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Staging profile of hypofertile male subjects.

Thirty-four hypofertile male subjects with either oligospermia or azoospermia underwent infertility evaluation with assay of serum follicle-stimulating hormone, luteinizing hormone, testosterone and testicular biopsy. Cytogenetic analysis of testicular tissue and peripheral leukocytes was competed on 11 patients. Fifteen male subjects underwnet bilateral contrast vasography. These studies permitted segregation of the hypofertile male population from those with post-germinal hypofertility, primary germinal hypofertility or pre-germinal hypofertility. Retrospective analysis indicates that segregation of the hypofertile male population permits optimum selection for treatment intervention.

Biopsy↗

Optical design of poly(methyl methacrylate) intraocular lenses.

The effect of poly(methyl methacrylate) intraocular lens shape on optical performance of pseudophakic eyes was investigated. Image quality criteria included wave aberrations, spot diagrams, longitudinal aberrations, the modulation transfer function, and an optimization procedure. For eyes with corneal asphericities encompassing most of the population, the optimum lens form for on-axis vision is close to plano-convex, with the more curved surface facing the cornea. This applies whether lenses are correctly centered, tilted, or decentered. For small off-axis angles, optimum lens shape varies with the ocular parameters. Good intraocular lens shapes range from the plano-convex to the equi-convex. Plano-convex lenses with the curved surface facing the retina are not recommended.

Humans↗

Aging: phenomena and theories.

Aging is the accumulation of diverse adverse changes that increase the risk of death. These changes can be attributed to development, genetic defects, the environment, disease, and the inborn aging process. The chance of death at a given age serves as a measure of the number of accumulated aging changes, that is, of physiologic age, and the rate of change of this measure, as the rate of aging. As living conditions in a population approach optimum, the curve of the logarithm of the chance of death versus age shifts towards a limit determined by the sum of (1) the irreducible contributions to the chance of death by aging changes that can be prevented to varying degrees, and (2) those due to the intrinsic aging process. In the developed countries living conditions are now near optimum, and the ALE-Bs are about 6-9 years less than the potential maximum of around 85 years. The inborn aging process is now the major risk factor for disease and death after about age 28. By age 28 only 1 to 2% of a cohort is dead, the remaining 98 to 99% die at an exponentially increasing rate determined by the aging process. This process ensures that few reach 100 years and none exceed about 122 years. Many theories have been advanced to account for the aging process. No single theory is generally accepted. Theories that can contribute to the important practical goal of increasing the healthy, useful span of humans will endure.

Adult↗

Reliability of assessing percentage of diffusion-perfusion mismatch.

BACKGROUND AND PURPOSE: Emergent neurovascular imaging holds promise in identifying new and optimum target populations for thrombolysis in stroke. Recent research has focused on patients with diffusion-weighted MRI (DWI)-perfusion-weighted MRI (PWI) mismatch as a marker of tissue at risk of infarction and a means to select the most suitable candidates for thrombolysis. The present study sought to estimate the reliability of assessing the percentage of DWI-PWI mismatch. METHODS: Thirteen patients with acute strokes had DWI and PWI within 7 hours of symptom onset. Six raters independently created relative mean transit time (rMTT) maps and then compared them with DWI images to assess the percentage of mismatch (PWI>DWI) in 10% increments. The MR scans were reassessed by 4 raters, tracing around the lesions to calculate the volume percentage of mismatch. RESULTS: Visual assessment had an interrater reliability of 0.68 (95% CI, 0.52 to 1.0; SEM=21.6%) and an intrarater reliability of 0.80 (95% CI, 0.47 to 1.0; SEM=16.9%). Hand-drawn assessment had an interrater reliability of 0.66 (95% CI, 0.45 to 1.0; SEM=26.2%) and an intrarater reliability of 0.94 (95% CI, 0.81 to 1.0; SEM=10.9%). CONCLUSIONS: Results from the present study suggest that quantifying mismatch by the human eye is reproducible but not reliable among observers. This raises doubts about using mismatch for clinical decision making and clinical trial enrollment.

Acute Disease↗

The effectiveness of combining hormone therapy and radiotherapy in the treatment of prostate cancer.

Hormone therapy is commonly used for many patients with prostate cancer. Radiotherapy occupies a prominent role in the treatment of locally-advanced, localised, and postsurgical prostate cancer. Hormone therapy and radiotherapy are often used in combination. In this article, the major features of the hormone/radiotherapy interactions are reviewed, with emphasis on the role of combination treatment for locoregional disease. The reported results suggest a biochemical survival advantage to the use of hormone therapy with radiotherapy, in virtually all settings of non-metastatic disease, with the weakest database being in the setting of low-risk, early-stage disease. Further data are needed in order to identify the optimum target population, combination of agents, and hormone duration, as a function of patient and disease factors.

Androgen Antagonists↗

The effectiveness of alcoholism screening in an ambulatory care setting.

Two hundred and eighty subjects in three ambulatory care clinics participated in this study designed to assess the psychometric properties of the SMAST using DSM-III criteria for alcoholism as the diagnostic standard. Eighty-two subjects (30%) who completed the NIMH Diagnostic Interview Schedule met DSM-III criteria for alcohol abuse and/or dependence. The sensitivity of the SMAST, using the generally accepted weighted cut-off score of five or greater, was .56 and the specificity was .83. An unweighted cut-off score of two or greater produced a sensitivity of .72 and a specificity of .64. The results of this study suggest that, when the SMAST is used for screening in an ambulatory care clinic population, the optimum balance of sensitivity and specificity is achieved using an unweighted cut-off score of two or greater. In addition, the alcohol subscale of the Diagnostic Interview Schedule was easy to administer and should be considered for use as the diagnostic standard in clinical settings.

Adolescent↗

Addition of dexmedetomidine to standard sedation regimens after cardiac surgery: an outcomes analysis.

STUDY OBJECTIVE: To characterize inpatient use of intravenous sedatives in the real-world setting, and to evaluate clinical and economic outcomes when dexmedetomidine was used with midazolam and propofol for select cardiovascular procedures. DESIGN: 12-month retrospective analysis. DATA SOURCE: An administrative claims database of operational data from a nationally representative sample of 250 medical and surgical hospitals. PATIENTS: Patients who received midazolam plus propofol (9996 patients) or dexmedetomidine, midazolam, plus propofol (356 patients) after cardiac valve or vessel surgery. MEASUREMENTS AND MAIN RESULTS: The source of patient demographics (e.g., age, sex, Charlson Comorbidity Index) and outcomes (e.g., charges, length of stay, mortality rate) was the hospital billing claim form. Patients in the dexmedetomidine-midazolam-propofol cohort tended to be younger and male and to have fewer comorbidities than those midazolam-propofol cohort. The primary outcomes for the three-drug cohort showed significant reductions in total charges/patient (approximately $18,000, p<0.05), total hospital length of stay (0.6 days, p<0.0001), days in the intensive care unit or cardiac care unit (3.87 days, p<0.0001), and mortality (2%, p=0.0142). Although pharmacy charges were higher (approximately $4000/patient), lower charges for the intensive care or cardiac care unit, operating room, room and board, and respiratory services were observed in the dexmedetomidinemidazolam-propofol cohort compared with the two-drug cohort. Also, mechanical ventilation was shorter by approximately 0.5 day in the three-drug cohort (p<0.01). CONCLUSION: These initial findings of a real-world assessment of dexmedetomidine use with other agents suggest favorable clinical and economic outcomes. Further research through randomized clinical trials of dexmedetomidine is warranted to better understand its optimum patient population, dosage, and the causality of the results, and to confirm the potential clinical and economic benefits observed in our patients.

Aged↗

The energy cost of overweight in the United States.

We have calculated the total fossil energy equivalent of the food calories saved by reducing the present degree of overweight (2.3 billion pounds for the adult United States population) to optimum body weight and the annual fossil energy reduction once all Americans reached their optimum weight. The energy saved by dieting to reach optimal weight is equivalent to 1.3 billion gallons of gasoline and the annual energy savings would more than supply the annual residential electrical demands of Boston, Chicago, San Francisco, and Washington, DC.

Adolescent↗

Exercise in therapy and prevention of type II diabetes. Implications for blacks.

The rationale for the use of exercise in the treatment of type II (non-insulin-dependent) diabetes and its special implications for Blacks are reviewed herein. When performed on a regular basis, exercise may improve glycemic control and improve several risk factors for coronary heart disease including hypertriglyceridemia, hypertension, and hyperinsulinemia. In addition, it may be a useful adjunct to diet in producing weight loss. The metabolic benefits of exercise in part appear to be related to its ability to enhance insulin sensitivity. Benefits are short lived after discontinuing exercise. Because of problems with compliance and concurrent medical problems, many patients with type II diabetes are not good candidates for an exercise-diet program. For this reason, the optimum target population may be people at risk for type II diabetes and premature atherosclerosis. Such a population might include the offspring of patients with these disorders and individuals with impaired glucose tolerance, hyperinsulinemia, gestational diabetes, and/or an android pattern of fat distribution. Type II diabetes is more common in Blacks than in the general population. In most instances, it is associated with cardiovascular risk factors benefited by exercise. Despite this, there are no available studies regarding the effects of regular exercise in Blacks with type II diabetes or those at risk for it.

Black or African American↗

[Biological characteristics of strains of lactobacilli, promising for use as eubiotics].

In the course of in vitro studies 3 Lactobacillus strains with pronounced antagonistic activity against some pathogenic and opportunistic bacteria (shigellae, enteropathogenic Escherichia, Proteus, staphylococci) were selected. In experiments on germ-free rats faint colonization by L. plantarum 37 was observed in the small intestine, as well as in the large intestine when low doses of these bacilli were introduced into the gastrointestinal tract of the animals. In vitro experiments demonstrated the decreased growth rate of this strain. The prophylactic administration of two eubiotic strains, L. plantarum 37 and L. fermentum 39, simultaneously with chloramphenicol to primates inhibited the growth of opportunistic bacteria, though L. fermentum 39 excessively suppressed the content of Escherichia coli in the enterobacterial population. The optimum biological effect was achieved with the therapeutic use of these three strains for the correction of dysbiotic disturbances caused by the administration of tetracycline in volunteers.

Adult↗

The clinical pharmacology and use of paroxetine, a new selective serotonin reuptake inhibitor.

Major depression afflicts a significant percentage of the population, and optimum therapy is often limited by the poor tolerability and lethality in overdose of the tricyclic antidepressants. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline, and, more recently, paroxetine are viewed as welcome additions to existing therapy. The SSRIs are as effective as the tricyclic antidepressants, but are not associated with their adverse effect profile. Paroxetine in dosages of 20-50 mg/day is as effective as the older classic antidepressants, including amitriptyline, imipramine, and doxepin. It is effective in the elderly and in patients with recurrent, resistant, or severe depression.

Aged↗

Epoetin alfa for autologous blood donation in patients with rheumatoid arthritis and concomitant anemia.

In patients scheduled for major orthopedic surgery, the presence of anemia can preclude the donation of sufficient autologous blood (AB) to meet transfusion requirements. Although a number of studies have investigated the use of epoetin alfa (in conjunction with parenteral iron supplementation) to facilitate AB donation and reduce exposure to allogeneic blood in this patient population, the optimum treatment regimen and route of administration has yet to be defined. In rheumatoid arthritis (RA) patients with a low predonation hematocrit (Hct; < or = 39%), intravenous (i.v.) treatment with epoetin alfa 300 IU/kg twice weekly for 3 weeks was the optimum dosage for facilitation of AB donation and minimization of the decrease in Hct prior to elective orthopedic surgery. However, the subcutaneous (s.c.) route of epoetin alfa administration may allow lower dosages of epoetin alfa to be used. Indeed, epoetin alfa 100 IU/kg s.c. twice weekly for 3 weeks (in conjunction with a single i.v. bolus of 200 IU/ kg at the first s.c. dose) was as effective as 300 IU/kg i.v. administered according to the same schedule. The number of AB units collected, total red blood cell (RBC) volume donated, and peak proportion of reticulocytes were similar regardless of the route of administration. Both treatment groups were associated with a significant reduction in allogeneic blood exposure compared with historical controls. Findings consistent to all of these studies were that epoetin alfa was well tolerated, and that i.v. iron supplementation was necessary to maximize its beneficial effects.

Anemia↗

Dynamics of inbreeding depression due to deleterious mutations in small populations: mutation parameters and inbreeding rate.

A multilocus stochastic model is developed to simulate the dynamics of mutational load in small populations of various sizes. Old mutations sampled from a large ancestral population at mutation-selection balance and new mutations arising each generation are considered jointly, using biologically plausible lethal and deleterious mutation parameters. The results show that inbreeding depression and the number of lethal equivalents due to partially recessive mutations can be partly purged from the population by inbreeding, and that this purging mainly involves lethals or detrimentals of large effect. However, fitness decreases continuously with inbreeding, due to increased fixation and homozygosity of mildly deleterious mutants, resulting in extinctions of very small populations with low reproductive rates. No optimum inbreeding rate or population size exists for purging with respect to fitness (viability) changes, but there is an optimum inbreeding rate at a given final level of inbreeding for reducing inbreeding depression or the number of lethal equivalents. The interaction between selection against partially recessive mutations and genetic drift in small populations also influences the rate of decay of neutral variation. Weak selection against mutants relative to genetic drift results in apparent overdominance and thus an increase in effective size (Ne) at neutral loci, and strong selection relative to drift leads to a decrease in Ne due to the increased variance in family size. The simulation results and their implications are discussed in the context of biological conservation and tests for purging.

Animals↗

Evolutionarily stable mutation rates.

I investigate the hypothesis that mutation rates in natural populations are determined by a balance between: (1) selection against deleterious mutations favouring lower mutation rates, and (2) selection opposing further reduction of the mutation rate, resulting from the costs incurred by more stringent proof-reading and repair (for example, a reduction in the rate of DNA replication). The influence of advantageous mutations is assumed to be negligible. In a previous paper, I analysed the dynamics of a modifier of the mutation rate in a large sexual population, where (infinitesimally rare) deleterious alleles segregate at an infinite number of unlinked loci with symmetric multiplicative fitness effects. A simple condition was obtained for a modifier allele to increase in frequency. Remarkably, this condition does not depend on the allele frequencies at the modifier locus. Here, I show that (as a consequence), given any set of possible values of the mutation rate (any set of possible modifier alleles), there always exists a single globally stable value of the mutation rate. This is an unusually strong form of "evolutionary stability" for a sexual population. Less surprisingly the optimum mutation rate in an asexual population has similar stability properties. Furthermore, in the case of an asexual population, it is not necessary to make any special assumptions about the selection acting against deleterious mutations, except that a deterministic mutation-selection equilibrium exists. I present a simple method for identifying the evolutionarily stable value of the mutation rate, given the function alpha(U) relating the value of the mutation rate to the fitness cost of maintaining this rate. I also argue that if there is a highly conserved relationship between the rate of replication per base, and the rate of mutation per base, and if this relationship has the form of a power law, then the remarkable uniformity of the per genome mutation rate in DNA based microbes can be explained.

Animals↗

Runtime analysis of the (mu+1) EA on simple Pseudo-Boolean functions.

Although Evolutionary Algorithms (EAs) have been successfully applied to optimization in discrete search spaces, theoretical developments remain weak, in particular for population-based EAs. This paper presents a first rigorous analysis of the (mu+1) EA on pseudo-Boolean functions. Using three well-known example functions from the analysis of the (1+1) EA, we derive bounds on the expected runtime and success probability. For two of these functions, upper and lower bounds on the expected runtime are tight, and on all three functions, the (mu+1) EA is never more efficient than the (1+1) EA. Moreover, all lower bounds grow with mu. On a more complicated function, however, a small increase of mu probably decreases the expected runtime drastically. This paper develops a new proof technique that bounds the runtime of the (mu+1) EA. It investigates the stochastic process for creating family trees of individuals; the depth of these trees is bounded. Thereby, the progress of the population towards the optimum is captured. This new technique is general enough to be applied to other population-based EAs.

Algorithms↗

Directed evolution of metabolic pathways in microbial populations. I. Modification of the acid phosphatase pH optimum in S. cerevisiae.

An experimental system for directing the evolution of enzymes and metabolic pathways in microbial populations is proposed and an initial test of its power is provided.-The test involved an attempt to genetically enhance certain functional properties of the enzyme acid phosphatase in S. cerevisiae by constructing an environment in which the functional changes desired would be "adaptive". Naturally occurring mutations in a population of 10(9) cells were automatically and continuously screened, over 1,000 generations, for their effect on the efficiency (K(m)) and activity of acid phosphatase at pH 6, and for their effect on the efficiency of orthophosphate metabolism.-The first adaptation observed, M1, was due to a single mutational event that effected a 30% increase in the efficiency of orthophosphate metabolism. The second, M2, effected an adaptive shift in the pH optimum of acid phosphatase and an increase in its activity over a wide range of pH values (an increment of 60% at pH 6). M2 was shown to result from a single mutational event in the region of the acid phosphatase structural gene. The third, M3, effected cell clumping, an adaptation to the culture apparatus that had no effect on phosphate metabolism.-The power of this system for directing the evolution of enzymes and of metabolic pathways is discussed in terms of the kinetic properties of the experimental system and in terms of the results obtained.

Acid Phosphatase↗