In Vitro and In Vivo Effects of the Bumped Kinase Inhibitor 1294 in the Related Cyst-Forming Apicomplexans Toxoplasma gondii and Neospora caninum.

We report on the in vitro effects of the bumped kinase inhibitor 1294 (BKI-1294) in cultures of virulent Neospora caninum isolates Nc-Liverpool (Nc-Liv) and Nc-Spain7 and in two strains of Toxoplasma gondii (RH and ME49), all grown in human foreskin fibroblasts. In these parasites, BKI-1294 acted with 50% inhibitory concentrations (IC50s) ranging from 20 nM (T. gondii RH) to 360 nM (N. caninum Nc-Liv), and exposure of intracellular stages to 1294 led to the nondisjunction of newly formed tachyzoites, resulting in the formation of multinucleated complexes similar to complexes previously observed in BKI-1294-treated N. caninum beta-galactosidase-expressing parasites. However, such complexes were not seen in a transgenic T. gondii strain that expressed CDPK1 harboring a mutation (G to M) in the gatekeeper residue. In T. gondii ME49 and N. caninum Nc-Liv, exposure of cultures to BKI-1294 resulted in the elevated expression of mRNA coding for the bradyzoite marker BAG1. Unlike in bradyzoites, SAG1 expression was not repressed. Immunofluorescence also showed that these multinucleated complexes expressed SAG1 and BAG1 and the monoclonal antibody CC2, which binds to a yet unidentified bradyzoite antigen, also exhibited increased labeling. In a pregnant mouse model, BKI-1294 efficiently inhibited vertical transmission in BALB/c mice experimentally infected with one of the two virulent isolates Nc-Liv or Nc-Spain7, demonstrating proof of concept that this compound protected offspring from vertical transmission and disease. The observed deregulated antigen expression effect may enhance the immune response during BKI-1294 therapy and will be the subject of future studies.

Total disc arthroplasty versus anterior cervical interbody fusion: use of the Spine Tango registry to supplement the evidence from randomized control trials.

BACKGROUND CONTEXT Several randomized controlled trials (RCTs) have compared patient outcomes of anterior (cervical) interbody fusion (AIF) with those of total disc arthroplasty (TDA). Because RCTs have known limitations with regard to their external validity, the comparative effectiveness of the two therapies in daily practice remains unknown. PURPOSE This study aimed to compare patient-reported outcomes after TDA versus AIF based on data from an international spine registry. STUDY DESIGN AND SETTING A retrospective analysis of registry data was carried out. PATIENT SAMPLE Inclusion criteria were degenerative disc or disc herniation of the cervical spine treated by single-level TDA or AIF, no previous surgery, and a Core Outcome Measures Index (COMI) completed at baseline and at least 3 months' follow-up. Overall, 987 patients were identified. OUTCOME MEASURES Neck and arm pain relief and COMI score improvement were the outcome measures. METHODS Three separate analyses were performed to compare TDA and AIF surgical outcomes: (1) mimicking an RCT setting, with admission criteria typical of those in published RCTs, a 1:1 matched analysis was carried out in 739 patients; (2) an analysis was performed on 248 patients outside the classic RCT spectrum, that is, with one or more typical RCT exclusion criteria; (3) a subgroup analysis of all patients with additional follow-up longer than 2 years (n=149). RESULTS Matching resulted in 190 pairs with an average follow-up of 17 months that had no residual significant differences for any patient characteristics. Small but statistically significant differences in outcome were observed in favor of TDA, which are potentially clinically relevant. Subgroup analyses of atypical patients and of patients with longer-term follow-up showed no significant differences in outcome between the treatments. CONCLUSIONS The results of this observational study were in accordance with those of the published RCTs, suggesting substantial pain reduction both after AIF and TDA, with slightly greater benefit after arthroplasty. The analysis of atypical patients suggested that, in patients outside the spectrum of clinical trials, both surgical interventions appeared to work to a similar extent to that shown for the cohort in the matched study. Also, in the longer-term perspective, both therapies resulted in similar benefits to the patients.

The mechanism of the pharmacological actions of dexrazoxane on different tissue types

Approximately 6,600 people die from acute myelogenous leukemia (AML) on an annual basis. During the past 10 to 15 years, there has been gradual overall improvements in the therapy of this disease, yet the majority of patients with AML succumb to this disease. In an attempt to improve current therapeutic strategies for AML, we became interested in a commercially available drug, dexrazoxane, which protects against anthracycline-induced cardiotoxicity. We have investigated dexrazoxane's (DEX) effects on different tissue types in an effort to determine its unique mechanism of action. Colony forming assays were used to evaluate stem-cell renewal of myeloid cells in vitro and median effect analysis was used to evaluate antagonism, synergism, or additivity. The anthracyclines, doxorubicin, daunorubicin, and idarubicin were individually combined with DEX in leukemic myeloid models to determine if the combination of the two drugs resulted in a synergistic, additive or antagonistic effect. Etoposide and cytosine arabinoside were also evaluated in combination with DEX using the same in vitro model and evaluated similarly. ^ Dexrazoxane in combination with any of the anthracyclines was schedule dependent. The combination of DEX and anthracycline resulted in a greater antitumor effect than anthracycline alone except for DEX administered 24 hours before doxorubicin or daunorubicin. These data were corroborated through median effect analysis. Etoposide in combination with dexrazoxane was synergistic for all combinations, and the combination of cytosine arabinoside and DEX was schedule dependent. In contrast, using an in vivo gastrointestinal model, DEX in combination with doxorubicin was antagonistic for almost all of the ratios used, except for the highest. A Withers' assay was used to evaluate toxicity on jejunal crypt cells. No effect was apparent for the combination of idarubicin and DEX, however, as seen with RZ, DEX in addition to radiation greatly potentiated the cytotoxic effects of radiation on crypts. These paradoxical effects of dexrazoxane were initially enigmatic, but after additional investigation, we propose a model that explains our findings. We conclude that DEX in combination with anthracyclines produces an additive to synergistic antileukemic response and may have therapeutic potential clinically. Additionally, DEX protects the gastrointestinal tract from doxorubicin toxicity, which could have clinical implications for the administration of greater doses of doxorubicin. ^

An analysis of the function of region 1.2 of the primary sigma factor, sigma 70, from Escherichia coli

The sigma (σ) subunit of eubacterial RNA polymerase is required for recognition of and transcription initiation from promoter DNA sequences. One family of sigma factors includes those related to the primary sigma factor from E. coli, σ70. Members of the σ70 family have four highly conserved domains, of which regions 2 through 4 are present in all members. Region 1 can be subdivided into regions 1.1 and 1.2. Region 1.1 affects DNA binding by σ 70 alone, as well as transcription initiation by holoenzyme. Region 1.2, present and highly conserved in most sigma factors, has not yet been assigned a putative function, although previous work demonstrated that it is not required for either association with the core subunits of RNA polymerase or promoter specific binding by holoenzyme. This study primarily investigates the functional role of region 1.2 during transcription initiation. In vivo and in vitro characterization of thirty-two single amino acid substitutions targeted to region 1.2 of E. coli σ70 as well as a deletion of region 1.2, revealed that mutations in region 1.2 can affect promoter binding, open complex formation, initiated complex formation, and the transition from abortive transcription to elongation. The relative degree of solvent exposure of several positions in region 1.2 has been determined, with positions 116 and 122 likely to be located near the surface of σ70. ^ During the course of this study, the existence of two “wild type” variants of E. coli σ70 was discovered. The identity of amino acid 149 has been reported variably as either arginine or aspartic acid in published articles and in online databases. In vivo and in vitro characterization of the two reported variations of E. coli σ70 (N149 and D149) has determined that the two variants are functionally equivalent. However, in vivo and in vitro characterization of single amino acid substitutions and a region 1.2 deletion in the context of each variant background revealed that the behavior of some mutations are greatly affected by the identity of amino acid 149. ^

Characterization of the interaction between local cerebral metabolic rate for glucose and acid -base index in ischemic rat brain employing a double-isotope methodology

The association between increases in cerebral glucose metabolism and the development of acidosis is largely inferential, based on reports linking hyperglycemia with poor neurological outcome, lactate accumulation, and the severity of acidosis. We measured local cerebral metabolic rate for glucose (lCMRglc) and an index of brain pH--the acid-base index (ABI)--concurrently and characterized their interaction in a model of focal cerebral ischemia in rats in a double-label autoradiographic study, using ($\sp{14}$C) 2-deoxyglucose and ($\sp{14}$C) dimethyloxazolidinedione. Computer-assisted digitization and analysis permitted the simultaneous quantification of the two variables on a pixel-by-pixel basis in the same brain slices. Hemispheres ipsilateral to tamponade-induced middle cerebral occlusion showed areas of normal, depressed and elevated glucose metabolic rate (as defined by an interhemispheric asymmetry index) after two hours of ischemia. Regions of normal glucose metabolic rate showed normal ABI (pH $\pm$ SD = 6.97 $\pm$ 0.09), regions of depressed lCMRglc showed severe acidosis (6.69 $\pm$ 0.14), and regions of elevated lCMRglc showed moderate acidosis (6.88 $\pm$ 0.10), all significantly different at the.00125 level as shown by analysis of variance. Moderate acidosis in regions of increased lCMRglc suggests that anaerobic glycolysis causes excess protons to be generated by the uncoupling of ATP synthesis and hydrolysis. ^

Molecular and evolutionary genetics of the X -linked visual pigment genes in humans and New World monkeys

Normal humans have one red and at least one green visual pigment genes. These genes are tightly linked as tandem repeats on the X chromosome and each of them has six exons. There is only one X-linked visual pigment gene in New World monkeys (NWMs) but the locus has three polymorphic alleles encoding red, yellow and green visual pigments, respectively. The spectral properties of the squirrel monkey and the marmoset (both NWMs) have been studied and partial sequences of the three alleles are available. To study the evolutionary history of these X-linked opsin genes in humans and NWMs, coding and intron sequences of the three squirrel monkey alleles and the three marmoset alleles were amplified by PCR followed by subcloning and sequencing. Introns 2 and 4 of the human red and green pigment genes were also sequenced. The results obtained are as follows: (1) The sequences of introns 2 and 4 of the human red and green opsin genes are significantly more similar between the two genes than are coding sequences, contrary to the usual situation where coding regions are better conserved in evolution than are introns. The high similarities in the two introns are probably due to recent gene conversion events during evolution of the human lineage. (2) Phylogenetic analysis of both intron and exon sequences indicates that the phylogenetic tree of the available primate opsin genes is the same as the species tree. The two human genes were derived from a gene duplication event after the divergence of the human and NWM lineages. The three alleles in each of the two NWM species diverged after the split of the two NWMs but have persisted in the population for at least 5 million years. (3) Allelic gene conversion might have occurred between the three squirrel monkey alleles. (4) A model of additive effect of hydroxyl-bearing amino acids on spectral tuning is proposed by treating some unknown variables as groups. Under the assumption that some residues have no effect, it is found that at least five amino acid residues, at positions 178 (3 nm), 180 (5 nm), 230 ($-$4 nm), 277 (9 nm) and 285 (13 nm), have linear spectral tuning effects. (5) Adaptive evolution of the opsin genes to different spectral peaks was observed at four residues that are important for spectral tuning. ^

The two -state model of receptor activation: The agonist and the efficacy

The Two State model describes how drugs activate receptors by inducing or supporting a conformational change in the receptor from “off” to “on”. The beta 2 adrenergic receptor system is the model system which was used to formalize the concept of two states, and the mechanism of hormone agonist stimulation of this receptor is similar to ligand activation of other seven transmembrane receptors. Hormone binding to beta 2 adrenergic receptors stimulates the intracellular production of cyclic adenosine monophosphate (cAMP), which is mediated through the stimulatory guanyl nucleotide binding protein (Gs) interacting with the membrane bound enzyme adenylylcyclase (AC). ^ The effects of cAMP include protein phosphorylation, metabolic regulation and transcriptional regulation. The beta 2 adrenergic receptor system is the most well known of its family of G protein coupled receptors. Ligands have been scrutinized extensively in search of more effective therapeutic agents at this receptor as well as for insight into the biochemical mechanism of receptor activation. Hormone binding to receptor is thought to induce a conformational change in the receptor that increases its affinity for inactive Gs, catalyzes the release of GDP and subsequent binding of GTP and activation of Gs. ^ However, some beta 2 ligands are more efficient at this transformation than others, and the underlying mechanism for this drug specificity is not fully understood. The central problem in pharmacology is the characterization of drugs in their effect on physiological systems, and consequently, the search for a rational scale of drug effectiveness has been the effort of many investigators, which continues to the present time as models are proposed, tested and modified. ^ The major results of this thesis show that for many b2 -adrenergic ligands, the Two State model is quite adequate to explain their activity, but dobutamine (+/−3,4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methylpropyl]- b -phenethylamine) fails to conform to the predictions of the Two State model. It is a weak partial agonist, but it forms a large amount of high affinity complexes, and these complexes are formed at low concentrations much better than at higher concentrations. Finally, dobutamine causes the beta 2 adrenergic receptor to form high affinity complexes at a much faster rate than can be accounted for by its low efficiency activating AC. Because the Two State model fails to predict the activity of dobutamine in three different ways, it has been disproven in its strictest form. ^

Microthermometry and Raman analysis of fluid inclusions in different generations of quartz veins of the Athabasca Basin

The Athabasca Basin (Canada) contains the highest grade unconformity-type uranium deposits in the world. Underlying the Athabasca Group sedimentary rocks of the Dufferin Lake zone are variably graphitic pelitic schists (VGPS), altered to chlorite and hematite (Red/Green Zone: RGZ), and locally bleached near the unconformity during paleoweathering and/or later fluid interaction, leading to a loss of graphite near the unconformity. Fluid inclusions were examined in different generations of quartz veins, using microthermometry and Raman analysis, to characterize and compare the different fluids that interacted with the RGZ and the VGPS. In the VGPS, CH4-, N2- and CO2-rich fluids circulated. CH4- and N2-rich fluids could be the result of the breakdown of graphite to CH4/CO2, whereas N2-rich fluid is interpreted to be the result of breakdown of feldspars/micas to NH4+/N2. In the RGZ, highly saline fluids interpreted to be basinally derived have been recorded. The circulation of the two types of fluids (carbonic and brines) occurred at two different distinct events: 1) during the retrograde metamorphism of the basement rocks before the deposition of the Athabasca Basin for the carbonic fluids, and 2) after the deposition of the Athabasca Basin for the brines. Thus, in addition to possibly be related to graphite depletion in the RGZ, the brines can be linked to uranium mineralization.

Rewriting the history of the tyrannicides : Thucydides versus Herodotus?

Este trabajo trata sobre la famosa digresión de Tucídides en el libro sexto de su historia acerca de la caída de la tiranía en Atenas (Tuc. 6.54-59) y su relación con el relato de Heródoto. La digresión de Tucídides (y más específicamente su tono polémico) ha provocado controversia entre los comentadores, que han analizado a fondo las narrativas de los dos historiadores tanto desde una perspectiva histórica como historiográfica. Este estudio tiende a contribuir a esta discusión a través de tres sugerencias: la primera, Tucídides se mete no solo con la pequeña sección sobre los tiranicidas de la Historia de Heródoto (esto es Hdt. 5.55-65), sino, más bien, con toda la narrativa de la Historia de Heródoto sobre la liberación de Atenas de la tiranía que se extiende hasta el discurso de Socles (esto es Hdt. 5.55-5.96.2); segunda, las correcciones de Tucídides al relato de Heródoto son menores, tercera, dado que las divergencias de Tucídides con respecto a Heródoto no son decisivas para la versión correcta de los hechos, el tono polémico de Tucídides en su digresión resulta todavía más difícil de explicar. En este trabajo se sugiere tentativamente que la actitud polémica de Tucídides tiene más sentido si es interpretada en el contexto de la rivalidad del historiador con Heródoto

Rewriting the history of the tyrannicides : Thucydides versus Herodotus?

Este trabajo trata sobre la famosa digresión de Tucídides en el libro sexto de su historia acerca de la caída de la tiranía en Atenas (Tuc. 6.54-59) y su relación con el relato de Heródoto. La digresión de Tucídides (y más específicamente su tono polémico) ha provocado controversia entre los comentadores, que han analizado a fondo las narrativas de los dos historiadores tanto desde una perspectiva histórica como historiográfica. Este estudio tiende a contribuir a esta discusión a través de tres sugerencias: la primera, Tucídides se mete no solo con la pequeña sección sobre los tiranicidas de la Historia de Heródoto (esto es Hdt. 5.55-65), sino, más bien, con toda la narrativa de la Historia de Heródoto sobre la liberación de Atenas de la tiranía que se extiende hasta el discurso de Socles (esto es Hdt. 5.55-5.96.2); segunda, las correcciones de Tucídides al relato de Heródoto son menores, tercera, dado que las divergencias de Tucídides con respecto a Heródoto no son decisivas para la versión correcta de los hechos, el tono polémico de Tucídides en su digresión resulta todavía más difícil de explicar. En este trabajo se sugiere tentativamente que la actitud polémica de Tucídides tiene más sentido si es interpretada en el contexto de la rivalidad del historiador con Heródoto

Nd and Pb isotope signatures of the clay-size fraction of sediment core MD99-2227

Nd and Pb isotopes were measured on the fine fraction of one sediment core drilled off southern Greenland. This work aims to reconstruct the evolution of deep circulation patterns in the North Atlantic during the Holocene on the basis of sediment supply variations. For the last 12 kyr, three sources have contributed to the sediment mixture: the North American Shield, the Pan-African and Variscan crusts, and the Mid-Atlantic Ridge. Clay isotope signatures indicate two mixtures of sediment sources. The first mixture (12.2-6.5 ka) is composed of material derived from the North American shield and from a "young" crustal source. From 6.5 ka onward the mixture is characterized by a young crustal component and by a volcanic component characteristic of the Mid-Atlantic Ridge. Since the significant decrease in proximal deglacial supplies, the evolution of the relative contributions of the sediment sources suggests major changes in the relative contributions of the deep water masses carried by the Western Boundary Undercurrent over the past 8.4 kyr. The progressive intensification of the Western Boundary Undercurrent was initially associated mainly with the transport of the Northeast Atlantic Deep Water mass until 6.5 ka and with the Denmark Strait Overflow Water thereafter. The establishment of the modern circulation at 3 ka suggests a reduced influence of the Denmark Strait Overflow Water, synchronous with the full appearance of the Labrador Seawater mass. Our isotopic data set emphasizes several changes in the relative contribution of the two major components of North Atlantic Deep Water throughout the Holocene.

Rewriting the history of the tyrannicides : Thucydides versus Herodotus?

Este trabajo trata sobre la famosa digresión de Tucídides en el libro sexto de su historia acerca de la caída de la tiranía en Atenas (Tuc. 6.54-59) y su relación con el relato de Heródoto. La digresión de Tucídides (y más específicamente su tono polémico) ha provocado controversia entre los comentadores, que han analizado a fondo las narrativas de los dos historiadores tanto desde una perspectiva histórica como historiográfica. Este estudio tiende a contribuir a esta discusión a través de tres sugerencias: la primera, Tucídides se mete no solo con la pequeña sección sobre los tiranicidas de la Historia de Heródoto (esto es Hdt. 5.55-65), sino, más bien, con toda la narrativa de la Historia de Heródoto sobre la liberación de Atenas de la tiranía que se extiende hasta el discurso de Socles (esto es Hdt. 5.55-5.96.2); segunda, las correcciones de Tucídides al relato de Heródoto son menores, tercera, dado que las divergencias de Tucídides con respecto a Heródoto no son decisivas para la versión correcta de los hechos, el tono polémico de Tucídides en su digresión resulta todavía más difícil de explicar. En este trabajo se sugiere tentativamente que la actitud polémica de Tucídides tiene más sentido si es interpretada en el contexto de la rivalidad del historiador con Heródoto

Geochemistry of foraminifera from sediment cores of the central California margin

Under present climate conditions, convection at high latitudes of the North Pacific is restricted to shallower depths than in the North Atlantic. To what extent this asymmetry between the two ocean basins was maintained over the past 20 kyr is poorly known because there are few unambiguous proxy records of ventilation from the North Pacific. We present new data for two sediment cores from the California margin at 800 and 1600 m depth to argue that the depth of ventilation shifted repeatedly in the northeast Pacific over the course of deglaciation. The evidence includes benthic foraminiferal Cd/Ca, 18O/16O, and 13C/12C data as well as radiocarbon age differences between benthic and planktonic foraminifera. A number of features in the shallower of the two cores, including an interval of laminated sediments, are consistent with changes in ventilation over the past 20 kyr suggested by alternations between laminated and bioturbated sediments in the Santa Barbara Basin and the Gulf of California [Keigwin and Jones, 1990 doi:10.1029/PA005i006p01009; Kennett and Ingram, 1995 doi:10.1038/377510a0; Behl and Kennett, 1996 doi:10.1038/379243a0]. Data from the deeper of the two California margin cores suggest that during times of reduced ventilation at 800 m, ventilation was enhanced at 1600 m depth, and vice versa. This pronounced depth dependence of ventilation needs to be taken into account when exploring potential teleconnections between the North Pacific and the North Atlantic.

Lead 210 and silicate profiles from sediments of the equatorial Pacific and South Atlantic

Particle mixing rates have been determined for 5 South Atlantic/Antarctic and 3 equatorial Pacific deep-sea cores using excess 210Pb and 32Si measurements. Radionuclide profiles from these siliceous, calcareous, and clay-rich sediments have been evaluated using a steady state vertical advection diffusion model. In Antarctic siliceous sediments210Pb mixing coefficients (0.04-0.16 cm**2/y) are in reasonable agreement with the 32Si mixing coefficient (0.2 or 0.4 cm**2/y, depending on 32Si half-life). In an equatorial Pacific sediment core, however, the 210Pb mixing coefficient (0.22 cm**2/y) is 3-7 times greater than the 32Si mixing coefficient (0.03 or 0.07 cm**2/y). The difference in 210Pb and 32Si mixing rates in the Pacific sediments results from: (1) non-steady state mixing and differences in characteristic time and depth scales of the two radionuclides, (2) preferential mixing of fine-grained clay particles containing most of the 210Pb activity relative to coarser particles (large radiolaria) containing the 32Si activity, or (3) the supply of 222Rn from the bottom of manganese nodules which increases the measured excess 210Pb activity (relative to 226Ra) at depth and artificially increases the 210Pb mixing coefficient. Based on 32Si data and pore water silica profiles, dissolution of biogenic silica in the sediment column appears to have a minor effect on the 32Si profile in the mixed layer. Deep-sea particle mixing rates reported in this study and the literature do not correlate with sediment type, sediment accumulation rate, or surface productivity. Based on differences in mixing rate among three Antarctic cores collected within 50 km of each other, local variability in the intensity of deep-sea mixing appears to be as important as regional differences in sediment properties.

Distribution of Cycladophora davisiana davisiana in upper Pliocene and Pleistocene sediments of the North Atlantic and Labrador Sea

Upper Pliocene and Pleistocene abundance fluctuations of the radiolarian Cycladophora davisiana (Ehrenberg) davisiana (Petrushevskaya) are documented from North Atlantic (Site 609) and Labrador Sea (Site 646B) to provide the first long-term correlation of its abundance fluctuations to oxygen isotope stages 1-114. Also examined are temporal and regional fluctuations in abundances C. d. davisiana and the global dispersal routes of the species. The first occurrence of C. d. davisiana in the eastern North Atlantic Ocean (Site 609) occurred between 2.586 and 2.435 Ma (oxygen isotope stages 109.66-102.19). During the early Matuyama Chron, prior to oxygen isotope stage 63, C. d. davisiana abundances were less than 1% and never greater than 12%, while abundances of greater than 5% are found in stages 65.71-73, 74, and 83-84. The initial major abundance peak (35.7%) of C. d. davisiana was noted near the stage 63/62 boundary. Abundance peaks of greater than 15%, between oxygen isotope stages 35 and 63, are limited to stages 63.02, 58.07, 55.07-54.26, and 50.76-50.22. These represent the only such abundance peaks detected during the first c. 1.5 million years of the species within the North Atlantic. The character of C. d. davisiana abundance fluctuations in Site 609 changes after oxygen isotope stage 35; average abundances are greater (7.7% vs. 4.3%) and abundance maxima of more than 15% are more frequent. Many, but not all, peak abundances of C. d. davisiana occur in glacial stages (e.g., 8, 14, 18, 20, 26, 30, 34, 50, 54, and 58). Increased abundances of the species are also noted in weak interglacial stages (e.g., stages 3, 23, 39, and 41), and significant cool periods of robust interglacial periods (e.g., late stage 11). Sample spacing is adequate in some stages to note some rapid changes in abundance near stage transitions (e.g., stages 4/5, 25/26, 62/63). The sample density in Holes 609 and 611 and the upper portion of 646B is sufficient to detect a synchroneity of many abundance maxima and minima among sites. Some abundance peaks are undetected in one or more of the two holes, warranting further sampling to obtain a more accurate record of regional abundance fluctuations. Prior to stage 36, few ages of Hole 611 peaks are the same as those in the more precisely dated Hole 609. The highest abundances of C. d. davisiana were noted in Labrador Sea Hole 646B where the earliest known occurrence of the species is documented (3.08-2.99 Ma). C. d. davisiana is inferred to have evolved in the Labrador Sea (or Arctic), and migrated next through the Arctic into the North Pacific (2.62-2.64 Ma, stage 114) before migrating into the Norwegian Sea (2.63-2.53 Ma) and North Atlantic (2.59-2.44 Ma, stages 109-102). Additional migration of C. d. dauisiana into the southern South Atlantic (Site 704) occurred much later (2.06 Ma, stage 83).