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R A Jacobs

Publications and source records attributed to R A Jacobs.

At least 37 records · Page 2Linked to original sources
PubMed1997

Induction of nitric oxide synthase and interleukin-1beta, but not heme oxygenase, messenger RNA in rat brain following peripheral administration of endotoxin.

Previous studies have suggested that both nitric oxide (NO) and carbon monoxide (CO) are important modulators of the inflammatory response, while more recent data have implicated both gases as regulators of hypothalamic neuroendocrine function, particularly the hypothalamo-pituitary-adrenal axis. We have, therefore, investigated the modulation of the transcripts for the synthetic enzymes for both NO and CO following the intraperitoneal administration of lipopolysaccharide, serotype B5 055, over the course of 24 h. The mRNA for type I or neuronal nitric oxide synthase (nNOS), and type II or inducible (iNOS), and heme oxygenase1 ('inducible') and heme oxygenase2 ('constitutive'), were reverse transcribed to cDNA, amplified by the polymerase chain reaction, and then quantified using a co-amplified internal standard, beta-actin. This allowed for assessment of relative changes in transcript concentration. In addition, these were compared to changes in expression of the cytokine, IL-1beta. Finally, absolute levels of the synthetic enzyme transcripts were assessed by means of co-amplification in the presence of varying amounts of mutant templates in a competitive PCR reaction. Our data revealed rapid induction of IL-1beta, iNOS and HO1 in the liver, returning to baseline at 24 h. In the hypothalamus, all transcripts were present under basal conditions, but only IL-1beta and iNOS were induced by the LPS. We conclude that hypothalamic IL-1beta and iNOS can be induced by a non-lethal dose of endotoxin, and are, thus, in a position to mediate certain of the neuroendocrine consequences to inflammatory stress.

Animals↗
PubMed1997

Bias/variance analyses of mixtures-of-experts architectures.

This article investigates the bias and variance of mixtures-of-experts (ME) architectures. The variance of an ME architecture can be expressed as the sum of two terms: the first term is related to the variances of the expert networks that comprise the architecture and the second term is related to the expert networks' covariances. One goal of this article is to study and quantify a number of properties of ME architectures via the metrics of bias and variance. A second goal is to clarify the relationships between this class of systems and other systems that have recently been proposed. It is shown that in contrast to systems that produce unbiased experts whose estimation errors are uncorrelated, ME architectures produce biased experts whose estimates are negatively correlated.

Analysis of Variance↗
PubMed1997

Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors.

The molecular basis of Cushing's disease is not known. One of the most characteristic features of such tumors is their resistance to corticosteroid feedback at the pituitary level. We have hypothesized that abnormalities of the glucocorticoid receptor (GR) gene might play a role in the development of Cushing's disease via an increase in the relative production of the nonligand-binding splice variant of the GR, GR beta, known to exert dominant negative effects over the ligand-binding isoform, GR alpha. Alternatively, a change in overall GR expression, or mutations of some functional domains of the GR gene, might be involved in the pathogenesis of corticotroph tumors. We studied 22 tumors (17 pituitary ACTH-secreting tumors, 2 ectopic ACTH-producing tumors, 2 prolactinomas, and 1 nonfunctioning adenoma) and three normal pituitaries. RT-PCR was performed with primers specific to GR alpha and GR beta complementary DNA, followed by Southern blotting using an internal probe, and the ratio of the two bands quantitated by densitometry. We also assessed the overall expression of GR relative to the message of both the POMC gene and a housekeeping gene. Single-strand conformation polymorphism analysis of the DNA-binding domain and splice junction region of the gene was also performed. GR alpha messenger RNA was expressed at 37.3-fold +/- 5.7 (range, 32 to 46) excess, as compared with the GR beta subform. This pattern was observed both in the tumor samples and in the normal pituitaries used as controls. A majority of the ACTH-secreting tumors (16/19), including the ectopic secretors, showed variable but increased overall GR expression, whereas 3 tumors showed an expression approximately equivalent to the normal controls; however, no correlation was found between these two groups and the response to the high-dose dexamethasone test, nor was there any correlation with tumor histology. No mutations were found in any of the tumors by PCR-single-strand conformation polymorphism analysis. In conclusion, although both pituitary and ectopic ACTH-secreting tumors are at least partially glucocorticoid-resistant, no significant abnormalities in the relative expression of the two main GR subforms were observed in a series of such tumors. Additionally, mutations of regions critical to normal function of the receptor do not seem to be a frequent event in these tumors.

ACTH Syndrome, Ectopic↗
PubMed1996

Bayesian inference for hierarchical mixtures-of-experts with applications to regression and classification.

This paper studies the problems of inference and prediction in a class of models known as hierarchical mixtures-of-experts (HME). The statistical model underlying an HME is a mixture model in which both the mixture coefficients and the mixture components are generalized linear models. Bayesian inference regarding an HME's parameters is presented in the contexts of regression and classification using Markov chain Monte Carlo methods. A benefit of this Bayesian approach is the ability to obtain a sample from the posterior distribution of any functional of the parameters of the given model. In this way, more information is obtained than provided by a point estimate. The methods are illustrated on a nonlinear regression problem and on a breast cancer classification problem. The results indicate that the HME showed good prediction performance, and also gave the additional benefit of providing for the opportunity to assess the degree of certainty of the model in its predictions.

Algorithms↗
PubMed1996

Vasopressin receptor expression and mutation analysis in corticotropin-secreting tumors.

Vasopressin is an important regulator of hypothalamo-pituitary-adrenal axis activation, primarily acting through the V3 receptor (V3R). Many patients with ACTH-secreting pituitary adenomas, but not normal individuals, respond to desmopressin, a relatively V2-specific vasopressin agonist, with increased ACTH and cortisol levels. We have searched for mutations of the V3R gene in ACTH-secreting pituitary adenomas and one ectopic ACTH-secreting tumor. No abnormalities were found in 12 tumors studied by PCR-single strand conformation polymorphism (PCR-SSCP) analysis. We then verified by RT-PCR whether the response to desmopressin was due to overexpression of the V3R or abnormal expression of the V2R in the pituitary tumor. We found that the V2R gene was expressed in a number of corticotroph tumors and in the ACTH-secreting ectopic tumor, and that the V3R gene appears to be overexpressed in these tumors. We conclude that V3R mutations are unlikely to be present in the ACTH-secreting tumors we examined, but that the V2R gene is expressed in the majority of the samples tested, and the V3R is expressed in all of these tumors. We speculate that the response to the desmopressin test observed in patients with Cushing's disease may be due to abnormal expression of V3R or V2R in ACTH-secreting tumors.

Adrenocorticotropic Hormone↗
PubMed1995

On computational evidence for different types of spatial relations encoding: reply to Cook et al. (1995).

Computational models in psychology play an increasingly important role in characterizing theoretical distinctions, understanding empirical results, and formulating new predictions. However, the proper use of models is subject to debate and interpretation, as Cook, Früh, and Landis (1995) have demonstrated in a critique of neural network simulations reported by Kosslyn, Chabris, Marsolek, and Koenig (1992). These simulation results supported a distinction between two types of spatial relations encoding. Cook et al. argue that Kosslyn et al.'s models did not process "spatial" representations and that input-output correlations rather than properties of spatial relations encoding processes explain the performance of the models. This article provides conceptual and analytic rebuttals of those criticisms.

Brain↗
PubMed1995

Prosthetic joint infection due to Mycobacterium tuberculosis: report of three cases.

Prosthetic joint infection due to Mycobacterium tuberculosis is uncommon. We describe three patients with delayed tuberculous prosthetic joint infection and review the eight other cases reported in the English-language literature. Infection results from local reactivation, which can occur up to 40 years after the initial infection, or from hematogenous spread. The diagnosis is often delayed because it is not considered in the initial evaluation, because it is difficult to confirm microbiologically, or because other bacteria may be isolated from the synovial fluid and thus be considered the etiology of the infection. Treatment usually consists of removal of the prosthesis in addition to administration of antituberculous agents.

Aged↗
PubMed1995

Methods for combining experts' probability assessments.

This article reviews statistical techniques for combining multiple probability distributions. The framework is that of a decision maker who consults several experts regarding some events. The experts express their opinions in the form of probability distributions. The decision maker must aggregate the experts' distributions into a single distribution that can be used for decision making. Two classes of aggregation methods are reviewed. When using a supra Bayesian procedure, the decision maker treats the expert opinions as data that may be combined with its own prior distribution via Bayes' rule. When using a linear opinion pool, the decision maker forms a linear combination of the expert opinions. The major feature that makes the aggregation of expert opinions difficult is the high correlation or dependence that typically occurs among these opinions. A theme of this paper is the need for training procedures that result in experts with relatively independent opinions or for aggregation methods that implicitly or explicitly model the dependence among the experts. Analyses are presented that show that m dependent experts are worth the same as k independent experts where k < or = m. In some cases, an exact value for k can be given; in other cases, lower and upper bounds can be placed on k.

Bayes Theorem↗
PubMed1995

Development of adrenocorticotropin-(1-39) and precursor peptide secretory responses in the fetal sheep during the last third of gestation.

Although it is known that concentrations of immunoreactive ACTH increase during late gestation in fetal sheep plasma, the nature of the ACTH has not been well characterized. We used two-site immunoradiometric assays to separately measure high mol wt ACTH precursors (POMC and pro-ACTH) and ACTH-(1-39) in plasma of fetal sheep with chronic arterial and venous catheters. We compared the ratio of these peptides as a function of gestational age under basal conditions and in response to exogenous vasopressin and/or corticotropin-releasing hormone. Under basal conditions, the concentration of precursors was not changed throughout the last third of gestation; however, ACTH-(1-39) increased significantly approaching term. The molar ratio of precursors to ACTH-(1-39), therefore, decreased from 15.8 +/- 1.0 at 110 days to 7.9 +/- 0.6 at 140 days gestation. At all gestational ages, vasopressin and corticotropin-releasing hormone increased ACTH-(1-39) and precursors, albeit with different time courses. At 120 days gestation, arginine vasopressin plus CRH produced synergistic increases in ACTH-(1-39) and precursors, whereas the response was only additive at other ages. The present results indicate that the elevation in the resting plasma immunoreactive ACTH concentration that occurs near term is constituted by an increase in the concentration of ACTH-(1-39) relative to those of POMC and pro-ACTH, which may have further physiological significance. Also, CRH and AVP are potent stimulators of both ACTH-(1-39) and ACTH precursors.

Adrenocorticotropic Hormone↗
PubMed1995

Peripheral chemoreceptor function in children with myelomeningocele and Arnold-Chiari malformation type 2.

Blunted rebreathing hyperoxic hypercapnic ventilatory and arousal responses are frequent in older children with myelomeningocele (MMC) and Arnold-Chiari malformation type 2 (ACM). In contrast, isocapnic hypoxic rebreathing ventilatory responses are only occasionally affected. Thus, regions mediating the hypoxic ventilatory response appear usually preserved in children with MMC and ACM. Peripheral chemoreceptor function (PCR), however, has not been critically assessed in these children. To study this, PCR was measured in ten children and adolescents with MMC and ACM with normal alveolar ventilation during wakefulness, and in ten sex- and age-matched controls by measuring the ventilatory responses induced by 100% O2 breathing, five tidal breaths of 100% N2, and vital capacity breaths of 15% CO2 in O2. In general, tidal breathing of 100% O2 resulted in smaller decreases in minute ventilation (VE) responses in patients with MMC, although absent VE responses to hyperoxia were found in four patients. Vital capacity breaths of 15% CO2 elicited similar increases in VE in five patients and in ten controls, but no changes in VE were found in the remaining five patients (p < 0.02). Acute hypoxia induced by N2 tidal breathing resulted in significant linear regression correlations between VE and SpO2 in five patients with MMC, while absent responses were measured in those same five patients with absent hypercapnic responses. We conclude that PCR, when assessed by acute hypoxia, hyperoxia, or hypercapnia is abnormal in some children with MMC and ACM, particularly in those demonstrating abnormal ventilation during sleep. We postulate that the large interindividual variability of PCR is dependent on the severity of brainstem involvement of PCR afferents or central respiratory integration sites.

Adolescent↗
PubMed1995

Gestational- and labour-associated changes in the relative abundance of prostaglandin G/H synthase-1 and -2 mRNA in ovine placenta.

The aim of this study was to establish the gestational- and labour-associated variation in the relative abundance of prostaglandin synthase-1 (PGHS-1) and prostaglandin synthase-2 (PGHS-2) mRNA in ovine placenta (cotyledons). Cotyledons were collected from non-labouring ewes at 40-145 days of gestation (n = 25) and from ewes in active labour (145-147 days, n = 5). The relative abundance of PGHS-1 and PGHS-2 mRNA transcripts was determined by Northern blot analysis and laser densitometry, using a 2.3 kb sheep and a 1.2 kb mouse cDNA probe respectively. Data were expressed as a ratio of PGHS transcript hybridization/18S rRNA hybridization. During pregnancy, the relative abundance of PGHS-2 mRNA increased sevenfold, from 0.19 +/- 0.04 at 40-85 days (n = 5) to 1.39 +/- 0.05 at 140-145 days (n = 4) (P < 0.01). PGHS-1 mRNA relative abundance did not change significantly (P > 0.05) during gestation. Neither PGHS-1 nor PGHS-2 mRNA relative abundance changed significantly in association with labour onset at term (n = 5) when compared with the relative abundance observed at 140-145 days (n = 4) (P > 0.05). The data obtained in this study are consistent with the hypothesis that PGHS-1 is constitutively expressed in ovine placenta during pregnancy and at the time of labour, and that PGHS-2 is induced during the second half of pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Case report: Nocardia osteomyelitis.

Osteomyelitis is an unusual manifestation of infection with Nocardia spp, and most cases result from direct extension from a primary lung or cutaneous lesion. The authors report what they believe to be the first case of Nocardia vertebral osteomyelitis occurring postoperatively, and review the literature on the 19 previously reported cases of Nocardia osteomyelitis due to hematogenous dissemination or direct inoculation, excluding those occurring from direct extension of a mycetoma or primary lung infection.

Adult↗
PubMed1994

Chronic administration of low doses of adrenocorticotropin to hypophysectomized fetal sheep leads to normal term labor.

Parturition in the sheep is preceded by an increase in the plasma concentration of fetal ACTH and an increase in the plasma cortisol concentration. The role and importance of the increase in fetal ACTH in stimulating fetal glucocorticoid synthesis and the subsequent onset of labor require closer examination, as it has been demonstrated that the fetal adrenal becomes more responsive to ACTH in late gestation. This study sets out to determine whether the increase in plasma ACTH in the late gestation fetal sheep is essential for maturation of the fetal adrenal gland and normal delivery. Fetal sheep were either hypophysectomized (HX) and cannulated or cannulated only (intact) at 125 days gestation. Immediately after surgery, HX fetuses were infused with a constant dose of ACTH-(1-24) (ACTH/HX; 100 ng/h.kg, i.v.) or saline (SAL/HX) until uterine electromyography indicated the onset of labor or 161 days gestation was reached (term = 147 +/- 2.6 days). The mean gestational age at labor of the ACTH/HX group was 147 +/- 2.9 days, whereas none of the animals in the SAL/HX entered labor, and they were killed at 161 days gestation. The concentration of ACTH in both ACTH/HX and SAL/HX fetal plasma was less than 2.2 pg/ml throughout the study. The concentration of cortisol in ACTH/HX fetuses mimicked that in intact fetuses in late gestation, reaching 80 ng/ml at term. The concentration of cortisol in SAL/HX fetuses remained less than 5 ng/ml. This study supports the hypothesis that the ovine fetal adrenal becomes increasingly responsive to ACTH in late gestation and indicates that ACTH may only be permissive in the activation of adrenal function. In intact fetal sheep there may be endogenous inhibition of the fetal adrenal, requiring relatively high plasma concentrations of ACTH [100-250 pg/ml ACTH-(1-39)] in late gestation.

Adrenal Glands↗