The mechanics of the baby boom: Unveiling the role of the epidemiologic transition.

Recent research on the baby boom and its causes has shown that common explanations, such as the recuperation of births following the Great Depression or Second World War, are not sufficient to account for the phenomenon. However, that research has stressed the role of increasing nuptiality. In this paper, we argue that the increase in survivorship of children and young people that resulted from the epidemiologic transition accounted for a large portion of the increased number of births during the baby boom. We use a microsimulation model to assess the respective roles of mortality, nuptiality, fertility, and immigration on the size and dynamics of the boom in Quebec, Canada. Results show that decreasing mortality contributed significantly to the baby boom, along with immigration and nuptiality changes, while fertility rates attenuated the phenomenon. These results substantiate the hypothesis that the epidemiologic transition was an important cause of the baby boom.

Neurobehavioral and Cardiovascular Effects of Potassium Cyanide Administered Orally to Mice.

The Food and Drug Administration Animal Rule requires evaluation of cardiovascular and central nervous system (CNS) effects of new therapeutics. To characterize an adult and juvenile mouse model, neurobehavioral and cardiovascular effects and pathology of a single sublethal but toxic, 8 mg/kg, oral dose of potassium cyanide (KCN) for up to 41 days postdosing were investigated. This study describes the short- and long-term sensory, motor, cognitive, and behavioral changes associated with oral dosing of a sublethal but toxic dose of KCN utilizing functional observation battery and Tier II CNS testing in adult and juvenile mice of both sexes. Selected tissues (histopathology) were evaluated for changes associated with KCN exposure with special attention to brain regions. Telemetry (adult mice only) was used to evaluate cardiovascular and temperature changes. Neurobehavioral capacity, sensorimotor responsivity or spontaneous locomotor activity, and rectal temperature were significantly reduced in adult and juvenile mice at 30 minutes post-8 mg/kg KCN dose. Immediate effects of cyanide included bradycardia, adverse electrocardiogram arrhythmic events, hypotension, and hypothermia with recovery by approximately 1 hour for blood pressure and heart rate effects and by 2 hours for body temperature. Lesions consistent with hypoxia, such as mild acute tubular necrosis in the kidneys corticomedullary junction, were the only histopathological findings and occurred at a very low incidence. The mouse KCN intoxication model indicates rapid and completely reversible effects in adult and juvenile mice following a single oral 8 mg/kg dose. Neurobehavioral and cardiovascular measurements can be used in this animal model as a trigger for treatment.

Characterization of a Mouse Model of Oral Potassium Cyanide Intoxication.

Potassium cyanide (KCN) is an inhibitor of cytochrome C oxidase causing rapid death due to hypoxia. A well-characterized model of oral KCN intoxication is needed to test new therapeutics under the Food and Drug Administration Animal Rule. Clinical signs, plasma pH and lactate concentrations, biomarkers, histopathology, and cyanide and thiocyanate toxicokinetics were used to characterize the pathology of KCN intoxication in adult and juvenile mice. The acute oral LD50s were determined to be 11.8, 11.0, 10.9, and 9.9 mg/kg in water for adult male, adult female, juvenile male, and juvenile female mice, respectively. The time to death was rapid and dose dependent; juvenile mice had a shorter mean time to death. Juvenile mice displayed a more rapid onset and higher incidence of seizures. The time to observance of respiratory signs and prostration was rapid, but mice surviving beyond 2 hours generally recovered fully within 8 hours. At doses up to the LD50, there were no gross necropsy or microscopic findings clearly attributed to administration of KCN in juvenile or adult CD-1 mice from 24 hours to 28 days post-KCN challenge. Toxicokinetic analysis indicated rapid uptake, metabolism, and clearance of plasma cyanide. Potassium cyanide caused a rapid, dose-related decrease in blood pH and increase in serum lactate concentration. An increase in fatty acid-binding protein 3 was observed at 11.5 mg/kg KCN in adult but not in juvenile mice. These studies provide a characterization of KCN intoxication in adult and juvenile mice that can be used to screen or conduct preclinical efficacy studies of potential countermeasures.

Accumulation of CD11b⁺Gr-1⁺ cells in the lung, blood and bone marrow of mice infected with highly pathogenic H5N1 and H1N1 influenza viruses.

Infection with pathogenic influenza viruses is associated with intense inflammatory disease. Here, we investigated the innate immune response in mice infected with H5N1 A/Vietnam/1203/04 and with reassortant human H1N1 A/Texas/36/91 viruses containing the virulence genes hemagglutinin (HA), neuraminidase (NA) and NS1 of the 1918 pandemic virus. Inclusion of the 1918 HA and NA glycoproteins rendered a seasonal H1N1 virus capable of inducing an exacerbated host innate immune response similar to that observed for highly pathogenic A/Vietnam/1203/04 virus. Infection with 1918 HA/NA:Tx/91 and A/Vietnam/1203/04 were associated with severe lung pathology, increased cytokine and chemokine production, and significant immune cell changes, including the presence of CD11b(+)Gr-1(+) cells in the blood, lung and bone marrow. Significant differential gene expression in the lung included pathways for cell death, apoptosis, production and response to reactive oxygen radicals, as well as arginine and proline metabolism and chemokines associated with monocyte and neutrophil/granulocyte accumulation and/or activation. Arginase was produced in the lung of animals infected with A/Vietnam/1204. These results demonstrate that the innate immune cell response results in the accumulation of CD11b(+)Gr-1(+) cells and products that have previously been shown to contribute to T cell suppression.

Macaque proteome response to highly pathogenic avian influenza and 1918 reassortant influenza virus infections.

The host proteome response and molecular mechanisms that drive disease in vivo during infection by a human isolate of the highly pathogenic avian influenza virus (HPAI) and 1918 pandemic influenza virus remain poorly understood. This study presents a comprehensive characterization of the proteome response in cynomolgus macaque (Macaca fascicularis) lung tissue over 7 days of infection with HPAI (the most virulent), a reassortant virus containing 1918 hemagglutinin and neuraminidase surface proteins (intermediate virulence), or a human seasonal strain (least virulent). A high-sensitivity two-dimensional liquid chromatography-tandem mass spectroscopy strategy and functional network analysis were implemented to gain insight into response pathways activated in macaques during influenza virus infection. A macaque protein database was assembled and used in the identification of 35,239 unique peptide sequences corresponding to approximately 4,259 proteins. Quantitative analysis identified an increase in expression of 400 proteins during viral infection. The abundance levels of a subset of these 400 proteins produced strong correlations with disease progression observed in the macaques, distinguishing a "core" response to viral infection from a "high" response specific to severe disease. Proteome expression profiles revealed distinct temporal response kinetics between viral strains, with HPAI inducing the most rapid response. While proteins involved in the immune response, metabolism, and transport were increased rapidly in the lung by HPAI, the other viruses produced a delayed response, characterized by an increase in proteins involved in oxidative phosphorylation, RNA processing, and translation. Proteomic results were integrated with previous genomic and pathological analysis to characterize the dynamic nature of the influenza virus infection process.

Temporal coding by populations of auditory receptor neurons.

Auditory receptor neurons of crickets are most sensitive to either low or high sound frequencies. Earlier work showed that the temporal coding properties of first-order auditory interneurons are matched to the temporal characteristics of natural low- and high-frequency stimuli (cricket songs and bat echolocation calls, respectively). We studied the temporal coding properties of receptor neurons and used modeling to investigate how activity within populations of low- and high-frequency receptors might contribute to the coding properties of interneurons. We confirm earlier findings that individual low-frequency-tuned receptors code stimulus temporal pattern poorly, but show that coding performance of a receptor population increases markedly with population size, due in part to low redundancy among the spike trains of different receptors. By contrast, individual high-frequency-tuned receptors code a stimulus temporal pattern fairly well and, because their spike trains are redundant, there is only a slight increase in coding performance with population size. The coding properties of low- and high-frequency receptor populations resemble those of interneurons in response to low- and high-frequency stimuli, suggesting that coding at the interneuron level is partly determined by the nature and organization of afferent input. Consistent with this, the sound-frequency-specific coding properties of an interneuron, previously demonstrated by analyzing its spike train, are also apparent in the subthreshold fluctuations in membrane potential that are generated by synaptic input from receptor neurons.

Kinetics of lethal factor and poly-D-glutamic acid antigenemia during inhalation anthrax in rhesus macaques.

Systemic anthrax manifests as toxemia, rapidly disseminating septicemia, immune collapse, and death. Virulence factors include the anti-phagocytic gamma-linked poly-d-glutamic acid (PGA) capsule and two binary toxins, complexes of protective antigen (PA) with lethal factor (LF) and edema factor. We report the characterization of LF, PA, and PGA levels during the course of inhalation anthrax in five rhesus macaques. We describe bacteremia, blood differentials, and detection of the PA gene (pagA) by PCR analysis of the blood as confirmation of infection. For four of five animals tested, LF exhibited a triphasic kinetic profile. LF levels (mean +/- standard error [SE] between animals) were low at 24 h postchallenge (0.03 +/- 1.82 ng/ml), increased at 48 h to 39.53 +/- 0.12 ng/ml (phase 1), declined at 72 h to 13.31 +/- 0.24 ng/ml (phase 2), and increased at 96 h (82.78 +/- 2.01 ng/ml) and 120 h (185.12 +/- 5.68 ng/ml; phase 3). The fifth animal had an extended phase 2. PGA levels were triphasic; they were nondetectable at 24 h, increased at 48 h (2,037 +/- 2 ng/ml), declined at 72 h (14 +/- 0.2 ng/ml), and then increased at 96 h (3,401 +/- 8 ng/ml) and 120 h (6,004 +/- 187 ng/ml). Bacteremia was also triphasic: positive at 48 h, negative at 72 h, and positive at euthanasia. Blood neutrophils increased from preexposure (34.4% +/- 0.13%) to 48 h (75.6% +/- 0.08%) and declined at 72 h (62.4% +/- 0.05%). The 72-h declines may establish a "go/no go" turning point in infection, after which systemic bacteremia ensues and the host's condition deteriorates. This study emphasizes the value of LF detection as a tool for early diagnosis of inhalation anthrax before the onset of fulminant systemic infection.

Behaviorally relevant burst coding in primary sensory neurons.

Bursts of action potentials in sensory interneurons are believed to signal the occurrence of particularly salient stimulus features. Previous work showed that bursts in an identified, ultrasound-tuned interneuron (AN2) of the cricket Teleogryllus oceanicus code for conspicuous increases in amplitude of an ultrasound stimulus, resulting in behavioral responses that are interpreted as avoidance of echolocating bats. We show that the primary sensory neurons that inform AN2 about high-frequency acoustic stimuli also produce bursts. As is the case for AN2, bursts in sensory neurons perform better as feature detectors than isolated, nonburst, spikes. Bursting is temporally correlated between sensory neurons, suggesting that on occurrence of a salient stimulus feature, AN2 will receive strong synaptic input in the form of coincident bursts, from several sensory neurons, and that this might result in bursting in AN2. Our results show that an important feature of the temporal structure of interneuron spike trains can be established at the earliest possible level of sensory processing, i.e., that of the primary sensory neuron.

Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus.

The mechanisms responsible for the virulence of the highly pathogenic avian influenza (HPAI) and of the 1918 pandemic influenza virus in humans remain poorly understood. To identify crucial components of the early host response during these infections by using both conventional and functional genomics tools, we studied 34 cynomolgus macaques (Macaca fascicularis) to compare a 2004 human H5N1 Vietnam isolate with 2 reassortant viruses possessing the 1918 hemagglutinin (HA) and neuraminidase (NA) surface proteins, known conveyors of virulence. One of the reassortants also contained the 1918 nonstructural (NS1) protein, an inhibitor of the host interferon response. Among these viruses, HPAI H5N1 was the most virulent. Within 24 h, the H5N1 virus produced severe bronchiolar and alveolar lesions. Notably, the H5N1 virus targeted type II pneumocytes throughout the 7-day infection, and induced the most dramatic and sustained expression of type I interferons and inflammatory and innate immune genes, as measured by genomic and protein assays. The H5N1 infection also resulted in prolonged margination of circulating T lymphocytes and notable apoptosis of activated dendritic cells in the lungs and draining lymph nodes early during infection. While both 1918 reassortant viruses also were highly pathogenic, the H5N1 virus was exceptional for the extent of tissue damage, cytokinemia, and interference with immune regulatory mechanisms, which may help explain the extreme virulence of HPAI viruses in humans.

Carrier-dependent temporal processing in an auditory interneuron.

Signal processing in the auditory interneuron Omega Neuron 1 (ON1) of the cricket Teleogryllus oceanicus was compared at high- and low-carrier frequencies in three different experimental paradigms. First, integration time, which corresponds to the time it takes for a neuron to reach threshold when stimulated at the minimum effective intensity, was found to be significantly shorter at high-carrier frequency than at low-carrier frequency. Second, phase locking to sinusoidally amplitude modulated signals was more efficient at high frequency, especially at high modulation rates and low modulation depths. Finally, we examined the efficiency with which ON1 detects gaps in a constant tone. As reflected by the decrease in firing rate in the vicinity of the gap, ON1 is better at detecting gaps at low-carrier frequency. Following a gap, firing rate increases beyond the pre-gap level. This "rebound" phenomenon is similar for low- and high-carrier frequencies.

Transcriptional responses in spleens from mice exposed to Yersinia pestis CO92.

Yersinia pestis is one of the most threatening biological agents due to the associated high mortality and history of plague pandemics. Identifying molecular players in the host response to infection may enable the development of medical countermeasures against Y. pestis. In this study, microarrays were used to identify the host splenic response mechanisms to Y. pestis infection. Groups of Balb/c mice were injected intraperitoneally with 2-257CFU of Y. pestis strain CO92 or vehicle. One group was assessed for mortality rates and another group for transcriptional analysis. The time to death at the 8 and 257CFU challenge doses were 5.0+/-2.3 and 3.8+/-0.4 days, respectively. Gene profiling using Affymetrix Mouse Genome 430 2.0 Arrays revealed no probe sets were significantly altered for all five mice in the low-dose group when compared to the vehicle controls. However, 534 probe sets were significantly altered in the high dose versus vehicle controls; 384 probe sets were down-regulated and 150 probe sets were up-regulated. The predominant biological processes identified were immune function, cytoskeletal, apoptosis, cell cycle, and protein degradation. This study provides new information on the underlying transcriptional mechanisms in mice to Y. pestis infection.

Evaluation of Acute Immunotoxicity of Aerosolized Aflatoxin B(1) in Female C57BL/6N Mice.

There is evidence for immunotoxicity of aflatoxin B1 (AFB(1)) in chronic animal feeding studies; however, little information is available as to the effects of inhalation exposure. This study evaluated the acute affects of aerosolized AFB(1) on systemic immune function of female C57BL/6N mice following a single aerosol exposure. Mice were exposed in nose-only inhalation tubes to 0, 2.86, 6.59 and 10 mug AFB(1) aerosol/L air for 90 minutes. A negative control group of untreated mice and a positive control group of cyclophosphamide-treated mice were included to account for day to day variation. Three days following exposure, mice were sacrificed and body, liver, lung, thymus and spleen weights, and complete blood counts and white blood cell differentials were measured. Splenocytes were isolated for flow cytometric analysis of CD4(+) and CD8(+) lymphocytes, CD19(+) B-cells and natural killer cells (NK 1.1(+)). The effect of AFB(1) on humoral immunity was assessed by measuring serum anti-keyhole limpet hemocyanin (KLH) IgM levels. Of the tissues examined, only the thymus weight of AFB(1) exposed mice decreased significantly compared to naive mice; however, the decrease was not dose related and was also observed in the 0 AFB(1) aerosol control group. A decrease in the mean white blood cell count of treated vs. naive mice was observed at all dose levels but was clearly not dose related and was statistically significant only in the 0 and 2.86 mug/L groups. Red blood cell and platelet counts and white blood cell differentials were not significantly affected by AFB(1). The number of CD4(+) (helper T-cells), CD8(+) (cytotoxic T-cells) and CD19(+) (B-cells) decreased in spleens of AFB(1) aerosol exposed mice compared to naive mice; however, the decrease was not dose-related and was also observed in the 0 AFB(1) exposure group. Dose-related changes in the CD4(+)/CD8(+) T-lymphocyte ratios were not observed. The IgM response to KLH was not significantly different in AFB(1) compared to naive mice, suggesting that AFB(1) did not effect antigen-specific antibody production. Based on the results of this study, a single AFB(1) inhalation exposure up to 10 mug/L for 90 minutes (CxT = 900 mug .min/L) did not significantly alter the immune parameters measured in this study. The aerosol vehicle (ethanol) and/or stress could have masked subtle AFB(1)-dependent changes in thymus and spleen weights, and in splenic lymphocyte subpopulations. However, for other immunological parameters, such as the IgM response to KLH, there was clearly no significant effect of AFB(1) aerosol exposure.