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Biomedical subjects

L J Scott

Publications and source records attributed to L J Scott.

At least 37 records · Page 2Linked to original sources
PubMed2000

Progression of microalbuminuria to proteinuria in type 1 diabetes: nonlinear relationship with hyperglycemia.

While small clinical trials have shown that improved glycemic control reduces the risk of progression of microalbuminuria to proteinuria, two recent clinical trials did not confirm this finding. We sought to reconcile the contradictory evidence by examining the dose-response relationship between hyperglycemia and progression of microalbuminuria to proteinuria in individuals with type 1 diabetes and microalbuminuria (n = 312) who were followed for 4 years with repeated assessments of urinary albumin excretion. Since 33 patients did not participate in follow-up (10.6%), data for 279 patients were analyzed. Urinary albumin excretion level worsened to proteinuria in 40 (4.1 per 100 person-years). To examine the dose-response relationship, baseline HbA1c was divided into four roughly equal groups using the cut points 8, 9, and 10%. The incidence rate varied significantly among the four groups (P = 0.008). Among those with HbA1c <8.0%, the incidence rate of progression was only 1.3 per 100 person-years, while it was 5.1, 4.2, and 6.7 per 100 person-years in the three other groups. We used generalized additive models to examine the dose-response curve using HbA1c as a continuous variable and found that the risk of progression rises steeply between an HbA1c of 7.5-8.5% and then remains approximately constant across higher levels. In conclusion, the results of this study suggest that, in patients with microalbuminuria, the risk of progression to overt proteinuria can be reduced by improved glycemic control only if the HbA1c is maintained below 8.5%. Moreover, below that value, the risk declines as the level of HbA1c decreases.

Adolescent↗
PubMed2000

APOE polymorphisms and the development of diabetic nephropathy in type 1 diabetes: results of case-control and family-based studies.

The goal of this study was to examine the association between known polymorphisms in the apolipoprotein E gene (APOE) and diabetic nephropathy (DN) in type 1 diabetes. We used both a case-control comparison and a family-based study design known as the transmission/disequilibrium test (TDT). For the case-control comparison, we collected DNA from 223 subjects with clinically diagnosed DN and 196 control subjects with normoalbuminuria and long-duration type 1 diabetes (> or = 15 years). For the family-based study, we obtained DNA from both parents of 154 DN subjects and 81 control subjects. The frequency of the epsilon2 allele of exon 4 of APOE was significantly higher in DN subjects than in control subjects. The risk of DN was 3.1 times higher (95% CI 1.6-5.9) in carriers of this allele than in noncarriers. In the family study, heterozygous parents for the E2 allele preferentially transmitted epsilon2 to DN offspring (64 vs. 36%, P < 0.03). Four additional polymorphisms (i.e., -491 A/T, -219 G/T, IE1 G/C, and APOCI insertion/deletion [I/D]) that flank the APOE locus were not associated with DN in either the case-control comparison or in the family-based study. In conclusion, the results of the case-control as well as the family-based study provide evidence that the epsilon2 allele of APOE increases the risk of DN in type 1 diabetes. The molecular mechanisms underlying this risk are unclear at present.

Adult↗
PubMed1999

Quantitative analysis of epidermal innervation in Fabry disease.

OBJECTIVE: To use skin biopsy specimens to quantitate the cutaneous innervation density of Fabry patients who had preserved renal function. BACKGROUND: The small fiber neuropathy of Fabry disease is difficult to detect and quantitate by conventional methods. Because this neuropathy is a common characteristic of Fabry disease, quantitating changes in this parameter would be helpful in demonstrating the effectiveness of enzyme or gene replacement therapy. METHODS: Patients underwent skin biopsy at the thigh and foot. Innervation density was determined by counting free nerve endings in the epidermis. These data were compared with nerve conduction studies, and in selected patients, fiber quantitation of sural nerve biopsy specimens. RESULTS: The Fabry patients had normal results of nerve conduction studies and large fiber quantitation by sural nerve biopsy. However, the involvement of small cutaneous fibers in these patients was easily demonstrable and quantifiable by skin biopsy. All patients showed severe loss of intraepidermal innervation at the ankle, but fiber loss at the distal thigh was proportionately less severe. CONCLUSIONS: The nerve damage in Fabry patients with preserved renal function involves exclusively small myelinated and unmyelinated fibers, and skin biopsy is a useful in detecting and quantitating such damage. Comparison of cutaneous innervation density with quantitation of sural nerve biopsy specimens demonstrated that skin biopsy specimens were as sensitive in detecting the presence of neuropathy as were the nerve specimens. It is speculated that analysis of cutaneous innervation may provide a useful marker of the nervous system's response to specific therapy for Fabry disease.

Adult↗
PubMed1999

Oxidation of alpha1-proteinase inhibitor by the myeloperoxidase-hydrogen peroxidase system promotes binding to immunoglobulin A.

We have demonstrated previously that patients with rheumatoid arthritis (RA) show an increase in serum and synovial fluid levels of complexes between alpha1-proteinase inhibitor (alpha1PI) and IgA. These are believed to form through disulfide binding between the Cys232 residue on alpha1PI and the penultimate cysteine residue (Cys471) of the IgA alpha chain. The mechanism for this has not been elucidated. We show here that alpha1PI oxidized by the myeloperoxidase-hydrogen peroxide (MPO-H2O2) system promotes the formation of IgA-alpha1PI complexes when incubated with IgA and that such complexes have no inhibitory activity against porcine pancreatic elastase (PPE). The activity of alpha1PI was considerably reduced also in IgA-alpha1PI complexes isolated from serum of an RA patient. We suggest that formation of IgA-alpha1PI complexes in inflammation may involve oxidation of alpha1PI, and as a consequence the alpha1PI in such complexes has reduced elastase inhibitory activity.

Animals↗
PubMed1999

Distinct structures and functions of related pre- and postsynaptic carbohydrates at the mammalian neuromuscular junction.

Carbohydrates that terminate in beta-linked N-acetylgalactosamine (betaGalNAc) residues are concentrated in the postsynaptic apparatus of the skeletal neuromuscular junction and have been implicated in the differentiation of the postsynaptic membrane. We now report that distinct synapse-specific betaGalNAc-containing carbohydrates are associated with motor nerve terminals. Two monoclonal antibodies that recognize distinct betaGalNAc-containing epitopes, CT1 and CT2, both stain synaptic sites on skeletal muscle fibers. However, CT1 selectively stains nerve terminal, whereas CT2 selectively stains the postsynaptic apparatus. Likewise, CT1 and CT2 selectively stain motoneuron-like and muscle cell lines, respectively. Using the cell lines, we identify distinct CT1- and CT2-reactive glycolipids and glycoproteins. Finally, we show that GalNAc modulates the adhesion of motoneuron-like cells to recombinant fragments of a synaptic cleft component, laminin beta2. Together, these results show that pre- as well as postsynaptic membranes bear and are affected by distinct but related synapse-specific carbohydrates.

Acetylgalactosamine↗
PubMed1999

Palivizumab.

The humanised monoclonal antibody palivizumab has been developed for prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in infants at high risk; RSV is the most common cause of lower respiratory tract infections in infants. Palivizumab specifically inhibits an epitope at the A antigenic site of the F protein of RSV subtypes A and B. RSV replication was inhibited in nasal and tracheal aspirates from infants receiving palivizumab 15 mg/kg. Mean 30-day trough serum concentrations of palivizumab were consistently about 70 mg/L in infants receiving repeated intramuscular or intravenous palivizumab 15 mg/kg. This is above the target serum concentration of 40 mg/L estimated to reduce pulmonary RSV replication by >99% in animal studies. In a large multicentre trial in 1502 infants at high risk of RSV infection, intramuscular palivizumab 15 mg/kg more than halved the incidence of RSV-attributable hospitalisation to 4.8% compared with 10.6% in placebo recipients. In the same group of high-risk infants, palivizumab significantly decreased total days in hospital attributable to RSV infection, days with increased supplemental oxygen requirement, days with moderate to severe lower respiratory tract infections and the incidence of admissions to intensive care. It had no effect on the incidence or total number of days of ventilation. Palivizumab was well tolerated during clinical trials in infants at risk of RSV infection. The incidence of adverse events was similar in placebo (10%) and palivizumab (11%) groups. Fever, irritability and injection site reaction were the most commonly reported adverse events.

Animals↗
PubMed1999

Tegaserod.

Tegaserod is a serotonin (5-hydroxytryptamine; 5-HT) receptor partial agonist which has been investigated for the treatment of irritable bowel syndrome (IBS). Specifically, it binds with high affinity to human 5-HT4 receptors, thereby stimulating the release of neurotransmitters and the peristaltic reflex in vitro. Small bowel transit (increased colonic filling over 6 hours) was accelerated in patients with constipation-predominant irritable bowel syndrome (IBS) receiving oral tegaserod 2mg twice daily for 1 week compared with those receiving placebo. In addition, there was a mean 20% increase of proximal colonic emptying in these patients. Oral tegaserod 2 (p < 0.05) or 6mg twice daily improved symptoms of abdominal discomfort, bloating and constipation (assessed using a Subjects' Global Assessment Scale) compared with placebo in patients with constipation-predominant IBS in a double-blind, dose-ranging study. The most frequent adverse events in patients with constipation-predominant IBS receiving oral tegaserod were transient diarrhoea and flatulence. No clinically relevant changes in blood pressure, pulse rate, QRS or QTc interval were reported with tegaserod doses of 25 to 100mg.

Clinical Trials as Topic↗
PubMed1999

Rofecoxib.

Rofecoxib selectively inhibits cyclo-oxygenase-2 in a dose-dependent manner in humans. No significant inhibition of cyclo-oxygenase-1 is observed with rofecoxib up to doses of 1000 mg. In 4 large double-blind randomised trials performed in patients with osteoarthritis, rofecoxib 12.5 and 25 mg/day significantly improved physical functioning, assessed using the Western Ontario and McMasters Universities Osteoarthritis Index and patient or investigator global assessment, compared with placebo. In addition, rofecoxib showed similar clinical efficacy to that observed with diclofenac 50 mg 3 times daily, ibuprofen 800 mg 3 times daily and nabumetone 1500 mg once daily. Rofecoxib is also an effective analgesic in patients with primary dysmenorrhoea or postoperative dental pain and demonstrates similar analgesic efficacy to that of naproxen sodium and ibuprofen. Rofecoxib is generally well tolerated. The most common adverse events associated with rofecoxib are diarrhoea, headache, nausea and upper respiratory tract infection. There was a significantly lower incidence of upper-gastrointestinal adverse events (perforations, ulcers and bleeds) in patients with osteoarthritis receiving rofecoxib 12.5, 25 or 50 mg/day than in those receiving ibuprofen, diclofenac or nabumetone.

Analgesics↗
PubMed1999

Exemestane.

Exemestane is a steroidal agent which causes inactivation of the aromatase enzyme by binding irreversibly to the substrate binding site. Oral exemestane 25 mg/day inactivates peripheral aromatase activity (approximately 98% inactivation) and reduces basal plasma estrone, estradiol and estrone sulphate levels by 85 to 95% in postmenopausal women with advanced breast cancer. Phase II trials indicate that oral exemestane 25 mg/day is an effective second- or third-line agent in the treatment of postmenopausal women with advanced breast cancer (achieving an objective response in up to 28 and 26% of patients, respectively). Results from a phase III trial indicate that exemestane achieves a similar objective response rate to megestrol as a second-line therapy; however, exemestane achieved a significantly longer duration of overall success, time to disease progression and survival time. Exemestane is at least as well tolerated as megestrol, but is associated with significantly fewer bodyweight changes, mainly bodyweight gain (> or = 10%). Other common adverse events are hot flushes, nausea and fatigue.

Androstadienes↗
PubMed1998

The C825T polymorphism in the human G-protein beta3 subunit gene is not associated with diabetic nephropathy in Type I diabetes mellitus.

In Type I (insulin-dependent) diabetes mellitus a genetic predisposition exists to nephropathy and is related to parental hypertension. Enhanced G-protein activation, a cellular phenotype observed in cultured cells from patients with essential hypertension, was recently documented in Type I diabetic subjects with nephropathy. This enhanced G-protein activation has been associated with a genetic variant in the G-protein beta3 subunit, GNB3. A C-->T polymorphism at position 825 in exon 10 is associated with G-protein activation, the T allele associated with enhanced activity. Furthermore the T allele was observed more frequently in a group with essential hypertension. In this report we have analysed the role of the C825T polymorphism in the predisposition to diabetic nephropathy in Type I diabetes. We have investigated the frequency of this polymorphism in a large case-control study and found no association of the T allele with diabetic nephropathy. Specifically carriage of the T allele as CT or TT was observed in 49% of 200 Type I diabetic control subjects with normoalbuminuria (diabetes duration 24 years) compared with 53% of 216 Type I diabetic subjects with nephropathy (overt proteinuria or end-stage renal failure). Within this group we have also examined the inheritance of C825T alleles in a family study and found no evidence for excess transmission of the T allele to Type I diabetic offspring with nephropathy (T allele transmitted to 51% of nephropathy offspring, C allele transmitted to 49% of nephropathy offspring, p = 0.79). In none of the Type I diabetic datasets examined was there any effect of genotype on variation in systolic or diastolic blood pressure. In conclusion we can find no evidence for the C825T polymorphism of the beta3 G-protein subunit as a major gene in the susceptibility to diabetic nephropathy in Type I diabetes.

Adolescent↗
PubMed1998

Comparison of IgA-alpha1-antitrypsin levels in rheumatoid arthritis and seronegative oligoarthritis: complex formation is not associated with inflammation per se.

Serum complexes between IgA and alpha1-antitrypsin (IgA alpha1AT) have been found at raised levels in early rheumatoid arthritis (RA), where they appear to be associated with more erosive disease. We have now measured the levels of these complexes in the sera and synovial fluid of patients with RA and seronegative oligoarthritis to determine whether there is a relationship between complex levels and joint inflammation, and if bacterial stimulation of the mucosa is associated with complex formation in seronegative oligoarthritis. IgA-alpha1AT complexes were measured in patients with RA (n = 75) and seronegative oligoarthritis, with or without definite reactive arthritis (n = 28), using a newly developed sandwich ELISA. The results were compared with serum levels from healthy volunteers (n = 30). IgA and alpha1AT were also measured using ELISA and radial immunodiffusion (RID) techniques, respectively. IgA-alpha1AT complex levels in the sera of RA patients [mean = 25.6 arbitrary units (au)] were significantly higher (P = 0.0034) than those in patients with seronegative oligoarthritis (mean = 12.36 au) and healthy controls (mean = 8.08 au). There was no evidence for the inflamed joint being the source of IgA-alpha1AT complexes since synovial fluid levels were lower than corresponding serum levels, although higher amounts were found in RA than seronegative oligoarthritis (12.84 au vs 4.11 au, P = 0.01). Serum levels of IgA and alpha1AT were similar in RA and seronegative oligoarthritis patients, and were higher than in normals. There was a significant correlation between complex and serum IgA levels in RA (r = 0.49, P < 0.001) and seronegative oligoarthritis (r = 0.53, P < 0.001) patients, although no relationship was found with alpha1AT levels. There was no correlation with other markers of the acute-phase response (C-reactive protein, erythrocyte sedimentation rate), nor with any clinical markers. In RA patients, serum complex levels were significantly higher in seropositive than seronegative patients (30.75 vs 16.48 au, P = 0.03), and we have demonstrated that a small amount of alpha1AT may be complexed with IgA rheumatoid factor. Our data suggest that the formation of IgA-alpha1AT complexes is not associated with inflammation per se, and does not appear to be related to bacterial stimulation of the mucosal immune system in patients with seronegative oligoarthritis.

Adult↗
PubMed1997

DNA profiling resolves the limited importance of flower colour in defining varieties of Lantana camara.

Randomly amplified polymorphic DNA (RAPD), successfully used to establish flower colour, is of limited importance in characterising weedy varieties of Lantana camara. Initially the internal transcribed spacer 1 (ITS1) region was sequenced for common pink and common pink-edged red varieties of L. camara from Australia and L. urticofolia from the neotropics. This proved unhelpful in differentiating varieties due to a lack of variation and the hybrid origin of L. camara, necessitating the utilisation of DNA profiling techniques. Unweighted pair group method arithmetic average (UPGMA) analysis of RAPD data demonstrated that geographical proximity contributes more significantly to genetic relatedness than flower colour. Analysis of molecular variance (AMOVA) likewise demonstrated that geography accounts for a relatively large variance component. These data indicate that the use of flower colour as a primary identification tool needs to be reevaluated. The use of RAPD may prove useful in characterising the weedy varieties of lantana present in Australia and the South Pacific. Since biological control efforts are being hindered by the inadequacy of current morphological taxonomy, it is expected that DNA profiling will underpin continuing studies on the management and control of L. camara.

Australia↗
PubMed1997

Biochemical and molecular identification of distinct forms of alkaline phosphodiesterase I expressed on the apical and basolateral plasma membrane surfaces of rat hepatocytes.

We have identified B10, a plasma membrane protein previously defined by a monoclonal antibody, as an alkaline phosphodiesterase I (APDE) expressed in the plasma membrane of rat hepatocytes and enterocytes, with a restricted apical distribution. B10 complementary DNA (cDNA) was cloned from a rat intestinal library screened with a polyclonal antibody directed to the hepatic protein. Two distinct B10 clones with an open reading frame of 2,625 bp were obtained that differed only by 12 bases in the coding region. One B10 clone had a single base difference with gp130RB13-6 cDNA, which was recently cloned in rat fetal brain. B10/gp130RB13-6 had 50% identity at the amino acid level with the plasma cell antigen PC-1, an APDE cloned in the mouse and in human. Anti-B10 antibodies immunoprecipitated 34% of the APDE activity in liver plasma membranes and over 95% of the APDE activity in intestinal cells. Most of the remaining activity in hepatocytes (44%) could be immunoprecipitated by antibodies directed to PC-1. APDE activity immunoprecipitated with anti-B10 antibodies was found in the apical rat liver plasma membrane fractions on a sucrose gradient whereas most of the remaining APDE activity was associated with the basolateral fractions, which contained PC-1. By immunofluorescence, B10 was localized to the apical surfaces of hepatocytes and enterocytes whereas PC-1 was present on the basolateral surfaces of hepatocytes. B10/gp130RB13-6 and rat PC-1 are a unique example of distinct molecules having similar enzymatic activity but different apical/basolateral location, and possibly different functions.

Amino Acid Sequence↗
PubMed1997

Sciatic nerve: paradoxic hypertrophy after amputation in young patients.

PURPOSE: To evaluate the appearance of the sciatic nerve after leg amputation. MATERIALS AND METHODS: Magnetic resonance (MR) images were obtained in seven patients (age at amputation, 11-19 years) who underwent above-knee amputation to treat osteogenic sarcoma. Images were evaluated for sciatic nerve enlargement. Findings were correlated with the time after amputation. RESULTS: All seven patients were found to have a markedly enlarged sciatic nerve in the stump of the amputated leg. The enlargement extended proximally from the point of nerve transection to a level posterior to the femoral neck (8-27 cm) depending on the length of the stump. No evidence of sciatic nerve enlargement was found in the opposite leg or on preoperative MR images that were available in three of the patients. Moreover, in one patient with a sarcoma who underwent a leg-sparing procedure, no sciatic nerve enlargement was seen postoperatively. The thickness of the distal sciatic nerve was related to the time after amputation. CONCLUSION: Hypertrophy of the sciatic nerve occurred after above-knee amputation in young patients. This finding differed from atrophy of the nerve that has been reported previously in older patients.

Adolescent↗
PubMed1995

Immunoadsorption of hepatic vesicles carrying newly synthesized dipeptidyl peptidase IV and polymeric IgA receptor.

Hepatocytes must transport newly synthesized apical membrane proteins from the basolateral to the apical plasma membrane. Our earlier morphological study showed that the apical proteins share a late (subapical) part of the transcytotic pathway with the well characterized polymeric immunoglobulin A receptor (Barr, V. A., and Hubbard, A. L. (1993) Gastroenterology 105, 554-571). Starting with crude microsomes from the livers of [35S]methionine-labeled rats, we sequentially immunoadsorbed first vesicles containing the endocytic asialoglycoprotein receptor and then (from the depleted supernatant) vesicles containing the polymeric IgA receptor. Biochemical characterization indicated that early basolateral and late endosomes were present in the first population but not in the second. Neither Golgi-, apical plasma membrane (PM)-, nor basolateral PM-derived vesicles were significant contaminants of either population. Both vesicle populations contained 35S-labeled receptor and 35S-labeled-dipeptidyl peptidase IV. Importantly, the elevated relative specific activity of the dipeptidyl peptidase (% of 35S-labeled/% immunoblotted) in the second population indicated that these vesicles must transport newly synthesized dipeptidyl peptidase IV. A distinct kind of vesicle was immunoadsorbed from a "carrier-vesicle fraction"; surprisingly, these vesicles contained little 35S-receptor and virtually no dipeptidyl peptidase IV. These results, together with previous kinetic data from in vivo experiments, are consistent with a computer-generated model predicting that newly synthesized dipeptidyl peptidase IV is delivered to basolateral endosomes, which also contain newly synthesized polymeric immunoglobulin A receptor. The two proteins are then transcytosed together to the subapical region.

Animals↗
PubMed1994

Failure in IgA secretion by surface IgA-positive B cells in common variable immunodeficiency (CVID).

CVID is an acquired disease with low serum immunoglobulins. Patients are classified into three groups on the ability of their B cells to secrete IgM and IgG in vitro in response to IL-2. We have now extended this patient classification to include IgA secretion and to assess whether the patients have IgA+ B cells in the circulation. B cells from almost all of the CVID patients studied were unable to secrete any IgA in vitro, with or without IL-2, although all B cells tested from normal donors showed some spontaneous IgA secretion. Thus, the defect with IgA secretion is more profound than with the secretion of IgM or IgG. Despite this failure to secrete IgA, using flow cytometry techniques all CVID patients tested were found to have IgA+ cells (expressed as a percentage of B cells) within the normal range. This suggests that CVID may involve a defect in the secretion of immunoglobulin isotypes rather than a defect in isotype switching.

B-Lymphocytes↗