Evaluating biological plausibility in supporting evidence for action through systematic reviews in public health.

OBJECTIVES: The objective of this research was to develop and test methods for accessing and evaluating information on the biological plausibility of observed associations between exposures or interventions and outcomes to generate scientific evidence for action consistent with practice in systematic reviews. STUDY DESIGN: To undertake this research, we used the example of the observed associations between antimicrobial use in food animals and increased risks of human exposures to antimicrobial-resistant pathogens of zoonotic origin. METHODS: We conducted a scoping search using terms related to biological plausibility or mechanism to identify key references. As recommended by these references, we also used expert consultation with researchers and a public health informationist. We used their recommendations, which included expert consultation, to identify mechanisms relevant to biological plausibility of the association we selected to test. We used the reviews conducted by the World Health Organization (WHO) Guidelines Development Group in support of reducing antimicrobial use in food animal production to populate our model for assessing biological plausibility. RESULTS: We were able to develop a transparent model for biological plausibility based on the adverse outcome pathway used in toxicology and ecology. We were also able to populate this model using the WHO reviews. CONCLUSIONS: This analysis of biological plausibility used transparent and validated methods to assess the evidence used in systematic reviews based on the observational studies accessed through searches of the scientific literature. Given the importance of this topic in systematic reviews and evidence-based decision-making, further research is needed to define and test the methodological approaches to access and properly evaluate information from the scientific literature.

Optical filtering enabled by cascaded parametric amplification.

A cascaded parametric amplifier consists of a first parametric amplifier, which amplifies an input signal and generates an idler, which is a copy of the signal, a signal processor, which controls the phases of the signal and idler, and a second parametric amplifier, which combines the signal and idler in a phase-sensitive manner. In this paper, cascaded parametric amplification is modeled and the conditions required to maximize the constructive-destructive extinction ratio are determined. The results show that a cascaded parametric amplifier can be operated as a filter: A desired signal-idler pair is amplified, whereas undesired signal-idler pairs are deamplified. For the desired signal and idler, the noise figures of the filtering process (input signal-to-noise ratio divided by the output ratios) are only slightly higher than those of the copying process: Signal-processing functionality can be achieved with only a minor degradation in signal quality.

Continuously active interferometer stabilization and control for time-bin entanglement distribution.

We describe a new method enabling continuous stabilization and fine-level phase control of time-bin entanglement interferometers. Using this technique we demonstrate entangled photon transmission through 50 km of standard single-mode fiber. This technique reuses the entangled-pair generation pump which is co-propagated with the transmitted entangled photons. The co-propagating pump adds minimal noise to the entangled photons which are characterized by measuring a two-photon interference fringe.

Signal replication by multiple sum- or difference-frequency generation.

In this paper, the coupled-mode equations for sum-frequency generation (SFG) and difference-frequency generation (DFG) driven by multiple pumps are solved, and the noise figures of idler generation are determined. For SFG, the (common) noise figure is n, the number of pumps (and idlers), whereas for DFG, the (common) noise figure is 2, independent of n. Thus, DFG driven by multiple pumps enables the generation of multiple low-noise idlers.

Generation of 21.3 Gbaud 8PSK signal using an SOA-based all-optical phase modulator.

We describe a novel SOA-based all-optical pure-phase modulator, and show how deleterious cross-gain modulation from the SOAs can be suppressed by utilizing an integrated interferometer structure. We experimentally demonstrate the use of the optical gate as a π/4 phase modulator producing 21.3 Gbaud 8PSK from 21.3 Gbit/s OOK and 21.3 Gbaud QPSK inputs. The modulator produces 3 dB of gain and coherent detection-based bit error rate measurements indicate a 2.4 dB excess penalty.

Phase discrimination and simultaneous frequency conversion of the orthogonal components of an optical signal by four-wave mixing in an SOA.

Simultaneous conversion of the two orthogonal phase components of an optical input to different output frequencies has been demonstrated by simulation and experiment. A single stage of four-wave mixing between the input signal and four pumps derived from a frequency comb was employed. The nonlinear device was a semiconductor optical amplifier, which provided overall signal gain and sufficient contrast for phase sensitive signal processing. The decomposition of a quadrature phase-shift keyed signal into a pair of binary phase-shift keyed outputs at different frequencies was also demonstrated by simulation.

All-optical technique for modulation format conversion from on-off-keying to alternate-mark-inversion.

We propose and numerically investigate for the first time a novel all-optical on-off-keying to alternate-mark-inversion modulation format converter operating at 40 Gbps employing a semiconductor optical amplifier (SOA)-based Mach-Zehnder interferometer (MZI). We demonstrate that this SOA-MZI operates as a pulse subtractor, and in the absence of patterning will produce perfectly phase inverted pulses regardless of the individual SOA phase excursions. We use a comprehensive computer model to illustrate the impact of patterning on the output phase modulation, which is quantified through the definition of the phase compression factor.

Pattern compensation in SOA-based gates.

We propose a novel scheme employing complementary data inputs to overcome the patterning normally associated with semiconductor optical amplifier based gates and demonstrate the scheme experimentally at 42.6Gb/s. The scheme not only avoids introducing patterning during switching, but also compensates for much of the patterning present on the input data. A novel gate was developed for the experiment to provide the complementary signals required for the scheme.

Effects of a concentrated lidocaine solution on the acute phase stress response to dehorning in dairy calves.

The objective of this study was to more fully define the surgical stress response to dehorning by heat cauterization in dairy calves by measuring behavioral, hormonal, inflammatory, and immunological markers of stress and to determine whether a nerve block of the surgical site with a concentrated solution of lidocaine (5%) reduces the degree of stress. Thirty-two 10- to 12-wk-old female Holstein calves were randomly allotted to 1 of 4 treatments: 5% lidocaine followed by dehorning, 2% lidocaine followed by dehorning, saline followed by dehorning, or 5% lidocaine followed by sham dehorning. Plasma cortisol concentration was measured in blood samples collected via a jugular catheter at -0.5, 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 24, 48, and 72 h. Various other blood constituents were measured in samples collected at -0.5, 12, 24, 48, and 72 h. Feeding, drinking, scratching, grooming, rubbing, licking, and inactivity behaviors were observed in the standing and recumbent positions using a 10-min scan sampling method analyzed on a time period and daily basis for 72 h following the dehorning procedure. The frequency of vocalization, kicking, and lying in the chute during the dehorning procedure were also assessed. The overall plasma cortisol concentrations were higher in calves subjected to dehorning than in control calves. Compared with the control group, the saline-treated calves had a higher cortisol concentration at 30 and 60 min postdehorning. Plasma cortisol concentrations were higher in all groups at 30 min postdehorning than at other sampling times. The percentage of circulating neutrophils and the neutrophil:lymphocyte ratio were increased in the saline and 2% lidocaine group. Total plasma protein, fibrinogen, and alpha1-acid glycoprotein concentrations were similar among treatments. The behavioral response to dehorning, as manifested by kicking while in the chute, was greater in the saline and 2% lidocaine group than in the control or 5% lidocaine treatment groups. In the postdehorning period, the percentage of time calves spent performing various maintenance behaviors did not differ among treatments. Thus, injection of 5% lidocaine may not provide any added comfort after the dehorning but may decrease the overall stress response during the procedure.

Dietary sodium and potassium-induced transient changes in blood pressure and catecholamine excretion in the Sprague-Dawley rat.

When Sprague-Dawley derived rats were changed from a chow type diet to a moderately high sodium diet, rapid transient changes in blood pressure (BP) and catecholamine excretion were observed. After 1 dietary week, BP increased from 122 +/- .1 mm Hg to approximately 145 mm Hg (p less than 0.001), and there was a concomitant 20% reduction in urinary norepinephrine (UNEV) and epinephrine (UEV) excretion (p less than 0.05). Heart rates were reduced (p less than 0.05). These data suggest that sodium-induced increases in BP were initially associated with suppressed sympathetic nervous system activity. During dietary Weeks 2 and 3, some animals had a persistent moderate elevation in BP (BP less than or equal to 150 mm Hg), while others developed more severe increases. UNEV in moderately hypertensive animals returned to control levels during this period; but UEV and heart rates remained suppressed. UNEV in severely hypertensive animals exceeded (13% +/- 3%, p less than 0.05) that of controls. This increase coincided with their most severe hypertension (171 +/- 1 mm Hg, p less than 0.001). UE values and heart rate data indicate that systemic adrenergic tone was likely suppressed at this time and that the increased UNEV was renal in origin. By dietary Week 4, the BP of severely hypertensive animals had begun to fall, and indices of sympathetic nervous system tone were indistinguishable among all groups. Inclusion of a dietary potassium supplement ameliorated the development of hypertension only in those animals that became severely hypertensive, and appeared to prevent the early suppression of indices of sympathetic activity.

Effect of increments in the concentration of dopamine in the central nervous system on audiogenic seizures in DBA/2J mice.

The effect on audiogenic seizures of drug-induced increments in biogenic amines in the brain was determined in DBA/2J mice. One group of mice was treated with L-dihydroxyphenylalanine (L-DOPA) which caused a large rise in levels of norepinephrine and dopamine in the central nervous system, but did not significantly alter the concentration of 5-hydroxytryptamine. This group of animals exhibited a dramatic reduction in the incidence of tonic extensor seizures. A second group of animals that had been pretreated with diethyldithiocarbamate, a dopamine-beta-hydroxylase inhibitor, was also given L-DOPA. In this group of mice, there was a highly significant rise in the concentration of dopamine in brain but no statistically-significant changes in levels of either norepinephrine or 5-hydroxytryptamine. These animals also had a dramatic decrease in the incidence of tonic extensor seizures. A third group of animals that received only diethyldithiocarbamate did not exhibit any statistically-significant changes in the incidence of seizure or in levels of biogenic amines. The drug-induced reduction in the incidence of seizure in the first two groups correlated with a large increase in levels of dopamine in brain. This reduction in seizures did not correlate with changes in levels of norepinephrine or 5-hydroxytryptamine in brain.

Effect of adrenalectomy on tyrosine hydroxylase activity.

Bilateral adrenalectomy produced a fall in blood pressure and an increase in tyrosine hydroxylase activity in the superior cervical ganglion in the rat. The fall in blood pressure and the increase in tyrosine hydroxylase activity in the superior cervical ganglion were prevented by giving the adrenalectomized animals 0.9% saline as their only drinking fluid. The increase in tyrosine hydroxylase activity was also prevented by decentralization (severing the preganglionic fiber) of the superior cervical ganglion. These results suggest that the induction of tyrosine hydroxylase activity results from a reflexly mediated increase in nerve impulse traffic that results from the adrenalectomy-induced fall in blood pressure. Further characterization of this response showed that the glucocorticoid, dexamethasone, did not cause a further induction of enzyme in adrenalectomized rats whereas, treatment with epinephrine as well as dexamethasone, did result in an augmentation of the enzyme activity above that seen in the already induced adrenalectomized animals.

Abnormalities in 5-HT1A and 5-HT1B receptor binding in severe-seizure genetically epilepsy-prone rats (GEPR-9s).

The present study was designed to determine whether abnormalities in serotonin receptor binding co-exist with the presynaptic serotonergic deficits that have previously been identified in the genetically epilepsy-prone rat (GEPR) brain. In vitro binding of [3H]8-OH-DPAT (0.16-10.3 nM) to 5-HT1A receptor sites was found to be decreased in the hippocampus of severe seizure GEPRs (GEPR-9s) when compared to nonepileptic control rats, while no difference in [3H]8-OH-DPAT binding was observed in the GEPR-9 corpora quadrigemina or midbrain tegmentum. The decreased binding of [3H]8-OH-DPAT to hippocampal membranes was due to a decrease in Bmax (P < 0.001), rather than to a change in the Kd. Conversely, in vitro binding of [125I]cyanopindolol (2-400 pM) to 5-HT1B receptor sites was increased in the GEPR-9 hippocampus, corpora quadrigemina and midbrain tegmentum when compared to nonepileptic control rats. The increased binding of [125I]cyanopindolol in all three regions resulted from an increase in the Bmax (P < 0.05), rather than a change in the Kd. These finding suggest that in addition to the innate reduction in 5-HT presynaptic markers, GEPR-9s also exhibit abnormalities in the density of 5-HT1A and 5-HT1B receptors in some regions of the brain. Inasmuch as serotonin acts to attenuate audiogenic seizures in GEPRs, these abnormalities in 5-HT receptor binding may contribute to the seizure susceptibility exhibited by these animals.

Drug excretion in human breast milk: principles, pharmacokinetics and projected consequences.

The excretion of drugs in human breast milk is reviewed with regard to milk production, composition, feeding patterns and mechanisms of drug transfer into milk. Fundamental principles of breast milk excretion are used to construct a pharmacokinetic approach useful for the study of most drugs. An infant-modulated 3-compartment open model is proposed for drug distribution and elimination in the breast feeding woman. Milk/plasma drug concentration ratios are projected on the basis of pH partitioning. While some studies confirm these projections, other studies demonstrate a need to consider additional factors such as lipid solubility and protein binding characteristics of a drug in milk. Data are lacking for most drugs and hence dosing via milk or risk to the infant remains speculative. Very few pharmacokinetic studies of both milk and infant plasma were found. A review of selected drug classes cites available information as a basis for future studies. Few drugs are contraindicated in breast feeding women, but supportive data for either proscriptions or permissive statements are often lacking. A neglected but potentially serious infant risk--impaired behaviour and development--is discussed from the standpoint of emerging animal data. Conceptually valid and comprehensive studies on drug excretion in breast milk are needed if this valuable nutrient for infants is to be made available safely.

Further evidence of anticonvulsant role for 5-hydroxytryptamine in genetically epilepsy-prone rats.

1. This study was designed to evaluate further the role of 5-hydroxytryptamine (5-HT) in regulating susceptibility and/or intensity of audiogenic seizures in genetically epilepsy-prone rats. 2. The effects of sertraline, a highly selective and potent inhibitor of 5-HT uptake, on both the intensity of the audiogenic seizures and the extracellular concentrations of 5-HT in the thalamus were evaluated in severe seizure genetically epilepsy-prone rats. 3. Sertraline (7.5, 15 and 30 mg kg-1, i.p.) produced a dose-dependent reduction in the intensity of the audiogenic seizures. 4. Brain microdialysis studies showed that the same doses of sertraline also caused dose-dependent increases in the extracellular 5-HT concentration in the thalamus of the freely moving rats. 5. The peak anticonvulsant effect correlated temporally with the peak increases in the extracellular 5-HT concentration for this drug. 6. It is concluded that enhancement of 5-hydroxytryptaminergic transmission may contribute to the anticonvulsant effect of sertraline in severe seizure genetically epilepsy-prone rats. 7. The present results coupled with earlier investigations support the hypothesis that 5-HT plays an anticonvulsant role in genetically epilepsy-prone rats.

Scope and contribution of genetic models to an understanding of the epilepsies.

Studies of the genetic models of the epilepsies emphasize that some seizure disorders result from an aberrant "wiring diagram" coupled with abnormal activity of individual neurons. These defects cause the unique seizer-triggering mechanisms operative within the epileptic nervous system but which are inactive or do not exist in normal subjects. Moreover, causes of epilepsy reside not only within the brain area, wherein initial appearance of epileptic EEG discharge occurs, but also outside that region. Etiologically significant neurochemical dysfunctions may be common features of the epileptic condition in genetic models across species. Accordingly, genetically determined convulsive epileptogenesis in rats, baboons, and humans may result partially from noradrenergic and GABAergic deficits. In contrast, genetically derived absence seizures in the rat and perhaps also humans may occur in response to GABAergic excess. The unique features of the genetically epileptic animals emphasize their usefulness in developing novel drugs that selectively ameliorate seizure predisposition.

A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders.

Noradrenergic and/or serotonergic deficits, as well as other abnormalities, may contribute to predisposition to some epilepsies and depressions. Evidence for this hypothesis stems from several sources. Epidemiological investigations are intriguing but incomplete. Pharmacological studies show that noradrenergic and/or serotonergic transmission are both anticonvulsant and antidepressant. Therapeutically pertinent investigations show that antidepressant drugs have anticonvulsant properties, whereas antiepileptic drugs are effective in the management of affective disorders. Additional investigations demonstrate that seizures, whether spontaneously occurring or therapeutically induced, protect against depression. Through studies of innate pathophysiology, noradrenergic and serotonergic deficits have been identified in individuals with depression and in animal models of epilepsy, as well as in some humans with epilepsy. Vagal nerve stimulation, a treatment already known to be effective in the epilepsies, is presently under investigation for effectiveness in affective disorder. New evidence suggests that vagal nerve stimulation exerts at least some of its therapeutic effects through its capacity to increase noradrenergic and serotonergic transmission. Finally, emerging evidence supports the concept that some genetic mammalian models of the human epilepsies exhibit analogous manifestations of depression.

Antidepressants and seizures: clinical anecdotes overshadow neuroscience.

Pharmacological treatment of depression in persons with epilepsy has been an area of controversy because some drugs commonly are perceived specifically to induce or exacerbate seizures in patients with seizure disorders. This prevailing misconception is unjustified by scientific studies, yet it continues to prevent afflicted persons from receiving appropriate therapy. The scientific literature shows that tricyclic antidepressant drugs cause seizures in overdose in both animals and humans. In lower doses, these drugs have anticonvulsant activity in humans and animals. Thus, the antidepressant drugs are like several antiepileptic drugs that can both prevent and cause seizures. The anticonvulsant activity of antidepressant drugs has been studied extensively in animals and almost certainly stems from their capacity to block norepinephrine and/or serotonin reuptake. The pharmacodynamic action responsible for their convulsant effects has not been well studied but may be due to their local anesthetic, antihistaminic, or antimuscarinic activity. The newer, more selective monoamine uptake blockers have very low convulsant liability, and it is suggested that their anticonvulsant activity, which is well documented in animals, be investigated further in humans. If their effects in humans are analogous to those in animals, these drugs can be used safely in epileptic patients with depression, and it is possible that their anticonvulsant activity can be exploited for use in the treatment of epilepsy.

Fetal raphe transplants reduce seizure severity in serotonin-depleted GEPRs.

This study investigated whether transplantation of fetal raphe tissue into genetically epilepsy-prone rats (GEPR-3s) would reduce the severity of seizures previously exacerbated by depletion of brain serotonin. Mild-seizure GEPR-3s were depleted of brain serotonin by 5,7-dihydroxytryptamine (DHT) and evaluated for seizure severity. Rats then received 15-day fetal raphe tissue, fetal neocortical tissue or were sham grafted. GEPR-3s treated with 5,7-DHT showed increased seizure severity following depletion of serotonin and subsequent reductions in severity as a result of fetal raphe transplantation. Sham- or neocortex-grafted rats maintained elevated seizure severity scores throughout the study. Prominent raphe or cortical grafts were observed within the third ventricle of GEPRs at autopsy. These findings show that transplantation of fetal raphe tissue promotes lasting reductions in increased seizure severity resulting from depletion of serotonin in the GEPR brain.

Intrauterine therapy for homozygous alpha-thalassemia.

BACKGROUND: Alpha-thalassemia is one of the most common genetic disorders in the world and is becoming more common in the United States with the increase in immigration of susceptible populations. This disease has been stated previously to be incompatible with extrauterine life. CASE: A Filipino woman with a prior loss due to hemoglobin Bart's underwent prenatal diagnosis that confirmed recurrence in the index pregnancy. Intravascular intrauterine exchange transfusions maintained appropriate fetal growth. A cesarean delivery yielded a 2190-g male infant with minor malformations. The postnatal course was characterized by mild respiratory insufficiency. Postnatal chronic transfusion therapy is underway pending consideration for bone marrow transplantation. CONCLUSION: Antenatal diagnosis and therapy of homozygous alpha-thalassemia can prevent the prenatal consequences of hydrops and fetal death. New technologies such as stem cell transplantation may help to avert both prenatal and postnatal consequences.