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PubMed1989

Increase in digyny explains polyploidy after in-vitro fertilization of frozen-thawed mouse oocytes.

Fewer frozen-thawed mouse oocytes cleaved to the 2-cell stage compared to fresh control oocytes fertilized in vitro (46% vs 79%). The reduced rate of 2-cell formation was only partly explained by a decreased rate of fertilization (63% vs 85%). However, subsequent development to expanded blastocysts was not different (75% vs 78%). An increased frequency of second polar body retention by fertilized frozen-thawed oocytes compared with controls (11.8% vs 1.3%) was shown to be largely responsible for the higher incidence of polyploidy (16.3% vs 3.7%). The frequency of polyspermic fertilization was not different in the two groups (3.9% vs 2.3%).

Animals↗

PubMed2005

The small introns of antisense genes are better explained by selection for rapid transcription than by "genomic design".

Several models have been proposed to explain why expression parameters of a gene might be related to the size of the gene's introns. These include the idea that an energetic cost of transcription should favor smaller introns in highly expressed genes (the "economy selection" argument) and that tissue-specific genes reside in genomic locations with complex chromatin level control requiring large amounts of noncoding DNA (the "genomic design" hypothesis). We recently proposed a modification of the economy model arguing that, for some genes, the time that expression takes is more important than the energetic cost, such that some weakly but rapidly expressed genes might also have small introns. We suggested that antisense genes might be such a class and showed that the data appear to be consistent with this. We now reexamine this model to ask (a) whether the effects described were owing solely to the fact that antisense genes are often noncoding RNA and (b) whether we can confidently reject the "genomic design" model as an explanation for the facts. We show that the effects are not specific to noncoding RNAs and that the predictions of the "genomic design" model for the most part are not upheld.

Antisense Elements (Genetics)↗

PubMed2005

Explaining the poor bacteriologic eradication rate of single-dose ceftriaxone in group a streptococcal tonsillopharyngitis: a reverse engineering solution using pharmacodynamic modeling.

OBJECTIVE: To explore pharmacokinetic factors underlying the poor bacteriologic eradication rate with a single 500-mg dose of ceftriaxone for streptococcal tonsillopharyngitis and to identify the minimum ceftriaxone dose required for effective treatment. METHODS: Population modeling techniques were applied to pharmacokinetic data derived from paired plasma and tonsil samples from 153 children to assess the contribution of pharmacokinetic variability to patients' responses to ceftriaxone. In addition, a Monte Carlo simulation was performed to determine (1) the amount of time that free ceftriaxone concentrations must exceed the minimum inhibitory concentration (MIC) of group A Streptococcus to achieve bacteriologic eradication and (2) the ceftriaxone dose required to maintain free drug concentrations above the target MIC for the requisite amount of time. Ceftriaxone MICs for group A Streptococcus were obtained from a previous trial, in which all MICs (n = 115) were < or = 0.064 mg/L; 33.9% were susceptible at < or = 0.016 mg/L, 66.4% were susceptible at 0.032 mg/L, and 1.7% were susceptible at 0.064 mg/L. RESULTS: Mean population pharmacokinetic parameters and their variances reflected substantial variability of clearance and half-life in the target population. Tonsillar ceftriaxone protein binding was 89.1%. The proportions of 1000 simulated patients with free ceftriaxone concentrations that exceeded MICs of 0.016 mg/L, 0.032 mg/L, and 0.064 mg/L at 24 hours were 71.7%, 65.4%, and 57.2%, respectively, and at 48 hours were 41.8%, 35.8%, and 28.6%, respectively. The amount of time that free ceftriaxone concentrations need to exceed MIC to achieve bacteriologic success was estimated to be 36 hours. Using this time criterion, two 500-mg doses of ceftriaxone separated by 18 hours should achieve a bacteriologic cure rate of approximately 95%. CONCLUSIONS: Pharmacokinetic variability and high ceftriaxone tonsillar protein binding explain the high microbiologic failure rate for a single 500-mg dose of ceftriaxone in group A streptococcal tonsillopharyngitis. Monte Carlo simulation suggests that a second dose administered 18 hours after the first will be required to achieve an acceptable bacteriologic cure rate.

Anti-Bacterial Agents↗

PubMedDate not supplied

The experimental granuloma. A hypothesis to explain the persistence of the lesion.

Granulomatous inflammation is the morphological substrate of a variety of important infectious diseases such as tuberculosis, leprosy, schistosomiasis and others. Nevertheless, although many aspects of this special type of inflammation are known, fundamental questions concerning granuloma formation, persistence, fate and significance for host-parasite relationships still remain to be elucidated. In this brief review, the basic and more relevant literature related to experimental investigations on granuloma physiopathology is presented. Based on recent investigations performed in our laboratory showing that MDF (Macrophage Deactivating Factor) secreted by epithelioid cells and characterized as the calcium-binding protein protein MRP-14 deactivates activated macrophages, a hypothesis to explain the persistence of granulomatous inflammation is put forward.

Animals↗

PubMed2000

Oxidative stress may explain how hypertension is maintained by normal levels of angiotensin II.

It is well known that essential hypertension evolves in most patients with "near normal" levels of plasma renin activity. However, these levels appear to be responsible for the high levels of arterial pressure because they are normalized by the administration of angiotensin II converting inhibitors or angiotensin receptor antagonist. In experimental animals, hypertension can be induced by the continuous intravenous infusion of small doses of angiotensin II that are not sufficient to evoke an immediate pressor response. However, this condition resembles the characteristics of essential hypertension because the high levels of blood pressure exist with normal plasma levels of angiotensin II. It is suggested that small amounts of angiotensin whose plasma levels are inappropriate for the existing size of extracellular volume stimulate oxidative stress which binds nitric oxide forming peroxynitrite. The latter compound oxidizes arachidonic acid producing isoprostaglandin F2alpha (an isoprostane) which is characterized by a strong antinatriuretic vasoconstrictor renal effect. In this chain of reactions the vasoconstrictor effects derived from oxygen quenching of nitric oxide and increased isoprostane synthesis could explain how hypertension is maintained with normal plasma levels of renin.

Angiotensin II↗

PubMed2006

Does health status explain gender dissimilarity in healthcare use among older adults?

This study investigates the extent to which gender dissimilarity in healthcare use in later life is explained by variation in health and social-economic statuses. It is based on a nationwide sample in Brazil of 12,757 men and 16,186 women aged 60+ years. Individuals with great difficulties or unable to perform at least one daily living activity and/or to walk 100m were classified as "established disability". Those who had interrupted their activities in the previous 15 days because of a health problem were regarded as "temporarily disabled". The remaining we classified as "healthy". These categories were analyzed by multinomial logistic regression, taking "healthy" as the reference category. Prevalences of established disability were 6% among men and 11% among women. Temporary disabilities were 7.9% and 10.1%, respectively. Poor health status was associated with increased use of healthcare among men and women, but men and women differed significantly in relation to use pattern after adjustment for age, health status, and income. Older women were greater consumers of outpatient services and older men of inpatient care.

Aged↗

PubMed2001

Methodological and biological factors explaining the reduction in dental caries in Jamaican school children between 1984 and 1995.

OBJECTIVE: To assess the methods used and results found in two surveys, one conducted in 1984 and the other in 1995, that indicated a large reduction in the prevalence and severity of dental caries among children in Jamaica, with special attention focused on methodological differences between the two surveys and the biological factors that may explain the large reduction in caries. METHODS: In 1984 a modified "pathfinder" methodology was used to measure the prevalence and severity of dental caries in 6-, 12-, and 15-year-old children in Jamaica. A similar survey was conducted in 1995. A comparison of the two surveys showed an 84% reduction in the severity of dental caries at age 12. Both surveys used the same diagnostic criteria and clinical procedures, but the 1984 survey included a higher proportion of rural residents than did the 1995 one. RESULTS: The data show an epidemiological transition between 1984, when dental caries was highly prevalent and severe, and 1995, when the disease was less prevalent and was concentrated in a smaller proportion of the population. CONCLUSIONS: Most of the reduction in dental caries between 1984 and 1995 is attributable to the introduction, in 1987, of salt fluoridation. While the 1995 survey included fewer rural areas than the 1984 survey did, that does not invalidate the observed reduction in dental caries. The use of fluoride toothpaste and dietary fluoride supplements as well as access to dental health promotion and preventive and curative services do not seem to be major contributors to the reductions observed.

Adolescent↗

PubMed2006

Borate protection of softwood from Coptotermes acinaciformis (Isoptera: Rhinotermitidae) damage: variation in protection thresholds explained.

Laboratory and field data reported in the literature are confusing with regard to "adequate" protection thresholds for borate timber preservatives. The confusion is compounded by differences in termite species, timber species and test methodology. Laboratory data indicate a borate retention of 0.5% mass/mass (m/m) boric acid equivalent (BAE) would cause > 90% termite mortality and restrict mass loss in test specimens to < or = 5%. Field data generally suggest that borate retentions appreciably > 0.5% m/m BAE are required. We report two field experiments with varying amounts of untreated feeder material in which Coptotermes acinaciformis (Froggatt) (Isoptera: Rhinotermitidae) responses to borate-treated radiata (Monterey) pine, Pinus radiata D. Don, were measured. The apparently conflicting results between laboratory and field data are explained by the presence or absence of untreated feeder material in the test environment. In the absence of untreated feeder material, wood containing 0.5% BAE provided adequate protection from Coptotermes sp., whereas in the presence of untreated feeder material, increased retentions were required. Furthermore, the retentions required increased with increased amounts of susceptible material present. Some termites, Nasutitermes sp. and Mastotermes darwiniensis Froggatt, for example, are borate-tolerant and borate timber preservatives are not a viable management option with these species. The lack of uniform standards for termite test methodology and assessment criteria for efficacy across the world is recognized as a difficulty with research into the performance of timber preservatives with termites. The many variables in laboratory and field assays make "prescriptive" standards difficult to recommend. The use of "performance" standards to define efficacy criteria ("adequate" protection) is discussed.

Animals↗

PubMed2006

Can promotion of initiated cells be explained by excess replacement of radiation-inactivated neighbor cells?

Recently, the observed promotion in the clonal expansion of a two-stage cancer model was attributed to a small excess replacement probability for the initiated cells. The proposed mechanism of excess replacement was evaluated for single intermediate cells surrounded by normal cells. This paper investigates this mechanism further using the same biological parameters. If the formation of clones of intermediate cells is taken into account in a quantitative analysis of the proposed mechanism, it turns out that (1) for the initial strong increase of the promotional effect with exposure, a much larger and unlikely excess replacement probability is needed, and (2) the leveling of the promotional effect for high exposures cannot be explained by multiple normal neighbors of an intermediate cell being inactivated within one cell cycle, as it had been suggested. Perhaps these discrepancies could be partly resolved by a re-scaling of the original parameters, but this should be investigated further.

Bystander Effect↗

PubMed2005

Crystal surface adhesion explains the pathological activity of calcium oxalate hydrates in kidney stone formation.

Renal tubular fluid in the distal nephron of the kidney is supersaturated with calcium oxalate (CaOx), which crystallizes in the tubules as either calcium oxalate monohydrate (COM) or calcium oxalate dihydrate (COD). Kidney stones are aggregates, most commonly containing microcrystals of COM as the primary inorganic constituent. Stones also contain small amounts of embedded proteins, which are thought to play an adhesive role in these aggregates, and they often are found attached to the tip of renal papilla, presumably through adhesive contacts. Voided urine, however, often contains COD in the form of single micron-sized crystals. This suggests that COD formation protects against stone disease because of its reduced capacity to form stable aggregates and strong adhesion contacts to renal epithelial cells. Using atomic force microscopy configured with tips modified with biologically relevant functional groups, we have compared the adhesion strengths of the morphologically important faces of COM and COD. These measurements provide direct experimental evidence, at the near molecular level, for poorer adhesion at COD crystal faces, which explains the benign character of COD and has implications for resolving one of the mysteries of kidney stone formation.

Adhesiveness↗

PubMed2006

Analyzing or explaining beta diversity? Understanding the targets of different methods of analysis.

It has been actively discussed recently what statistical methods are appropriate when one is interested in testing hypotheses about the origin of beta diversity, especially whether one should use the raw-data approach (e.g., canonical analysis such as RDA and CCA) or the distance approach (e.g., Mantel test and multiple regression on distance matrices). Most of the confusion seems to stem from uncertainty as to what is the response variable in the different approaches. Here our aim is to clarify this issue. We also show that, although both the raw-data approach and the distance approach can often be used to address the same ecological hypothesis, they target fundamentally different predictions of those hypotheses. As the two approaches shed light on different aspects of the ecological hypotheses, they should be viewed as complementary rather than alternative ways of analyzing data. However, in some cases only one of the approaches may be appropriate. We argue that S. P. Hubbell's neutral theory can only be tested using the distance approach, because its testable predictions are stated in terms of distances, not in terms of raw data. In all cases, the decision on which method is chosen must be based on which addresses the question at hand, it cannot be based on which provides the highest proportion of explained variance in simulation studies.

Biodiversity↗

PubMed2004

Testing three competing hypotheses for explaining lethal violence.

This study tests three competing hypotheses for explaining lethal violence that is conceptualized as the combination of both suicide and homicide. These three hypotheses differ on how lethal violence can be expressed as either suicide or homicide. Suicide and homicide data, from 1989 to 1991, were obtained from the Multiple Cause of Death study conducted by the National Center for Health Statistics. A bivariate analysis shows that there is a positive correlation between suicide and homicide rates for 458 large counties in the US. A weighted least square regression analysis reveals that the attribution hypothesis is supported by the results. Counties with a higher degree of others-blame-worthiness are more likely to express violence as homicide. Neither the socialization nor the social disorder hypotheses is supported by the analysis. Results of this study suggest that it is fruitful to study both suicide and homicide under the same theoretical and empirical framework.

Cause of Death↗

PubMed2004

Investigating the mechanics of multimedia box models: how to explain differences between models in terms of mass fluxes?

The simple mathematical structure of multimedia fate models makes it possible to change the process descriptions and geometry of such models relatively easily. With different versions of a model, the effect of a process or compartment that is included in one version of the model but excluded in another version can be investigated. Here, a new method for performing such a model comparison in a quantitative way is presented. Based on the mass balances for the two model versions, it can be shown that, for a compartment contained in both model versions, the difference between a chemical's concentrations in this compartment is related directly to the difference in those mass fluxes that have different rate constants in the two models. Moreover, it is possible to identify the contributions to the concentration difference that stem from individual mass fluxes so that the concentration difference can be tracked back to specific differences in the process descriptions of the two models. This flux analysis method is illustrated with two versions of a unit-world model, one with and one without a vegetation compartment. With DDT and six polychlorinated biphenyl (PCB) congeners as example chemicals, the differences of the chemicals' concentrations in air and soil caused by the vegetation compartment are explained by using the flux analysis method. The future potential of the method for comparing not only versions of the same model but also models of different structure is discussed.

DDT↗

PubMed1988

Maximizing present value: A model to explain why moderate response rates obtain on variable-interval schedules.

In Phases 1 and 3, two Japanese monkeys responded on a multiple variable-ratio 80 variable-interval X schedule, where the value of X was adjusted to ensure equal between-schedule reinforcement rates. Components strictly alternated following the delivery of a food pellet, and each session ended following 50 components. Phase 2 differed from the others only in that the 50 pellets previously earned during the session were delivered together at session's end. Variable-ratio response rates did not decrease across phases, but variable-interval response rates decreased substantially during the Phase 2 procedure. This rate decrease was attributed to the food-at-session's-end manipulation removing the greater immediacy of reinforcement provided by short interresponse times relative to long interresponse times. Without this time preference for short interresponse times, the variable-interval interresponse-time reinforcement feedback function largely controlled response emission, dictating a response-rate reduction. This result was explained in terms of the economic notion of "maximizing present value."

Journal Article↗

PubMed1998

Explaining recent increases in students' marijuana use: impacts of perceived risks and disapproval, 1976 through 1996.

OBJECTIVES: Marijuana use among high school seniors increased during most of the 1970s, decreased throughout the 1980s, and has been increasing again during the 1990s. Earlier analyses of the classes of 1976 through 1986 attributed the historic trends during that period to specific changes in views about marijuana. This study examined whether recent increases in marijuana use among seniors and among students in earlier grades reflect similar processes. METHODS: Multivariate regression analyses were conducted on data from large annual nationwide surveys of high school seniors from 1976 through 1996 (approximate n = 61,000) and 8th and 10th graders from 1991 through 1996 (n's = 87,911 and 82,475, respectively). RESULTS: Individual lifestyle factors (grades, truancy, religious commitment, evenings out for recreation) correlated substantially with marijuana use but did not explain the historic changes in marijuana use. Rather, decreases in perceived risk of harmfulness and in disapproval can account for the recent increases in all 3 grades and for earlier decreases among seniors. CONCLUSIONS: These findings indicate that perceived risks and disapproval are important determinants of marijuana use. Accordingly, prevention efforts should include realistic information about risks and consequences of marijuana use.

Adolescent↗

PubMed2005

Explaining the 2001-2002 infant mortality increase in the United States: data from the linked birth/infant death data set.

The U.S. infant mortality rate (IMR) increased from 6.8 infant deaths per 1,000 live births in 2001 to 7.0 in 2002, the first increase in more than 40 years. From 2001 to 2002, IMR increased for very low birthweight infants as well as for preterm and very preterm infants. Although IMR for very low birthweight infants increased, most of the increase in IMR from 2001 to 2002 was due to a change in the distribution of births by birthweight and, more specifically, to an increase in infants born weighing less than 750 grams. The majority of infants born at less than 750 grams die within the first year of life; thus, these births contribute disproportionately to overall IMR. Increases in births at less than 750 grams occurred fornon-Hispanic white, non-Hispanic black, and Hispanic women. Most of the increase occurred among mothers 20 to 34 years of age. Although multiple births contributed disproportionately, most of the increase in births at less than 750 grams occurred among singletons. Three hypotheses were evaluated to assess their possible impact on the increase in less than 750-gram births: possible changes in (1) the reporting of births or fetal deaths, (2) the risk profile of births, and (3) medical management of pregnancy. Although each of these factors may have contributed to the increase, the relative effects of these and other factors remain unclear. More detailed studies are needed to further explain the 2001-2002 infant mortality increase.

Birth Rate↗

PubMed2002

The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations : distinct metabolic effects of two fat compartments.

Obesity is associated with insulin resistance, particularly when body fat has a central distribution. However, insulin resistance also frequently occurs in apparently lean individuals. It has been proposed that these lean insulin-resistant individuals have greater amounts of body fat than lean insulin-sensitive subjects. Alternatively, their body fat distribution may be different. Obesity is associated with elevated plasma leptin levels, but some studies have suggested that insulin sensitivity is an additional determinant of circulating leptin concentrations. To examine how body fat distribution contributes to insulin sensitivity and how these variables are related to leptin levels, we studied 174 individuals (73 men, 101 women), a priori classified as lean insulin-sensitive (LIS, n = 56), lean insulin-resistant (LIR, n = 61), and obese insulin-resistant (OIR, n = 57) based on their BMI and insulin sensitivity index (S(I)). Whereas the BMI of the two lean groups did not differ, the S(I) of the LIR subjects was less than half that of the LIS group. The subcutaneous and intra-abdominal fat areas, determined by computed tomography, were 45 and 70% greater in the LIR subjects (P < 0.001) and 2.5- and 3-fold greater in the OIR group, as compared with the LIS group. Fasting plasma leptin levels were moderately increased in LIR subjects (10.8 +/- 7.1 vs. 8.1 +/- 6.4 ng/ml in LIS subjects; P < 0.001) and doubled in OIR subjects (21.9 +/- 15.5 ng/ml; P < 0.001). Because of the confounding effect of body fat, we examined the relationships between adiposity, insulin sensitivity, and leptin concentrations by multiple regression analysis. Intra-abdominal fat was the best variable predicting insulin sensitivity in both genders and explained 54% of the variance in S(I). This inverse relationship was nonlinear (r = -0.688). On the other hand, in both genders, fasting leptin levels were strongly associated with subcutaneous fat area (r = 0.760) but not with intra-abdominal fat. In line with these analyses, when LIS and LIR subjects were matched for subcutaneous fat area, age, and gender, they had similar leptin levels, whereas their intra-abdominal fat and insulin sensitivity remained different. Thus, accumulation of intra-abdominal fat correlates with insulin resistance, whereas subcutaneous fat deposition correlates with circulating leptin levels. We conclude that the concurrent increase in these two metabolically distinct fat compartments is a major explanation for the association between insulin resistance and elevated circulating leptin concentrations in lean and obese subjects.

Abdomen↗

PubMed2005

Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans.

The intraislet insulin hypothesis for the signaling of the glucagon secretory response to hypoglycemia states that a decrease in arterial glucose --> a decrease in beta-cell insulin secretion --> a decrease in tonic alpha-cell inhibition by insulin --> an increase in alpha-cell glucagon secretion. To test this hypothesis in humans, a hyperinsulinemic- euglycemic ( approximately 5.0 mmol/l [90 mg/dl] x 2 h) and then a hypoglycemic ( approximately 3.0 mmol/l [55 mg/dl] x 2 h) clamp was performed in 14 healthy young adults on two occasions, once with oral administration of the ATP-sensitive potassium channel agonist diazoxide to selectively suppress baseline insulin secretion and once with the administration of a placebo. The decrement in plasma C-peptide during the induction of hypoglycemia was reduced by approximately 50% in the diazoxide clamps (from 0.3 +/- 0.0 to 0.1 +/- 0.0 nmol/l [0.8 +/- 0.1 to 0.4 +/- 0.1 ng/ml]) compared with the placebo clamps (from 0.4 +/- 0.0 to 0.1 +/- 0.0 nmol/l [1.2 +/- 0.1 to 0.4 +/- 0.1 ng/ml]) (P = 0.0015). This reduction of the decrement in intraislet insulin during induction of hypoglycemia caused an approximately 50% reduction (P = 0.0010) of the increase in plasma glucagon in the diazoxide clamps (from 29 +/- 3 to 35 +/- 2 pmol/l [102 +/- 9 to 123 +/- 8 pg/ml]) compared with the placebo clamps (from 28 +/- 2 to 43 +/- 5 pmol/l [98 +/- 7 to 151 +/- 16 pg/ml]). Baseline glucagon levels, the glucagon response to intravenous arginine, and the autonomic (adrenomedullary, sympathetic neural, and parasympathetic neural) responses to hypoglycemia were not altered by diazoxide. These data indicate that a decrease in intraislet insulin is a signal for the glucagon secretory response to hypoglycemia in healthy humans. The absence of that signal plausibly explains the loss of the glucagon response to falling plasma glucose concentrations, a key feature of the pathogenesis of iatrogenic hypoglycemia, in insulin-deficient (type 1 and advanced type 2) diabetes.

Adult↗