Biomedical subjects
Publications and source records attributed to D Bennett.
25 older adults with vision loss participated in a communication screen which included hearing, speech-language, and a self-assessment of communication. 64% failed at least two of the three screenings, suggesting that routine screening might identify older adults with vision loss who need rehabilitation in communication as a complement to visual rehabilitation.
Explore the source record for details and available documents.
We developed a set of informant-based items describing performance of activities of daily living (ADL) by patients with Alzheimer's disease (AD) to identify which ADL are useful for assessment of patients in clinical trials. Evaluation of ADL is an important outcome measure in AD clinical trials. For clinical trial measurement, ADL should have broad applicability, good test-retest reliability, scaling to cover a range of performance, and sensitivity to detect change in disease progression. A total of 45 ADL items developed from literature review and clinical experience were administered to informants of 242 AD patients and 64 elderly controls as part of the multicenter Alzheimer's Disease Cooperative Study Instrument protocol. Half of the subjects were re-evaluated at 1 and 2 months and all at 6 and 12 months. Controls performed virtually all ADL items optimally at baseline and at 12 months. Among subjects with AD, 27 of the 45 ADL were widely applicable, i.e., performed at baseline or premorbidly by > 90% of subjects; showed good test-retest reliability between baseline and 1 and 2 months; correlated with MMSE scores of AD patients cross-sectionally; and showed a decline in performance from baseline to 12 months in at least 20% of AD patients. ADL could be identified that capture change in functional ability in patients across the entire range of the MMSE. The remaining 18 ADL included several that may be useful for trials that target specific populations, e.g., women with AD. Because change on specific items depends on baseline MMSE, ADL evaluation should include items relevant to the severity of dementia of patients enrolled in a clinical trial.
Reverse transcription-PCR (RT-PCR) techniques were used to identify the expression of ryanodine receptor (RyR) isoforms in gut epithelial cells. Restriction digest and sequence analysis of the PCR product showed the presence of RyR 2 and RyR 3. [3H]Ry binding studies on a microsome preparation, in a high-salt buffer, showed specific binding with an EC50 of 15 microM. In order to determine a potential functional role for these RyRs, we first characterized the response of the cells to acetylcholine. At all concentrations used acetylcholine induced sinusoidal cytosolic Ca2+ concentration ([Ca2+]i) oscillations. In response to 10(-4) M acetylcholine, levels of inositol 1,4,5-trisphosphate (InsP3) showed a peak of six times the basal level, at 30 s after stimulation. Application of caffeine alone failed to elicit a rise in cytosolic Ca2+. However, caffeine (5-50 mM) did rapidly and reversibly inhibit the acetylcholine-induced [Ca2+]i oscillations. The effects of Ry were more complex. Applied alone, Ry had no effect on the [Ca2+]i signal. When applied during agonist-evoked [Ca2+]i oscillations, Ry (10 microM) slowly blocked the response. In the continuous presence of Ry (10 microM) a short application of acetylcholine elicited a [Ca2+]i response that continued as oscillations even when the agonist was removed. The oscillations, in the presence of Ry (10 microM) but absence of agonist, were blocked either by removal of extracellular Ca2+ or by an application of a higher concentration of Ry (100 microM). These effects are consistent with the known use-dependence and dose-dependence for Ry action at the RyR. We conclude that the RyR 2 and RyR 3, identified by RT-PCR, play a central role in [Ca2+]i oscillations in gut epithelial cells.
Markers of joint disease are much sought after in human and veterinary rheumatology. This study investigated the relationship between markers of bone and cartilage turnover in sera and synovial fluids in naturally occurring canine joint diseases. Osteocalcin (OC) was measured by radioimmunoassay; enzyme-linked immunosorbent assays were used to measure keratan sulphate, chondroitin sulphate, hyaluronan and antibodies to collagen I and II. Dimethylmethylene blue binding assay was used for the estimation of sulphated glycosaminoglycans. Compared to normal dogs significantly higher serum OC was seen in dogs with osteoarthritis (P < 0.005), rheumatoid arthritis (RA) (P < 0.01) and rupture/stretching of cranial cruciate ligament (P < 0.02). Reduced OC was found in RA synovial fluids but this finding is probably of little value as there was too much overlap with normal joint data. Apart from a weak correlation between synovial fluid OC and keratan sulphate, there were generally no correlations between markers of bone and cartilage turnover probably reflecting the lack of any relationship between bone and cartilage metabolism in most canine arthropathies.
The integrity of joint function depends on both the extracellular matrix and the chondrocytes of articular cartilage. It has been suggested that there is a reciprocal relationship between these two components, which is altered in osteoarthritis. The immunohistochemical distribution of type VI collagen in normal and osteoarthritic canine cartilage was investigated by immunofluorescence and immunoelectron microscopy. Immunogold labelling showed that in normal cartilage type VI collagen was concentrated in the capsule adjacent to the chondrocyte complex. However, in osteoarthritic cartilage, type VI collagen was also observed throughout the cartilage matrix and was greatly increased in the territorial matrix and pericellular capsule surrounding the chondrocytes. Naturally occurring canine osteoarthritis provides a useful model for the study of the human disease, particularly the early stages. The changes in type VI collagen observed in osteoarthritis suggest an attempt at cartilage repair, resulting in the reorganization of the matrix.
Examined the adjustment of 6- to 18-year-old children and adolescents (n = 38) 2 to 5 years postdiagnosis of brain tumor with respect to standardized measures of anxiety and depression; self-perceptions; and adaptive living skills. Child, mother, and teacher report data were used. Maternal adjustment (anxiety and depression, parenting stress) was also assessed. Children and adolescents surviving brain tumors reported themselves to be generally within the normal range. However, maternal ratings of social problems were higher than normative scores and significantly lower than norms on social problems, scholastic competence, and communication skills. Teacher ratings on the Teacher Rating Form were all within normal limits. Maternal adjustment measures were within the normal range, although the Parent-Child Dysfunctional Interaction subscale of the Parenting Stress index was elevated. No differences in scores were found between children in regular and special education, or between children who had received radiation and those who did not. This sample of survivors of pediatric brain tumors and their mothers had relatively mild problems in adjustment, supporting a competency-based view of the adaptation of pediatric patients and their families.
AIM: To elucidate the diurnal variation in human corneal thickness over a 48 hour period. METHOD: Changes in central corneal thickness were monitored in eight healthy subjects (four male, four female) aged between 10 and 63 years using an ultrasonic pachymeter. Measurements were made over a 48 hour period-immediately before sleep, immediately upon waking and at 15, 30, 45 minutes, 1, 1.5, 2, 2.5, 3 hours, and at 2 hour intervals thereafter throughout the remainder of each day. RESULTS: The mean corneal thickness for the group (SD) was 546 (14) microns, with a mean overnight increase of 5.5% (2.9%) (range 1.9-12.6%) and a maximum diurnal increase of 7.2% (2.8%) (range 2.1-14.3%). Individual differences in the extent of diurnal and overnight variation occurred within the group. For three subjects, the first reading taken on waking was not the highest and corneal thickness continued to increase. CONCLUSION: These data confirm an increase of corneal thickness during sleep, but also reveal considerable variation during waking hours. Thus, the overnight changes in corneal thickness are not truly representative of diurnal variations in human corneal thickness and, in fact, much greater diurnal variation occurs than the 3.0-4.4% previously reported.
This investigation was undertaken to determine the magnitude of, and interrelations between, reservoirs of coagulase negative staphylococci on infants' skin at various sites (including sites used for insertion of intravascular catheters) and in faeces during the first six months of life. Sites with large numbers of coagulase negative staphylococci were identified by sampling 16 skin sites and stools from 20 preterm neonates at 8-30 days of life. A more detailed survey of numbers and types of coagulase negative staphylococci in stool and at six skin sites of 10 preterm infants was then performed over the first six months of life. Isolates of coagulase negative staphylococci were collected and characterised by speciation, antibiotic susceptibility profiling, and plasmid restriction fragment length polymorphism analysis. Large, relatively stable reservoirs were identified in the faeces, around the ear, and in the axilla and nares. Skin on the forearm and leg, sites at which peripheral catheters are frequently sited, carried small unstable numbers of coagulase negative staphylococci, which were usually indistinguishable from coagulase negative staphylococci isolated from other body sites on the same baby. Contamination of catheter insertion sites with coagulase negative staphylococci from reservoir sites on the same baby could explain these observations. These data suggest that interventions reducing cross-contamination between sites on the same baby might be as important in preventing coagulase negative staphylococcal bacteraemias as measures taken to prevent cross infection between babies. Procedures which are likely to result in heavy coagulase negative staphylococcal contamination of the hands of healthcare staff, such as changing soiled nappies, should receive particular attention.
Assays for tumor mutations need to be sufficiently sensitive that a mutation can be readily detected in a high background of wild-type sequence. We have evaluated competitive allele-specific oligonucleotide (cASO) hybridization, the amplification refractory mutation system (ARMS), and a combination of cASO with mutant-enriched polymerase chain reaction (ME-PCR) for their respective sensitivities in detecting the K-ras Val-12 mutation. cASO hybridization detected 1 mutant allele in 100 wild-type alleles and identified 6 of 74 (8%) colorectal tumors as having the Val-12 mutation. ARMS detected 1 mutant in 1000 and 12 of 74 (16%) tumor samples, and the ME-PCR with cASO hybridization detected 1 in 5000 and 20 of 74 (27%) tumor samples. The mutation was not detected in normal bowel mucosa from selected Val-12 tumor-positive patients. ME-PCR combined with cASO resulted in a threefold higher detection rate than has previously been reported and suggests that other studies may have underestimated the frequency of K-ras mutations.
OBJECTIVE: Recent reports suggest that appendectomy may protect against the development of ulcerative colitis. Depletion of mucosal helper T-cells is the suggested mechanism. Because mucosal T-cell activity has an even more critical role in the pathogenesis of celiac disease, our objective was to determine whether the development or mode of presentation of this disorder is influenced by appendectomy and/or tonsillectomy. METHODS: One hundred fifty consecutive adult celiac patients were compared with 138 consecutive patients examined at orthopedic clinics. One hundred twenty consecutive patients with ulcerative colitis from the same ethnogeographic population were included as positive disease control. RESULTS: Contrary to the previous findings in ulcerative colitis, which were again confirmed in this study, appendectomy and/or tonsillectomy did not influence the occurrence of celiac disease. In addition, presenting features, predefined in the study protocol, did not differ significantly in the appendectomy and nonappendectomy celiac patients. CONCLUSION: Resection of mucosa-associated lymphoid tissue (MALT) does not influence the occurrence or the mode of presentation of adult celiac disease. Therefore, in this classical example of a T-cell-mediated disorder, the hypothesis that surgical depletion of mucosal T-cells has a protective effect or influences the clinical manifestations cannot be supported.
The complex pathway seen in patients with the systemic inflammatory response syndrome (SIRS) does not readily respond to mediator blockade. All such trials conducted in SIRS patients have shown no benefit in reducing mortality. We have shown experimentally that in sepsis, the administration of beta 2-adrenoceptor agonists reduces hepatic cellular injury, whereas administration of an alpha 1-adrenoceptor agonist increases hepatic cellular injury. Inflammatory mediators can cause a dose-related reversible change in target endothelial cells (ECs). There is a substantial body of literature describing the anti-inflammatory effects of beta 2-adrenoceptor agonists. They reduce both the increased permeability and the production of inflammatory mediators from ECs. Cellular transduction processes are involved when adrenergic receptor agonists modify either the anti-inflammatory or proinflammatory response to sepsis in ECs. Inflammatory mediators and alpha 1-adrenoceptor agonists stimulate their trimeric G protein-linked receptors to produce diacylglycerol (DAG) and increase the intracellular concentration of calcium. DAG is involved in the production of both inflammatory proteins and lipids. In addition, mitogen-activated protein kinase (MAPK) is activated which is also involved in the production of inflammatory proteins and lipids. beta 2-adrenoceptor agonists activate their trimeric G protein-linked receptors to produce the stimulatory G protein (Gs). Gs stimulates adenyl cyclase to form cyclic adenosine monophosphate (cAMP) and activate protein kinase A (PKA). PKA is involved in activating gene transcription agents to produce anti-inflammatory proteins such as interleukin-10. PKA also inhibits phospholipase C and MAPK. Although promising, the use of beta-adrenoceptor agonists or agonists that increase cellular cAMP to activate the cells' endogenous anti-inflammatory pathway requires further study.
A comparison is made of the use of selective intra-arterial subtraction angiography and doppler sonography in the assessment of disease in 206 carotid arteries. Maximal stenoses in each of the internal, external and common carotid arteries were recorded and compared using both modalities. In 93% of cases, arteries reported as normal ultrasonically were also found to be normal on angiography. However, agreement between the modalities in the assessment of severe stenoses was rather less at 79%. Overall agreement between the two modalities was good using statistical analysis (weighted Kappa). It is our view that ultrasound is reliable in normal vessels, but where significant disease is present the rate of error between the two modalities is too high to warrant omission of angiography.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
This laboratory has established in previous studies that Pmel 17, a gene expressed specifically in melanocytes, maps near the silver coat color locus (si/si) on mouse chromosome 10. In the current study, we have focused on determining whether or not the si allele carries a mutation in Pmel 17. Pmel 17 cDNA clones, isolated from wild-type and si/si murine melanocyte cDNA libraries, were sequenced and compared. A single nucleotide (A) insertion was found in the putative cytoplasmic tail of the si/si Pmel 17 cDNA clone. This insertion is predicted to alter the last 24 amino acids at the C-terminus. Also predicted is the extension of the Pmel 17 protein by 12 residues because a new termination signal created downstream from the wild-type reading frame. The mutation was confirmed by the sequence of the PCR-amplified genomic region flanking and including the mutation site. The fact that si/si Pmel 17 was not recognized by antibodies directed toward the C-terminal 15 amino acids of wild-type Pmel 17, indicated a defect in this region. We conclude from these results that silver pmel 17 protein has a major defect at the carboxyl terminus. The chromosomal location and the identification of a potentially pathologic mutation in si-Pmel 17 support our conclusion that Pmel 17 is encoded at the silver locus.
An investigation was made into the possible contribution of autoimmune mechanisms to equine arthropathies. Serum and synovial fluid (SF) immune complexes and anti-collagen Type II antibodies were measured, by ELISA, in groups of horses with naturally occurring osteoarthritis (OA), osteochondritis dissecans (OCD), bone fracture, traumatised joints, synovitis, infected joints and non-diseased (control) joints. Significantly raised anti-collagen Type II antibodies were found in osteoarthritic (P < 0.02) and traumatised joint synovial fluids (P < 0.01) compared with the control, where ten of 38 (26%) OA and five of eight (63%) traumatised joint synovial fluid samples had raised anti-collagen Type II antibodies (above mean and 2 SD of control group; P < 0.05). Significantly raised levels of C1q-binding immune complexes were found in the synovial fluids of horses with OA (P < 0.001), OCD (P < 0.02), fractured articular bone (P < 0.001), infected (P < 0.01) and traumatised joints (P < 0.001) as compared with the control horses. Raised C1q-binding activity (above mean and 2 SD of control group; P < 0.05) was shown in synovial fluids in 18 of 38 (47%) OA, four of 16 (25%) OCD, four of nine (44%) fractured bone, one of eight (14%) synovitis, two of four (50%) infected joints and seven of eight (88%) traumatised joints. No raised anti-collagen Type II antibodies or C1q-binding activity were detected in sera from any clinical group. Correlations were found, in synovial fluids, between anti-collagen Type II antibodies and C1q-binding activity in OA (P < 0.02), synovitis (P < 0.01) and infected joint (P < 0.05) groups. Within individual horses, there were no correlations between the SF and sera measurements of either anti-collagen II or C1q-binding activity. The relationship between cause and effect of these immunological findings cannot be determined; as they are common to many types of equine joint disorder it is probable that they are not an initiating factor in pathology.