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Biomedical subjects

R L Bennett

Publications and source records attributed to R L Bennett.

At least 19 recordsLinked to original sources

Does individual programme size affect screening performance? Results from the United Kingdom NHS breast screening programme.

OBJECTIVE: The size (number of women screened) of the 95 individual NHS breast screening programmes (NHSBSPs) varies by a factor of 10. This study investigates the impact of size on the performance of individual programmes. METHOD: Data were collated from the 95 United Kingdom screening programmes on the standard statistical returns for the past 5 years (1 April 1995-31 March 2000). Additional information was obtained from questionnaires. The number of women screened between 1 April 1999 and 31 March 2000 determined the size of a programme. The bottom 25% were defined as small, the middle 50% as medium, and the top 25% as large. On average large programmes screened about four times as many women as small programmes and medium programmes about twice as many. Performance was evaluated using cancer detection rates, referral rates for assessment, and positive predictive value (PPV) of assessment using PPV referral diagrams. RESULTS: The performance of smaller programmes was shown to be marginally poorer than medium and large sized programmes in that they detected fewer cancers and had a lower PPV. The smallest 25% of programmes had an invasive cancer detection rate 13% less than the medium and large programmes. However, if these programmes had an equivalent detection rate to the medium/large programmes the national detection rate would only increase by about 2%. This is because the 75% of programmes described as medium and large screen about 90% of all women. It is therefore important to place the clinical importance of these findings in context when considering any envisaged possible solutions. CONCLUSIONS: Although the performance of smaller programmes was shown to be poorer than that of the larger programmes, it is not clear from this study exactly why this is so. A likely contributory factor based on experience of evaluating the NHSBSP is that performance problems in larger programmes have been easier to detect by quality assurance staff. The size of the small programmes and the few screen detected cancers (and inherent statistical instability in detection rates) mean that problems are difficult to identify. As a consequence small programmes which are genuinely performing marginally below specific standards are likely to receive less attention than larger programmes, and even under close scrutiny the causes are less likely to be found.

Breast Neoplasms↗

A RecA homologue in Ustilago maydis that is distinct and evolutionarily distant from Rad51 actively promotes DNA pairing reactions in the absence of auxiliary factors.

Two RecA homologues have been identified to date in Ustilago maydis. One is orthologous to Rad51 while the other, Rec2, is structurally quite divergent and evolutionarily distant. DNA repair and recombination proficiency in U. maydis requires both Rec2 and Rad51. Here we have examined biochemical activities of Rec2 protein purified after overexpression of the cloned gene. Rec2 requires DNA as a cofactor to hydrolyze ATP and depends on ATP to promote homologous pairing and DNA strand exchange. ATPgammaS was found to substitute for ATP in all pairing reactions examined. With superhelical DNA and a homologous single-stranded oligonucleotide as substrates, Rec2 actively promoted formation and dissociation of D-loops. When an RNA oligonucleotide was substituted it was found that R-loops could also be formed and utilized as primer/template for limited DNA synthesis. In DNA strand exchange reactions using oligonucleotides, we found that Rec2 exhibited a pairing bias that is opposite that of RecA. Single-stranded oligonucleotides were activated for DNA strand exchange when attached as tails protruding from a duplex sequence due to enhanced binding of Rec2. The results indicate that Rec2 is competent, and in certain ways even better than Rad51, in the ability to provide the fundamental DNA pairing activity necessary for recombinational repair. We propose that the emerging paradigm for homologous recombination featuring Rad51 as the essential catalytic component for strand exchange may not be universal in eukaryotes.

Adenosine Triphosphatases↗

Distinct roles of the homeotic genes Ubx and abd-A in beetle embryonic abdominal appendage development.

Insects are easily distinguishable by the absence of legs on the adult abdomen. Studies performed on the Dipteran, Drosophila melanogaster, indicate that this is because of the repressive effects of the homeotic genes Ultrabithorax (Ubx) and abdominal-A (abd-A) on the limb promoting gene Distal-less (Dll) during embryonic development. However, in many species appendage-like structures are present on abdominal segments in embryonic and juvenile stages. Here, by using classical genetics and double-stranded RNA-mediated gene silencing in the red flour beetle, Tribolium castaneum, a species that develops an appendage on the first abdominal segment, we investigate the roles of Ubx and Abd-A in abdominal limb development. We find that in Tribolium, Abd-A, but not Ubx, represses early expression of Dll in the embryonic abdomen. Ubx appears to modify the A1 appendage. This difference in the activities of Abd-A and Ubx is critical for proper development of this appendage. We suggest that an ancestral role of Abd-A in insect abdominal appendage development was in the repression of Dll initiation and that of Ubx was in modulation of abdominal appendage morphology.

Abdomen↗

Fibrinogen bellingham: a gamma-chain R275C substitution and a beta-promoter polymorphism in a thrombotic member of an asymptomatic family.

Congenital dysfibrinogenemia is a rare cause of unexplained thrombosis. However, most individuals with dysfibrinogenemia are asymptomatic, suggesting that co-morbid factors contribute to thrombo-embolic events. The potential roles of additional genetic or acquired prothrombotic risk factors are poorly understood because detailed family studies are lacking. Herein, we describe a family whose propositus was a young Caucasian man with recurrent venous thrombo-emboli and dysfibrinogenemia due to heterozygosity for an Arg-->Cys substitution at residue 275 in the gamma-chain. The only additional thrombophilic abnormality found in the proband was heterozygosity for a G/A transition at position -455 in the fibrinogen beta-chain promoter; a genotype associated with high acute phase levels of fibrinogen. The proband's father, who died of a cerebral artery thrombosis, carried the gammaR275C substitution but not the beta-promoter -455 variant. Among 14 living relatives, eight were heterozygous for one or the other mutation and only one, a 21-year-old niece, was dually affected. None had suffered bleeding or thrombosis. In vitro studies of the proband's purified fibrinogen revealed markedly abnormal thrombin-catalyzed polymerization and delayed fibrin clot lysis by tPA-activated plasmin. We hypothesize that the gammaR275C substitution predisposes to thrombosis by generating clots that are relatively resistant to fibrinolysis. The clinical risk is low, however, in the absence of an additional thrombophilic mutation. The beta-promoter variant could, theoretically, contribute to this risk by augmenting expression of the dysfibrinogen under conditions of stress. Like the common hereditary thrombophilias, heterozygous familial dysfibrinogenemia induces thrombosis in the setting of multiple prothrombotic influences.

Adult↗

Pedigree parables.

Pedigrees are a foundation of genetic counseling and human genetic research. To protect patient/subject and family privacy and confidentiality it is not unusual to find published pedigrees that have been masked (i.e. a pedigree that has been changed in ways that are obvious to the reader such as diamonds to mask gender) or altered (i.e. changing pedigree information in ways that are not obvious to the reader such as changing gender and birth order or deleting unaffected siblings from the pedigree). Failure to report pedigree data (e.g. omitting ages, ethnicity, etc.) is another measure used to protect subject and family confidentiality. At what point do such practices hinder the recognition of genetic processes? Is there evidence that harm has occurred to subjects who have appeared in published pedigrees? How does the researcher or clinician determine which information is essential to record on the pedigree? The author uses a historical perspective and case examples to illustrate the issues of balancing protection of the genetic subject's privacy with the reporting of unaltered family data. The author presents several critical questions for peer reviewers and investigators to consider when a pedigree is included in a manuscript, or for researchers involved in family studies.

Eugenics↗

Additional kinematic variables to describe differences in the trot between clinically normal dogs and dogs with hip dysplasia.

OBJECTIVE: To describe the abnormal gait of dogs with hip dysplasia by use of kinematic gait analysis. ANIMALS: 19 large-breed dogs with moderate to severe clinical and radiographic evidence of hip dysplasia and 10 clinically normal dogs (controls). PROCEDURE: Kinematic and force plate data were collected, and degree of coxofemoral joint abduction-adduction, mediolateral foot movement, distance between hind feet, maximum hind foot elevation, mediolateral pelvic movement, and coxofemoral joint angular acceleration were calculated. Essential Fourier coefficients were determined and used to reconstruct mean angular acceleration curves. Fourier coefficients and foot and pelvic movement data were compared between groups. RESULTS: Dogs with hip dysplasia had a greater degree of coxofemoral joint adduction and range of abduction-adduction and greater lateral pelvic movement, compared with controls. Foot movement variables did not differ significantly between groups. Coxofemoral joint angular acceleration was greater in the middle to end of the stance phase, whereas deceleration was greater in the late stance to early swing phase and middle to end of the swing phase in dogs with hip dysplasia, compared with controls. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in degree of coxofemoral joint abduction-adduction, amount of mediolateral pelvic movement, and coxofemoral joint angular acceleration between clinically normal dogs and dogs with hip dysplasia may indicate a compensation in gait of affected dogs as a result of discomfort or biomechanical effects attributable to hip dysplasia and degenerative joint disease. Information gained from kinematic and kinetic gait analyses may be useful in evaluating treatments for hip dysplasia in dogs.

Animals↗

Molecular and genetic analysis of the Tribolium Ultrabithorax ortholog, Ultrathorax.

Ultrabithorax (Ubx) is essential for the proper patterning of the posterior thorax and anterior abdomen in Drosophila. The Coleoptera and Diptera differ in the organization and structure of their thorax and anterior abdomen. Changes in the regulation of Ubx and/or its downstream target genes are predicted to underlie these altered morphologies. We exploited the feasibility of genetic analysis in the red flour beetle, Tribolium castaneum, to examine the role of its Ubx ortholog in development. We analyzed genomic and cDNA clones that predict a polypeptide with nearly 100% identity with the Drosophila Ubx gene in the homeodomain and flanking sequences. Southern blot analysis indicates that these clones represent DNA sequences within the Homeotic complex (HOM-C) of Tribolium. Phenotypic analysis of mutant variants of the Ultrathorax (Utx) gene, and its location within the beetle HOM-C, strongly supports Utx being the Tribolium ortholog of Ubx. The embryonic expression pattern of Ubx-homologous transcripts coincides with the phenotypes associated with Utx mutations, providing support that the Ubx-homologous cloned DNA represents the Utx locus. By mid-germband extension Utx transcripts are expressed in a pattern similar to Ubx in Drosophila. However, during early germband formation Utx transcripts differ in both spatial and temporal progression. Utx expression is initially detected in parasegments 4 and 5 (T1p-T3a) as they are established during early germband formation. This is the first report of the wild-type parasegmental expression of an insect Ubx ortholog extending through parasegment 4. The earlier and more anterior expression in the thorax may underlie the modification of the Coleopteran thorax.

Amino Acid Sequence↗

Racial variation in the use of laparoscopic cholecystectomy in the Department of Veterans Affairs medical system.

BACKGROUND: While studies have found racial differences in the rates of use of established invasive cardiac and cerebrovascular procedures, no study has evaluated racial variation in the rates of adoption of new surgical procedures. For patients undergoing laparoscopic cholecystectomy, the procedure represents a new and safe option that shortens the duration of postoperative hospitalization by almost one week. In this study, we evaluated whether, in the equal access Veterans Affairs (VA) medical system, the rate of adoption of this procedure and improvements in the duration of postoperative hospitalization differed between African-American and Caucasian patients. STUDY DESIGN: Data were obtained from two sources-administrative claims files and prospectively compiled dinical data from medical records and patient interviews. In both data sets, frequency of use, length of stay, and outcomes for African-American and Caucasian patients undergoing minimally invasive and open gallbladder surgery were analyzed for the first four years of use of the procedure in the VA system (1992 to 1995). RESULTS: Analyses based on claims files indicated that, after adjustment for potentially confounding variables, African-American patients who underwent cholecystectomy in VA medical centers were 25% less likely to undergo a minimally invasive cholecystectomy during the first 4 years of use of the new procedure (adjusted odds ratio, 0.74; 95% confidence interval, 0.66-0.83). Shortening of the average postoperative length of stay from 9 days or more in the prelaparoscopic era to less than 4.5 days for patients undergoing the laparoscopic procedure occurred in the first year for Caucasian patients, but did not occur until the fourth year for African-American patients (p<0.001). The overall difference in postoperative length of stay between African-American and Caucasian patients more than doubled from 1.7 days before introduction of laparoscopic cholecystectomy to 3.8 days in the fourth year. In comparison, analyses based on nurse-compiled clinical data indicated that, after adjustment for relevant clinical factors, racial variations in the rate of laparoscopic surgery were even larger (adjusted odds ratio for laparoscopic versus open cholecystectomy for African-American versus Caucasian veterans, 0.68; 95% confidence interval, 0.55-0.84). CONCLUSIONS: Compared to Caucasian patients, African-American patients who underwent cholecystectomy in VA medical centers had an approximately 25% to 32% lower likelihood of undergoing minimally invasive cholecystectomy procedures. The differences in rates of adoption of laparoscopic surgery did not appear to be from more comorbid illnesses among African-American patients. African-American and Caucasian veterans may differ in their preference for new surgical procedures like laparoscopic cholecystectomy. Conversely, VA physicians may have been less likely to recommend laparoscopic cholecystectomies to African-American patients.

Adult↗

Postpartum home visits: extending the continuum of care from hospital to home.

Crucial maternal, newborn, and family healthcare needs arise during the early postpartum period, providing the opportunity for home care nurses to extend the continuum of care from hospital to home. This study identifies common early postpartum problems discovered on home health visits and describes the related interventions of home health nurses. Correlational analysis revealed that young mothers, first-time mothers, breastfeeding mothers, and single mothers are priority candidates for follow-up home care.

Adolescent↗

The REC1 gene of Ustilago maydis, which encodes a 3'-->5' exonuclease, couples DNA repair and completion of DNA synthesis to a mitotic checkpoint.

Mutation in the REC1 gene of Ustilago maydis results in extreme sensitivity to killing by ultraviolet light. The lethality of the rec1-1 mutant was found to be partially suppressed if irradiated cells were held artificially in G2-phase by addition of a microtubule inhibitor. This mutant was also found to be sensitive to killing when DNA synthesis was inhibited by external means through addition of hydroxyurea or by genetic control in a temperature-sensitive mutant strain defective in DNA synthesis. Flow cytometric analysis of exponentially growing cultures indicated that wild-type cells accumulated in G2 after UV irradiation, while rec1-1 cells appeared to exit from G2 and accumulate in G1/S. Analysis of mRNA levels in synchronized cells indicated that the REC1 gene is periodically expressed with the cell cycle and reaches maximal levels at G1/S. The results are interpreted to mean that a G2-M checkpoint is disabled in the rec1-1 mutant. It is proposed that the REC1 gene product functions in a surveillance system operating during S-phase and G2 to find and repair stretches of DNA with compromised integrity and to communicate with the cell cycle apparatus.

Base Sequence↗

Aortic root complications in Marfan's syndrome: identification of a lower risk group.

OBJECTIVES: The purpose of this study was to examine clinical and echocardiographic predictors of outcome in a cohort of patients with Marfan's syndrome. BACKGROUND: Serial echocardiographic measurements of aortic root dimensions are an important clinical method for monitoring patients with Marfan's syndrome. However, there are few data on the prognostic importance of echocardiographic variables for risk stratification and timing of aortic root replacement. METHODS: In 89 consecutive patients with Marfan's syndrome (age range 1-54 years) clinical and serial echocardiographic data (n = 62) were evaluated as potential predictors of outcome (mean (range) follow up 4 (< 1-16) years). Aortic sinus diameter and an aortic ratio normalised for age and body surface area were examined using Kaplan-Meier life table and Cox regression analysis, with the end point defined as death or surgery for ascending aortic dissection and events defined as an end point or surgery for ascending aortic aneurysm. RESULTS: Overall actuarial survival at two and five years was 96% and 92% and event free survival was 85% and 76%, respectively. There were five deaths due to aortic dissection, four patients survived surgery for ascending dissection, and nine underwent root replacement with a composite graft for ascending aneurysm. Those with aortic events were older (35 (12) v 25 (13) years, P = 0.007) and had greater initial aortic root dimensions (47 (14) v 33 (8) mm, P < 0.0001) and ratios (1.6 (0.5) v 1.3 (0.2), P < 0.0001). In the 62 patients with serial echocardiographic follow up, the rate of aortic root dilatation was more rapid in those with events (15 (17) v 0 (3)%/year, P < 0.0001). Utilising a Cox proportional hazards model, the groups with an initial aortic ratio > or = 1.3 or an annual change in aortic ratio > or = 5% had a relative risk of an aortic complication of 2.7 and 4.1, respectively (95% confidence limits 1.5 to 4.8 and 1.8 to 9.3). Only one of 31 patients with an initial aortic ratio of < 1.3 and a rate of change of < 5% had an event (five year event free survival 97%). CONCLUSIONS: A low risk subgroup of patients with Marfan's syndrome can be identified as those with an aortic ratio < 1.3 and an annual change in aortic ratio of < 5%. These findings are helpful in optimising echocardiographic monitoring and risk stratification of patients with Marfan's syndrome.

Adolescent↗

Kinematic gait analysis in dogs with hip dysplasia.

OBJECTIVE: To define alterations of movement in dogs with hip dysplasia by use of noninvasive, 3-dimensional, computer-assisted kinematic gait analysis. DESIGN: Kinematic and force plate data were collected at the trot from clinically normal dogs and from dogs with hip dysplasia. ANIMALS: 12 large adult dogs of various breeds with clinical and radiographic evidence of hip dysplasia, and 12 clinically normal adult large dogs of various breeds with body weight similar to that of the dogs with hip dysplasia. PROCEDURE: Dynamic flexion and extension angles and angular velocities were calculated for the coxofemoral, femorotibial, and tarsal joints. Temporal and distance variables were also computed. Essential Fourier coefficients were determined and used to reconstruct mean dynamic flexion and extension curves for all joints, and to compare differences in movement between dogs with hip dysplasia and clinically normal dogs. RESULTS: Dogs with hip dysplasia had subtle characteristic changes in dynamic flexion and extension angles and angular velocities of each joint, verified by significant differences in essential Fourier coefficients between the 2 study groups. Stride length was increased and peak vertical force was decreased in dogs with hip dysplasia. Subject velocity, maximal foot velocity, stance duration, stride frequency, and impulse area did not differ between the 2 groups. CONCLUSIONS: Kinematic gait analysis indicated that hip dysplasia is associated with alterations in movement of the coxofemoral, femorotibial, and tarsal joints. Computer-assisted kinematic gait analysis provided a noninvasive, objective tool with which to evaluate these complex motion alterations. CLINICAL RELEVANCE: The information obtained may be useful in future evaluations of various modes of treatment for hip dysplasia.

Animals↗

Inconsistencies in pedigree symbols in human genetics publications: a need for standardization.

To determine consistency in usage of pedigree symbols by genetics professionals, we reviewed pedigrees printed in 10 human genetic and medical journals and 24 medical genetics textbooks. We found no consistent symbolization for common situations such as pregnancy, spontaneous abortion, death, or test results. Inconsistency in pedigree design can create difficulties in the interpretation of family studies and detract from the pedigree's basic strength of simple and accurate communication of medical information. We recommend the development of standard pedigree symbols, and their incorporation into genetic publications, professional genetics training programs, pedigree software programs, and genetic board examinations.

Genetics, Medical↗

The learning curve for AIDS-related Pneumocystis carinii pneumonia: experience from 3,981 cases in Veterans Affairs Hospitals 1987-1991.

Previous studies have found lower mortality rates for AIDS-related Pneumocystis carinii pneumonia (PCP) in hospitals with higher levels of experience with PCP. It is not known if patients are selectively referred to better hospitals or if there is a learning curve whereby outcomes improve as physicians gain experience in treating PCP. We assessed cases of PCP at 140 Veterans Administration (VA) Medical Centers in the United States. During 1987-1991, 3,981 patients were hospitalized with first-episode AIDS-related PCP. Mortality at 30 days after admission. For these 3,981 hospitalizations at the 140 study hospitals, the 30-day mortality was 19%. Logistic regression models indicate that older age, race, geographic area, earlier year of treatment, hospitalization in the previous 12 months, and lower levels of hospital experience with AIDS were significant predictors of mortality at 30 days after admission. Compared with hospitals that had treated three cases or fewer of first-episode PCP, the odds of mortality at 30 days at hospitals that treated > 50 cases of first-episode PCP were 0.73 (95% confidence interval 0.58-0.91), after controlling for differences in characteristics of the patients, year, and region. Mortality of patients with AIDS-related PCP decreases as VA hospitals gain experience. Longitudinal analyses over a 5-year period suggest that a learning curve best explains this finding.

AIDS-Related Opportunistic Infections↗

Why do DNA testing? Practical and ethical implications of new neurogenetic tests.

Direct DNA tests for mutations in neurogenetic disorders are establishing a new era in diagnostic neurology. These highly accurate and specific tests will greatly improve diagnosis and genetic counseling, lead to more accurate assessment of prognosis, and reduce the cost of diagnostic evaluations. However, the use and interpretation of the tests can be complicated, and there are numerous social, psychological, and ethical implications of the testing that need to be recognized and anticipated. To provide the best care for our patients, neurologists need to understand the benefits and risks of this testing and properly apply it in the context of each individual clinical situation.

Ethics↗