The estimation of the number of mutationally silent loci in saturation-mapping experiments.
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Chromosome Mapping↗
Biomedical subjects
J A Barrett
Publications and source records attributed to J A Barrett.
Phenotype-phenotype analysis: field application of the gene-for-gene hypothesis in host-pathogen relations.
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Genotype↗
Pulmonary microembolism associated with massive transfusion: I. Physiologic effects and comparison in vivo of standard and dacron wool (swank) blood transfusion filters in its prevention.
Pulmonary microembolism of microaggregates associated with massive blood transfusion may be a cause of post-traumatic pulmonary embolism. The purpose of this study was to investigate in the dog the influence on certain physiologic parameters of transfusion of blood containing platelet: white blood cell: fibrin (PWF) aggregates and to evaluate the effects of using blood transfusion filters of varying pore sizes during such transfusions. Exchange transfusions of approximately twice blood volume were performed in three groups of animals. Screen filtration pressure measurements verified the presence of large numbers of PWF aggregates in the transfusions. When no transfusion filters or standard commercially available blood transfusion filters of pore size 170 mu were used, experimental animals developed pulmonary hypertension, a decrease in total body 92 consumption, and metabolic acidosis. Interposition of Dacron wool (Swank) blood transfusion filters prevented these changes.
Animals↗
The relationship of presenting physical complaints to depressive symptoms in primary care patients.
OBJECTIVE: To assess the relationship of specific patient chief physical complaints to underlying depressive symptoms in primary care practice. DESIGN: A cross-sectional study that was part of a larger prevalence study of depression in primary care. SETTING: A general medical primary care practice in a teaching medical center in rural New England. PATIENTS: 1,042 consecutive outpatients screened for depression with the Hopkins Symptom Checklist 49-item depression scale and for whom physicians filled out a form recording both specific chief complaints and two aspects of complaint presentation style, clarity and amplification. INTERVENTIONS: None. RESULTS: Complaints that discriminated between depressed and non-depressed patients (at the p = 0.05 level) were sleep disturbance (PPV 61%), fatigue (PPV 60%), multiple (3+) complaints (PPV 56%), nonspecific musculoskeletal complaints (PPV 43%), back pain (PPV 39%), shortness of breath (PPV 39%), amplified complaints (PPV 39%), and vaguely stated complaints (PPV 37%). CONCLUSIONS: Depressed patients are common in primary care practice and important to recognize. Certain specific complaints and complaint presentation styles are associated with underlying depressive symptoms.
Adolescent↗
Outcome in an urban pediatric trauma system with unified prehospital emergency medical services care.
HYPOTHESIS: Pediatric mortality is predicted by age, presence of head trauma, head trauma with a low Glasgow Coma Scale (GCS) score, a low Pediatric Trauma Score (PTS), and transport directly to a pediatric trauma center. POPULATION: Studied were 1,429 patients younger than 16 years old admitted to or declared dead on arrival (DOA) in a pediatric trauma center from January through October, 1988. The trauma system, which served 3-million persons, included six pediatric trauma centers. METHODS: Data were obtained by a retrospective review of summary statistics provided to the Chicago Department of Health by the pediatric trauma centers. RESULTS: Overall mortality was 4.8% (68 of 1429); 32 of the patients who died (47.1%) were DOA. The in-hospital mortality rate was 2.6%. Head injury was the principal diagnosis in 46.2% of admissions and was a factor in 72.2% of hospital deaths. The mortality rate was 20.3% in children with a GCS < or = 10 and 0.4% when the GCS was > 10 (odds ratio [OR] = 67.0, 95% CI = 15.0-417.4). When the PTS was < or = 5, mortality was 25.6%; with a PTS > 5, the mortality was 0.2% (OR = 420.7, 95% CI = 99.3-2,520). Although transfers to a pediatric trauma center accounted for 73.6% of admissions, direct field triage to a pediatric trauma center was associated with a 3.2 times greater mortality risk (95% CI = 1.58-6.59). Mortality rates were equal for all age groups. Pediatric trauma center volume did not influence mortality rates. CONCLUSIONS: Head injury and death occur in all age groups, suggesting the need for broad prevention strategies. Specific GCS and PTS values that predict mortality can be used in emergency medical services (EMS) triage protocols. Although the high proportion of transfers mandates systemwide transfer protocols, the lower mortality in these patients suggests appropriate EMS field triage. These factors should be considered as states develop pediatric trauma systems.
Adolescent↗
99mTc-labeling of a hydrazinonicotinamide-conjugated vitronectin receptor antagonist useful for imaging tumors.
This report describes the (99m)Tc labeling of a HYNIC-conjugated vitronectin receptor antagonist (SQ168 = [2-[[[5-[carboonyl]-2-pyridinyl]hydrazono]methyl]benzenesulfonic acid]-Glu(cyclo[Lys-Arg-Gly-Asp-D-Phe])-cyclo[Lys-Arg-Gly-Asp-D-Phe]). The ternary ligand complex [(99m)Tc(SQ168)(tricine)(TPPTS)] (RP593) was prepared using a non-SnCl(2)-containing formulation. The corresponding (99)Tc analogue, [(99)Tc]RP593, was also prepared and characterized by HPLC and LC-MS. A HPLC concordance experiment using RP593 and [(99)Tc]RP593 showed that the same technetium complex was prepared at both the tracer and macroscopic levels. The LC-MS data is completely consistent with the 1:1:1:1 composition for Tc:SQ168:tricine:TPPTS and provides direct evidence that the two radiometric peaks in the radio-HPLC chromatogram of RP593 are indeed due to the resolution of diastereomers. In an in vitro receptor binding assay, [(99)Tc]RP593 was shown to have comparable binding affinity for the vitronectin receptor to that of SQ168 itself.
Binding, Competitive↗
Labeling a hydrazino nicotinamide-modified cyclic IIb/IIIa receptor antagonist with 99mTc using aminocarboxylates as coligands.
A series of 99mTc complexes containing a hydrazinonicotinamide-conjugated cyclic IIb/IIIa receptor antagonist, cyclo(D-Val-NMeArg-Gly-Asp-Mamb-(hydrazinonicotinyl-5- (6-aminocaproic acid))), were synthesized in high yield using tricine or other aminocarboxylates as coligands. These 99mTc complexes have the potential to be used as thrombus imaging agents. The radiolabeling of the HYNIC-conjugated cyclic IIb/IIIa peptide (HYNICtide) was carried out by reaction with pertechnetate in the presence of excess tricine and stannous chloride at pH 4-5. The reaction time and temperature depend on the amount of the HYNICtide and pertechnetate used for the radiolabeling. Very high specific activity (> or = 20,000 mCi/mumol) can be achieved for the complex [99mTc(HYNICtide)(tricine)2] without postlabeling purification. The complex [99mTc(HYNICtide)(tricine)2] was found by two reversed phase HPLC methods to exist as multiple species, some of which interconvert, depending on the temperature, reaction time, and pH of the reaction mixture. The presence of these multiple species is most likely due to different bonding modalities of either the hydrazine moiety of the HYNICtide or the two tricine coligands. The complex [99mTc(HYNICtide)(EDDA)] (EDDA = ethylenediamine-N,N'-diacetic acid) was prepared either by reacting the cyclic IIb/IIIa HYNICtide with pertechnetate, excess EDDA, and stannous chloride at pH 4-5 and 75 degrees C for 30 min or by reacting excess EDDA with [99mTc(HYNICtide)(tricine)2]. The complex [99mTc(HYNICtide)(EDDA)] was found to be stable for at least 12 h in the reaction mixture. Three major species were detected in the radio-HPLC chromatograms, presumably due to the more limited number of possible coordination isomers. Similar results were obtained using other polydentate aminocarboxylates (such as HEDTA, N-(2-hydroxyethyl)ethylenediaminetriacetic acid) as coligands. It is clear that the replacement of tricine by other polydentate aminocarboxylates produces 99mTc-HYNICtide complexes with higher stability and fewer coordination isomers.
Amino Acid Sequence↗
Biological evaluation of 99mTc-labeled cyclic glycoprotein IIb/IIIa receptor antagonists in the canine arteriovenous shunt and deep vein thrombosis models: effects of chelators on biological properties of [99mTc]chelator-peptide conjugates.
A series of 99mTc-labeled cyclic glycoprotein IIb/IIIa receptor antagonists, [99mTcO(L1-III)]-, [99mTcO-(L6-III)]-, [99mTcO(L1-V)]-, and [99mTcO(L6-V)]-, were evaluated in a canine arteriovenous (AV) shunt model for their potential use as thrombus imaging agents. The thrombus formed consists of a platelet-rich head and a fibrin-rich tail. All four agents were incorporated into the growing thrombus under both arterial (platelet-rich) and venous (platelet-poor) conditions. The rank order for uptake was [99mTcO(L1-V)]- > [99mTcO(L6-V)]- > [99mTcO(L6-III)]- > [99mTcO(L1-III)]- (arterial range, 5.8-0.47% id/g; venous range, 0.58-0.04% id/g). The uptakes of both [99mTcO(L6-III)]- and [99mTcO-(L1-III)]- under both arterial and venous conditions were not significantly greater than that of [99mTc]-albumin and [125I]fibrinogen. In contrast, the uptakes of both [99mTcO(L1-V)]- and [99mTcO(L6-V)]- were significantly greater than those of [99mTc]albumin and [125I]fibrinogen and comparable to that of [111In]platelets under both arterial and venous conditions. All four [99mTc]chelator-peptide conjugates are cleared faster than the controls with the clearance of the conjugates of peptide III faster than that of the conjugates of peptide V. The differences in incorporation are attributable to the effect of both the cyclic peptide and the chelator. The conjugate [99mTcO(L1-V)]- was also studied using a canine DVT (deep vein thrombosis) model. [99mTcO(L1-V)]- was actively incorporated into the growing thrombus with images clearly detectable within 15 min postinjection. At 2 h postinjection, thrombus/blood and thrombus/muscle ratios [region of interest (ROI)/background] were approximately 7/1 and 10/1, respectively. This clearly demonstrated that the conjugate [99mTcO(L1-V)]- has the potential for rapid diagnosis of thrombolic events occurring under both arterial and venous conditions.
Animals↗
Biological evaluation of thrombus imaging agents utilizing water soluble phosphines and tricine as coligands when used to label a hydrazinonicotinamide-modified cyclic glycoprotein IIb/IIIa receptor antagonist with 99mTc.
A hydrazinonicotinamide-functionalized cyclic glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist [cyclo(D-Val-NMeArg-Gly-Asp-Mamb(5-(6-(6-hydrazinonicotin amido)hexanamide))) (HYNICtide)] was labeled with 99mTc using tricine and a water soluble phosphine [trisodium triphenylphosphine-3,3',3"-trisulfonate (TPPTS); disodium triphenylphosphine-3,3'-disulfonate (TPPDS); or sodium triphenylphosphine-3-monosulfonate (TPPMS)] as coligands. Three complexes, [99mTc(HYNICtide)(L)(tricine)] (1, L = TPPTS; 2, L = TPPDS; 3, L = TPPMS), were evaluated in the canine arteriovenous shunt (AV shunt) model and canine deep vein thrombosis imaging (DVT) model. All three agents were adequately incorporated into the arterial and venous portions of the growing thrombus (7.8-9.9 and 0.2-3.7% ID/g, respectively) in the canine AV shunt model. In the canine DVT model all three complexes had thrombus uptake that far exceeded the negative control, [99mTc]albumin. The findings indicate similar incorporation into a venous thrombus (% ID/g = 2.86 +/- 0.4, 3.4 +/- 0.9, and 3.38 +/- 1.1 for complexes 1, 2, and 3, respectively) and similar blood clearance with a t1/2 of approximately 90 min. Gamma camera scintigraphy allowed visualization of deep vein thrombosis in as little as 15 min with the thrombus/muscle ratios being 3.8 +/- 0.8, 2.8 +/- 0.4, and 3.0 +/- 0.8 for complexes 1, 2, and 3, respectively. The visualization of the thrombus improved over time, and the thrombus/muscle ratios were 9.7 +/- 1.9, 13.8 +/- 3.6, and 9.4 +/- 2 for complexes 1, 2, and 3, respectively, at 120 min postinjection. The administration of complexes 1-3 did not alter platelet function, hemodynamics, or the coagulation cascade. Furthermore, complexes 1-3 did not significantly differ in their uptake into the growing thrombus, blood clearance, and target to background ratios. Therefore, all three complexes have the capability to detect rapidly growing venous and arterial thrombi.
Animals↗
New and versatile ternary ligand system for technetium radiopharmaceuticals: water soluble phosphines and tricine as coligands in labeling a hydrazinonicotinamide-modified cyclic glycoprotein IIb/IIIa receptor antagonist with 99mTc.
A hydrazinonicotinamide-functionalized cyclic platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist [cyclo(D-Val-NMeArg-Gly-Asp-Mamb(5-(6-(6-hydrazinonicotin amido) hexanamide))) (HYNIC-tide)] was labeled with 99mTc using tricine and a water soluble phosphine (TPPTS, trisodium triphenylphosphine-3,3',3"-trisulfonate; TPPDS, disodium triphenylphosphine-3,3'-disulfonate; or TPPMS, sodium triphenylphosphine-3-monosulfonate] as coligands. The synthesis of technetium complexes, [99mTc(HYNICtide)(L)(tricine)] (1, L = TPPTS; 2, L = TPPDS; 3, L = TPPMS), can be performed in one or two steps in high yield and with high specific activity (> or = 20,000 Ci/mmol). For example, the reaction of the HYNICtide, [99mTc]pertechnetate, stannous chloride, and tricine at pH 4-5 and room temperature results in the complex [99mTc(HYNICtide)(tricine)2], which reacts with TPPTS (50 degrees C for 30 min) to give complex 1 in > or = 90% yield as determined by radio-HPLC. Complexes 1-3 are formed as equal mixtures of two isomeric forms and are stable for > or = 6 h in the reaction mixture and in dilute solution. Both isomeric forms of complex 1 were found by a platelet-binding assay to contain the 99mTc-labeled HYNICtide and possess biological activity. The composition of these complexes was determined to be 1:1:1:1 for Tc:HYNICtide:L:tricine through a series of mixed ligand experiments on the tracer (99mTc) level. Surprisingly, this composition is maintained over a wide range of relative ligand ratios. The relative bonding capability of the three phosphine coligands to the Tc was determined by spiking various amounts of TPPDS or TPPMS into TPPTS and falls in the order TPPMS > TPPDS > TPPTS. The lipophilicity of the [99m Tc]HYNICtide complexes can be systematically varied by the choice of the phosphine and aminocarboxylate coligands. Using the combination of tricine and a phosphine ligand, HYNIC-derivatized peptides or other small molecules can be labeled with 99mTc in high specific activity and with high stability for potential use as radiopharmaceuticals.
Animals↗
99mTc labeling of highly potent small peptides.
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Animals↗
RP463: a stabilized technetium-99m complex of a hydrazino nicotinamide derivatized chemotactic peptide for infection imaging.
A HYNIC-conjugated chemotactic peptide (fMLFK-HYNIC) was labeled with (99m)Tc using tricine and TPPTS as coligands. The combination of fMLFK-HYNIC, tricine, and TPPTS with (99m)Tc produced a ternary ligand complex [(99m)Tc(fMLFK-HYNIC)(tricine)(TPPTS)] (RP463). RP463 was synthesized either in two steps, in which the binary ligand complex [(99m)Tc(fMLFK-HYNIC)(tricine)(2)] (RP469) was formed first and then reacted with TPPTS, or in one step by direct reduction of [(99m)Tc]pertechnetate with stannous chloride in the presence of fMLFK-HYNIC, tricine, and TPPTS. The radiolabeling yield for RP463 was usually >/=90% using 10 microg of fMLFK-HYNIC and 100 mCi of [(99m)Tc]pertechnetate. Unlike RP469, which decomposed rapidly in the absence of excess tricine coligand, RP463 was stable in solution for at least 6 h. [(99)Tc]RP463 was prepared and characterized by HPLC and electrospray mass spectrometry. In an in vitro assay, [(99)Tc]RP463 showed an IC(50) of 2 nM against binding of [(3)H]fMLF to receptors on PMNs. [(99)Tc]RP463 also induces effectively the superoxide release of polymorphonuclear leukocytes (PMNs) with an EC(50) value of 0.2 +/- 0.2 nM. The localization of RP463 in the infection foci was assessed in a rabbit infection model. RP463 was cleared from the blood faster than RP469 and was excreted mainly through the renal system. As a result of rapid blood clearance and increased uptake, the target-to-background ratios continuously increased from 1.5 +/- 0.2 at 15 min postinjection to 7.5 +/- 0.4 at 4 h postinjection. Visualization of the infected area could be as early as 2 h. A transient decrease in white blood cell count of 35% was observed during the first 30 min after injection of the HPLC-purified RP463 in the infected rabbit. This suggests that future research in this area should focus on developing highly potent antagonists for chemotactic peptide receptor or other receptors on PMNs and monocytes.
Abscess↗
Detection of deep venous thrombosis by DMP 444, a platelet IIb/IIIa antagonist: a preliminary report.
BACKGROUND: We report a method for detection of deep venous thrombosis with a technetium 99m-labeled peptide (DMP 444). The N-methyl-arginine-glycine-aspartic acid sequence on DMP 444 binds the glycoprotein IIb/IIIa receptor on activated platelets (inhibition constant [IC50] for fibrinogen binding = 6 nmol/L). METHODS: DMP 444 (23 to 27 mCi) was injected into 11 patients with clinical suspicion of deep venous thrombosis, diagnostic confirmation by ultrasound, and a positive D-dimer test result. Planar images in the anterior and posterior projections were obtained at 10 to 40 minutes, 50 to 80 minutes, and 120 to 150 minutes after injection. RESULTS: No clinically significant adverse effects were noted after DMP 444 administration. One patient (excluded from the analysis) withdrew consent, so image acquisition was not complete. By 10 to 40 minutes after injection, 8 of 10 patients demonstrated an area of increased activity that was clearly related to the abnormality noted on ultrasound. Most patients were taking warfarin (Coumadin) and heparin (n = 8) or heparin (n = 1) and warfarin (n = 1) alone at the time of the imaging. The average time from onset of symptoms to injection of DMP 444 was 5 days (range 1 to 18 days). CONCLUSION: These preliminary human studies indicate that DMP 444 is safe and may be of value in the diagnosis of deep venous thrombosis.
Aged↗
Adipose tissue response to insulin following injury.
Derangements of posttraumatic glucose metabolism have long been recognized, with observed changes implicating abnormal action of insulin on target tissues. Insulin is important as well in fat metabolism, and "resistance" to insulin's effects on lipid metabolism after injury has been demonstrated. Although fat-derived fuels are the body's major energy source during starvation and after injury, most studies of posttraumatic insulin "resistance" have focused on carbohydrate metabolism. This study investigated adipose tissue response to insulin in vitro in rats subjected to starvation and/or trauma. Relationships between various parameters, including adipocyte size and weight, plasma glucose, insulin, and glycerol, and basal and insulin-suppressed lipolytic rates, were also studied. Results observed include a decrease in adipocyte size and an increase in basal lipolysis in both starved and traumatized rats, with both decreased sensitivity (T greater than S) and responsiveness (S greater than T) to insulin. These results support the concept that adipocytes of injured animals retain the ability to respond to insulin but lipolytic rates at maximal suppression are still quite high as compared to fed controls. Only minor differences were observed between starved animals and those with starvation and superimposed trauma.
Adipose Tissue↗
Intravenous fat emulsion acutely suppresses neutrophil chemiluminescence.
The immediate effect of intravenous fat emulsion on neutrophil oxidant release was studied. Opsonized nonencapsulated S. aureus was used to stimulate neutrophil activity. Luminol enhanced chemiluminescence was followed over 15 min and recorded as peak output (P; mV), integral under the curve (I; V-sec) and rate of increase (R; mV/sec). Eighteen chronically ill patients receiving glucose based total parenteral nutrition were studied before and after a 4- to 6-hr test infusion of 500 ml of 10% fat emulsion. P decreased from 719 +/- 46 to 461 +/- 42 mV (p less than 0.001), I decreased from 169 +/- 17 to 111 +/- 12 V-sec (p less than 0.001) and R decreased from 6.9 +/- 1.0 to 4.0 +/- 0.6 mV/sec (p less than 0.001). Preincubation of normal whole blood with fat emulsion in vitro did not adversely affect chemiluminescence (11 studies), nor did incubation of normal neutrophils with patient postinfusion plasma (10 studies). We conclude that fat emulsion infusion acutely suppresses neutrophil chemiluminescence. The suppression is not a direct effect of the fat emulsion per se and is not due to inhibitory substances in the plasma following infusion.
Adult↗
Breast-feeding problems in the first week postpartum.
Pre- and perinatal variables commonly found to predict breast-feeding duration were examined to see whether they also predicted breast-feeding problems in the first week postpartum. One hundred and twenty-eight families who prenatally committed to breast-feeding for at least 6 weeks comprised the sample. The families were randomly assigned to one of two groups: a group in which bottle feedings would be avoided in Weeks 2-6 postpartum and a group in which approximately one bottle per day would be given during the same period. Breast-feeding events most commonly experienced as problems in previous studies were also reported by mothers in this sample. Multiple regression analyses revealed that bottle use in the hospital, lower satisfaction with first breast-feeding, and group assignment were weakly predictive of the Breast-feeding Problem Score at 1 week, R2 = .154, p = .0004. The negative effect of hospital bottle use was greater for women in the bottle-restricted group than for women in the planned-bottle group.
Adult↗
Prospective study of the effect of safety belts on morbidity and health care costs in motor-vehicle accidents.
To assess the impact of safety belt use on the extent of injuries sustained in motor-vehicle accidents and the incurred health care costs, 1364 patients were prospectively evaluated at four Chicago-area hospitals. Of these, 791 (58%) were wearing a safety belt whereas 573 (42%) were not. The mean injury severity score for safety belt wearers was 1.8 +/- 0.07 vs 4.51 +/- 0.31 in those not wearing a safety belt. Only 6.8% of safety belt wearers required admission vs 19.2% of those not wearing a safety belt. Restrained occupants incurred mean charges of $534 +/- $67 compared with $1583 +/- $201 in unrestrained occupants. Thus, safety belt wearers had a 60.1% reduction in severity of injury, a 64.6% decrease in hospital admissions, and a 66.3% decline in hospital charges. Our findings demonstrate the significant societal burden of nonuse of safety belts in terms of morbidity and the costs of medical care.
Accidents, Traffic↗