Biomedical subjects
Publications and source records attributed to M D Phillips.
We describe the use of heparinase-guided thrombelastography in the assessment of a parturient who had been anticoagulated with heparin for suspected thromboembolic disease. Reversal of the heparin effect in the heparinase-treated sample facilitated administration of protamine and successful subarachnoid analgesia for delivery.
The primary purpose of the study was to compare maximal accumulated oxygen deficit (MAOD) in resistance-trained (RT), endurance-trained (ET), and untrained men (UT). A secondary purpose was to determine the influence of leg muscle mass (MM) on MAOD by examining the relationship between MM and MAOD and by comparing MAOD expressed relative to MM between the groups. MAOD was determined during 2-4 min of constant-load fatiguing cycling. MM, estimated via anthropometric measurements, was higher (p < .05) for RT (mean +/- SE; 25.5 +/- 3.4 kg) compared to ET (20.3 +/- 3.5) and UT (21.6 +/- 3.4). MAOD in liters O2eq was larger in RT (4.75 +/- 0.3) compared to UT (3.07 +/- 0.3) and ET (3.75 +/- 0.3). A significant positive correlation was observed between MAOD (LO2eq) and MM (kg) for RT only (RT, r = .85; ET, r = .55; UT, r = .20). Based on the correlational and mean MM data, the higher MAOD (LO2eq) in RT relative to ET and UT is predominantly the result of their larger leg muscle mass.
Hereditary factor VII deficiency is a rare autosomal recessive condition, usually associated with normal or reduced levels of a functionally defective molecule. The available means of treating this condition in North America presents serious health risks to the patient. Transfusion with fresh frozen plasma carries a risk of volume overload and a significant risk for viral transmission. Sustained prothrombin complex therapy is associated with a high risk for thrombogenic complications. This communication describes the use of Factor VII Concentrate (Human) Immuno, Vapor Heated--an intermediate purity factor VII concentrate from Immuno A.G.--for the treatment of 13 patients with factor VII deficiency. Treatment regimens described include those for long-term prophylaxis (three children), acute hemorrhages (two children, one adult), peripartum prophylaxis (one patient), and surgical coverage (two children, four adults). Prophylaxis and therapy were successful in all cases, the medication was well-tolerated, and there were no complications. In the three cases of long-term prophylaxis in children, doses of 10-50 IU/kg were given one to three times a week; one patient has undergone long-term prophylaxis for approximately 8 years, one patient for 1 year, and one patient for 1 1/2 years. Three cases in which Factor VII Concentrate was principally used for treatment of acute episodes of bleeding are described. One infant received Factor VII Concentrate on about 50 occasions for treatment of mucosal bleeding; a correction to 40-100% resulted in cessation of bleeding within 15 min in all cases. For treatment of an episode of intracranial bleeding, an 8-year-old boy received a dose of 37 IU/kg Factor VII Concentrate every 6 hr for peak factor VII levels of approximately 100% and troughs as low as 4% over the 11-day treatment period. A 37-year-old adult male with intracranial bleeding received alternating doses of 16 IU/kg and 8 IU/kg every 6 hr for 10 days with peak factor VII levels in the upper thirties (%). The peak favor VII level during surgical coverage with Factor VII Concentrate (neurosurgery, open reduction of ankle bones, dental surgery, pituitary adenoma surgery, closed liver biopsy) was approximately 100% in all cases, with trough levels ranging from 8 to 65% over treatment periods of 24 hr to 16 days using treatment intervals of 6-12 hr.
A review of systemic anticoagulant use in 517 free flap procedures was performed to determine the associated risk of hematoma formation. Patients were divided retrospectively (not randomly) into five groups: no anticoagulation (227 flaps, 5.3 percent hematomas), low-dose heparin bolus of 2000 to 3000 units and postoperative infusion at a rate of 100 to 400 units/hr for 5 to 7 days (192 flaps, 6.7 percent hematomas), intraoperative bolus of 5000 units of heparin without postoperative anticoagulation (46 flaps, 6.5 percent hematomas), high-dose heparin infusion at a rate of 500 to 1200 units/hr (30 flaps, 20 percent hematomas), and dextran 40 infusion at a rate of 25 ml/hr (22 flaps, 9.1 percent hematomas). Intraoperative blood loss was similar for all groups. The flap loss rate was lower in the bolus (1.0 percent) and low-dose (1.0 percent) heparin groups than in the no-anticoagulation group (4.4 percent), but this difference was not statistically significant. The pedicle thrombosis rate also was lower in the bolus (2.2 percent) and low-dose (2.1 percent) heparin groups than in the no-anticoagulation group (6.2 percent). A cause-and-effect relationship between the use of anticoagulants and flap loss or prevention of thrombosis could not be established. We can conclude, however, that the use of low-dose heparin does not increase significantly the risk of hematoma or intraoperative bleeding.
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PURPOSE: To test graded fontanelle compression during Doppler ultrasound (US) scanning to identify and monitor infants with altered cranial compliance. MATERIALS AND METHODS: An ophthalmodynamometer exerted pressure on the anterior fontanelle during Doppler US scanning of the middle cerebral artery. Sixty examinations were performed in 43 infants--13 full-term and 11 premature healthy control subjects, 10 with increased intracranial volume, and nine with suspected abnormal cranial compliance but without increased intracranial volume. Resistive index (RI) and angle-corrected time-averaged mean velocities (TAV) of blood flow were compared at three different pressures. RESULTS: Baseline RI values in healthy full-term infants were significantly lower than in healthy premature infants and infants with abnormal compliance (P < .05). Values for healthy premature infants and infants with abnormal compliance were indistinguishable (P > .5). Neither RI nor TAV changed significantly in healthy infants, but both changed significantly with compression in infants with abnormal cranial compliance. CONCLUSION: This procedure may be more useful than measurement of RI of the anterior cerebral artery alone to evaluate infants with altered cranial compliance.
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ATA is a novel anticoagulant polymeric anionic aromatic compound that inhibits von Willebrand factor binding to platelet glycoprotein Ib and thereby prevents ristocetin- and shear stress-induced platelet aggregation. To investigate its mechanism of action, ATA fractions of homogeneous M(r) have been prepared by size exclusion chromatography. ATA fractions of M(r) > or = 2,500 are most effective at inhibiting vWF-mediated platelet aggregation, and ATA of M(r) = 2,500 also inhibits thrombin-induced platelet activation. Paradoxical results were observed in studies of ATA with M(r) = 6,400. This fraction of ATA stimulates aggregation of washed platelets or platelet-rich-plasma. The dose/response of aggregation shows a bell-shaped curve with maximal aggregation at approximately 2 micrograms/ml. Platelet aggregation is associated with phosphoinositide turnover and protein kinase C- and calcium-dependent protein phosphorylation. Platelet signalling responses to ATA are inhibited by platelet pretreatment with PGI2 or dibutyryl-cyclic AMP, but are unaffected by inhibiting platelet cyclooxygenase with aspirin. These results suggest that M(r) 6,400 ATA directly activates platelet phospholipase C to initiate platelet aggregation. This effect, unique to M(r) 6,400 ATA, could potentially mitigate ATA's beneficial anti-thrombotic effect on vWF-mediated platelet responses, and should be considered when analyzing results of experiments that utilize unfractionated ATA.
Two likely mechanisms for the initiation of arterial platelet thrombus formation under conditions of elevated fluid shear stresses are: (1) excessive adhesion and aggregation of platelets from rapidly flowing blood onto the exposed sub-endothelium of injured, atherosclerotic arteries; or (2) direct, fluid shear stress-induced aggregation of platelets in constricted arteries with intact endothelial cells. Mechanism (1) was simulated using a parallel plate flow chamber, fibrillar collagen type I-coated slides, and mepacrine-labeled (fluorescent) platelets in whole blood anticoagulated with citrate, hirudin, unfractionated porcine heparin, or low molecular weight heparin flowing for 1 to 2 minutes at wall shear rates of 100 to 3,000 seconds-1 (4 to 120 dynes/cm2). The precise sequence of interactions among von Willebrand factor (vWF), glycoprotein (GP)Ib, and GPIIb-IIIa during platelet adhesion and subsequent aggregation were resolved by direct real-time observation using a computerized epifluorescence video microscopy system. Adhesion at high shear rates was the result of the adsorption of large vWF multimers onto collagen and the binding of platelet GPIb to the insolubilized vWF. Aggregation occurred subsequently and required the binding of ligands, including vWF via its RGD binding domain, to GPIIb-IIIa. Mechanism (2) was modeled by producing shear stresses of 90 to 180 dynes/cm2 in a rotational cone and plate viscometer, which aggregates platelets from platelet-rich-plasma (PRP) anti-coagulated with citrate, hirudin, or either type of heparin in reactions that require large vWF multimers, Ca2+, adenosine diphosphate, and both GPIb and GPIIb-IIIa. Both vWF-mediated shear-aggregation in PRP and platelet-collagen adhesion in flowing whole blood (anticoagulated with citrate and hirudin) are inhibited by two potentially useful anti-arterial thrombotic agents: polymeric aurin tricarboxylic acid (ATA; 28.5 to 114 micrograms/mL), which binds to vWF and inhibits its attachment of GPIb, and a recombinant vWF fragment (rvWF445-733; 30 to 200 micrograms/mL) that binds to platelet GPIb (in the absence of any modulator) and blocks attachment of vWF multimers. Unfractionated heparin, but not low molecular weight heparin, apparently binds to rvWF445-733 and counteracts the inhibitory effects of the vWF fragment in vitro on shear-aggregation and platelet-collagen adhesion.
An interdisciplinary task force at the authors' institution developed a design for a new film library that placed heavy emphasis on service to its customers. The task force established locations and staffing for "satellite" inpatient film libraries organized by clinical specialties. Inpatient films were not permitted to be taken from the radiology department but were available for 24-hour viewing. Film locations were recorded in the radiology information system. Reorganization led to important improvements in film library operations and in the clinical staff's opinion of film library service. Objective measures of performance, such as the fraction of requested films available for conferences, showed significant improvement (P less than .001). Closer working relationships developed between film librarians, radiologists, and their clinical colleagues. Film library personnel were recruited more easily and stayed on the job longer. Several hundred thousand film-tracking transactions per year were recorded. The authors conclude that decentralization of certain film library activities improved many critical aspects of performance.
The unusually large von Willebrand factor (ULvWF) multimers present within endothelial cells and platelets are larger than the vWF multimers normally found in adult human plasma. Furthermore, ULvWF multimers are cleared rapidly from the circulation if they are released by intense endothelial cell stimulation. The mechanisms by which the ULvWF multimers are processed to large plasma vWF multimers are not known. It has been demonstrated that granulocyte proteases are capable of decreasing vWF multimer size in vitro, and that some patients with myeloproliferative syndromes have a relative absence of large plasma vWF multimers in sodium citrate-anticoagulated plasma samples. In order to assess the influence of granulocyte proteases on vWF multimer size, we evaluated the vWF multimeric patterns in 94 plasma samples from 60 patients with neutrophil counts that were either considerably elevated or extremely reduced. In 83 of 94 plasma samples, the vWF multimeric patterns were normal. No patients with very low neutrophil counts had ULvWF multimers present. These observations suggest that granulocyte proteases are not likely to be involved in vivo in the processing of ULvWF multimers from endothelial cells to the smaller vWF forms in circulation.
Various nucleoside analogues are being used or are being considered for use as therapeutic drugs to inhibit replication of the HTLV-III/LAV virus in infected human cells. Here, the ability of seven nucleoside analogues, a combination of two analogues, and two other therapeutic compounds to induce genotoxic and cytotoxic damage in vivo was evaluated in the mouse bone marrow micronucleus test. Using a 3-consecutive-day oral treatment protocol, almost all of the test chemicals induced a significant increase in the frequency of micronucleated polychromatic erythrocytes (MN-PCE) in male B6C3F1 mice, ranked in decreasing potency as 6-thioguanine greater than Cytarabine HCl greater than 3'-azido-3'-deoxythymidine (AZT)/2',3'-dideoxycytidine combination = AZT greater than Ribavirin = 2',3'-didehydro-3'-deoxythymidine greater than 2',3'-dideoxyadenosine = 2',3'-dideoxycytidine. The frequency of MN-PCE was not increased significantly by treatment with 2',3-dideoxyinosine (DDI) or pentamidine isethionate (PI). The differential ability of AZT and DDI to induce MN in mouse bone marrow was verified from peripheral blood smears prepared from subchronic (90 day) oral studies. The lack of genotoxic activity by DDI was route-specific since, when tested by intraperitoneal injection, a small but significant increase in MN-PCE was observed. A number of these chemicals induced a significant depression in erythropoiesis. However, there was not a significant correlation between the increase in MN-PCE and the depression in the percentage of PCE. This lack of a correlation suggests that factors other than DNA damage may contribute to the inhibition in the rate of erythropoiesis. The presence of increased levels of micronuclei in bone marrow PCE following treatment with various nucleoside analogues suggests that intrinsic genotoxic activity in mammalian cells should be one factor considered during drug selection for AIDS therapy.
The polycomb-group genes, a set of genes characterized by mutations that cause similar phenotypes and dosage-dependent interactions, are required for the normal expression of segment-specific homeotic loci. Here we report that polycombeotic (formerly 1(3)1902), originally identified by a lethal mutation that causes a small-disc phenotype, is also a member of this group of essential genes. Adults homozygous for temperature-sensitive pco alleles that were exposed to the restrictive temperature during larval life display the second and third leg to first leg transformation characteristic of polycomb-group mutants. Adult females homozygous for temperature-sensitive alleles exposed to the restrictive temperature during oogenesis produce embryos that show anterior segments with structures normally unique to the eighth abdominal segment, another transformation characteristic of polycomb-group mutants. Mutations in the polycombeotic gene also cause defects not reported for mutations in other polycomb-group genes. Females homozygous for the most extreme temperature-sensitive allele are sterile, and larvae homozygous for null alleles have small imaginal discs and reduced frequencies of mitotic figures in the brain. Dominant mutations originally identified as enhancers or suppressors of zeste are gain-of-function alleles of polycombeotic. The type and variety of defects displayed by different mutations in this gene indicate that the product might be involved in chromosome structure and/or function.
In addition to the von Willebrand factor (vWF) multimers found in normal plasma, cultured human umbilical vein endothelial cells (HUVECs) synthesize and release unusually large vWF multimers (ULvWFM). ULvWFM are more effective than the largest plasma vWF forms in attaching to platelets and promoting platelet aggregation in the presence of elevated fluid shear forces (as in narrowed atherosclerotic vessels), and they may be involved in arterial thrombosis. ULvWFM are produced within HUVECs exposed for 48-60 h either to steady venous-like or pulsatile arterial-like wall shear stresses and are produced and released from HUVECs grown in serum-free as well as in serum (bovine or human)-containing media. An activity of 140,000-200,000 Da in the cryosupernatant fraction of both normal and severe von Willebrand's disease plasma, which is not obviously a protease, prevents specifically the accumulation of ULvWFM in the fluid above HUVEC monolayers but does not impair the release by HUVECs of ULvWFM in the retrograde direction into subendothelial collagen. The ULvWF regulatory activity in cryosupernatant may inhibit inappropriate platelet aggregation and thrombosis by preventing the accumulation of endothelial cell-derived ULvWFM in circulating blood.
Functional nicotinic cholinergic receptors are found on mammalian retinal ganglion cell neurons in culture. The neurotransmitter acetylcholine (ACh) can be detected in the medium of many of these retinal cultures, after release presumably from the choline acetyltransferase-positive amacrine cells. The postsynaptic effect of endogenous or applied ACh on the ganglion cells can be blocked with specific nicotinic antagonists. Here it is shown that within 24 hours of producing such a pharmacologic blockade, the retinal ganglion cells begin to sprout or regenerate neuronal processes. Thus, the growth-enhancing effect of nicotinic antagonists may be due to the removal of inhibition to growth by tonic levels of ACh present in the culture medium. Since there is a spontaneous leak of ACh in the intact retina, the effects of nicotinic cholinergic drugs on process outgrowth in culture may reflect a normal control mechanism for growth or regeneration of retinal ganglion cell processes that is exerted by ACh in vivo.
Shear stress activated platelets undergo aggregation in the presence of large or unusually large von Willebrand factor (vWF) multimers without the addition of ristocetin or any other exogenous chemical. This phenomenon may be analogous to the platelet aggregation that leads to thrombosis in the narrowed arteries and arterioles of patients with atherosclerosis or vasospasm. A triphenyl-methyl compound, aurin tricarboxylic acid (ATA), inhibits shear-induced, vWF-mediated platelet aggregation in platelet-rich plasma (PRP) in concentrations above 200 mumol/L and in buffer suspensions of washed platelets at a concentration of 0.1 mumol/L. In a concentration-dependent manner, ATA also inhibits ristocetin-induced, vWF-mediated platelet clumping in both fresh and formaldehyde-fixed platelet suspensions. This inhibition can be overcome by increasing the concentration of vWF, following the kinetics of first order competitive inhibition. ATA prevents the attachment to platelets of the largest vWF multimeric forms found in normal plasma and of the unusually large vWF multimers derived from endothelial cells. The rate of aggregation and degree of inhibition by ATA is not accounted for by the binding of ristocetin or calcium. Arachidonic acid- and adenosine diphosphate (ADP)-induced aggregation are not inhibited by ATA. Platelets incubated with ATA can be easily separated from the compound. However, ATA binds to large vWF multimeric forms and inhibits their ristocetin-induced interaction with platelet glycoprotein Ib. Because ATA also inhibits shear-induced, vWF-mediated platelet aggregation in vitro in the absence of ristocetin, it may be a useful prototype compound to impede the development of arterial thrombosis in vivo.
Multisection computed tomography (CT) was introduced in 1992 with the advent of dual-section-capable scanners and was improved in 1998 following the development of quad-section technology. With a recent increase in gantry speed from one to two revolutions per second, multisection CT scanners are now up to eight times faster than conventional single-section helical CT scanners. The benefits of quad-section CT relative to single-section helical CT are considerable. They include improved temporal resolution, improved spatial resolution in the z axis, increased concentration of intravascular contrast material, decreased image noise, efficient x-ray tube use, and longer anatomic coverage. These factors substantially increase the diagnostic accuracy of the examination. The multisection CT technique has enabled faster and superior evaluation of patients across a wide spectrum of clinical indications. These include isotropic viewing, musculoskeletal applications, use of multiplanar reformation in special situations, CT myelography, long coverage and multiphase studies, CT angiography, cardiac scoring, evaluation of brain perfusion, imaging of large patients, evaluation of acute chest pain or dyspnea, virtual endoscopy, and thin-section scanning with retrospective image fusing. Multisection CT is superior to single-section helical CT for nearly all clinical applications.
BACKGROUND AND PURPOSE: Magnetization transfer ratio histogram peak height (MTR-HPH) has been shown to correlate with macroscopic and microscopic brain disease in patients with multiple sclerosis (MS). We studied the changes in MTR-HPH and in Kurtzke's Expanded Disability Status Scale (EDSS) scores over time in a group of patients with relapsing-remitting MS. METHODS: Twenty adult patients with relapsing-remitting MS (four men and 16 women) were followed up for a period of 334 to 1313 days. In all, 86 MR imaging studies of the brain were obtained, and MTR-HPH was calculated for each MR examination by using a semiautomated technique. Changes in MTR-HPH were compared between patients over the study's duration. A neurologist specialized in the care of MS patients assessed the EDSS score for each patient as a measure of clinical disability. RESULTS: Serial MR data showed a subtle but significant decline in MTR-HPH with time. No significant changes in EDSS scores were noted over the same period. CONCLUSION: Patients with relapsing-remitting MS have a significant progressive decline in normalized MTR-HPH, which is independent of EDSS score. MTR-HPH measurements can be used to monitor subclinical disease in patients with relapsing-remitting MS over a short time frame of 1 to 4 years. This parameter might be applied in future therapeutic trials to assess its usefulness.