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Attitude of Health Personnel↗
Biomedical subjects
R J Morris
Publications and source records attributed to R J Morris.
The MODEL project: a scoring system to manage demand for cataract and joint replacement surgery.
Cataract surgery and joint replacement are highly cost-effective procedures; however, their availability is inequitable and doctors lack guidance on whom to refer and treat. We investigated the feasibility of using a scoring system to assess patients' suitability for operation. Wefound acceptable correlations between the scores ofgeneral practitioners and surgeons for both procedures. Scoring systems can be used in a consistent way bygeneralpractitioners and surgeons, and can make a contribution towards matching patients' needs with available treatment capacity.
Arthroplasty, Replacement↗
On the enzymatic activation of NADH.
Atomic (1 A) resolution x-ray structures of horse liver alcohol dehydrogenase in complex with NADH revealed the formation of an adduct in the active site between a metal-bound water and NADH. Furthermore, a pronounced distortion of the pyridine ring of NADH was observed. A series of quantum chemical calculations on the water-nicotinamide adduct showed that the puckering of the pyridine ring in the crystal structures can only be reproduced when the water is considered a hydroxide ion. These observations provide fundamental insight into the enzymatic activation of NADH for hydride transfer.
Alcohol Dehydrogenase↗
Both (+/-)syn- and (+/-)anti-7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxides initiate tumors in mouse skin that possess -CAA- to -CTA- mutations at Codon 61 of c-H-ras.
We have determined the tumor-initiating activity of (+/-)syn- and (+/-)anti-7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxide (syn- and anti-DMBADE), the two metabolically formed bay-region diol epoxides of DMBA, and we have also analyzed mutations in the H-ras gene from tumors induced by these compounds. Using a two-stage, initiation-promotion protocol for tumorigenesis in mouse skin, we have found that both syn- and anti-DMBADE are active tumor initiators, and that the occurrence of papillomas is carcinogen dose dependent. All of the papillomas induced by syn-DMBADE (a total of 40 mice), 96% of those induced by anti-DMBADE (a total of 25 mice), and 94% of those induced by DMBA (a total of 16 mice) possessed a -CAA- to -CTA- mutation at codon 61 of H-ras. No mutations in codons 12 or 13 were detected in any tumor. Topical application of syn- and anti-DMBADE produced stable adducts in mouse epidermal DNA, most of which comigrated with stable DNA adducts formed after topical application of DMBA. Further analysis of the data showed that levels of the major syn- and anti-DMBADE-deoxyadenosine adducts formed after topical application of DMBA are sufficient to account for the tumor-initiating activity of this carcinogen on mouse skin. Previously, we showed that both the syn- and anti-DMBADE bind to the adenine (A182) at codon 61 of H-ras. Collectively, these results indicate that the adenine adducts induced by both bay-region diol epoxides of DMBA lead to the mutation at codon 61 of H-ras and, consequently, initiate tumorigenesis in mouse skin.
9,10-Dimethyl-1,2-benzanthracene↗
Enrichment for murine keratinocyte stem cells based on cell surface phenotype.
The identification and physical isolation of epithelial stem cells is critical to our understanding of their growth regulation during homeostasis, wound healing, and carcinogenesis. These stem cells remain poorly characterized because of the absence of specific molecular markers that permit us to distinguish them from their progeny, the transit amplifying (TA) cells, which have a more restricted proliferative potential. Cell kinetic analyses have permitted the identification of murine keratinocyte stem cells (KSCs) as slowly cycling cells that retain [(3)H]thymidine ([(3)H]Tdr) label, termed label-retaining cells (LRCs), whereas TA cells are visualized as rapidly cycling cells after a single pulse of [(3)H]Tdr, termed pulse-labeled cells (PLCs). Here, we report on the successful separation of KSCs from TA cells through the combined use of in vivo cell kinetic analysis and fluorescence-activated cell sorting. Specifically, we demonstrate that murine dorsal keratinocytes characterized by their high levels of alpha(6) integrin and low to undetectable expression of the transferrin receptor (CD71) termed alpha(6)(bri)CD71(dim) cells, are enriched for epithelial stem cells because they represent a minor ( approximately 8%) and quiescent subpopulation of small blast-like cells, with a high nuclear:cytoplasmic ratio, containing approximately 70% of label-retaining cells, the latter being a well documented characteristic of stem cells. Conversely, TA cells could be enriched in a phenotypically distinct subpopulation termed alpha(6)(bri)CD71(bri), representing the majority ( approximately 60%) of basal keratinocytes that are actively cycling, and importantly contain approximately 70% of [(3)H]Tdr pulse-labeled cells. Importantly, immunostaining of dorsal skin revealed the presence of CD71(dim) cells in the hair follicle bulge region, a well documented location for KSCs.
Animals↗
Mice lacking the cell adhesion molecule Thy-1 fail to use socially transmitted cues to direct their choice of food.
BACKGROUND: Thy-1 is a major cell-surface glycoprotein of mature neurons and certain other cells, including those of the lymphoreticular system. Despite being the simplest member of the immunoglobulin superfamily, the biological role of Thy-1 has proved elusive. Analysis of Thy-1 null mice has shown the presence of excessive GABAergic inhibition of neurotransmission in the dentate gyrus of the hippocampal formation selectively, without any neurological or behavioural effects being apparent. RESULTS: We show here that Thy-1 null mice are unable to make the appropriate dietary choice in the test for social transmission of food preference, despite showing a normal level of social interaction with the demonstrator mouse, normal neophobia, and normal learning in a T-maze using scented food as cues. The mice also performed normally in tests of anxiety, locomotor activity, exploration of a novel environment, habituation to novelty and spatial learning. This phenotype is maintained on two different strain backgrounds, is rescued by transgenic expression of Thy-1 and by administration of the GABA(A) receptor antagonist pentylenetetrazole. CONCLUSIONS: The test for social transmission of food preference is based on the normal ability of mice in a colony to learn from each other which foods are safe to eat. The lack of this key survival behaviour in Thy-1 null mice could act as an evolutionary pressure point to conserve expression of Thy-1. Furthermore, the specific cognitive defect caused by inactivation of the Thy-1 gene suggests that it would be worthwhile to determine the role of Thy-1 in certain human familial forms of mental retardation that map to chromosome 11q22-23 in the region of the Thy-1 locus rather than the nearby ataxia telangiectasia locus.
Animal Communication↗
Evidence that the epidermal targets of carcinogen action are found in the interfollicular epidermis of infundibulum as well as in the hair follicles.
Actively cycling, transit-amplifying cells and quiescent cells including stem cells are found in the layer of the epidermis and hair follicles. To determine the origin of skin tumors, we completely removed the interfollicular epidermis of carcinogen-initiated mice by an abrasion technique known to leave the hair follicles undisturbed. The interfollicular epidermis of the abraded mice quickly regenerated from cells in the hair follicles, after which time tumor promotion was begun. Mice in which the interfollicular epidermis had been removed developed papillomas and carcinomas; however, the number of papillomas throughout 40 weeks was half that of the unabraded mice. Carcinoma responses were not significantly different in the abraded and unabraded groups. These results are consistent with the hypothesis that the targets of tumor initiation are stem cells found in the hair follicles and, to a lesser degree, in the interfollicular epidermis.
9,10-Dimethyl-1,2-benzanthracene↗
The likelihood of homoploid hybrid speciation.
New species may be formed through hybridization and without an increase in ploidy. The challenge is for hybrid derivatives to escape the homogenizing effects of gene flow from parental species. The mechanisms hypothesized to underlie this process were modelled using a computer simulation. The model is of recombinational speciation, in which chromosomal rearrangements between parental species result in poor fertility of F1 hybrids, but through recombination, novel homozygous types are formed that have restored fertility. In simulations, stable populations bearing the recombinant karyotypes originated frequently and were maintained when the fertility of F1 hybrids was high. However, this high rate of origination was offset by low genetic isolation, and lower F1 hybrid fertility increased the evolutionary independence of derived populations. In addition, simulations showed that ecological and spatial isolation were required to achieve substantial reproductive isolation of incipient species. In the model, the opportunity for ecological isolation arose as a result of adaptation to extreme habitats not occupied by parental species, and any form of spatial isolation (e.g. founder events) contributed to genetic isolation. Our results confirmed the importance of the combination of factors that had been emphasized in verbal models and illustrate the trade-off between the frequency at which hybrid species arise and the genetic integrity of incipient species.
Animals↗
An unusual scalp swelling.
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Acid Phosphatase↗
Determinants of within-subject variation of fasting serum leptin concentrations in healthy subjects.
The hormone leptin is considered to contribute to body weight regulation through modulation of feeding behavior and energy expenditure. The aim of the present study was 1) to assess the day-to-day within-subject variation (biovariability) of serum leptin concentrations in healthy subjects and 2) to investigate whether this variation is associated with food intake, exercise, anthropometric measurements or various metabolic covariates (insulin, C-peptide and glucagon, glucose, lactate, 3-hydroxybutyrate (3-OHB), triglycerides, non-esterified-fatty acids and glycerol). Serum leptin levels were taken daily on 12 consecutive days after an overnight fast in 12 healthy subjects with a mean (SD) age of 22.7 (1.5) yr. and a BMI of 22.8 (1.6) kg/m2. Food intake, exercise, anthropometric measurements and various metabolic covariates were also determined during this period. The overall mean of serum leptin concentration was 33.3 pmol/L with a within-subject SD range of 27-41 pmol/L and a between-subject SD range of 18-61 pmol/L. The within-subject variance of serum leptin as a proportion of total variance was 9.5%. Within-subject variation of serum leptin concentrations is small in relation to between-subject variation in healthy, normal weight subjects. This has implications for the power of interventional or prospective studies. In men, 6.7% of the variation in serum leptin concentration was associated with body weight measured on the same day (p= 0.037). In women, however, 66% of the variation was negatively associated with 3-OHB measured on both the same and the previous day (p=0.0003 and 0.002), and positively associated with triglyceride concentration measured on the previous day (p=0.0017) and insulin measured on the same day (p=0.0002). Within-subject associations in women could be due to phasic changes in unmeasured variables, possibly related to the menstrual cycle or might suggest that energy balance may exert a delayed influence on serum leptin levels, with plasma 3-OHB and triglycerides acting as markers for the state of the fat stores that regulate leptin secretion. The differences between the genders remain unexplained, however.
3-Hydroxybutyric Acid↗
Early detection of acute allograft rejection by linear and nonlinear analysis of heart rate variability.
OBJECTIVE: The first months after orthotopic heart transplantation are associated with the highest risk of acute allograft rejection. This study explores the utility and reliability of linear and novel nonlinear metrics of heart rate variability as predictors of graft rejection. The underlying hypothesis is that the transplanted heart, in response to inflammatory mediators, alters the dynamic properties of its rhythm-generating system. METHODS: In a cross-sectional study of 45 patients who had undergone heart transplantation, spanning a period of 4 months after the operation, heart rate variability was examined by time- and frequency-domain analysis. The nonlinear features of heart rate variability were studied by computing a pointwise correlation dimension of R-R interval time series. The results of heart rate variability analysis were compared with those of endomyocardial surveillance biopsy studies using the International Society for Heart and Lung Transplantation scoring system. RESULTS: Duration of heart transplantation itself exhibited a significant (P<.05) association with the onset of rejection. Specific predictors of acute rejection based on heart rate variability were identified, including shortening of the R-R interval (from 700 +/- 68 to 648 +/- 72 ms), an increase in the ratio of low-frequency (0.04-0.15 Hz) to high-frequency (0.15-0.40 Hz) spectral power (from 0.3 +/- 0.2 to 0.6 +/- 0.4), and a decrease in pointwise correlation dimension values (from 1.7 +/- 0.7 to 0.9 +/- 0.3 units). Multivariable logistic regression analysis (R (2) = 0.4) revealed that the only significant independent risk predictors were pointwise correlation dimension (odds ratio, 2.2 per 0.1 unit) and duration of heart transplantation (odds ratio, 1.7 per week). CONCLUSION: Nonlinear measures of heart rate variability provide noninvasive means for identifying patients undergoing cardiac transplantation with acute rejection, thereby enabling the assessment of the time-dependent adaptive response of the donor heart to its host.
Adult↗
Prophylactic mastectomy, oophorectomy, hysterectomy, and immediate transverse rectus abdominis muscle flap breast reconstruction in a BRCA-2-negative patient.
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BRCA2 Protein↗
Keratinocyte stem cells: targets for cutaneous carcinogens.
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Animals↗
Experimental observation of bonding electrons in proteins.
We demonstrate with two examples the success and potential of recent developments in x-ray protein crystallography at ultra high resolution. Our preliminary structural analyses using diffraction data collected for the two proteins crambin and savinase show meaningful deviations from the conventional independent spherical atom approximation. A noise-reduction averaging technique enables bonding details of electron distributions in proteins to be revealed experimentally for the first time. We move one step closer to imaging directly the fine details of the electronic structure on which the biological function of a protein is based.
Animals↗
Comparison of insulin sensitivity tests across a range of glucose tolerance from normal to diabetes.
AIMS/HYPOTHESIS: Adequate comparison of the relative performance of insulin sensitivity tests is not yet available. We compared the discrimination of four insulin sensitivity tests, commonly used in vivo, across a range of glucose tolerance. METHODS: Normal (n = 7), impaired glucose tolerant (n = 8) and Type II (non-insulin-dependent) diabetic subjects (n = 9) had in random order two tests from the following: frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT-MinMod); homeostasis model assessment (HOMA) and 2-h continuous infusion of glucose with model assessment (CIGMA) with immunoreactive or specific insulin; short insulin tolerance tests (ITT). The discriminatory power of tests was assessed by the ratio of the within-subject standard deviation to the underlying between-subject standard deviation (discriminant ratio - DR). The degree to which tests measured the same variable was assessed by comparing rank correlation with the maximum expected correlation given the imprecision of the tests. The unbiased lines of equivalence taking into account the precision of tests were constructed. RESULTS: Reciprocal fasting plasma insulin (FPI(-1)), HOMA %S and 2-h CIGMA %S, had similar DRs with ITT being less informative. The FSIVGTT-MinMod analysis was able to assess 13 out of 24 subjects and had a performance similar to ITT. Using specific rather than immunoreactive insulin for HOMA-CIGMA did not improve the DR. Reciprocal fasting plasma insulin FPI(-1), HOMA %S, 2-h CIGMA %S and S(I) FSIVGTT intercorrelated more than 90% of the expected rank correlation given the imprecision of the tests, but ITT gave only limited correlation. CONCLUSION/INTERPRETATION: The HOMA-CIGMA test with immunoreactive insulin provides similar information in distinguishing insulin sensitivity between subjects with normal glucose tolerance, those with impaired glucose tolerance and those with Type II diabetes as does FSIVGTT, whereas ITT is less informative.
Adult↗
Coronary artery disease in identical twins.
The incidence of coronary artery disease in identical twins is unknown. The knowledge of ischemic heart disease in this patient population is represented by case reports. There is considerable controversy regarding the environmental and genetic factors that play a role in the pathogenesis of this disorder. The natural history of coronary artery disease in an asymptomatic twin with a symptomatic counterpart is unclear. We present a case report and literature review of coronary artery disease in identical twins. On the basis of our patient and the information of other patients, asymptomatic twins of symptomatic counterparts require aggressive assessment and management for occult coronary artery disease.
Aged↗
Open heart surgery in patients with chronic lymphocytic leukemia.
BACKGROUND: Chronic leukemia is a disease characterized by the malignant proliferation of immunologically incompetent lymphocytes. The knowledge of open heart surgery in patients with this disorder is limited. METHODS: Twelve patients with chronic lymphocytic leukemia underwent open heart surgery (nine coronary artery bypass grafting (CABG), two aortic valve replacement (AVR), one CABG and AVR) from September 1991 to September 1996. There were nine males and three females with a mean age of 68 years (41-81 years). Staging was assigned according to the Rai Classification. There were seven Stage 0, two Stage I, zero Stage II, one Stage III and two Stage IV patients. Cardiopulmonary bypass (CPB) was performed using standard techniques of cannulation, moderate hypothermia and antegrade/retrograde cardioplegia. RESULTS: Hospital mortality occurred in two (17%) patients. Both patients died of sepsis. Hospital morbidity occurred in seven (58%) patients. The most common complications were infections. Five patients were found to have other malignancies (basal cell, laryngeal, prostate, bladder and breast cancers). Transfusion of blood products was required in eight (67%) patients. The average length of stay was 15 days (7-50 days). Follow-up was complete. Late mortality occurred in four patients at a mean of 7 months (1-18 months). All deaths were non-cardiac related (ruptured AAA, kidney failure, respiratory failure and sepsis). Six patients remain alive at a mean of 25 months (1-48 months). CONCLUSION: Hospital mortality and morbidity in patients with chronic lymphocytic leukemia undergoing open heart surgery are high. Infection is the leading cause of hospital death, as well as the most common complication. The majority of patients receive blood products during the course of their hospitalization. Late mortality is high and non-cardiac related. Based on these findings, a re-definition of the aims, goals and expectations of open heart surgery in patients with chronic leukemia is necessary. Suggestions in management are presented.
Aged↗
Highly persistent label-retaining cells in the hair follicles of mice and their fate following induction of anagen.
We have identified some unusually persistent label-retaining cells in the hair follicles of mice, and have investigated their role in hair growth. Three-dimensional reconstruction of dorsal underfur follicles from serial sections made 14 mo after complete labeling of epidermis and hair follicles in neonatal mice disclosed the presence of highly persistent label-retaining cells associated with the first-generation follicle involved in the production of the first wave of hairs, commonly called the bulge. The label-retaining cells were most often found on the ventral surface of the first-generation follicle, five cell positions from the base, near the attachment site of the arrector pilorum muscle. No label-retaining cells were found in the hair canal, sebaceous gland, or hair germ. These label-retaining cells remained in the follicle following induction of anagen by plucking of the hairs. Surprisingly, they were not part of the first wave of mitotic activity following plucking, but instead underwent mitosis beginning 42 h after plucking. Label-retaining cells or their labeled daughters were not found in the hair germs through 48 h following induction of anagen by plucking, but instead remained in their subsebaceous follicular location even upon completion of the hair growth cycle 21 d later. These label-retaining cells are, therefore, unlikely to contribute to the formation of a new anagen follicle.
Animals↗