has not been reported previously. One patient had a renal transplant. Vascular compromise as a pathologic mechanism for some characteristics of the syndrome is also suggested by the presence of small bowel stenosis and atresia, tracheal and bronchial stenosis, renal artery stenosis, middle aortic syndrome, and avascular necrosis of the humeral and femoral heads. Twenty (47%) patients underwent liver transplantation. Five of six who underwent Kasai procedure required liver transplantation. Twelve died (28%), five after liver transplantation. One patient died of intracranial bleeding. Sixteen (37%) without liver transplantation and 15 (35%) who underwent liver transplantation are alive. CONCLUSIONS: Some patients with early-onset and more severe liver disease can benefit from liver transplantation. Careful and complete assessment should be made of infants with a cholestatic syndrome, to avoid misdiagnosis and unnecessary Kasai procedures. Our observation of vascular compromise in various organ systems suggests that notch signaling pathway defects affect angiogenesis in Alagille syndrome.

Adolescent↗
PubMed1997

Optic nerve hypoplasia secondary to intracranial teratoma.

PURPOSE: To postulate a causal relation between optic nerve hypoplasia and a suprasellar teratoma. METHOD: Case report. RESULTS: A 6-month-old infant with suprasellar teratoma was visually inattentive and had searching nystagmus. He had moderately severe, bilateral optic nerve hypoplasia with the left eye being somewhat worse than the right eye. CONCLUSIONS: Optic nerve hypoplasia is a major cause of impaired vision in children and rarely has been attributed to an intracranial tumor. Our case, involving a patient with a suprasellar teratoma and optic nerve hypoplasia, supports a causal relation between the two.

Brain Neoplasms↗
PubMed1995

Cloning and expression of the mammalian cytosolic branched chain aminotransferase isoenzyme.

The cDNA for the rat cytosolic branched chain aminotransferase (BCATc) has been cloned. The BCATc cDNA encodes a polypeptide of 410 amino acids with a calculated molecular mass of 46.0 kDa. By Northern blot analysis, BCATc message of approximately 2.7 kilobases was readily detected in rat brain, but was absent from liver, a rat hepatoma cell line, kidney, and skeletal muscle. When expressed in COS-1 cells, the enzyme is immunologically indistinguishable from the native enzyme found in rat brain cytosol. Comparison of the rat BCATc sequence with available data bases identified the Escherichia coli (and Salmonella typhimurium) branched chain aminotransferase (BCAT) and revealed a Haemophilus influenzae BCAT, a yeast BCAT, which is hypothesized to be a mitochondrial form of the enzyme, and the murine BCATc (protein ECA39). Calculated molecular masses for the complete proteins are 33.9 kDa, 37.9 kDa, 42.9 kDa, and 43.6 kDa, respectively. The rat BCATc sequence was 84% identical with murine BCATc, 45% identical with yeast, 33% identical with H. influenzae, 27% identical with the E. coli and S. typhimurium BCAT, and 22% identical with the evolutionary related D-amino acid aminotransferase (D-AAT) (Tanizawa, K., Asano, S., Masu, Y., Kuramitsu, S., Kagamiyama, H., Tanaka, H., and Soda, K. (1989) J. Biol. Chem. 264, 2450-2454). Amino acid sequence alignment of BCATc with D-AAT suggests that the folding pattern of the overlapping mammalian BCATc sequence is similar to that of D-AAT and indicates that orientation of the pyridoxal phosphate cofactor in the active site of the eukaryotic BCAT is the same as in D-AAT. Thus, BCAT are the only eukaryotic aminotransferases to abstract and replace the proton on the re face of the pyridoxal phosphate cofactor. Finally, requirements for recognition of substrate L-amino acid and alpha-carboxylate binding are discussed.

Amino Acid Sequence↗
PubMed1995

The value of portal vein pulsatility on duplex sonograms as a sign of portal hypertension in children with liver disease.

OBJECTIVE: The purpose of this study was to determine the significance of portal vein pulsatility on duplex Doppler waveforms in children with end-stage hepatic failure undergoing liver transplantation. SUBJECTS AND METHODS: Thirty-eight children with end-stage hepatic decompensation were examined with color-assisted spectral Doppler waveform analysis of the hepatic artery and the portal vein. Correlation was made with age, duration of illness, clinical and pathologic diagnosis, and presence of portal hypertension. Findings were compared with those for six patients with acute viral hepatitis and 12 healthy control subjects. RESULTS: Portal vein pulsatility was noted in all 36 patients in whom portal vein flow was detected by Doppler imaging. The majority of these (34) had clinical or sonographic evidence of portal hypertension. In two patients, no portal vein flow was identified in the liver hilum; both had a large portosystemic shunt through collaterals or surgical graft. Significantly increased pulsatility of the hepatic artery waveform (resistive index [RI] = 0.89 +/- 0.15, p < .0001) was seen in patients with end-stage liver disease. In contrast, no portal vein pulsatility and normal hepatic artery pulsatility (RI = 0.60 +/- 0.11) was noted in all patients with acute hepatitis and control subjects. CONCLUSION: Portal vein waveform pulsatility is 94% sensitive and 90% specific for portal hypertension in end-stage liver disease.

Acute Disease↗
PubMed1994

Imaging of the adrenal gland in children.

Ultrasonography (US), computed tomography (CT), and magnetic resonance (MR) imaging have replaced intravenous urography and angiography in evaluation of children with suspected disease of the adrenal glands. Although the spatial resolution of MR imaging is still somewhat inferior to that of CT, it allows tissue characterization and better evaluation of tumor extension owing to its multiplanar imaging capability. Initial diagnosis of an adrenal mass in a child is made with US, which is also used to document regression of uncomplicated neonatal adrenal hemorrhage. MR imaging is used for evaluation of tumor extension when surgery is to be performed. Imaging findings such as size, shape, and signal intensity are often not specific for a pathologic condition and must be interpreted in conjunction with the patient's age, the clinical history (eg, trauma), results of physical examination (eg, palpable mass or presence of an endocrine syndrome), and hormone levels in blood and urine.

Adrenal Gland Diseases↗
PubMed1993

Branched chain aminotransferase isoenzymes. Purification and characterization of the rat brain isoenzyme.

This paper presents the first complete purification of the branched chain aminotransferase (EC 2.6.1.42) from rat brain cytosol (BCATc). On sodium dodecyl sulfate-polyacrylamide gel electrophoresis the enzyme appeared as a single band with a molecular mass of 47 kDa; however, gel exclusion chromatography suggested that BCATc is a dimer. Comparison of tryptic peptide maps of BCATc and the mitochondrial form of the enzyme (BCATm) indicated that they are different proteins. Experiments with protein labeling reagents, in particular sulfhydryl reagents, also suggested that there may be some distinct structural differences in BCATc and BCATm. Nevertheless, BCATc and BCATm showed similar specificities for amino acid and alpha-keto acid substrates. Both enzymes transaminated branched chain amino acids, their straight chain analogs, L-alloisoleucine and glutamate. A broader range of alpha-keto acids than amino acids was accepted as substrate including alpha-ketobutyrate and the alpha-keto acid of methionine. Both enzymes exhibited ping-pong kinetics with apparent Km values for leucine and isoleucine of about 1 and 5 mM for valine, respectively. Km values for alpha-ketoglutarate ranged from about 0.6 to 3 mM depending on the amino acid substrate. Polyclonal antibodies were raised in rabbits against purified BCATc. BCATc antiserum neutralized branched chain aminotransferase activity in rat brain cytosol but did not affect the activity in a heart mitochondrial extract. However, immunoblotting showed that BCATc and BCATm do share common epitopes since BCATm antiserum recognized BCATc on the immunoblots. The tissue distribution of BCATc was examined using BCATc and BCATm antisera. These data showed that BCATc was found in adult and fetal rat brain, cultured cells from fetal rat brain cortex, ovary, and placenta. Brain had the highest activity followed by ovary, fetal brain, and placenta. BCATc was not found in fetal liver, adult rat liver, or a rat hepatoma cell line. These data provide clear evidence that BCATc, unlike BCATm, is restricted to several highly specialized tissues.

Animals↗
PubMed1993

Identification of the mitochondrial branched chain aminotransferase as a branched chain alpha-keto acid transport protein.

Conditions were developed which optimized reconstitution of branched chain alpha-keto acid transport activity, which was measured as alpha-ketoisocaproate (KIC) transport, and pyruvate transport activity. Reconstitutable KIC transport activity was about 40-fold higher in heart than in liver mitochondrial extracts and 40-fold higher than heart pyruvate transport activity but only about 7-fold higher than liver pyruvate transport activity. A purification procedure was developed for the branched chain alpha-keto acid and pyruvate transport proteins which resulted in partial purification of the proteins from rat heart mitochondria. Pyruvate transport activity appeared to be associated with a 32.5-kDa protein, whereas KIC transport activity appeared to be associated with two proteins around 41 kDa. As shown by immunoblotting and immunoaffinity chromatography, these proteins were recognized by an antiserum raised against purified rat heart mitochondrial branched chain aminotransferase (BCATm). Procedures used to extract BCATm from mitochondria effectively solubilized KIC transport activity, and both transaminase and transport activities in the sonicate supernatant were immunoprecipitated by BCATm antiserum. The tissue distribution of reconstitutable KIC transport activity was identical with the tissue distribution of BCATm. On the other hand, the distribution of reconstitutable pyruvate transport activity was distinct from that of KIC transport and branched chain aminotransferase activities, and pyruvate transport activity could not be immunoprecipitated by BCATm antiserum. When incorporated into phospholipid vesicles, purified BCATm exhibited branched chain alpha-keto acid transport activity but did not transport pyruvate. Transport was saturable, and Km values for KIC and alpha-ketoisovalerate uptake were 10 and 25 microM, respectively. Substrate competition experiments indicated that KIC transport could be inhibited substantially by branched chain alpha-keto acids and their derivatives but not by substrates for the pyruvate transporter. Transport was also inhibited by several aromatic carboxylic acid derivatives and alpha-ketoglutarate, but not by N-butylmalonate and succinate. Studies with covalent protein-modifying reagents indicated that transport was inhibited by sulfhydryl reagents, the histidine reagent diethyl pyrocarbonate, and the tyrosine reagent N-acetylimidazole. When BCATm was incorporated into phospholipid vesicles, pyridoxal 5-phosphate was an inhibitor of transport (75% inhibition at 10 mM) but had little effect on aminotransferase activity. The data indicate BCATm is a bifunctional protein catalyzing branched chain amino acid transamination and branched chain alpha-keto acid transport. The transport properties of BCATm suggest that this protein may be the branched chain alpha-keto acid transporter that was originally identified and characterized kinetically in isolated rat heart mitochondria (Hutson, S.M., and Rannels, S.L. (1985) J. Biol. Chem. 260, 14189-14193).

Animals↗
PubMed1993

Endogenous growth hormone controls high plasma levels of 3,3',5-triiodothyronine (T3) in growing chickens by decreasing the T3-degrading type III deiodinase activity.

The influence of endogenous GH levels on peripheral monodeiodination activity has been investigated in growing chickens at the age of 4 weeks, when they normally show no T3 increase after GH injection. Injection of anti-GH serum decreased plasma T3 and increased plasma T4. Three d and 1 week after hypophysectomy, plasma T3 was also markedly decreased, while T4 was only slightly affected, hepatic 5'D-I activity showed a transient decrease, but 5D-III activity was highly increased, as were the number of hepatic GH receptor sites. Injection of GH in hypophysectomized chickens decreased 5D-III activity and increased plasma T3. GH receptor-deficient dwarf chickens had decreased plasma T3 and increased plasma T4 and hepatic 5'D-I and 5D-III activities compared to their normally-growing siblings. GH administration could only affect T3 and 5D-III in the non-dwarf siblings, which showed higher basal 5D-III activity compared to the non-responsive age-matched chickens of the Hisex strain used in the other experiments. It can be concluded that endogenous GH is an important factor in the control of plasma T3 levels in growing chickens due to its influence on the activity of the T3-degrading type III deiodinase. The effectiveness of exogenous GH administration to acutely increase plasma T3 probably depends on the balance between the injected dose and the endogenous GH concentration, the hepatic GH receptor availability and the hepatic type III deiodinase level.

Analysis of Variance↗
PubMed1993

Imaging in pediatric liver transplantation.

Liver transplantation is an accepted and successful mode of treatment for pediatric end-stage liver disease. On the basis of a review of 229 liver transplantations in 185 children, the authors describe the imaging findings of the preoperative evaluation, the uncomplicated transplantation, various postoperative complications, and the suggested percutaneous treatment of some of these complications. The most frequent indications for liver transplantation encountered in this review were biliary atresia (52%), acute fulminant hepatic failure (11%), alpha 1-antitrypsin deficiency (9%), cryptogenic cirrhosis (6%), and chronic active hepatitis (4%). (The remaining 18% were various rare indications, representing < 4% each.) Routine Doppler ultrasound is the modality of choice for the screening of postoperative complications, supplemented with computed tomography, hepatobiliary scintigraphy, and cholangiography or angiography as needed. Familiarity with the normal graft appearance, as influenced by various surgical and technical factors, and knowledge of the underlying condition of the patient and the clinical course of postoperative complications are crucial for a correct interpretation of the findings from imaging studies.

Biliary Atresia↗
PubMed1993

Pediatric intracranial vascular malformations: evaluation of treatment results with color Doppler US. Work in progress.

To determine the value of color Doppler ultrasound (US) in the preoperative assessment and evaluation of treatment results in children with intracranial vascular malformations (VMs), the authors performed 36 color Doppler US studies in nine children who underwent endovascular embolization. Color flow imaging with spectral waveform analysis of feeding arteries, nidus, draining veins, and uninvolved cranial vasculature was performed, and correlation was made with other imaging findings. In most VMs, color Doppler US enabled the authors to map the lesion completely. Hemodynamic changes after embolization included improvement in blood supply to uninvolved portions of the brain and increase in caliber and flow of feeding vessels that were not occluded during embolization. Serial volume flow measurements were performed with Doppler US in major extracranial arteries. Success of embolization was indicated by substantial decrease of total carotid artery flow. Color Doppler US is a noninvasive modality that adds important imaging and hemodynamic data to those provided by angiography.

Cerebral Angiography↗
PubMed1993

Insulin therapy and weight change in Native-American NIDDM patients.

OBJECTIVE: To determine whether NIDDM patients exposed to insulin therapy in a clinical setting gain weight. RESEARCH DESIGN AND METHODS: This study, an historical cohort chart review, was conducted at the IHS clinic on the Navajo Reservation in Northern Arizona. We studied 27 Native Americans with NIDDM and 102 Native-American nondiabetic control subjects. RESULTS: Insulin therapy consisting of a mean of 105 U/day was associated with a mean weight gain of 3.0 +/- 2.2 kg/yr. When insulin was discontinued or decreased, a mean weight loss of 5.2 +/- 2.7 kg/yr was observed in the same patients. No significant weight gain was noted in 102 nondiabetic control subjects, nor in 20 of 27 insulin-treated patients given oral hypoglycemic agents before initial insulin therapy. CONCLUSIONS: Insulin therapy appeared to be associated with weight gain in this group of NIDDM patients. This suggests that observations for weight gain be undertaken when treating NIDDM patients with insulin, because it may exacerbate the underlying pathophysiology of the disease.

Diabetes Mellitus, Type 2↗
PubMed1992

Identification of mitochondrial branched chain aminotransferase and its isoforms in rat tissues.

The tissue distribution and subcellular location of branched chain aminotransferase was analyzed using polyclonal antibodies against the enzyme purified from rat heart mitochondria (BCATm). Immunoreactive proteins were visualized by immunoblotting. The antiserum recognized a 41-kDa protein in the 100,000 x g supernatant from a rat heart mitochondrial sonicate. The 41-kDa protein was always present in mitochondria which contained branched chain aminotransferase activity, skeletal muscle, kidney, stomach, and brain, but not in cytosolic fractions. In liver mitochondria, which have very low levels of branched chain aminotransferase activity, the 41-kDa protein was not present. However, two immunoreactive proteins of slightly higher molecular masses were identified. These proteins were located in hepatocytes. The 41-kDa protein was present in fetal liver mitochondria but not in liver mitochondria from 5-day neonates. Thus disappearance of the 41-kDa protein coincided with the developmental decline in liver branched chain aminotransferase activity. Two-dimensional immunoblots of isolated BCATm immunocomplexes showed that the liver immunoreactive proteins were clearly different from the heart and kidney proteins which exhibited identical immunoblots. Investigation of BCATm in subcellular fractions prepared from different skeletal muscle fiber types revealed that branched chain aminotransferase is exclusively a mitochondrial enzyme in skeletal muscles. Although total detergent-extractable branched chain aminotransferase activity was largely independent of fiber type, branched chain aminotransferase activity and BCATm protein concentration were highest in mitochondria prepared from white gastrocnemius followed by mixed skeletal muscles with lowest activity and protein concentration found in soleus mitochondria. These quantitative differences in mitochondrial branched chain aminotransferase activity and enzyme protein content suggest there may be differential expression of BCATm in different muscle fiber types.

Aging↗
PubMed1992

The pediatric patient with suspected adrenal neoplasm: which radiological test to use?

To establish which radiological test to use in a pediatric patient with suspected neoplasm, we retrospectively studied 19 children with proven adrenal neoplasm who had a combination of ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI). The results show that US should remain the initial imaging modality for evaluating abdominal masses in children but that MRI is more accurate than CT and US in detecting the organ of origin and the extent of an adrenal lesion and should, therefore, be the modality of choice for the definitive evaluation of adrenal neoplasm in children.

Adolescent↗