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Biomedical subjects

R L Bennett

Publications and source records attributed to R L Bennett.

At least 37 records · Page 2Linked to original sources
PubMed1996

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↗
PubMed1996

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↗
PubMed1996

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

Mutation avoidance and DNA repair proficiency in Ustilago maydis are differentially lost with progressive truncation of the REC1 gene product.

The REC1 gene of Ustilago maydis has an uninterrupted open reading frame, predicted from the genomic sequence to encode a protein of 522 amino acid residues. Nevertheless, an intron is present, and functional activity of the gene in mitotic cells requires an RNA processing event to remove the intron. This results in a change in reading frame and production of a protein of 463 amino acid residues. The 3'-->5' exonuclease activity of proteins derived from the REC1 genomic open reading frame, the intronless open reading frame, and several mutants was investigated. The mutants included a series of deletions constructed by removing restriction fragments at the 3' end of the cloned REC1 gene and a set of mutant alleles previously isolated in screens for radiation sensitivity. All of these proteins were overproduced in Escherichia coli as N-terminal polyhistidine-tagged fusions that were subsequently purified by immobilized metal affinity chromatography and assayed for 3'-->5' exonuclease activity. The results indicated that elimination of the C-terminal third of the protein did not result in a serious reduction in 3'-->5' exonuclease activity, but deletion into the midsection caused a severe loss of activity. The biological activity of the rec1-1 allele, which encodes a truncated polypeptide with full 3'-->5' exonuclease activity, and the rec1-5 allele, which encodes a more severely truncated polypeptide with no exonuclease activity, was investigated. The two mutants were equally sensitive to the lethal effect of UV light, but the spontaneous mutation rate was elevated 10-fold over the wild-type rate in the rec1-1 mutant and 100-fold in the rec1-5 mutant. The elevated spontaneous mutation rate correlated with the ablation of exonuclease activity, but the radiation sensitivity did not. These results indicate that the C-terminal portion of the Rec1 protein is not essential for exonuclease activity but is crucial in the role of REC1 in DNA damage repair.

Amino Acid Sequence↗
PubMed1995

Familial pancreatic adenocarcinoma: association with diabetes and early molecular diagnosis.

We report a large pedigree in which pancreatic cancer is inherited in an autosomal dominant fashion. Diabetes and exocrine insufficiency was observed in all family members who eventually developed pancreatic cancer. The presence of diabetes, often years before the diagnosis of cancer, allowed identification of those people who had inherited the predisposing allele and who were thus at high risk for the development of malignancy. This family shows that genetic factors can have a striking effect on the development of pancreatic malignancy and diabetes mellitus. Moreover, preclinical diagnosis of pancreatic cancer in family members provided a unique opportunity to study early molecular changes that accompany the development of human pancreatic cancer. Finally, the molecular approach applied here to the early diagnosis of pancreatic cancer may prove valuable in this family for identification of subjects at risk.

Adenocarcinoma↗
PubMed1995

Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors.

The construction of an accurate family pedigree is a fundamental component of a clinical genetic evaluation and of human genetic research. Previous surveys of genetic counselors and human genetic publications have demonstrated significant inconsistencies in the usage of common pedigree symbols representing situations such as pregnancy, termination of pregnancy, miscarriage, and adoption, as well as less common scenarios such as pregnancies conceived through assisted reproductive technologies. The Pedigree Standardization Task Force (PSTF) was organized through the Professional Issues Committee of the National Society of Genetic Counselors, to establish recommendations for universal standards in human pedigree nomenclature. Nomenclature was chosen based on current usage, consistency among symbols, computer compatibility, and the adaptability of symbols to reflect the rapid technical advances in human genetics. Preliminary recommendations were presented for review at three national meetings of human genetic professionals and sent to > 100 human genetic professionals for review. On the basis of this review process, the recommendations of the PSTF for standardized human pedigree nomenclature are presented here. By incorporating these recommendations into medical genetics professional training programs, board examinations, genetic publications, and pedigree software, the adoption of uniform pedigree nomenclature can begin. Usage of standardized pedigree nomenclature will reduce the chances for incorrect interpretation of patient and family medical and genetic information. It may also improve the quality of patient care provided by genetic professionals and facilitate communication between researchers involved with genetic family studies.

Genetic Counseling↗
PubMed1994

Insect gravitational biology: ground-based and shuttle flight experiments using the beetle Tribolium castaneum.

Many of the traditional experimental advantages of insects recommend their use in studies of gravitational and space biology. The fruit fly, Drosophila melanogaster, is an obvious choice for studies of the developmental significance of gravity vectors because of the unparalleled description of regulatory mechanisms controlling oogenesis and embryogenesis. However, we demonstrate that Drosophila could not survive the conditions mandated for particular flight opportunities on the Space Shuttle. With the exception of Drosophila, the red flour beetle, Tribolium castaneum, is the insect best characterized with respect to molecular embryology and most frequently utilized for past space flights. We show that Tribolium is dramatically more resistant to confinement in small sealed volumes. In preparation for flight experiments we characterize the course and timing of the onset of oogenesis in newly eclosed adult females. Finally, we present results from two shuttle flights which indicate that a number of aspects of the development and function of the female reproductive system are not demonstrably sensitive to microgravity. Available information supports the utility of this insect for future studies of gravitational biology.

Animals↗
PubMed1994

Heterogeneous AVPR2 gene mutations in congenital nephrogenic diabetes insipidus.

Mutations in the AVPR2 gene encoding the receptor for arginine vasopressin in the kidney (V2 ADHR) have been reported in patients with congenital nephrogenic diabetes insipidus, a predominantly X-linked disorder of water homeostasis. We have used restriction-enzyme analysis and direct DNA sequencing of genomic PCR product to evaluate the AVPR2 gene in 11 unrelated affected males. Each patient has a different DNA sequence variation, and only one matches a previously reported mutation. Cosegregation of the variations with nephrogenic diabetes insipidus was demonstrated for two families, and a de novo mutation was documented in two additional cases. Carrier detection was accomplished in one family. All the variations predict frameshifts, truncations, or nonconservative amino acid substitutions in evolutionarily conserved positions in the V2 ADHR and related receptors. Of interest, a 28-bp deletion is found in one patient, while another, unrelated patient has a tandem duplication of the same 28-bp segment, suggesting that both resulted from the same unusual unequal crossing-over mechanism facilitated by 9-mer direct sequence repeats. Since the V2 ADHR is a member of the seven-transmembrane-domain, G-protein-coupled receptor superfamily, the loss-of-function mutations from this study and others provide important clues to the structure-function relationship of this and related receptors.

Arginine Vasopressin↗
PubMed1993

A new anti-inflammatory leucine derivative, NPC-15669, inhibits growth of cultured human aortic smooth muscle cells.

We have observed that NPC-15669, a leucine derivative with anti-inflammatory activity, reduced the proliferation of human aortic smooth muscle cells (HASMCs) in culture. We used a colorimetric assay and tritiated thymidine to measure the cell density and proliferation of HASMC cultures treated with this agent. We also studied the effect of NPC-15669 on the proliferation and migration of human aortic endothelial cells (HAECs). Subconfluent HASMC cultures were growth arrested for 2 days. On the third day, growth was stimulated with either growth media (medium M199 containing 10% fetal bovine serum [FBS]), human platelet-derived growth factor (hPDGF), or fibroblast growth factor (FGF) in the absence or presence of NPC-15669 (0.1-50 microM). Regardless of the stimulating agent for HASMCs (FBS, hPDGF, or FGF), NPC-15669 at concentrations of 10-25 microM caused a significant reduction in thymidine incorporation (36.7% and 77.2% in 10 microM and 25 microM, respectively; p < 0.005) and cell density (25-87%, p < 0.001) compared with control. NPC-15669 did not, however, have an effect on the rate of proliferation or migration of HAECs, even at concentrations up to 50 microM. Two other anti-inflammatory agents, aspirin and dexamethasone, caused substantially and significantly less inhibition, even at high concentrations (50 and 25 microM, respectively). This study demonstrates that in vitro, NPC-15669 significantly inhibits HASMC proliferation but has no effect on proliferation or migration of HAECs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Improved outcomes in intensive care units for AIDS-related Pneumocystis carinii pneumonia: 1987-1991.

Respiratory failure due to Pneumocystis carinii pneumonia (PCP) is the most common complication requiring an intensive care unit (ICU) for persons with AIDS. In this study, we evaluated patterns of ICU use for ICU patients with first-episode PCP in 15 Veterans Administration Medical Centers from 1987 to 1991. Twelve percent of all patients with PCP received care in the ICU. The survival rates improved steadily during these years. Although there was little variation in the relative frequency of ICU use, the effectiveness of ICU use appeared to improve over time. In the more recent years, relatively more survivors and relatively fewer nonsurvivors received care in an ICU. Changes in medical practice such as adjunctive use of steroids for severe cases of PCP and more effective use of scarce resources may account for the improved survival rates for patients with PCP who are treated in an ICU.

AIDS-Related Opportunistic Infections↗
PubMed1992

Large de novo DNA deletion in a patient with sporadic neurofibromatosis 1, mental retardation, and dysmorphism.

A mildly dysmorphic, mentally retarded male with neurofibromatosis 1 (NF1) was found to have a de novo deletion of chromosome 17. The deletion occurred on the paternally derived chromosome 17 as shown by the absence of a D17S73 paternal allele. Densitometric analysis indicated that, in addition to the D17S73 locus, the patient has only one copy of four other adjacent loci. The deletion involved the loci D17S120, NF1, D17S57, D17S115, and D17S73 and was estimated to encompass more than 380 kb of DNA. The deletion of the entire paternal NF1 allele argues strongly that this disorder is not caused by the action of an abnormal NF1 protein. The extent of the deletion suggests that the mental retardation and dysmorphism of this patient may result from a deletion involving both the NF1 gene and contiguous genetic material.

Abnormalities, Multiple↗
PubMed1992

Increased levels of the Drosophila Abelson tyrosine kinase in nerves and muscles: subcellular localization and mutant phenotypes imply a role in cell-cell interactions.

Mutations in the Drosophila Abelson tyrosine kinase have pleiotropic effects late in development that lead to pupal lethality or adults with a reduced life span, reduced fecundity and rough eyes. We have examined the expression of the abl protein throughout embryonic and pupal development and analyzed mutant phenotypes in some of the tissues expressing abl. abl protein, present in all cells of the early embryo as the product of maternally contributed mRNA, transiently localizes to the region below the plasma membrane cleavage furrows as cellularization initiates. The function of this expression is not yet known. Zygotic expression of abl is first detected in the post-mitotic cells of the developing muscles and nervous system midway through embryogenesis. In later larval and pupal stages, abl protein levels are also highest in differentiating muscle and neural tissue including the photoreceptor cells of the eye. abl protein is localized subcellularly to the axons of the central nervous system, the embryonic somatic muscle attachment sites and the apical cell junctions of the imaginal disk epithelium. Evidence for abl function was obtained by analysis of mutant phenotypes in the embryonic somatic muscles and the eye imaginal disk. The expression patterns and mutant phenotypes indicate a role for abl in establishing and maintaining cell-cell interactions.

Animals↗
PubMed1991

Identification of the site of autophosphorylation of the bacterial protein kinase/phosphatase NRII.

Previous studies have established that the Escherichia coli protein kinase/phosphatase nitrogen regulator II (NRII also known as NtrB) becomes autophosphorylated on a histidine residue when incubated with ATP. We show that the major site at which NRII was autophosphorylated was contained within a peptide consisting of amino acid residues 136-142 of NRII, and thus probably corresponds to His-139. A minor site of phosphorylation, accounting for about 2% of the phosphate in NRII-P, was found in a peptide that corresponds to residues 158-169.

Amino Acid Sequence↗
PubMed1991

Recurrent rhabdomyolysis in association with cocaine use.

As the popularity of cocaine increases in our society, so does the frequency and variety of medical complications associated with its use. A growing number of cases have implicated cocaine use in the development of rhabdomyolysis and its complication, acute renal failure. We have reported the first case of recurrent rhabdomyolysis and acute renal failure directly associated with cocaine use. Although adulterants might cause muscle damage, we believe cocaine should be added to the list of drugs that are capable of producing rhabdomyolysis.

Acute Kidney Injury↗