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Biomedical subjects

K L Gould

Publications and source records attributed to K L Gould.

At least 19 recordsLinked to original sources
PubMed1998

Intensive lifestyle changes for reversal of coronary heart disease.

CONTEXT: The Lifestyle Heart Trial demonstrated that intensive lifestyle changes may lead to regression of coronary atherosclerosis after 1 year. OBJECTIVES: To determine the feasibility of patients to sustain intensive lifestyle changes for a total of 5 years and the effects of these lifestyle changes (without lipid-lowering drugs) on coronary heart disease. DESIGN: Randomized controlled trial conducted from 1986 to 1992 using a randomized invitational design. PATIENTS: Forty-eight patients with moderate to severe coronary heart disease were randomized to an intensive lifestyle change group or to a usual-care control group, and 35 completed the 5-year follow-up quantitative coronary arteriography. SETTING: Two tertiary care university medical centers. INTERVENTION: Intensive lifestyle changes (10% fat whole foods vegetarian diet, aerobic exercise, stress management training, smoking cessation, group psychosocial support) for 5 years. MAIN OUTCOME MEASURES: Adherence to intensive lifestyle changes, changes in coronary artery percent diameter stenosis, and cardiac events. RESULTS: Experimental group patients (20 [71%] of 28 patients completed 5-year follow-up) made and maintained comprehensive lifestyle changes for 5 years, whereas control group patients (15 [75%] of 20 patients completed 5-year follow-up) made more moderate changes. In the experimental group, the average percent diameter stenosis at baseline decreased 1.75 absolute percentage points after 1 year (a 4.5% relative improvement) and by 3.1 absolute percentage points after 5 years (a 7.9% relative improvement). In contrast, the average percent diameter stenosis in the control group increased by 2.3 percentage points after 1 year (a 5.4% relative worsening) and by 11.8 percentage points after 5 years (a 27.7% relative worsening) (P=.001 between groups. Twenty-five cardiac events occurred in 28 experimental group patients vs 45 events in 20 control group patients during the 5-year follow-up (risk ratio for any event for the control group, 2.47 [95% confidence interval, 1.48-4.20]). CONCLUSIONS: More regression of coronary atherosclerosis occurred after 5 years than after 1 year in the experimental group. In contrast, in the control group, coronary atherosclerosis continued to progress and more than twice as many cardiac events occurred.

Aged↗
PubMed1998

Role of polo kinase and Mid1p in determining the site of cell division in fission yeast.

The fission yeast Schizosaccharomyces pombe divides symmetrically using a medial F-actin- based contractile ring to produce equal-sized daughter cells. Mutants defective in two previously described genes, mid1 and pom1, frequently divide asymmetrically. Here we present the identification of three new temperature-sensitive mutants defective in localization of the division plane. All three mutants have mutations in the polo kinase gene, plo1, and show defects very similar to those of mid1 mutants in both the placement and organization of the medial ring. In both cases, ring formation is frequently initiated near the cell poles, indicating that Mid1p and Plo1p function in recruiting medial ring components to the cell center. It has been reported previously that during mitosis Mid1p becomes hyperphosphorylated and relocates from the nucleus to a medial ring. Here we show that Mid1p first forms a diffuse cortical band during spindle formation and then coalesces into a ring before anaphase. Plo1p is required for Mid1p to exit the nucleus and form a ring, and Pom1p is required for proper placement of the Mid1p ring. Upon overexpression of Plo1p, Mid1p exits the nucleus prematurely and displays a reduced mobility on gels similar to that of the hyperphosphorylated form observed previously in mitotic cells. Genetic and two-hybrid analyses suggest that Plo1p and Mid1p act in a common pathway distinct from that involving Pom1p. Plo1p localizes to the spindle pole bodies and spindles of mitotic cells and also to the medial ring at the time of its formation. Taken together, the data indicate that Plo1p plays a role in the positioning of division sites by regulating Mid1p. Given its previously known functions in mitosis and the timing of cytokinesis, Plo1p is thus implicated as a key molecule in the spatial and temporal coordination of cytokinesis with mitosis.

Actins↗
PubMed1998

Coronary arteriography and lipid lowering: limitations, new concepts, and new paradigms in cardiovascular medicine.

Coronary arteriography has played a central role in improving our understanding of the mechanisms of unstable coronary syndromes and the benefits of cholesterol lowering. However, coronary arteriography as currently used is outmoded and inadequate for new clinical algorithms based on vigorous lipid and other risk factor control as alternatives to invasive procedures for the primary treatment of coronary artery disease. What is needed is a way of viewing or analyzing noninvasive myocardial perfusion images and coronary arteriograms so as to identify and quantify the extent or severity of diffuse coronary atherosclerosis. Determining the relative contribution of diffuse and segmental narrowing by definitive myocardial perfusion imaging or coronary arteriography would provide the optimal basis for determining the need for revascularization procedures. In the absence of significant segmental stenoses, mild or diffuse disease identified by coronary arteriography would also provide a definitive diagnosis as the basis for lifelong cholesterol-lowering drugs and risk factor modification, even for patients with normal cholesterol levels. Thus, it is important to consider several new concepts for analyzing coronary arteriograms. More physiologically accurate invasive and noninvasive technology allows improved diagnosis and management of coronary atherosclerosis as new paradigms in cardiovascular medicine.

Anticholesteremic Agents↗
PubMed1998

New concepts and paradigms in cardiovascular medicine: the noninvasive management of coronary artery disease.

Coronary atherosclerosis is a diffuse heterogeneous process that occurs throughout the length of epicardial coronary arteries. Myocardial infarction and unstable coronary syndromes are caused most commonly by plaque rupture of lipid rich, less severe coronary artery stenoses. Vigorous cholesterol lowering by low fat food and lipid active drugs, control of hypertension, and smoking abstinence stabilize plaque and markedly reduce coronary events and angina pectoris with greater improvement in survival than reported for elective invasive revascularization procedures. The term "regression" or "reversal" of coronary artery disease (CAD) as used clinically incorporates the spectrum of beneficial changes in plaque composition and pathology, modest improvement in anatomic severity, endothelial healing, increased coronary flow and flow capacity, decreased symptoms, and improved survival. Standard coronary arteriography and standard noninvasive diagnostic tests (as commonly used) are inadequate for identifying or assessing severity of diffuse CAD. Newer technology or approaches using noninvasive positron emission tomography (PET), invasive intravascular ultrasound or pressure or flow velocity guide wires provide important new insights into the presence and severity of both segmental and diffuse CAD. Revascularization procedures may be beneficial in selected, restricted circumstances, primarily for 3-vessel disease and reduced left ventricular function and for "hibernating" or "stunned" myocardium. However, the benefits of revascularization procedures on survival in patients with good left ventricular function have not been convincingly documented, with substantive evidence that adverse outcomes outweigh the potential benefits. This collective new knowledge provides the basis for a shift in the management of CAD from an invasive, procedure-oriented viewpoint currently dominant in cardiology toward a noninvasive orientation that views the problem as a graded, continuous, heterogeneously diffuse disease process for which reversal treatment is optimal. Noninvasive management of CAD based on reversal treatment is a valid, safe, effective primary step, but it requires patient and physician knowledge. CAD should be treated immediately at the time of a firm diagnosis by simultaneous, vigorous risk factor management, low fat diet and a statin class drug. For control of high-density lipoprotein and triglycerides, other lipid active drugs should be added or substituted for statins if side effects prevent their use. Low fat food and weight control by appropriate caloric carbohydrate restriction are essential for reducing the highly atherogenic postprandial lipid surge that is not affected by statins. This vigorous reversal treatment, with aggressive anti-anginal and anti-platelet management as needed, should be used in every patient with diagnosed CAD before elective revascularization procedures are considered. In the author's experience, the majority of patients will pursue an effective reversal regimen when it is presented and managed appropriately with strong support by a knowledgeable participating physician providing sustained, intense guidance and pharmacologic control. For the minority of patients not responding to vigorous medical treatment or demonstrating progression, coronary arteriography and revascularization procedures are then appropriate.

Angioplasty, Balloon, Coronary↗
PubMed1998

A phosphorylation site mutant of Schizosaccharomyces pombe cdc2p fails to promote the metaphase to anaphase transition.

The protein kinase cdc2p is a key regulator of the G1-S and G2-M cell cycle transitions in the yeast Schizosaccharomyces pombe. Activation of cdc2p is regulated by its phosphorylation state and by interaction with other proteins. We have analyzed the consequences for cell cycle progression of altering the conserved threonine phosphorylation site, within the activation loop of cdc2p, to glutamic acid. This mutant, T167 E, promotes entry into mitosis, as judged by the accumulation of mitotic spindles and condensed chromosomes, despite the fact that it lacks demonstrable kinase activity both in vitro and in vivo. However, T167 E cannot promote the metaphase-anaphase transition. Since a component of the anaphase-promoting complex (APC) in S. pombe, cut9p, remains hypophosphorylated at the T167 E arrest point, the cell cycle block might be due to the inability of T167 E to activate the APC. T167 E is lethal when overexpressed, and overproduction also causes a mitotic arrest. Multicopy suppressors of the dominant negative phenotype were isolated, and identified as cdc13+ and suc1+. Overexpression of suc1+ suppresses the effects of T167 E overproduction by restoring sufficient amounts of suc1p to the cell to allow passage through mitosis.

Anaphase↗
PubMed1998

The cdr2(+) gene encodes a regulator of G2/M progression and cytokinesis in Schizosaccharomyces pombe.

Schizosaccharomyces pombe cells respond to nutrient deprivation by altering G2/M cell size control. The G2/M transition is controlled by activation of the cyclin-dependent kinase Cdc2p. Cdc2p activation is regulated both positively and negatively. cdr2(+) was identified in a screen for regulators of mitotic control during nutrient deprivation. We have cloned cdr2(+) and have found that it encodes a putative serine-threonine protein kinase that is related to Saccharomyces cerevisiae Gin4p and S. pombe Cdr1p/Nim1p. cdr2(+) is not essential for viability, but cells lacking cdr2(+) are elongated relative to wild-type cells, spending a longer period of time in G2. Because of this property, upon nitrogen deprivation cdr2(+) mutants do not arrest in G1, but rather undergo another round of S phase and arrest in G2 from which they are able to enter a state of quiescence. Genetic evidence suggests that cdr2(+) acts as a mitotic inducer, functioning through wee1(+), and is also important for the completion of cytokinesis at 36 degrees C. Defects in cytokinesis are also generated by the overproduction of Cdr2p, but these defects are independent of wee1(+), suggesting that cdr2(+) encodes a second activity involved in cytokinesis.

ATP-Binding Cassette Transporters↗
PubMed1998

Fission yeast cdc24(+) encodes a novel replication factor required for chromosome integrity.

A mutation within the Schizosaccharomyces pombe cdc24(+) gene was identified previously in a screen for cell division cycle mutants and the cdc24(+) gene was determined to be essential for S phase in this yeast. We have isolated the cdc24(+) gene by complementation of a new temperature-sensitive allele of the gene, cdc24-G1. The DNA sequence predicts the presence of an open reading frame punctuated by six introns which encodes a pioneer protein of 58 kD. A cdc24 null mutant was generated by homologous recombination. Haploid cells lacking cdc24(+) are inviable, indicating that cdc24(+) is an essential gene. The transcript of cdc24(+) is present at constant levels throughout the cell cycle. Cells lacking cdc24(+) function show a checkpoint-dependent arrest with a 2N DNA content, indicating a block late in S phase. Arrest is accompanied by a rapid loss of viability and chromosome breakage. An S. pombe homolog of the replicative DNA helicase DNA2 of S. cerevisiae suppresses cdc24. These results suggest that Cdc24p plays a role in the progression of normal DNA replication and is required to maintain genomic integrity.

Alleles↗
PubMed1998

Isolation and characterization of new fission yeast cytokinesis mutants.

Schizosaccharomyces pombe is an excellent organism in which to study cytokinesis as it divides by medial fission using an F-actin contractile ring. To enhance our understanding of the cell division process, a large genetic screen was carried out in which 17 genetic loci essential for cytokinesis were identified, 5 of which are novel. Mutants identifying three genes, rng3(+), rng4(+), and rng5(+), were defective in organizing an actin contractile ring. Four mutants defective in septum deposition, septum initiation defective (sid)1, sid2, sid3, and sid4, were also identified and characterized. Genetic analyses revealed that the sid mutants display strong negative interactions with the previously described septation mutants cdc7-24, cdc11-123, and cdc14-118. The rng5(+), sid2(+), and sid3(+) genes were cloned and shown to encode Myo2p (a myosin heavy chain), a protein kinase related to budding yeast Dbf2p, and Spg1p, a GTP binding protein that is a member of the ras superfamily of GTPases, respectively. The ability of Spg1p to promote septum formation from any point in the cell cycle depends on the activity of Sid4p. In addition, we have characterized a phenotype that has not been described previously in cytokinesis mutants, namely the failure to reorganize actin patches to the medial region of the cell in preparation for septum formation.

Actins↗
PubMed1998

Myb-related Schizosaccharomyces pombe cdc5p is structurally and functionally conserved in eukaryotes.

Schizosaccharomyces pombe cdc5p is a Myb-related protein that is essential for G2/M progression. To explore the structural and functional conservation of Cdc5 throughout evolution, we isolated Cdc5-related genes and cDNAs from Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and Homo sapiens. Supporting the notion that these Cdc5 gene family members are functionally homologous to S. pombe cdc5(+), human and fly Cdc5 cDNAs are capable of complementing the temperature-sensitive lethality of the S. pombe cdc5-120 mutant. Furthermore, S. cerevisiae CEF1 (S. cerevisiae homolog of cdc5(+)), like S. pombe cdc5(+), is essential during G2/M. The location of the cdc5-120 mutation, as well as mutational analyses of Cef1p, indicate that the Myb repeats of cdc5p and Cef1p are important for their function in vivo. However, we found that unlike in c-Myb, single residue substitutions of glycines for hydrophobic residues within the Myb repeats of Cef1p, which are essential for maintaining structure of the Myb domain, did not impair Cef1p function in vivo. Rather, multiple W-to-G substitutions were required to inactivate Cef1p, and many of the substitution mutants were found to confer temperature sensitivity. Although it is possible that Cef1p acts as a transcriptional activator, we have demonstrated that Cef1p is not involved in transcriptional activation of a class of G2/M-regulated genes typified by SWI5. Collectively, these results suggest that Cdc5 family members participate in a novel pathway to regulate G2/M progression.

Amino Acid Sequence↗
PubMed1998

Improvement of reversible ischemia in severe post-transplantation coronary artery disease.

Coronary artery disease is a major cause of morbidity and mortality in patients who have undergone heart transplantation. Patients are often asymptomatic during the onset of the disease, and managing the disease is difficult. This report describes the case of a patient with post-transplantation coronary artery disease who, despite the severe, progressive appearance of the disease on angiographic examination, showed evidence of autorevascularization and collateralization.

Cardiac Catheterization↗
PubMed1997

Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]).

Despite the potential for reduced morbidity and mortality, aggressive intervention against mild to moderate hypercholesterolemia in patients with coronary heart disease (CHD) remains controversial and infrequently practiced. Eligible patients in the 2.5-year Lipoprotein and Coronary Atherosclerosis Study were men and women aged 35 to 75 years with angiographic CHD and mean low-density lipoprotein (LDL) cholesterol of 115 to 190 mg/dl despite diet. Patients (n = 429; 19% women) were randomized to fluvastatin 20 mg twice daily or placebo. One fourth of patients were also assigned open-label adjunctive cholestyramine up to 12 g/day because prerandomization LDL cholesterol remained > or = 160 mg/dl. The primary end point, assessed by quantitative coronary angiography, was within-patient per-lesion change in minimum lumen diameter (MLD) of qualifying lesions. Across 2.5 years, mean LDL cholesterol was reduced by 23.9% in all fluvastatin patients (+/- cholestyramine) (146 to 111 mg/dl) and by 22.5% in the fluvastatin only subgroup (137 to 106 mg/dl). Primary end point analysis (340 patients) showed significantly less lesion progression in all fluvastatin versus all placebo patients, deltaMLD -0.028 versus -0.100 mm (p <0.01), and for fluvastatin alone versus placebo alone, deltaMLD -0.024 versus -0.094 mm (p <0.02). A consistent angiographic benefit with treatment was seen whether baseline LDL cholesterol was above or below 160 or 130 mg/dl. Beneficial trends with treatment were also consistently seen in clinical event rates but were not statistically significant. Thus, lipid lowering by fluvastatin in patients with mildly to moderately elevated LDL cholesterol significantly slowed CHD progression.

Adult↗
PubMed1997

Fission yeast dim1(+) encodes a functionally conserved polypeptide essential for mitosis.

In a screen for second site mutations capable of reducing the restrictive temperature of the fission yeast mutant cdc2-D217N, we have isolated a novel temperature-sensitive mutant, dim1-35. When shifted to restrictive temperature, dim1-35 mutant cells arrest before entry into mitosis or proceed through mitosis in the absence of nuclear division, demonstrating an uncoupling of proper DNA segregation from other cell cycle events. Deletion of dim1 from the Schizosaccharomyces pombe genome produces a lethal G2 arrest phenotype. Lethality is rescued by overexpression of the mouse dim1 homolog, mdim1. Likewise, deletion of the Saccharomyces cerevisiae dim1 homolog, CDH1, is lethal. Both mdim1 and dim1(+) are capable of rescuing lethality in the cdh1::HIS3 mutant. Although dim1-35 displays no striking genetic interactions with various other G2/M or mitotic mutants, dim1-35 cells incubated at restrictive temperature arrest with low histone H1 kinase activity. Morevoer, dim1-35 displays sensitivity to the microtubule destabilizing drug, thiabendazole (TBZ). We conclude that Dim1p plays a fundamental, evolutionarily conserved role as a protein essential for entry into mitosis as well as for chromosome segregation during mitosis. Based on TBZ sensitivity and failed chromosome segregation in dim1-35, we further speculate that Dim1p may play a role in mitotic spindle formation and/or function.

Amino Acid Sequence↗
PubMed1997

A wat1 mutant of fission yeast is defective in cell morphology.

The organization of the actin cytoskeleton plays an integral role in cell morphogenesis of all eukaryotes. We have isolated a temperature-sensitive mutant in Schizosaccharomyces pombe, wat1-1, in which acting patches are delocalized, resulting in an elliptically shaped cell phenotype. Molecular cloning and DNA sequencing of wat1+ showed that the gene encodes a 314 residue protein containing WD-40 repeats. Cells lacking wat1+ are slow growing but viable at 25 degrees C and temperature-sensitive for growth above 33 degrees C. At restrictive temperature, wat1-d strains are phenotypically indistinguishable from wat1-1. When combined with a deletion for the wat1+ gene, cdc mutants failed to elongate at restrictive temperature and exhibited alterations in actin patch localization. This analysis suggests that wat1+ is required directly or indirectly for polarized cell growth in S. pombe. Wat1p and a functional, epitope-tagged, version of Wat1p can be overproduced without inducing alterations in cell morphology.

Actins↗
PubMed1997

Effects of duration of epilepsy on the uncoupling of metabolism and blood flow in complex partial seizures.

We derived interhemispheric asymmetry indices (AIs) in interictal glucose uptake and blood flow in the temporal lobes of patients with intractable complex partial seizures from 18F and 15O positron emission tomograms. All patients subsequently underwent either left (n = 16) and right (n = 18) temporal lobectomy. We determined the effects on AIs of clinical seizure variables, including duration of seizure disorder, age at seizure onset, frequency of complex partial seizures, history of secondary generalization, history of febrile seizures, and magnetic resonance imaging evidence for mesial temporal sclerosis. Duration of seizure disorder produced the only significant effects. Degree of interhemispheric asymmetry in both glucose uptake and blood flow increased with duration of seizure disorder. However, the rate of increase in asymmetry was significantly greater for glucose uptake than for blood flow. These results indicate that uncoupling of metabolism and blood flow is a progressive process that results from the differential response of glucose metabolism and blood flow to chronic seizure activity. The results also suggest that duration of seizure disorder may be an important variable to consider in the interpretation of PET studies for evaluation of seizure surgery candidates.

Adult↗