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PubMed1979

Initiation of each avian inspiration by a CO2 threshold mechanism.

The avian respiratory oscillator has been investigated in a unidirectionally ventilated chicken by changing the dynamic pattern of inflow CO2 concentration (FCO2). Stimulation with periodic FCO2 results in a one-to-one synchronization of the respiratory movements that we have called pacing (Respir. Physiol. 22: 167--177, 1974). A two-parameter CO2 threshold model is proposed to explain this behavior. The model states that when FCO2 reaches a threshold level (L), it initiates the beginning of inspiration a constant time interval (LB) later. According to this model, when a triangular FCO2 concentration is used to synchronize the breathing pattern, the time from the minimum of the wave form to the beginning of inspiration (C-B interval) is dependent on the mean value and the rate of rise of FCO2 as determined by period and amplitude of the triangle. Particularly interesting is the prediction that the direction of the relationship (increasing or decreasing) between FCO2 amplitude and the C-B interval is dependent on whether the mean value of FCO2 is above or below the threshold level. Experimental data obtained during amplitude changes support the above prediction.

Animals↗

PubMed2025

Genomic prediction and genome-wide association study for liver abscesses in crossbred beef cattle.

Liver abscesses are a concern in feedlot cattle, and little is known about the role of genetics in their development. This study aimed to estimate genetic parameters and to identify single-nucleotide polymorphisms (SNPs) associated with liver abscesses. Crossbred cattle representing 18 breeds in the U.S. Meat Animal Research Center Germplasm Evaluation Program were phenotyped for liver abscesses at slaughter (n = 9,044). Seventeen percent of cattle had liver abscesses. These cattle had genotypes that were imputed to sequence variant genotypes. After filtering and quality control, 340,723 SNPs were used in the analysis. Liver abscess prevalence was modeled with a single-step genomic best linear unbiased prediction (ssGBLUP) threshold model using a Bayesian framework. The model included contemporary group (sex, treatment group, and slaughter date), additive genomic, and residual effects. Genomic heritability was 0.039 (95% highest posterior density = 0.005, 0.081), which was very small. To assess prediction quality, a 5-fold random cross-validation structure was used. Method Linear Regression was used to assess accuracy, bias, and dispersion by comparing estimated breeding values (EBV) from full and reduced analyses. Cross-validation metrics showed EBV based on genotypes had 0.05 reliability (SD < 0.01) with no bias relative to EBV based on genotypes and phenotypes. For the genome-wide association study, SNP effects were back calculated from the EBV solutions from ssGBLUP. No SNPs were associated with liver abscesses at a Benjamini-Hochberg adjusted 0.05 significance level. Although a large dataset was used, this result was because of the low genomic heritability and imprecise EBV used to calculate SNP effects. Based on these results, environmental factors contribute to most of the variation in liver abscesses. Genetic selection to reduce liver abscesses would be slow because of the low genomic heritability, measurement late in life, and inability to measure breeding animals. A faster approach would be finding additional environmental interventions that maintain animal performance.

Animals↗

PubMed1992

Dobutamine pharmacokinetics and pharmacodynamics in pediatric intensive care patients.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of dobutamine in critically ill children. DESIGN: A prospective study of pediatric patients receiving continuous infusions of dobutamine in a stepwise format from 2.5 to 10.0 micrograms/kg/min. SETTING: A pediatric critical care unit. PATIENTS: Twelve children ranging in age from 1 month to 17 yrs with primary medical conditions. MEASUREMENTS: Plasma dobutamine concentrations and hemodynamic responses were measured at each infusion rate at steady state. Dose response data were analyzed to determine the threshold or minimum plasma dobutamine concentration necessary for discernible hemodynamic effects. MAIN RESULTS: Dobutamine plasma clearance rates ranged from 40 to 130 mL/kg/min. Each patient presented a linear increase in the plasma dobutamine concentration at each infusion rate (r2 = .97, p less than .001). Plasma clearance rate vs. actual dobutamine concentration did not vary. Cardiac output, BP, and heart rate increased 30%, 17%, and 7%, respectively, at maximal dose. The dobutamine concentration thresholds for changes in cardiac output, BP, and heart rate were 13 +/- 6, 23 +/- 14, and 65 +/- 30 ng/mL, respectively. CONCLUSIONS: There was no effect of plasma dobutamine concentration or infusion rate on plasma clearance rate. For this group of patients, over the range of the intravenous doses studied, dobutamine pharmacokinetics followed a first-order kinetic model. Threshold values for dobutamine usually show increases in cardiac output before changes in heart rate. These data demonstrate that dobutamine is an effective inotropic agent in critically ill pediatric patients and has minimal chronotropic action.

Blood Pressure↗

PubMed1992

The molecular mechanism of peroxisome proliferator action: a model for species differences and mechanistic risk assessment.

An increasing number of chemicals that produce tumours in rodent bioassays belong to the non-genotoxic class of carcinogens. There are no suitable tests for these carcinogens and our understanding of their mechanism of action is poor. Importantly, assessment of their potential hazard to man is usually difficult without extensive research. Peroxisome proliferators (PP) are a diverse group of rodent non-genotoxic carcinogens that include hypolipidemic drugs, plasticizers and herbicides. We have reported previously the cloning of a member of the nuclear hormone receptor superfamily and, through the use of chimeric receptors, discovered that it could be activated by PPs. The receptor is therefore termed the PP activated receptor (PPAR). The most widely used marker of PP action is the peroxisomal beta-oxidation enzyme acyl CoA oxidase (ACO). Interestingly, it has been speculated that the hydrogen peroxide produced as a result of ACO activity could lead to DNA damage and tumorigenesis. We have now demonstrated that PPAR recognizes a specific PP response element (PPRE) located in the ACO gene promoter and that the response is dependent upon the presence of receptor and the addition of the PP Wy-14,643. These data therefore support a model in which the mechanism of PP action is mediated by PPAR in a manner similar to that of steroid hormone action. Learning more about the function of PPAR offers a unique opportunity to understand the mechanism of action of some non-genotoxic carcinogens. Furthermore, this knowledge when combined with comparison of receptor expression between rodents and man will be important in providing a framework for a new threshold model of risk assessment based upon receptor-mediated carcinogenesis.

Acyl-CoA Oxidase↗

PubMed1975

Experimental brain damage from fluid pressures due to impact acceleration. 4. comparative studies with acceleration-concussion.

In order to elucidate the cause of brain damage in head injuries experiments are often designed to cause impacts to the intact skull of animals. To study the injurious significance of the contre-coup part of the impact acceleration pressure pattern we have previously applied direct loading through a parietal opening to the rabbit skull cavity. In order to evaluate the effects of the acceleration, similar impacts were delivered with greater magnitudes of such movements of the intact reinforced rabbit skull with the same equipment attached but without trephine opening. Varied and predictable acceleration, velocity and displacement of the head, and minimized skull deformation were possible with this model. Threshold levels of such impact acceleration were studied with regard to changes in respiratory and vasomotor activities ("concussive response"). Vascular permeability changes in the brain and spinal cord were studied with Ean's blue-albumin injection before the impact. Morphological observations were also made at the end of the experiments. No significant pathophysiological or morphological effects were elicited below peak acceleration of 2000 gn (duration 0.7 ms), peak velocity of 5 m/s or total dislocation of the head of 30 mm. At higher levels of impact a "concussive response" was elicited without fractures of the skull bone or significant brain lesions. Thus, in impact tests resulting in acceleration magnitudes far below those levels the signs of brain damage induced might mainly be related to the mechanical effects added--i.e. the fluid pressure loading.

Acceleration↗

PubMed1979

A family study of congenital inguinal hernia.

In fathers and mothers of 707 index patients with operated indirect congenital inguinal hernia (CIH) born in Budapest during the years 1962-1966 the frequency of CIH was two and five to six times higher, respectively, than in the general population. The rate of affected sibs was higher than that of parents but was greatly dependent on the sex of the index patient. Heritability estimates of CIH vary significantly in parents (0.35 +/- 0.12) and in sibs (0.78 +/- 0.14). In twins the heritability is 0.77. These data agree with the multifactorial threshold model involving dominance variance.

Adult↗

PubMed1978

The course of affective disorders. II. Typology of bipolar manic-depressive illness.

A representative sample of 95 hospitalized bipolar manic-depressive patients was followed up from 1959 to 1975. The mean age of the group at the time of this study was 61 years. It was observed that female bipolar patients demonstrate depression much more frequently than mania, while male patients show a symmetric distribution of both manic and depressive syndromes. The longitudinal occurrence of syndromes remains more or less constant; for instance, individual patients do not tend to go into depression with increasing age. The study shows that even after three episodes 29% of all bipolar patients would still have been misdiagnosed as unipolar depression. An attempt is made to classify bipolar patients into three subtypes, 'preponderantly manic,' 'preponderantly depressed,' and a 'nuclear' type. Male patients belong mainly to the latter with an equal proportion of the first and third subtype. In contrast, female patients belong mainly to the depressed subtype. The findings are discussed assuming either a heterogeneity of bipolar disorders or a threshold model of affective disorders suggested by Gershon et al. (1976).

Adult↗

PubMed1992

A clinical and biological validation of the DSM-III melancholia diagnosis in men: results of pattern recognition methods.

Pattern recognition methods were carried out on a sample of 80 depressed men, assessed by means of 14 items relevant to depressive symptomatology of the Structured Clinical Interview for DSM-III-R. 1985 edition (SCID). A cluster analysis generated two classes, which were described as a vital (n = 35) and a nonvital cluster (n = 45). Vital depressives were characterized by psychomotor disorders, loss of energy, cognitive disturbances, a distinct quality of mood, early morning awakening and nonreactivity (the "vital" symptoms). Our findings support the descriptive validity of the DSM-III melancholia diagnostic category, although the DSM-III criteria are too conservative and include nonrelevant symptoms (e.g., diurnal variation, anorexia-weight loss) whilst excluding some important items (e.g., loss of energy, cognitive disorders). Vital depressed men were significantly older, more severely depressed and they exhibited biological disturbances (abnormal dexamethasone suppression test, lower basal thyroid secreting hormone) as opposed to nonvital depressives. There are several arguments to support the possibility that both clusters constitute relevant stages in the overall severity of illness continuum, whilst showing qualitative differences with regard to the vital symptoms. In other words, both clusters are continuous categories within the overall severity of illness continuum and form discrete categories with regard to the vital symptoms. By merging the dimensional and categorical hypotheses, we were able to construct a new integrated threshold model: unipolar depression in men is probably a homogeneous disease with reference to overall severity of illness, but--as severity increases--vital symptoms emerge, grouping together into a distinct profile, i.e., vital depression.

Adult↗

PubMed1976

Allelic restriction: a biologic alternative to multifactorial threshold inheritance.

Contrary to the argument regarding the conservatism of the multifactorial threshold model for describing the inheritance of congenital malformations, little biological insight has resulted from the series of tautological, albeit grandiose, mathematical assumptions currently comprising the basis for this hypothesis. The working hypothesis of this presentation is to apply the "allelic restriction" model to the genesis of common human congenital malformations. New population data concerning isolated cleft palate closely fit the predictions of the proposed hypothesis. Recognising the heterogeneity of cleft palate as well as other common congenital malformations (namely, the difference between phenocopies, definable syndromes, and true hereditary cases), the "allelic restriction" model accords with the apparent greatly "reduced penetrance" of the heriditary cases. This model is meant to apply only to those congenital malformations which have both a high population frequency and a relatively small number of families showing an atypical type of vertical transmission.

Adult↗

PubMed1979

Holzinger's Hc revised.

The formula H'C = 1 - CDZ/CMZ is suggested as a better summary of twin concordance data than the familiar Holzinger concordance formula, HC = (CMZ - CDZ)/(1 - CDZ). The new formula better estimates degree of genetic determination, G, as calculated from a threshold model, but never exceeds unity, as G sometimes does. For high concordance rates, if CMZ + CDZ greater than 1, HC may be more useful than either G or H'C.

Female↗

PubMed1992

Chromosomal aberrations in human lymphocytes induced in vitro by very low doses of X-rays.

This paper presents results of a collaborative experiment between six laboratories which examined the yields of unstable chromosomal aberrations in human lymphocytes induced in vitro by X-rays over the dose range 0-300 mGy. The work included data points of nominal doses of 0, 3, 5, 6, 10, 20, 30, 50 and 300 mGy. Cells from 24 donors were examined and a total of about 300,000 metaphases were scored. The work was undertaken to determine the limits of sensitivity of the system taking into account variations in scoring data due to inter-donor sample and inter-laboratory effects. Despite the existence of these effects, aberration yields significantly in excess of control values were seen at doses greater than 20 mGy and these were consistent with a linear extrapolation from higher doses. Below 20 mGy the observed dicentric yields were generally lower than background, but not significantly so. Excess acentric aberrations, on the other hand, and centric rings, were higher than the controls but the increase was usually not significant. It is concluded that the statistical uncertainties are such that below 20 mGy this technique cannot distinguish between a linear or a threshold model.

Chromosome Aberrations↗

PubMed2025

Genomic study for pregnancy loss in Brahman cattle.

Reproduction has major influence on productivity of beef cattle operations. Maintaining an animal in the herd for an extended period without producing a marketable product can result in significant economic losses, compromising the efficiency of the production system. Understanding genetic variation's role in pregnancy loss (PL) is crucial for improving reproductive success in cattle. Identifying genomic regions that influence embryo and fetal survival, as well as pinpointing candidate genes associated with PL, can enhance breeding strategies. The objective of this study was to estimate variance components and investigate genetic factors associated with PL in Brahman cattle. Phenotypic records consisted of 29,905 pregnancy (28,691) and abortion (1,214) records from nulliparous, primiparous, and multiparous cows. A total of 921 animals were genotyped using a medium-density SNP chip (∼52K markers). Variance components were estimated using a threshold model to assess the binary response to PL through a single-step genomic BLUP procedure. The heritability estimate for PL was low (0.11), but the presence of genetic variance suggests that selection for improved reproductive performance is feasible. Genome-wide association analyses identified 17 candidate regions containing 92 genes. Regions on BTA4, 7, 8, 9, 11, 12, 16, 18, 19, 21, 22, and 29 harbored genes associated with embryonic development and implantation, fertilization, G protein-coupled receptors, embryonic brain development, olfactory receptor activity, and calcium signaling. Orthologous genes were also identified in humans (Homo sapiens), rats (Rattus norvegicus), and mice (Mus musculus). The candidate regions reported in this study provide insights for identifying and selecting animals with improved reproductive performance, ultimately enhancing the productivity of Brahman cattle. Moreover, our findings contribute to a better understanding of the genetic and physiological mechanisms underlying pregnancy retention in beef cattle.

Animals↗

PubMed2025

Tulp3 quantitative alleles titrate requirements for viability, brain development, and kidney homeostasis but do not suppress Zfp423 mutations in mice.

Tubby-like protein 3 (TULP3) regulates receptor trafficking in primary cilia and antagonizes SHH signaling. Tulp3 knockout mice are embryonic lethal with developmental abnormalities in multiple organs, while tissue-specific knockouts and viable missense alleles cause polycystic kidney disease. Human patients with TULP3 mutations present with variable, but often multi-organ fibrotic disease. We previously showed that mouse and human Tulp3 expression is negatively regulated by ZNF423, which is required for SHH sensitivity in some progenitor cell models. The level of TULP3 function required to prevent mutant phenotypes has not been known. Here we report a Tulp3 quantitative allelic series, designed by targeting the polypyrimidine tract 5' to the splice acceptor of a critical exon, that shows distinct dose-response effects on viability, brain overgrowth, weight gain, and cystic kidney disease. We find limited evidence for genetic interaction with Zfp423 null or hypomorphic mutations. Together, these results establish an approach to developing quantitative allelic series by exon exclusion, rank-order dose-sensitivity of Tulp3 phenotypes, and model thresholds for TULP3 function to prevent severe outcomes.

Journal Article↗

PubMed1976

Estimation of polygenic recurrence risk for cleft lip and palate.

Data on cleft lip with or without cleft palate are utilized to evaluate a new method for estimating recurrence risk under the polygenic threshold model. The influence of critical factors on the accuracy of the estimated risks are evaluated. The model is relatively sensitive to the estimate of heritability employed and relatively robust to the population prevalence estimate and to family size. The calculated risks for cleft lip with or without cleft palate are contrasted with the empiric figures from studies on Caucasians and Japanese populations.

Cleft Lip↗

PubMed1979

Aetiological studies of hypospadias in Hungary.

A complex aetiological (epidemiological, teratological and genetic) study was made in 294 index patients with simple isolated hypospadias. The epidemiological study conducted by the help of personal interviews of the mothers revealed a higher frequency of index patients among children born between August and December, among twins, mainly monozygotic, and finally in the lower birth weight groups and among first-borns. The teratological study showed a higher frequency in mothers of index patients who had had sex hormone treatment, mainly progestogen, before the 16th gestational week. This seems to indicate the aetiological role of fetal androgen deficit caused by the regulation disturbances of human choriogonadotropin. The genetic family study completed by personal examination of first-degree male relatives showed a familial clustering (4.0% versus a point prevalence of 0.44% in live-births). Both the pattern of affected relatives (h2 values 0.62 +/- 0.21 and 0.72 +/- 0.33 in fathers and brothers, respectively, not differing significantly from each other) and further characteristics (other malformations were not frequent in relatives) correspond to the multifactorial-threshold model.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

The peripheral hearing mechanism: a biochemical and biological approach.

A new approach is described to the problem or hearing at energy levels near threshold. Models depending on the macro-physics of levers are rejected. Instead, evidence is presented for frequency analysis, signal placement and energy transduction by the properties (known or experimentally determined) or the cochlea and of the structures within the scala media. The hypothesis developed rests on the established theorems of Gabor and Brillouin, and at the same time is based on the data of enzymology. Care is taken not only that the hypothesis does not conflict but that it is actually consonant with recent solid state physics. The cochlea by virtue of its internal geometry and contained column of fluid is considered to perform a Fourier analysis to a first approximation. This crude "placement" of the acoustic signal is refined by the semi-solid-state lattice of the tectorial membrane which far from permitting dissipation of the signal energy actually "concentrates" the energy at the membrane surface of the hair processes of a hair cell. Here biochemical transduction, akin to the processes known for other sensory cells, transforms acoustic energy through an ion-shuttling mechanism to the form of energy characteristic of living cells, viz. enzyme conformational changes.

Cochlea↗

PubMed1992

Preference can be more powerful than detection of oddity as a test of discriminability.

Subjects presented with sets of three samples, two of distilled water and one of tap water, were significantly more consistent in choosing the tap water as preferable than they were in identifying it as the odd sample in the set. The result is opposite to the prediction of high-threshold models of sensory discrimination, which say that if a difference is not noticed, preferences will be random, whereas if a difference is noticed, preferences may still be in either direction. The result can be quantitatively explained by a model advanced by Frijters to explain an analogous anomaly found with the triangle test used in the food industry. Applying his model to the observed proportions yields essentially equivalent estimates of sensory difference (d' = 1.5, approximately) from the two tasks, and a direction of preference almost unanimously in favor of the tap water that was used. Since the model predicts that the proportion of subjects choosing the odd item will depart further from chance in the preference task than in the oddity task, the former has greater power to reject the null hypothesis of no sensory difference if one exists and if preference is overwhelmingly in one direction.

Adult↗

PubMed1992

Does chronic lung failure lead to cognitive failure?

This study seeks to find out whether impaired cognition is associated with Chronic Obstructive Pulmonary Disease (COPD). Two experiments have been carried out to address two aspects of selective attention: a focused attention paradigm with a random and a facilitated condition and a divided attention paradigm with and without interference. Twenty-eight COPD patients and 28 matched healthy controls took part in both experiments. Reaction time (RT) was the variable considered. COPD patients had slower RTs than controls, however facilitation and interference had the same effect on both groups. No correlation was found between neuropsychological measures and lung failure indices. A threshold model in the lung-failure/brain-failure trade-off is envisaged.

Adult↗