Biomedical subjects

K A O'Connor

Publications and source records attributed to K A O'Connor.

At least 19 recordsLinked to original sources

PubMed2006

Ovulation detection methods for urinary hormones: precision, daily and intermittent sampling and a combined hierarchical method.

BACKGROUND: We evaluate the performance of ovulation detection methods and present new approaches, including evaluation of methods for precision, combining multiple markers into a hierarchical system and using ovulation markers in intermittent sampling designs. METHODS: With serum LH peak day as the 'gold standard' of ovulation, we estimated accuracy and precision of ovulation day algorithms using 30 ovulatory menstrual cycles with daily urinary and serum hormones and transvaginal ultrasound. Sensitivity and specificity for estimating the presence of ovulation were tested using visually assessed ovulatory (30) and anovulatory (22) cycles. RESULTS: Sensitivity and specificity ranged from 70 to 100% for estimating presence of ovulation with twice-per-cycle, weekly, twice weekly, every-other-day and daily specimens. A combined hierarchical method estimated ovulation day using daily specimens within +/-2 days of the gold standard in 93% of cases. Accuracy of estimating ovulation day within +/-2 days using intermittent sampling ranged from 40% (weekly sampling) to 97% (every-other-day). CONCLUSIONS: A combined hierarchical algorithm using precise and accurate markers allows maximal use of available data for efficient and objective identification of ovulation using daily specimens. In intermittent sampling designs, the presence and the timing of ovulation can be estimated with good sensitivity, specificity and accuracy.

Adult↗

PubMed2006

Inappropriate prescribing in the elderly: a comparison of the Beers criteria and the improved prescribing in the elderly tool (IPET) in acutely ill elderly hospitalized patients.

BACKGROUND: In appropriate prescribing is a significant and persistent problem in elderly people, both in hospital and the community and has been described in several countries in Europe and also the USA. The problem of inappropriate prescribing has not been quantified in the Republic of Ireland. The most commonly used criteria for the identification of inappropriate prescribing are the Beers' criteria [both independent of diagnosis (ID) and considering diagnosis (CD) - 2003 version]. The Beers' criteria ID includes 48 different categories of either single medications or multiple medications of a similar class identified as inappropriate prescriptions and the Beers' criteria CD contains 19 different categories containing possible drug-disease interactions. A second tool, the improved prescribing in the elderly tool (IPET) has also been validated and used in hospital and community studies and has 14 categories of either explicitly contraindicated medications or possible drug-disease interactions. OBJECTIVES: The primary aim of the study is to measure the incidence of inappropriate prescribing among older community-dwelling individuals presenting to an acute hospital in the Republic of Ireland. A secondary aim of this study was also therefore to compare the efficacy of the above two tools in identifying inappropriate prescribing. METHODS: A prospective, consecutive observational cohort study was carried out over a 4-month period. The setting was an urban-based university hospital acute geriatric medicine assessment unit. Subjects in this study (n = 350) were consecutively screened on admission to hospital (mean age = 80.3 +/- 6.1 years) and all patients had both Beers' criteria ID and CD and IPET applied to their list of prescription drugs on admission, cross-referenced with their list of current active medical diagnosis. RESULTS: The results of the study identified a high rate of inappropriate prescribing among this population of community-dwelling subjects. The total number of inappropriate prescriptions identified using the Beers' criteria (ID) was 148 affecting 121 patients. The Beers' criteria (CD) identified 69 inappropriate prescriptions in 60 patients and the IPET identified 112 inappropriate prescriptions in 78 patients. The Beers criteria (ID and CD combined) identified at least one inappropriate prescription in 34% of subjects and the IPET identified one in at least 22% of subjects. CONCLUSIONS: This study identifies high rates of use of inappropriate medications in community-dwelling elderly presenting with acute illness to hospital. These are comparable with inappropriate prescribing rates identified in previous studies. The revised Beers' criteria (2003) identified more inappropriate prescriptions than the IPET in this population of elders.

Aged↗

PubMed2006

Specific and time-dependent effects of glucocorticoid receptor agonist RU28362 on stress-induced pro-opiomelanocortin hnRNA, c-fos mRNA and zif268 mRNA in the pituitary.

This study examined the effects of the glucocorticoid receptor (GR) agonist RU28362 on stress-induced gene expression in the pituitary of rats to investigate mechanisms of glucocorticoid negative feedback in vivo. In an initial experiment, acute restraint stress produced rapid (within 15 min) induction of c-fos mRNA, zif268 mRNA and pro-opiomelanocortin (POMC) hnRNA within the anterior and intermediate/posterior pituitary as determined by quantitative real-time polymerase chain reaction. Treatment with RU28362 (150 microg/kg, i.p.) 60 min before restraint inhibited adrenocorticotrophic hormone (ACTH) and corticosterone secretion and selectively suppressed the stress-induced increase in POMC hnRNA in the anterior pituitary gland. The failure of RU28362 to surpress the stress-induced rise in c-fos and expression of zif268 mRNA suggests that the central release of ACTH secretagogues was not affected at this time point by treatment with the GR agonist. Rather, the inhibition of ACTH release appeared to be due to a direct effect of RU28362 within the pituitary. A follow-up time-course study varied the interval (10, 60 or 180 min) between RU28362 pretreatment and the onset of restraint. The stress-induced increase in POMC hnRNA was completely blunted by RU28362 treatment within 10 min of treatment, although the stress induced hormone secretion, c-fos mRNA and zif268 mRNA were unaffected. The rapid inhibition of the stress-induced rise in POMC hnRNA in the anterior pituitary appears to reflect direct, GR-mediated suppression of POMC gene expression. RU28362 pretreatment 180 min before restraint onset was sufficient to suppress the stress-induced expression in the anterior pituitary gland of all three genes examined. Thus, the delayed negative feedback effects on hypothalamic-pituitary-adrenal axis activity that emerged after 180 min after glucocorticoid treatment were not evident at 60 min. Taken together, the data suggest that the inhibition of the stress-induced release of ACTH apparent within the first hour of glucocorticoid exposure is effected at the level of the pituitary gland. The delayed glucocorticoid effects evident 180 min after RU28362 treatment may include glucocorticoid actions in the brain and additional actions within the pituitary.

Adrenocorticotropic Hormone↗

PubMed2004

The role of IL-1beta in stress-induced sensitization of proinflammatory cytokine and corticosterone responses.

Proinflammatory cytokines often sensitize neuronal, hormonal, and behavioral responses to subsequent challenge. Recently, it was observed that exposure to inescapable tailshock enhances peripheral and central proinflammatory cytokine and corticosterone (CORT) responses to subsequent immune challenge up to 4 days later. Thus, we examined the role of central interleukin-1beta (IL-1beta) in stress-induced sensitization of proinflammatory cytokine and CORT responses to a subsequent immune challenge. Rats were administered IL-1 receptor antagonist (IL-1ra) or vehicle into the intra-cisterna magna 1 h prior to tailshock (100, 1.6 mA 5 s shocks) exposure. Twenty-four hours later, rats were challenged i.p. with 10 microg/kg lipopolysaccharide (LPS) and killed 1 h later. IL-1ra had no effect on basal proinflammatory cytokines, but completely blocked the stress-induced enhancement in central and pituitary IL-1beta and plasma IL-6 release following LPS challenge. IL-1ra had no effect on stress-induced enhancement in CORT responses following LPS challenge. Additional rats were administered i.c.v. hrIL-1beta or vehicle and returned to their home cage. Twenty-four hours later, rats were challenged i.p. with either saline or 10 microg/kg LPS and killed 1 h later. Central hrIL-1beta administration significantly elevated central IL-1beta levels and plasma CORT following LPS challenge compared with vehicle-injected controls. These data demonstrate that elevations in central IL-1beta, whether stress-induced or exogenously administered, are sufficient for sensitizing central IL-1beta and CORT responses to subsequent immune challenge. However, during times of stress, exogenous central IL-1ra administration only blocked sensitization of subsequent central IL-1beta responses, not CORT responses, suggesting other factors during the stress response can sensitize CORT responses.

Animals↗

PubMed2004

Antibiotic prescribing policy and Clostridium difficile diarrhoea.

BACKGROUND: Broad-spectrum antibiotics, particularly intravenous cephalosporins, are associated with Clostridium difficile diarrhoea. Diarrhoea due to C. difficile is a growing problem in hospitals, especially among elderly patients. AIM: To establish whether changing an antibiotic policy with the aim of reducing the use of injectable cephalosporins leads to a reduction in the incidence of C. difficile diarrhoea in elderly patients. DESIGN: Retrospective analysis. METHODS: A group of patients who were subject to the new antibiotic policy from the period following July 2000, were compared with patients who were admitted prior to July 2000 and were not subject to the new policy. Infections, antibiotic prescriptions and mortality rates were determined from case notes, and C. difficle diarrhoea rates from microbiological data. RESULTS: Intravenous cephalosporin use fell from 210 to 28 defined daily doses (p < 0.001) following the change in antibiotic policy, with a corresponding increase in piperacillin-tazobactam (p < 0.001) and moxifloxacin (p < 0.001) use. The new policy led to a significant reduction in C. difficile diarrhoea cases. The relative risk of developing C. difficile infection with the old policy compared to the new policy was 3.24 (95%CI 1.07-9.84, p = 0.03). DISCUSSION: The antibiotic policy was successfully introduced into an elderly care service. It reduced both intravenous cephalosporin use and C. difficile diarrhoea.

Aged↗

PubMed2004

Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats.

Recent evidence suggests that spinal cord glia can contribute to enhanced nociceptive responses. However, the signals that cause glial activation are unknown. Fractalkine (CX3C ligand-1; CX3CL1) is a unique chemokine expressed on the extracellular surface of spinal neurons and spinal sensory afferents. In the dorsal spinal cord, fractalkine receptors are primarily expressed by microglia. As fractalkine can be released from neurons upon strong activation, it has previously been suggested to be a neuron-to-glial signal that induces glial activation. The present series of experiments provide an initial investigation of the spinal pain modulatory effects of fractalkine. Intrathecal fractalkine produced dose-dependent mechanical allodynia and thermal hyperalgesia. In addition, a single injection of fractalkine receptor antagonist (neutralizing antibody against rat CX3C receptor-1; CX3CR1) delayed the development of mechanical allodynia and/or thermal hyperalgesia in two neuropathic pain models: chronic constriction injury (CCI) and sciatic inflammatory neuropathy. Intriguingly, anti-CX3CR1 reduced nociceptive responses when administered 5-7 days after CCI, suggesting that prolonged release of fractalkine may contribute to the maintenance of neuropathic pain. Taken together, these initial investigations of spinal fractalkine effects suggest that exogenous and endogenous fractalkine are involved in spinal sensitization, including that induced by peripheral neuropathy.

Animals↗

PubMed2003

Circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response produced by peripheral E. coli challenge.

Peripheral administration of a variety of inflammatory stimuli, such as endotoxin or cytokines, induces an orchestrated set of brain-mediated events referred to as the sickness response. The mechanism for how immune products signal the brain is not clear, but accumulating evidence supports the existence of neural as well as blood-borne pathways. Although endotoxin or cytokine administration results in sickness responses, few data exist regarding the role of circulating endotoxin or cytokines in the induction of sickness during a real bacterial infection. Thus the present studies examined whether subcutaneously administered Escherichia coli can activate sickness responses and whether circulating endotoxin and/or proinflammatory cytokines are a prerequisite for these responses. Male Sprague-Dawley rats were injected subcutaneously with one of three doses (2.5 x 10(7), 2.5 x 10(8), 2.5 x 10(9) colony-forming units) of replicating E. coli, a ubiquitous bacterial strain, or vehicle. Core body temperature (Tc) and activity were measured for 3 days after the injection. A second set of groups of animals were killed 3, 6, 12, 18, 24, and 48 h after the injection, and blood samples and brains were collected. Injections dose dependently and consistently increased Tc and decreased activity, with increases in Tc beginning 4 h after the injection. In addition, E. coli significantly increased serum interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha and brain IL-1beta levels beginning at the 6-h time point. Corticosterone and endotoxin were first elevated in the circulation at 3 and 18 h after the injection, respectively. Because fever onset preceded brain cytokine induction, we also examined cytokine levels in the serum, brain, and inflammation site 2 and 4 h after injection. Cytokines were elevated at the inflammation site but were not detectable in the serum or brain at 2 and 4 h. We conclude that subcutaneous injection of replicating E. coli induces a consistent and naturalistic infection that includes features of the sickness response as well as increases in circulating, brain, and inflammation site tissue cytokines. In addition, injection of replicating E. coli produces a robust fever and corticosterone response at a time when there are no detectable increases in circulating cytokines or endotoxin. These results suggest that elevated levels of circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response. Therefore, fever, activity reduction, and corticosterone elevation induced by E. coli infection may have been evoked by a neural, rather than a humoral, pathway from the periphery to the brain.

Animals↗

PubMed2003

Inescapable shock induces resistance to the effects of dexamethasone.

Administration of bacterial endotoxin (lipopolysachharide; LPS) elevates proinflammatory cytokines, such as interleukin-1beta (IL-1beta) and IL-6, and activates the hypothalamic-pituitary-adrenal (HPA) axis. Corticosterone (CORT), the glucocorticoid (GC) effector hormone of the HPA axis in rats, inhibits both proinflammatory cytokine production/release and activity of the HPA axis itself. Exposure to chronic or repeated stressors often induces resistance to the effects of GCs. The following experiments were conducted to test the hypothesis that an acute stressor, inescapable tailshock (IS), alters responsivity of the HPA axis and proinflammatory cytokine system to dexamethasone (DEX), a synthetic GC. First, we examined the ability of various doses of DEX to suppress proinflammatory cytokine and HPA activity in response to LPS challenge 24 h after either home cage (HCC) or IS treatment. Upon finding resistance to DEX in IS animals, we examined the duration of the altered response to DEX by testing animals 1, 4 and 21 days after IS. To test whether IS animals were selectively resistant to the suppressive effects of DEX on the response to LPS, the ability of DEX to suppress HPA activity in response to a non-inflammatory stressor, exposure to an elevated "pedestal", was assessed. Again, DEX resistance was observed in IS animals. Finally, we examined whether changes in the responsivity to DEX were dependent upon the controllability of the stressor. The induction of DEX resistance was independent of the degree of behavioral control that the animal had over the stressor. Thus, a single session of IS induces DEX resistance of both HPA axis and cytokine responses measured in vivo.

Adaptation, Physiological↗

PubMed2002

Blockade of alpha1 adrenoreceptors in the dorsal raphe nucleus prevents enhanced conditioned fear and impaired escape performance following uncontrollable stressor exposure in rats.

Previous research has shown that the effect of exposure to uncontrollable stressors on conditioned fear responding and escape behavior in rats is dependent on serotonergic neural activity in the dorsal raphe nucleus (DRN). The role that norepinephrine released in the DRN plays in producing the behavioral consequences of exposure to inescapable tail shock in rats was investigated in the present study. The selective alpha1 adrenoreceptor antagonist benoxathian was injected into the DRN before exposure to inescapable tail shock or before behavioral testing conducted 24 h later. Benoxathian prevented the impairment of escape responding produced by inescapable shock, but did not reverse this effect when given before testing. The enhancement of conditioned fear produced by prior inescapable shock was attenuated by benoxathian administered before inescapable shock or before behavioral testing. These results support the view that noradrenergic input to the DRN is necessary to produce the behavioral effects of inescapable tail shock.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2001

Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord proinflammatory cytokines.

Perispinal (intrathecal) injection of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein gp120 creates exaggerated pain states. Decreases in response thresholds to both heat stimuli (thermal hyperalgesia) and light tactile stimuli (mechanical allodynia) are rapidly induced after gp120 administration. gp120 is the portion of HIV-1 that binds to and activates microglia and astrocytes. These glial cells have been proposed to be key mediators of gp120-induced hyperalgesia and allodynia because these pain changes are blocked by drugs thought to affect glial function preferentially. The aim of the present series of studies was to determine whether gp120-induced pain changes involve proinflammatory cytokines [interleukin-1beta (IL-1) and tumor necrosis factor-alpha (TNF-alpha)], substances released from activated glia. IL-1 and TNF antagonists each prevented gp120-induced pain changes. Intrathecal gp120 produced time-dependent, site-specific increases in TNF and IL-1 protein release into lumbosacral CSF; parallel cytokine increases in lumbar dorsal spinal cord were also observed. Intrathecal administration of fluorocitrate (a glial metabolic inhibitor), TNF antagonist, and IL-1 antagonist each blocked gp120-induced increases in spinal IL-1 protein. These results support the concept that activated glia in dorsal spinal cord can create exaggerated pain states via the release of proinflammatory cytokines.

Animals↗

PubMed2001

Sciatic inflammatory neuritis (SIN): behavioral allodynia is paralleled by peri-sciatic proinflammatory cytokine and superoxide production.

We have recently developed a model of sciatic inflammatory neuritis (SIN) to assess how immune activation near peripheral nerves influences somatosensory processing. Administration of zymosan (yeast cell walls) around a single sciatic nerve produces dose-dependent low-threshold mechanical allodynia without thermal hyperalgesia. Low (4 microg) doses produce both territorial and extraterritorial allodynia restricted to the injected hindleg. In contrast, higher (40 microg) doses produce territorial and extraterritorial allodynias of both hindlegs, an effect not accounted for by systemic spread of the zymosan. The aim of these experiments was to determine whether these behavioral allodynias were correlated with immunological and/or anatomical changes in or around the sciatic nerve. These experiments reveal that zymosan-induced bilateral allodynia was associated with the following: (a) increased release of both interleukin-1beta and tumor necrosis factor-alpha from peri-sciatic immune cells; (b) increased release of reactive oxygen species from perisciatic immune cells; (c) no change in circulating levels of proinflammatory cytokine; (d) no apparent zymosan-induced influx of immune cells into the sciatic nerve from the endoneurial blood vessels; (e) mild edema of the sciatic, which was predominantly restricted to superficial regions closest to the peri-sciatic immune cells; and (f) no anatomic evidence of changes in either the ipsilateral saphenous nerve or contralateral sciatic nerve that could account for the appearance of extraterritorial or contralateral ("mirror") allodynia, respectively. No reliable differences were found when the low-dose zymosan was compared with vehicle controls. Taken together, these data suggest that substances released by peri-sciatic immune cells may induce changes in the sciatic nerve, leading to the appearance of bilateral allodynia.

Animals↗

PubMed2001

Systemic administration of CNI-1493, a p38 mitogen-activated protein kinase inhibitor, blocks intrathecal human immunodeficiency virus-1 gp120-induced enhanced pain states in rats.

Intrathecal administration of the human immunodeficiency virus-1 envelope glycoprotein, gp120, activates astrocytes and microglia to release products that induce thermal hyperalgesia and mechanical allodynia. Both pain states are disrupted by intrathecal CNI-1493, a p38 mitogen-activated protein (MAP) kinase inhibitor. Whether CNI-1493, or any other p38 MAP kinase inhibitor, can cross the blood-brain barrier to affect spinal cord function is unknown. Given that several such drugs are in clinical trials, it is of interest to determine whether they may be potentially useful in treating centrally mediated pain. The aim of the present studies was to determine whether systemic CNI-1493 could block intrathecal gp120-induced thermal hyperalgesia and/or mechanical allodynia. Because p38 MAP kinase inhibition would be expected to prevent proinflammatory cytokine release and/or signal transduction, we sought to determine from the same animals the likely mechanism by which CNI-1493 blocks gp120-induced pain states. These studies show that systemic CNI-1493 blocks intrathecal gp120-induced thermal hyperalgesia and mechanical allodynia. Because CNI-1493 did not block proinflammatory cytokine release, this may suggest disruption at the level of signal transduction. These studies provide the first evidence that systemic p38 MAP kinase inhibitors can prevent centrally mediated exaggerated pain states. Thus, CNI-1493 may provide a novel therapeutic approach for the treatment of pain.

Journal Article↗

PubMed2001

The contribution of the vagus nerve in interleukin-1beta-induced fever is dependent on dose.

It has been suggested that proinflammatory cytokines communicate to the brain via a neural pathway involving activation of vagal afferents by interleukin-1beta (IL-1beta), in addition to blood-borne routes. In support, subdiaphragmatic vagotomy blocks IL-1beta-induced, brain-mediated responses such as fever. However, vagotomy has also been reported to be ineffective. Neural signaling would be expected to be especially important at low doses of cytokine, when local actions could occur, but only very small quantities of cytokine would become systemic. Here, we examined core body temperature after intraperitoneal injections of three doses of recombinat human IL-1beta (rh-IL-1beta). Subdiaphragmatic vagotomy completely blocked the fever produced by 0.1 microg/kg, only partially blocked the fever produced by 0.5 microg/kg, and had no effect at all on the fever that followed 1.0 microg/kg rh-IL-1beta. Blood levels of rh-IL-1beta did not become greater than normal basal levels of endogenous rat IL-beta until the 0.5-microg/kg dose nor was IL-1beta induced in the pituitary until this dose. These results suggest that low doses of intraperitoneal IL-1beta induce fever via a vagal route and that dose may account for some of the discrepancies in the literature.

Animals↗

PubMed2000

Developmental aggregation of Myxococcus xanthus requires frgA, an frz-related gene.

Myxococcus xanthus is a gram-negative bacterium which has a complex life cycle that includes multicellular fruiting body formation. Frizzy mutants are characterized by the formation of tangled filaments instead of hemispherical fruiting bodies on fruiting agar. Mutations in the frz genes have been shown to cause defects in directed motility, which is essential for both vegetative swarming and fruiting body formation. In this paper, we report the discovery of a new gene, called frgA (for frz-related gene), which confers a subset of the frizzy phenotype when mutated. The frgA null mutant showed reduced swarming and the formation of frizzy aggregates on fruiting agar. However, this mutant still displayed directed motility in a spatial chemotaxis assay, whereas the majority of frz mutants fail to show directed movements in this assay. Furthermore, the frizzy phenotype of the frgA mutant could be complemented extracellularly by wild-type cells or strains carrying non-frz mutations. The phenotype of the frgA mutant is similar to that of the abcA mutant and suggests that both of these mutants could be defective in the production or export of extracellular signals required for fruiting body formation rather than in the sensing of such extracellular signals. The frgA gene encodes a large protein of 883 amino acids which lacks homologues in the databases. The frgA gene is part of an operon which includes two additional genes, frgB and frgC. The frgB gene encodes a putative histidine protein kinase, and the frgC gene encodes a putative response regulator. The frgB and frgC null mutants, however, formed wild-type fruiting bodies.

ATP-Binding Cassette Transporters↗

PubMed1999

Induction of beta-lactamase influences the course of development in Myxococcus xanthus.

Myxococcus xanthus is a gram-negative bacterium that develops in response to starvation on a solid surface. The cells assemble into multicellular aggregates in which they differentiate from rod-shaped cells into spherical, environmentally resistant spores. Previously, we have shown that the induction of beta-lactamase is associated with starvation-independent sporulation in liquid culture (K. A. O'Connor and D. R. Zusman, Mol. Microbiol. 24:839-850, 1997). In this paper, we show that the chromosomally encoded beta-lactamase of M. xanthus is autogenously induced during development. The specific activity of the enzyme begins to increase during aggregation, before spores are detectable. The addition of inducers of beta-lactamase in M. xanthus, such as ampicillin, D-cycloserine, and phosphomycin, accelerates the onset of aggregation and sporulation in developing populations of cells. In addition, the exogenous induction of beta-lactamase allows M. xanthus to fruit on media containing concentrations of nutrients that are normally too high to support development. We propose that the induction of beta-lactamase is an integral step in the development of M. xanthus and that this induction is likely to play a role in aggregation and in the restructuring of peptidoglycan which occurs during the differentiation of spores. In support of this hypothesis, we show that exogenous induction of beta-lactamase can rescue aggregation and sporulation of certain mutants. Fruiting body spores from a rescued mutant are indistinguishable from wild-type fruiting body spores when examined by transmission electron microscopy. These results show that the signal transduction pathway leading to the induction of beta-lactamase plays an important role in aggregation and sporulation in M. xanthus.

Ampicillin↗

PubMed1998

Declining fecundity and ovarian ageing in natural fertility populations.

Worldwide, human fertility declines with increasing maternal age, after contraceptive-use patterns and behavioral factors are taken into consideration. Here, we summarize some of our theoretical and empirical work examining the biological factors contributing to this age pattern of fertility. We undertook an 11 month prospective endocrinological study in a natural fertility (non-contracepting) population (rural Bangladesh) to estimate the contributions of fetal loss and fecundability (the probability of conception) to declining fecundity with age. Prospective interviews and urine samples for pregnancy tests were collected twice weekly from up to 700 women. These data were used to test mathematical models of the underlying biological processes contributing to changing fecundability and fetal loss risk with maternal age. The results indicate that much of the decline in fecundity can be attributed to an increasing risk of fetal loss with maternal age. Much of this fetal loss is due to chromosomal abnormalities--a result of ageing oocytes. Fecundability, on the other hand, does not begin to decline until the early 40s. We hypothesize that this is also a result of ageing at the ovarian level, namely follicular atresia, in the years just prior to menopause. The irregularity of menstrual cycles--longer cycles and increasingly variable hormonal patterns--at these ages may be a direct result of the small and rapidly dwindling remaining pool of follicles. We present a simple mathematical model of this process, and some preliminary laboratory results that support the model.

Adult↗

PubMed1998

A commercial pregnancy test modified for field studies of fetal loss.

We describe simple modifications to the ICON II hCG (URINE) pregnancy test to provide a sensitive and specific urinary assay for hCG in field studies of fetal loss. The modified assay had a qualitative lower limit of detection of 0.30 IU/l, a 50% qualitative limit of 0.61 IU/l, a 100% qualitative limit of 1.16 IU/l, and a quantitative limit of 0.80 IU/l. Coefficients of variation ranged from 9.9% to 21.1%. Parallelism was observed among serially diluted subject samples. We used the assay in an 11-month prospective study of fetal loss in rural Bangladesh in which urine samples were collected twice-weekly from 494 women; 330 pregnancies and 93 fetal losses were detected. The median time to a positive pregnancy diagnosis was day 26 from last menses. The modified assay provided qualitative detection of early pregnancy comparable to laboratory assays, and appears to be well suited for use in epidemiologic or rural-population fetal loss studies.

Adult↗

PubMed1997

Starvation-independent sporulation in Myxococcus xanthus involves the pathway for beta-lactamase induction and provides a mechanism for competitive cell survival.

Myxococcus xanthus is a Gram-negative, soil-dwelling bacterium with a complex life cycle which includes fruiting body formation and sporulation in response to starvation. This developmental process is slow, requiring a minimum of 24-48 h, and requires cells to be at high cell density on a solid surface. It is known that, in the absence of starvation, vegetatively growing cell suspensions can form 'glycerol spores' when exposed to high levels of glycerol, usually 0.5 M. The cells differentiate from rods to resistant spheres rapidly (2-4 h) and synchronously. We have found that the chromosomally encoded beta-lactamase of M. xanthus can be induced by numerous beta-lactam antibiotics as well as by non-specific inducers including glycine and many D-amino acids. In addition, D-cycloserine, phosphomycin, and hen egg-white lysozyme also induce beta-lactamase in this bacterium. Unexpectedly, agents which induce beta-lactamase can induce 'glycerol spores'; all of the agents tested which induce glycerol spores (glycerol, DMSO, ethylene glycol) also induce beta-lactamase. During the induction of sporulation, beta-lactamase activity increases, reaching a peak during the morphological transition from rod-shaped cells to spherical spores. These spores are viable and resistant to many treatments which disrupt vegetatively growing rods but are not as resistant as fruiting body spores. The concomitant induction of beta-lactamase and starvation-independent sporulation suggests that these processes share a common signal-transduction pathway. These results also suggest that starvation-independent sporulation may be an adaptation of cells in order to resist agents that damage peptidoglycan structure and therefore threaten cell survival.

Amino Acids↗