Rate constants and activation parameters for the mobility of bulk and DNA-associated glycol-water solvents.
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DNA↗
Biomedical subjects
J G Milton
Publications and source records attributed to J G Milton.
Platelet size and shape in hereditary giant platelet syndromes on blood smear and in suspension: evidence for two types of abnormalities.
Platelet size on blood smear is compared with platelet size and shape in suspension (i.e., whole blood and citrated platelet-rich plasma [PRP]) for normal donors and 16 patients with hereditary "giant" platelet syndromes (HGPS), including Bernard-Soulier syndrome (BSS) (seven patients), Montreal platelet syndrome (MPS) (three patients), May-Hegglin anomaly (one patient) and Rafael platelet defect (one patient). In whole blood platelet shape is normal for HGPS, but in PRP for 10 of 16 patients with HGPS there is a decrease in the proportion of smooth, discoid-shaped platelets (discocytes [D]). The platelets of all patients with HGPS had abnormally large mean volume (VT) and increased size on peripheral blood smear. Furthermore, 12 of 16 patients with HGPS, including six of seven donors with BSS, had abnormally large discocytes. The measured size of HGPS shape-changed platelets was compared with the size predicted from the size of the D by assuming that the relationship between the size of shape-changed platelets and D was the same as observed for normal donors. In this manner it was shown that for all donors with BSS and MPS, the shape-changed platelets are disproportionately larger than the D. In contrast, in the remaining patients with HGPS the size of the shape-changed platelets was consistent with the size predicted from the D. Examination of VT for MPS as a function of time after addition of 10 mumol/L adenosine diphosphate to PRP revealed an abnormal time course, thereby pointing to an abnormality in the mechanisms that regulate platelet size during shape change. With the lone exceptions of BSS and MPS, the size of platelets on blood smear was well correlated with the total platelet plasma membrane surface area as measured by the osmotic spherocyte method. Our observations point to two distinct abnormalities in platelet size in HGPS: a disproportion between the size of D and "shape-changed" platelets, which may be related to an abnormal shape change and which is observed only for MPS and BSS, and an abnormal increase in platelet size on blood smear, which appears to reflect the increased amount of platelet plasma membrane in other HGPS platelets.
Adenosine Diphosphate↗
Reversal of acute experimental cerebral vasospasm by calcium antagonism with verapamil.
Acute vasospasm of the transclivally exposed basilar artery of anesthetised cats was produced by the subarachnoid injection of platelet-rich plasma (PRP) treated with enough adenosine diphosphate (ADP) to induce platelet aggregation and secretion. Vasorelaxation was produced by the topical application of the calcium antagonist verapamil. Changes in the internal diameter of the basilar artery were determined by measuring the blood column diameter from photomicrographs taken sequentially, at 5 minute intervals, through the operating microscope. Changes in blood vessel diameter are expressed as a plus or minus percentage of the pretreatment diameter. Arterial blood pressure and blood gas values were kept in the physiological range for the cat. The subarachnoid injection of PRP-ADP produced severe constriction of the basilar artery (mean constriction at 5 minutes after injection: -40.7% +/- 2.8 SEM). Platelet-free plasma, ADP alone and Elliott's A solution had no spasmogenic effect when injected into the subarachnoid space. The topical application of the calcium channel blocker verapamil (0.1 mg per kg) 30 minutes after the injection of PRP-ADP, with the basilar artery still in spasm (mean constriction: -23% +/- 3.5 SEM), produced prompt and dramatic vasodilation (mean dilation at 5 minutes after application: +52.7% +/- 18.1 SEM). This spasmolytic effect persisted in a decremental fashion for the 60 minute period of observation, by which time the previously constricted vessel had returned to its normal size. These observations indicate that the platelet fraction of whole blood may be involved in the genesis of acute vasospasm following subarachnoid hemmorrhage and that this phenomenon can be readily reversed by calcium antagonism.
Acute Disease↗
Adrenaline and adenosine diphosphate-induced platelet aggregation require shape change. Importance of pseudopods.
The requirement of platelet shape change for early platelet aggregation measured from the disappearance of singlet platelets is compared for ADP and adrenaline. Platelet shape change is measured from pseudopod formation or from a change in main body volume or axial ratio. In the absence of shape change, platelets have a smooth discoid form and are referred to as discocytes. Citrated platelet-rich plasma prepared at 37 degrees C contains approximately 65% discocytes and approximately 35% discoid platelets, which possess pseudopods. The addition of ADP causes all platelets to change shape (pseudopods axial ratio and body volume) and 80% to 90% platelet aggregation. On the other hand, adrenaline causes only an approximately 15% increase in shape-changed platelets (pseudopods only) and approximately 33% platelet aggregation, in the presence of apyrase to minimize the effects of released ADP. Measurements of the shape of the nonaggregated platelets in the presence and absence of ongoing platelet aggregation induced by either ADP or adrenaline indicate that discocytes are not recruited into aggregates. For both ADP and adrenaline, the extent of platelet aggregation exceeds the extent of platelet shape change as measured from the disappearance of discocytes. However, in both cases, platelet aggregation does not exceed the total number of shape-changed platelets (i.e., pseudopods plus newly shape-changed discocytes), indicating that the pseudopods are also participating in platelet aggregation. Our results suggest that pseudopod formation is a common requirement for ADP- and adrenaline-induced platelet aggregation and is of greater importance than either changes in main body volume or axial ratio.
Adenosine Diphosphate↗
Spontaneous platelet aggregation in a hereditary giant platelet syndrome (MPS).
The characteristics of spontaneous platelet aggregation (SPA) in a hereditary giant platelet syndrome (Montreal platelet syndrome, MPS) are examined. SPA was quantitated by microscopy from the decrease in single platelets in platelet-rich plasma (PRP). In contrast to normal donors, a significant proportion (20-50%) of platelets in MPS whole blood and PRP occurred in microaggregates typically containing 2-6 disk-shaped platelets. Stirring MPS-PRP at 1000 rpm for 10 minutes further increased the fraction of platelets in aggregates by 10-170%, the percentage increase not being correlated to the donor's platelet count (5000-220,000 microliters-1). Normal platelets resuspended in MPS platelet-poor plasma (PPP) did not undergo SPA, whereas MPS platelets resuspended in normal PPP or Ca2+-free, fibrinogen-free Tyrode's continued to show SPA. The increase in SPA could be inhibited by 10 microM prostaglandin (PG) E1, 150 mM ASA or glutaraldehyde or formaldehyde fixation; however, it was not inhibited by 10 nM PGI2 and was only partially inhibited by 1 microM 2-chloroadenosine and 1-10 units/ml apyrase. SPA in Acid-citrate-dextrose-PRP was much less than in PRP; however, SPA reoccurred on returning the platelets to platelet-free plasma or Tyrode's. Platelet aggregation (PA) could be increased over that due to SPA alone by the addition of adenosine diphosphate, adrenaline, collagen, ionophore A-23187, arachidonic acid and ristocetin, with results suggesting that the response to these agents is normal. The ristocetin-induced increase in PA was completely blocked by an IgG specific for Bernard-Soulier syndrome. In contrast, MPS platelets had a reduced sensitivity to thrombin, which appeared to be more pronounced at low platelet counts. There was no correlation between the thrombin insensitivity and the extent of SPA. Total adenosine triphosphate (ATP) and thrombin-induced release of ATP and platelet factor 4 appeared normal for MPS platelets. The ultrastructural features of MPS platelets were within normal limits except for an increased frequency of giant granules. SPA was observed for 5/5 MPS donors, but only one of three MPS donors' platelets evaluated for glycoprotein I and sialic acid content showed any measurable reduction as compared with normal controls. The above observations point to the existence of an as yet undetermined anomaly of MPS plasma membrane related to a fibrinogen and Ca2+ independent form of platelet aggregation.
Adenosine Triphosphate↗
Sex-related differences in platelet morphology in whole blood (WB) and platelet-rich plasma (PRP).
The proportion of smooth, disc-shaped platelets (D) in freshly drawn, glutaraldehyde fixed whole blood (WB) and citrated platelet-rich plasma prepared at 37 degrees C is compared for male (N = 55) and female (N = 31) donors. Female donors have significantly more %D than male donors and the variability in %D measured on repeated occasions over a period of 3-69 months is less for female donors. WB and PRP gave similar results. The sex-related differences in %D were not related to hematocrit or to concomitant use of oral contraceptives. There were no significant sex-related differences in platelet mean volume or in platelet plasma membrane surface area as determined by the osmotic spherocyte method. However, the volume of D is smaller for male donors. It is concluded that the sex-related differences in platelet morphology do not represent intrinsic differences in platelet size or measurable total plasma membrane but represent a selective shape change activation of the larger D in the circulation of male donors. The significance of these observations for the sex-related differences in risk of cardiovascular disease and efficacy of anti-thrombotic therapy awaits appropriate prospective epidemiological studies.
Adolescent↗
Turbidometric evaluations of platelet activation: relative contributions of measured shape change, volume, and early aggregation.
The relative contributions of ADP-induced changes in mean platelet axial ratio (R), mean volume (VT), pseudopod formation, refractive index, and early platelet aggregation to the changes in light transmission (%T) through stirred platelet suspensions (aggregometer) are determined. Measurement of the change in R within the first 10s of ADP addition indicates that the slope of the initial decrease in %T (5s) is in good agreement with that predicted from the theory of Latimer et al. (1977). However, when the changes in %T due to changes in VT are also considered, the observed rate of change of %T is shown to be 20-210% larger than predicted. These observations point to an additional process which produces a decrease in %T. It is shown that platelet aggregation occurring on this early time scale does not contribute to the initial changes in %T. Aggregation does lead to an increase in %T once there are greater than or equal to 30-40% singlet platelets aggregated which occurs at greater than or equal to 4-5s for 1-10 microM ADP. In the absence of aggregation, the extent of %T decrease at greater than 40s is greater than 25% smaller than predicted from the change in R and VT. It is suggested that at early times, changes in platelet refractive index produce significant decreases in %T which are on average offset by comparable increases due to the early volume increase, whereas at later times pseudopod formation has an important influence on %T.
Adenosine Diphosphate↗
Physical, chemical and functional changes following platelet activation in normal and "giant" platelets.
Unactivated discocytes in healthy human donors have mean volumes of approximately 6.0 microns3 (range 3.8-7.5 microns3), while mean values for similarly-shaped discocytes obtained from donors with the hereditary "giant" platelet syndromes were either normal (one Bernard-Soulier syndrome (BSS) and all five members of a family with the Montreal platelet syndrome (MPS) or, on average, up to twice normal (range 6.4-13.8 microns3). This apparent heterogeneity is complicated by the much more consistent and significant observation that both BSS and MPS platelets undergo a defective hypervolumetric shape change following activation which is prolonged indefinitely, in contrast to a transient hypervolumetric change measureable in 1-5 s following ADP addition to normal platelets. It is suggested that the hypervolumetric shape change in both normal and "giant" platelets is accompanied by an increase in externalized plasma membrane surface area, with the most probable source being surface-connected canalicular system. Membrane glycoprotein I abnormalities were not detectable in platelets for 2/3 sibling MPS donors. The precise relation of these membrane changes to altered platelet functions is compared for normal and "giant" platelets, but largely remains to be experimentally determined. Early shape change appears tightly associated with early microscopically-measured aggregation (PA), with both PA and turbidimetrically-measured macroaggregation generally appearing normal to elevated for "giant" platelets.
Blood Coagulation Disorders↗
Microscopic measurements of platelet aggregation reveal a low ADP-dependent process distinct from turbidometrically measured aggregation.
Platelet aggregation measured from the decrease in the number of nonaggregated platelets (PA) is compared with that measured from the increase in %T (TA) after ADP addition to a stirred platelet suspension. A number of properties distinguish PA from TA. Half-maximal extent of PA, measured at 3 or 10 sec after ADP addition is attained at significantly lower ADP concentrations ([ADP]) than for TA (velocity and extent), and in particular at [ADP] equal to or less than that required for shape change. PA appears minimally refractory to ADP under conditions causing maximal refractoriness of TA. Examination of the effect of three inhibitors of platelet aggregation acting on extracellular ionized calcium (EDTA) and on platelet adenylate cyclase (PGE1) and phosphodiesterase (anagrelide; BL-4162A) indicates that PA is generally less sensitive to these inhibitors than TA but, of greater significance, that PA and TA reveal aggregation processes with differing ADP sensitivities. It is suggested that these differences reflect different processes determining the strength of interplatelet interactions. Conventional aggregometry is insensitive for measuring the low ADP-dependent aggregation process.
Adenosine Diphosphate↗
Human platelet size, shape, and related functions in health and disease.
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Adenosine Diphosphate↗
Dependence of platelet volume measurements on heterogeneity of platelet morphology.
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Blood Platelets↗
Kinetics of ADP-induced human platelet shape change: apparent positive cooperativity.
The kinetics of ADP-induced human platelet shape change have been examined. Initial velocities of platelet shape change were estimated by two methods: (1) the slope of the initial decrease in light transmission through stirred, citrated platelet-rich plasma, and (2) direct examination of platelet morphologies by phase-contrast microscopy. In both cases, a value of the Hill coefficient, NH, significantly greater than 1 is obtained (2.0 +/- 0.2 and 1.8 +/- 0.2, respectively). The observed elevated value of NH is not due to a substantial fraction of the ADP being platelet bound, the presence of factors in the plasma, platelet heterogeneity, or the influence of the rate of platelet shape change reversion. Our observations suggest that ADP-induced platelet shape change may be a positively cooperative or "threshold" type response.
Adenosine Diphosphate↗
Shape-changing agents produce abnormally large platelets in a hereditary "giant platelets syndrome (MPS)".
Geometries of platelets in citrated PRP obtained from normal donors (17) and donors (5) with a hereditary dominant giant platelet syndrome, herein referred to as "Montreal platelet syndrome" (MPS), are compared. The measured geometric axial ratio (rp = thickness/diameter) is used to classify platelet morphologies into three groups: discocytes (rp less than 0.5), disco-echinocytes (rp = 0.5 to 0.9), sphero-echinocytes (rp greater than 0.9). MPS discocytes are normal sized; however, MPS sphero-echinocytes and disco-echinocytes have mean volumes approximately two times larger than normal. It is demonstrated that these larger-than-normal sized MPS platelets can be produced directly from MPS discocytes by treatment with agents known to induce platelet shape change (adenosine diphosphate, thrombin, and incubation at 4 degrees C). Treatment of platelets obtained from normal donors which have been resuspended in MPS PPP and ADP or incubation at 4 degrees C causes the formation of normal-sized disco-echinocytes and sphero-echinocytes. The diameters of MPS disco-echinocytes are identical to the diameters of MPS platelets observed on peripheral blood smear, whereas those of MPS sphero-echinocytes are approximately 20% lower. It is suggested that the appearance of abnormally large platelets in MPS is related to a defect in the mechanism which regulates platelet size and shape during shape change.
Adult↗
Invaginated plasma membrane of human platelets: evagination and measurement in normal and "giant" platelets.
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Adult↗
Platelets from "giant platelet syndrome (BSS)" are discocytes and normal sized.
A comparison is made between the shape of human platelets obtained from nine normal donors and two BSS donors. Sizes are evaluated from a cinematographic analysis of freely rotating, unfixed, and glutaraldehyde-hardened platelets in citrated PRP and of platelets on blood smear. On blood smeae, the mean diameters of BSS platelets are 1.7 to 1.8 times larger than those of normal platelets, with a major fraction having a diameter greater than 2.5 micrometer. As for normal donors, 80% to 90% BSS platelets in PRP are in the disc form (discocyte). In addition, they are essentially indistinguishable from a normal discocyte. Echinocytes (spherical forms with pseudopods) for BSS have a main body diameter (i.e., excluding pseudopods) 1.6 times larger than normal and in addition a reduced number of pseudopods. The results demonstrate that the giant size of BSS platelets results from abnormal behavior of these platelets during the preparation of the blood smear. It is suggested that this disorder is associated with a defect in the mechanism of platelet shape change.
Adult↗
Neural ensemble coding and statistical periodicity: speculations on the operation of the mind's eye.
Statistical periodicity is a statistical property of densities which arises in the description of retarded dynamical systems. This property is particularly attractive as a possible mechanism for the ensemble coding of information in the nervous system because it operates rapidly and has high storage capacity. For a population of neurons which exhibits statistical periodicity, information would not be encoded by the periodicity, but rather by the spatio-temporal distributions of neural activity. Statistical periodicity is discussed in relation to the temporal binding hypothesis and to the occurrence of multistability in neural systems.
Animals↗
Timing of seizure recurrence in adult epileptic patients: a statistical analysis.
Seizure diaries were maintained prospectively in 24 epileptic patients (19 with partial complex, three with partial simple, and three with primary generalized seizures) who were selected consecutively, had stable seizure patterns, were reliable historians, and were known to be compliant with medications. Diaries were maintained for an average of 237 days (range, 61-365), and an average of 18 seizures were recorded per patient (range, 5-76). Seizure patterns were analyzed by using the methods appropriate for a time series of events (point process). Two patients had a decreasing trend in seizure frequency. For 12 patients, seizure occurrence was indistinguishable from that of a Poisson process. The remaining 10 patients had an exponential distribution of seizure intervals, but did not fit other criteria for a Poisson process; 3 of these showed evidence for seizure clustering; none showed evidence for a seizure cycle. It is concluded that the pattern of seizure occurrence in most epileptic people is random, but in approximately 50%, it is not occurring according to a Poisson process. These observations indicate that seizure cycling and/or clustering are not common in epileptic patients, but do not exclude the possibility that seizures have been precipitated by some randomly occurring event, such as sleep deprivation or increased stress.
Adolescent↗
The effects of calcium antagonism on the epicerebral circulation in early vasospasm.
We have studied the effects of the calcium antagonist verapamil on the epicerebral arteriovenous transit time and regional epicerebral circulation of dogs by direct measurement of arterial diameters, fluorescein angiography, and krypton-85 regional epicerebral blood flow analysis. A large craniectomy was performed and vasoconstriction was induced by the subarachnoid injection of human platelet-rich plasma (PRP) pretreated with 25 mu M of ADP to cause maximum aggregation. Once vasoconstriction was established, verapamil (0.1 mg/kg) was topically applied to the perforated arachnoid. The PRP-ADP produced a mean decrease in the arterial diameters of 38.2 +/- 1.6% (p less than 0.01) at 10 minutes after its injection and verapamil produced a mean dilatation of 19.5 +/- 2.5% (p less than 0.01), compared to control values. Regional epicerebral blood flow was 54.9 +/- 3.4 ml/100 g/min in the control state, 34.8 +/- 3.2 ml/100 g/min (p less than 0.01) during vasospasm, and 78.2 +/- 4.5 ml/100 g/min (p less than 0.01) after verapamil. Fluorescein angiography, after verapamil, demonstrated a mean acceleration of the arteriovenous circulation time of 4.5 +/- 0.8 seconds (p less than 0.01) compared to the spasm value. We concluded that the topical application of verapamil can dilate previously constricted cortical arteries and that this dilatation is associated with acceleration of the epicerebral transit time and increased cerebral blood flow.
Administration, Topical↗