Vigilance against bioterrorism.
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Animal Diseases↗
Biomedical subjects
C Kirby
Publications and source records attributed to C Kirby.
Influence of environmental parameters on the accuracy of nitrogen dioxide passive diffusion tubes for ambient measurement.
Two studies at three sites in the UK provided confirmation that systematic positive bias in NO2 diffusion tube measurement occurred because of changes to "within-tube" chemistry, rather than eddy diffusion at the mouth of the tube. In the first study in Cambridge, UK, sampler overestimation for 1 and 2 week exposures was compared to corresponding time-averaged monitor measurements (NO-NO2-NOx, O3) and weather variables. Noninearity between sampler and monitor NO2 measurements was interpreted in terms of spatial and temporal variations in relative and absolute availability of NO, NO2 and O3 at the site. A maximum overestimation occurred for an exposure mean NO2/NOx approximately 0.5. The separate contributions of reduced NO2 photolysis and eddy diffusion were compared in Study II using samplers of two materials, acrylic and quartz, and of different lengths (40, 55, 71 and 120 mm) at three sites: Norwich background, Cambridge intermediate, London kerbside. For compared sites, NO2 measured by acrylic samplers was significantly higher than for equivalent quartz samplers. For quartz samplers [NO2]mean was only just above the monitor at Norwich and London; sampler/monitor NO2 = 1.04 (P = 0.59) and 1.01(P = 0.76), respectively. For acrylic samplers the order of [NO2]mean was 40 mm > 120 mm > 71 mm > or = 55 mm. Excepting 40 mm samplers, this accords with a chemical bias where co-diffusing NO and 03 molecules in longer tubes have more time to react to form excess NO2. Bias in 40 mm samplers is discussed. Eddy diffusion is negligible for standard samplers because [NO2]mean was equivalent for 55 mm and 71 mm acrylic samplers and close to monitor NO2 for 71 mm quartz tubes. Both studies showed that sampler accuracy was dependent on location. Significantly, overestimation was greatest (approximately 3-4 ppb) where the NO2 annual mean was approximately 20 ppb, close to the UK and EU air quality standard of 21 ppb.
Air Pollutants↗
Crystal structures of mutant monomeric hexokinase I reveal multiple ADP binding sites and conformational changes relevant to allosteric regulation.
Hexokinase I, the pacemaker of glycolysis in brain tissue, is composed of two structurally similar halves connected by an alpha-helix. The enzyme dimerizes at elevated protein concentrations in solution and in crystal structures; however, almost all published data reflect the properties of a hexokinase I monomer in solution. Crystal structures of mutant forms of recombinant human hexokinase I, presented here, reveal the enzyme monomer for the first time. The mutant hexokinases bind both glucose 6-phosphate and glucose with high affinity to their N and C-terminal halves, and ADP, also with high affinity, to a site near the N terminus of the polypeptide chain. Exposure of the monomer crystals to ADP in the complete absence of glucose 6-phosphate reveals a second binding site for adenine nucleotides at the putative active site (C-half), with conformational changes extending 15 A to the contact interface between the N and C-halves. The structures reveal distinct conformational states for the C-half and a rigid-body rotation of the N-half, as possible elements of a structure-based mechanism for allosteric regulation of catalysis.
Adenosine Diphosphate↗
Reliability of nitrogen dioxide passive diffusion tubes for ambient measurement: in situ properties of the triethanolamine absorbent.
Factors concerning NO2 uptake by the absorbent triethanolamine (TEA) in NO2 diffusion tubes are examined. Although the nominal freezing point of TEA is 17.9-21.2 degrees C, we show that, for a range of aqueous TEA solutions (0-20%, H2O), no freezing occurs even at -10 degrees C. Therefore NO2 collection efficiency is unlikely to be impaired by low temperature exposure. The recovery of TEA from the meshes of exposed samplers is determined as approximately 98%, even after 42 days, showing that the stability in situ of TEA is unaffected by long-term exposure. A model of a diffusion tube sampling array for simultaneous exposures, with a 0.1 m sampler spacing, shows that NO2 uptake by individual samplers is not affected by the presence of neighbouring tubes in the array. This is confirmed by sampler precision at two Cambridge sites. Four sampler preparation methods are compared for differences in NO2 uptake of exposed samplers. All methods employ TEA as absorbent, transferred by either dipping meshes in a TEA-acetone solution or pipetting aliquots of a TEA-H2O solution onto the meshes. For samplers prepared by three of the methods, no difference in NO2 uptake is found, but for samplers prepared using a 50% v/v TEA-H2O solution, a mean reduction of 18% is found. Student's t-tests show that the difference is highly significant (P < or = 0.001). Reasons for the difference are discussed.
Absorption↗
Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity.
Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors.
Amphetamines↗
An overview of Medicaid managed care litigation.
Since the enactment of Medicaid in 1965, states have had the option of offering beneficiaries enrollment in managed care arrangements. With the advent of mandatory managed care reaching millions of beneficiaries (including a growing proportion of disabled recipients), the amount and scope of litigation involving Medicaid managed care plans can be expected to grow. A review of the current litigation regarding Medicaid managed care reveals two basic types of lawsuits: (1) those that challenge the practices of managed care companies under various federal and state laws that safeguard consumer rights, protect health care quality, and prohibit discrimination; and (2) suits that assert claims arising directly under the Medicaid statute and implementing regulations, as well as claims related to Constitutional safeguards that undergird the program. Lawsuits asserting claims arising under Medicaid tend to raise two basic questions: (1) the extent to which enrollment in a Medicaid managed care plan alters existing Medicaid beneficiary rights and state agency duties under federal or state Medicaid law; and (2) the extent to which managed care companies, as agents of the state, act under "color of law" (i.e., undertaking to perform official duties or acting with the imprimatur of state authority). Additionally, states might see an increase in litigation brought by prospective and current contractors who assert that they have been wrongfully denied contracts or improperly penalized for poor performance. These assertions may involve claims that are grounded in federal and state law, the Medicaid statute, and the Constitution. Moreover, in light of the consumer protection elements of the managed care reforms contained in the Balanced Budget Act, future managed care litigation may focus on the manner in which companies carry out states' obligations toward managed care enrollees. Resolution of Medicaid managed care cases involves the application of general principles of administrative and regulatory law. Thus, Medicaid managed care cases have implications for other public purchasers of managed care arrangements, including state mental health and alcohol and substance abuse agencies.
Consumer Advocacy↗
Reduced pregnancy rates following the transfer of human embryos frozen or thawed in culture media supplemented with normal serum albumin.
Over a 26 month period 17% of couples having treatment in our clinical programmes selected a commercially available protein (normal serum albumin, NSA) prepared from pooled human sera instead of using their own serum as a supplement for their embryo culture media. In a retrospective analysis of >2000 gonadotrophin-stimulated cycles and 1000 cycles where frozen/thawed embryos were transferred, fertilization, embryo quality and pregnancy rates following in-vitro fertilization (IVF), gamete intra-Fallopian transfer (GIFT) or intracytoplasmic sperm injection (ICSI) were unaffected by the type of protein used to supplement the culture medium. When embryos were thawed in medium containing NSA, both pregnancy (PR) and implantation rates (IR) were significantly lower (P <0.05) than if the medium was supplemented with serum (PR 8.3% and 17.5%; IR 4.6% and 10.5%). Inclusion of NSA before freezing reduced the IR of thawed embryos. To further test this observation all cycles where embryos were cultured and frozen in medium containing NSA (173 cycles) were matched to cycles where serum was used and the outcome was compared. At the end of 1995 just over half of the embryos in both groups had been thawed. No statistical difference was noted in the pregnancy rates (NSA, 5.6% versus serum, 11.3%) but the IR per embryo was significantly lower when embryos were cultured and frozen in medium supplemented with NSA (2.2%) than when serum was used as the supplement (6.6%).
Blood↗
Morphological observations on the fate of liposomes in the regional lymph nodes after footpad injection into rats.
Multilamellar liposomes composed of equimolar egg phosphatidylcholine and cholesterol and containing carboxyfluorescein or colloidal gold were injected subcutaneously into the footpad of the hind-leg of rats. The draining popliteal lymph nodes of animals killed at time intervals after injection were then dissected and sections examined by fluorescence microscopy (carboxyfluorescein), light microscopy using an immunogold silver kit to enhance gold particles or by transmission electron microscopy. Morphological observations confirmed that subcutaneously injected liposomes accumulate in large numbers in the draining lymph node. The majority of liposomes arrived at the subcapsular sinuses, probably via afferent lymphatic vessels, as such, i.e., in a non-cell bound form. Subsequently, liposomes were dispersed throughout the lymph node either by permeation as free vesicles along the sinuses or by cells involved in vesicle uptake. The majority of such cells were free macrophages, littoral cells and reticular cells (fixed macrophages). Once within cells, liposomes were seen digested by the lysosomal apparatus with varying loss of their lamellar structure, leaving free gold particles within the lysosomes.
Animals↗
Prevention of trauma-induced neurodegeneration in infant rat brain.
Recent evidence implicates the endogenous excitatory neurotransmitters, glutamate (Glu) and aspartate, in the pathophysiology of traumatic injury in the adult CNS, but it is not known whether similar excitotoxic mechanisms mediate traumatic injury in the immature CNS. Therefore, we developed a model of brain contusion injury in infant rats and used this model to study the nature and evolution of the acute cytopathologic changes and to evaluate the ability of Glu receptor antagonists to protect the immature brain against such changes. Seven-day-old rat pups were subjected to contusion injury and were killed 0, 0.5, 1, 2, 4, and 6 h later for histologic evaluation of the brain. Physical tearing of the dura and minor disruption of underlying brain tissue was noted at 0 h. At 30 min a discrete zone of neuronal necrosis began to appear at the border of the trauma site; this zone progressively expanded over a period of 4 h. The cytopathologic changes closely resembled the type of changes Glu is known to cause; these changes consisted of swollen dendrites, degenerating neurons with pyknotic nuclei and markedly swollen cytoplasm, and dark cells with vacuolated cytoplasm. The noncompetitive N-methyl-D-aspartate (NMDA) antagonist, dizocilpine maleate, when administered 30 min before or 1 h after trauma, significantly attenuated the lesion. The competitive NMDA antagonist, 3-((-2)-carboxypiperazine-4-yl)-propyl-1-phosphonate, was also neuroprotective. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate receptor antagonist 2,3-dihydro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline did not significantly suppress the lesion when given as three treatments (30 mg/kg each) 30 min before plus 15 and 75 min after the insult. These findings suggest that traumatic injury in the infant rat brain is mediated by endogenous excitotoxins (Glu and aspartate) acting at NMDA receptors and can be substantially mitigated by timely treatment with NMDA receptor antagonists.
Animals↗
Time-temperature effects on microbial, chemical and sensory changes during cooling and aging of cheddar cheese.
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Bacteria↗
The Boston Teacher Questionnaire. 2. Assessments of validity.
We assessed the validity of the Boston Teacher Questionnaire in a sample of 3451 9-year-old children. Those identified by the questionnaire as having a learning difficulty syndrome were compared to those without any characteristic of that syndrome. The validity reference measures were individually administered neuropsychological assessments at age 7 years and a group-administered reading achievement test at age 9 years. Girls and boys with the reading syndrome had much lower reading scores at age 9 years than did their peers. Boys, but not girls, with the arithmetic syndrome were much more likely than their peers to have arithmetic scores more than one grade below the expected level at age 7 years. Girls and boys with the tasks syndrome, characterized by impersistence, dependence, and inflexibility, were more likely than those without any features of the syndrome to be classified as having little or no goal orientation by a neuropsychologist who assessed the children in an office setting. Similarly, the neuropsychologist was much more likely than expected to have classified children with the attention syndrome as having a short attention span, and to have classified boys, but not girls, with the hyperactivity syndrome as having an unusual/extreme level and nature of overactivity. Children with any syndrome were more likely than others to have low scores on components of the Wechsler Intelligence Scale for Children, items of the Bender-Gestalt Test that assessed integration and distortion, and measures of reading comprehension. We conclude that the Boston Teacher Questionnaire validly identifies children with learning problems.
Attention Deficit Disorder with Hyperactivity↗
The effects of cooling mouse oocytes.
The effects of cooling and warming on meiotic spindles of mouse oocytes have been assessed by transmission electron microscopy. Intact cumulus-oocyte complexes were immediately cooled from 37 to 15, 4, 0, and -7 degrees C (seeding temperature) for 15 min in a programmed biological freezer and fixed at these temperatures. Other complexes, cooled to these temperatures, were rapidly warmed to 37 degrees C and incubated for 2 hr before fixation at 37 degrees C. Of 334 oocytes assessed at various temperatures, at least 100 were examined for metaphase II spindles. Spindle microtubules completely disappear at 0 and -7 degrees C, while complete or partial depolymerization of microtubules was observed at 4 degrees C. Cooling to 15 degrees C did not cause major disruptions of spindle structure in most oocytes. Chromosomes tended to rotate or clump at lower temperatures but chromosome scatter outside the spindle zone was rarely observed. Centrosomal material was fragmented at 4 degrees C and occasionally at 15 degrees C and was not evident at the spindle poles at 0 and -7 degrees C. Kinetochores were seen at all temperatures. Spindle structure was evidently restored in the majority of oocytes on rewarming at 37 degrees C. Changes in the ooplasm induced by cooling were elongation and disruption of vesicular smooth endoplasmic reticulum, especially between lipid globules and disappearance of fibrillar inclusions. Cortical granule exocytosis was not observed on cooling, while microfilaments were intact. Swelling of membranous organelles was also observed in cumulus cells. Most of the cytoplasmic changes were also reversed on rewarming. The response of mouse oocytes to cooling is compared to that of human oocytes, reported previously.
Animals↗
Mechanisms of accelerated proteolysis in rat soleus muscle atrophy induced by unweighting or denervation.
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Animals↗
Mutations in the par genes of Caenorhabditis elegans affect cytoplasmic reorganization during the first cell cycle.
A dramatic reorganization of cytoplasm occurs during the first cell cycle in embryos of the nematode, Caenorhabditis elegans. We present here the results of a quantitative study of some of the events during this reorganization in wild-type embryos and in par mutant embryos. The par mutations define a set of genes required for cytoplasmic localization in early embryos. We show that par mutations lead to defects in several events of the reorganization. Mutations in all four of the par genes we studied lead to defects in pseudocleavage and asymmetric redistribution of cortical microfilaments. In addition, some of the par mutations affect streaming of cytoplasm, migration of the pronuclei, and asymmetric shortening of the embryo. We propose that the major function of the par genes might be to orchestrate this initial reorganization of cytoplasm.
Actin Cytoskeleton↗
Problems in the cryopreservation of unfertilized eggs by slow cooling in dimethyl sulfoxide.
The survival, fertilization, development, and viability in vitro and in vivo of unfertilized mouse eggs frozen by slow cooling to -36 degrees C or -80 degrees C in 1.5 M dimethyl sulphoxide (DMSO) was examined in a series of experiments which explored some of the problems in freezing the egg. DMSO was added to the eggs at either room temperature or at 0 degrees C. Maximum success rate (42% of frozen eggs developing to two cells) was obtained when DMSO was added at 0 degrees C and the eggs slow cooled to -80 degrees C. Removal of cumulus failed to improve freezing success rates. Addition of DMSO at temperatures above 0 degrees C significantly reduced the fertilizing capacity of eggs. Excessive exposure of eggs to temperatures around 15 degrees C also caused a significant reduction in fertilization rates. The effects of DMSO and cooling on fertilization are likely to be due to zona hardening by cortical granule release and to disorganization of the egg cytoskeleton and plasma membrane. These problems will be difficult to overcome if cryopreservation of the unfertilized human egg is preferred to the fertilized egg or early cleavage stage embryo in clinical in vitro fertilization.
Animals↗
Changes in muscles accompanying non-weight-bearing and weightlessness.
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Ammonium Chloride↗
Vitrification of mouse oocytes results in aneuploid zygotes and malformed fetuses.
Vitrification of mouse oocytes adversely affected the subsequent developmental potential of embryos and fetuses derived from the fertilization of such oocytes after thawing. Only 5% of oocytes vitrified formed viable fetuses on the 15th day of gestation as compared to 47% in the controls. The incidence of chromosomally aneuploid zygotes, derived from cryopreserved oocytes, was approximately threefold higher than the controls irrespective of whether the oocytes were cryopreserved by vitrification or DMSO slow-freezing. Malformed fetuses were obtained from oocytes that had been vitrified as well as those that had been exposed to vitrification solutions only, whereas no malformed fetuses were obtained in oocytes slow-frozen by DMSO or fresh controls--thus demonstrating that the exposure of oocytes to the vitrification chemicals was responsible for the fetal malformations. The data in this study suggest that the vitrification technique should be cautiously applied to human oocyte cryopreservation. Furthermore, the data also demonstrate that the exposure of female gametes to carcinogenic and/or teratogenic chemicals may result in malformed embryos when such oocytes are subsequently fertilized.
Aneuploidy↗
Ultrarapid freezing of early cleavage stage human embryos and eight-cell mouse embryos.
Early cleavage stage human embryos and 8-cell mouse embryos were snap-frozen after a brief exposure to high concentrations of dimethyl sulfoxide (DMSO; 2 or 3.5 M) and 0.25 M sucrose and thawed in a warm water bath. Eleven of 12 3- to 8-cell human embryos survived freezing and thawing with more than 50% of their original blastomeres intact. However, pregnancy was not initiated when the 11 embryos were transferred to six patients. It was shown that continuation of embryonic development in vitro and in vivo was significantly better when 8-cell mouse embryos were snap-frozen in 3.5 M DMSO than in 2 M DMSO. When frozen in 3.5 M DMSO, 78% of 8-cell embryos survived on thawing, 84% developed to blastocysts in vitro, 63% implanted, and 42% developed to fetuses. Ultrarapid freezing is a quick and inexpensive method for mouse embryo cryobanking, but further studies are required to confirm the viability of frozen human embryos.
Animals↗