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Biomedical subjects

David Green

Publications and source records attributed to David Green.

At least 37 records · Page 2Linked to original sources
PubMed2003

Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AalphaIVS4 + 1G>T mutation and an AalphaGln328 truncation (fibrinogen Keokuk).

Two siblings with hypofibrinogenemia have lifelong trauma-related bleeding. Recently, the brother experienced recurrent thrombosis after cryoprecipitate infusions following surgery. The sister had 6 miscarriages. Plasma clots in each were resistant to compression and fibrinolysis and were soluble in 5 M urea. Examination by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed only the presence of crosslinked gamma-gamma fibrin chain dimers without high polymers of alpha n. Fibrin clots contained an abnormal 35-kDa constituent recognized by an antibody to the mature fibrinogen Aalpha-chain residues 241-476 but not by antibodies to Aalpha219-348 or Aalpha349-406. DNA analysis revealed a heterozygous CAA-->TAA mutation at the codon for amino acid 328 of the Aalpha gene in these siblings and 2 asymptomatic family members. The Gln328stop mutation (fibrinogen Keokuk) predicted a 46% truncation and the production of a 35-kDa Aalpha chain. Analysis of purified fibrinogen revealed expression of the abnormal Aalpha chain in 4 family members but found no normal fibrinogen in the 2 hypofibrinogenemic patients. This paradox was resolved when they and their asymptomatic mother were found to be heterozygous for a second Aalpha mutation, a GT-->TT splice site mutation in intron 4 (IVS4 + 1 G> T). However, compound heterozygosity for both mutations was required for the expression of severe hypodysfibrinogenemia and for clinical symptoms.

Blood Coagulation Disorders↗
PubMed2003

A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome.

BACKGROUND: Many patients with the antiphospholipid antibody syndrome and recurrent thrombosis receive doses of warfarin adjusted to achieve an international normalized ratio (INR) of more than 3.0. However, there are no prospective data to support this approach to thromboprophylaxis. METHODS: We performed a randomized, double-blind trial in which patients with antiphospholipid antibodies and previous thrombosis were assigned to receive enough warfarin to achieve an INR of 2.0 to 3.0 (moderate intensity) or 3.1 to 4.0 (high intensity). Our objective was to show that high-intensity warfarin was more effective in preventing thrombosis than moderate-intensity warfarin. RESULTS: A total of 114 patients were enrolled in the study and followed for a mean of 2.7 years. Recurrent thrombosis occurred in 6 of 56 patients (10.7 percent) assigned to receive high-intensity warfarin and in 2 of 58 patients (3.4 percent) assigned to receive moderate-intensity warfarin (hazard ratio for the high-intensity group, 3.1; 95 percent confidence interval, 0.6 to 15.0). Major bleeding occurred in three patients assigned to receive high-intensity warfarin and four patients assigned to receive moderate-intensity warfarin (hazard ratio, 1.0; 95 percent confidence interval, 0.2 to 4.8). CONCLUSIONS: High-intensity warfarin was not superior to moderate-intensity warfarin for thromboprophylaxis in patients with antiphospholipid antibodies and previous thrombosis. The low rate of recurrent thrombosis among patients in whom the target INR was 2.0 to 3.0 suggests that moderate-intensity warfarin is appropriate for patients with the antiphospholipid antibody syndrome.

Adult↗
PubMed2003

Relation of levels of hemostatic factors and inflammatory markers to the ankle brachial index.

Associations between hemostatic and inflammatory markers relative to the ankle brachial index (ABI), an indicator of the presence and severity of peripheral arterial disease (PAD), are not fully understood. We studied relations among selected hemostatic factors, inflammatory markers, and the ankle brachial index (ABI) in patients with and without peripheral arterial disease (PAD). Participants were 370 men and women with ABI <0.90 and 231 patients with ABI 0.90 to 1.50 identified from noninvasive vascular laboratories and general medicine practice. Blood factors were D-dimer, prothrombin 1.2, tissue plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1), and inflammatory markers (high-sensitivity C-reactive protein [CRP], fibrinogen, and serum amyloid A [SAA]). Among patients without a history of cardiac or cerebrovascular disease, the ABI was significantly inversely associated with log D-dimer (p <0.001), log prothrombin 1.2 (p = 0.001), log CRP (p <0.001), and log fibrinogen (p = 0.005) in unadjusted analyses. In multivariable regression analyses adjusting for all blood factors as well as potential confounders, D-dimer was associated independently with ABI in participants with a history of cardiac or cerebrovascular disease (p = 0.003) and in participants without a history of cardiac or cerebrovascular disease (p = 0.017). In these analyses, CRP was associated independently with ABI among participants with a history of cardiac or cerebrovascular disease (p = 0.026). CRP was not associated independently with ABI in participants without a history of cardiac or cerebrovascular disease. We conclude that D-dimer levels may be more sensitive than other blood markers for measuring the extent of atherosclerosis in lower extremity arteries.

Aged↗
PubMed2003

D-dimer, inflammatory markers, and lower extremity functioning in patients with and without peripheral arterial disease.

BACKGROUND: We determined whether higher levels of D-dimer, C-reactive protein (CRP), fibrinogen, and serum amyloid A are associated independently with functional impairment in patients with and without peripheral arterial disease (PAD). METHODS AND RESULTS: Participants were 370 men and women with PAD (ankle brachial index <0.90) and 231 without PAD. Functional outcomes were 6-minute walk distance and 4-meter walking velocity. A summary performance score combined performance in walking speed, standing balance, and time for 5 repeated chair rises into an ordinal score ranging from 0 to 12 (12=best). Adjusting for age, sex, ankle brachial index, comorbidities, and other potential mediators and confounders, D-dimer levels were associated independently and inversely with performance on all 3 functional measures in the entire cohort and among patients with and without PAD, respectively. Adjusting for known and potential confounders, CRP levels were associated independently with 6-minute walk distance and the summary performance score among participants with PAD. No significant associations were observed between CRP and the functional measures among participants without PAD. Fibrinogen and SAA levels were not associated independently with the functional measures. CONCLUSIONS: Higher D-dimer levels are associated with poorer functioning among individuals with and without PAD. Higher CRP levels were associated with poorer 6-minute walk performance and a lower summary performance score among participants with PAD but not among those without PAD. Additional study is needed to determine whether D-dimer and CRP are involved in the pathophysiology of functional impairment or whether they are simply sensitive markers of the extent of systemic atherosclerosis.

Aged↗
PubMed2003

Statin use and leg functioning in patients with and without lower-extremity peripheral arterial disease.

BACKGROUND: We determined whether statin use (versus nonuse) is associated with superior lower-extremity functioning independently of cholesterol levels and other confounders in patients with and without peripheral arterial disease. METHODS AND RESULTS: Participants included 392 men and women with an ankle brachial index (ABI) <0.90 and 249 with ABI 0.90 to 1.50. Functional outcomes included 6-minute walk distance and 4-meter walking velocity. A summary performance score combined performance in walking speed, standing balance, and time for 5 repeated chair rises into an ordinal score ranging from 0 to 12 (12=best). Adjusting for age, sex, ABI, comorbidities, education level, medical insurance status, cholesterol, and other confounders, participants taking statins had better 6-minute walk performance (1276 versus 1218 feet, P=0.045), faster walking velocity (0.93 versus 0.89 m/s, P=0.006), and a higher summary performance score (10.2 versus 9.4, P<0.001) than participants not taking statins. Positive associations were attenuated slightly after additional adjustment for C-reactive protein level but remained statistically significant for walking velocity and the summary performance score. We did not find significant associations between lower-extremity functioning and aspirin, ACE inhibitors, vasodilators, or beta-blockers. CONCLUSIONS: Statin use is associated with superior leg functioning compared with no statin use, independent of cholesterol levels and other potential confounders. These data suggest that non-cholesterol-lowering properties of statins may favorably influence functioning in persons with and without peripheral arterial disease.

Adrenergic beta-Antagonists↗
PubMed2003

The psycho-social impact of infertility on young male cancer survivors: a qualitative investigation.

Intensive treatment regimes that are known to have a potential risk of infertility sometimes have to be given to boys who have aggressive malignant disease. Long-term care must therefore include further discussion of these patients' impaired fertility. This study describes the results of a series of semi-structured interviews with 15 young male cancer survivors regarding their experience of receiving feedback on their probable fertility status. All the interviews were conducted by a psychologist formerly uninvolved with their treatment. The interviews were analysed qualitatively using a grounded theory approach. The findings of the study are organised under four headings: (a) Emotional reaction to news of probable infertility. (b) Coping style adopted. (c) Response to the offer of semen analysis. (d) Implications for clinical practice.The results of this thematic analysis are compared to the wider research literature in oncology and health psychology.

Adaptation, Psychological↗
PubMed2003

Diagnosis, prevalence, and management of thromboembolism in patients with spinal cord injury.

BACKGROUND: Deep vein thrombosis and pulmonary embolism (thromboembolism) are frequent causes of morbidity and mortality in patients with spinal cord injury. DIAGNOSIS: Strong clinical suspicion and confirmation with objective studies such as color-flow Doppler ultrasonography and helical CT. MANAGEMENT: In most patients, anticoagulation therapy with low-molecular-weight heparin (LMWH) is initiated when thrombosis is suspected, and continued if it is confirmed. Warfarin is started concomitantly, and the LMWH is discontinued when the International Normalized Ratio exceeds 2.0 for at least 48 hours. DURATION OF TREATMENT: At least 6 months; whether low-dose warfarin should be continued for an indefinite period is still under study. VENA CAVA FILTERS: Indicated for patients who cannot tolerate anticoagulants because of active or imminent bleeding. Whether filters are ever indicated for prophylaxis is controversial; both benefits and risks have been emphasized. Retrievable filters may be preferable, but their safety and efficacy have not been established. THE FUTURE: A variety of new anticoagulants-including fondaparinux, idraparinux, and ximelagatran-currently are in clinical trials and may replace current agents because of improved efficacy, safety, and ease of administration.

Anticoagulants↗
PubMed2003

Spinal Cord Injury Risk Assessment for Thromboembolism (SPIRATE Study).

OBJECTIVE: To identify risk factors for venous thromboembolism (VTE) during the rehabilitation phase of spinal cord injury. DESIGN: A comprehensive review of the charts of all patients admitted between 1992 and 1995 for rehabilitation after spinal cord injury. Only records including evidence for objective testing for thromboembolism were included. The analysis variables included type and location of spinal cord injury, American Spinal Injury Association classification, concomitant injuries, surgical procedures, complications, preexisting illnesses, and use of antithrombotic prophylaxis. Hierarchically optimal classification tree analysis was employed to develop a nonlinear model for predicting deep vein thrombosis. RESULTS: The analysis sample consisted of these 243 persons with acute spinal cord injury, 51 of whom had venous thromboembolism, and eight of whom died. A three-variable model emerged that identified patient groups differing in relative likelihood of experiencing deep vein thrombosis. The highest likelihood group were patients with cancer over the age of 35 yrs. Women between the ages of 36 and 58 yrs without cancer were also at increased risk, as were cancer-free men with flaccid paralysis. CONCLUSIONS: Venous thromboembolism is more likely to develop in spinal cord injury patients who are older, obese, and have flaccid paralysis or cancer. These patients should receive vigorous prophylaxis against venous thromboembolism.

Adult↗
PubMed2003

Thrombophilia and stroke.

Thrombophilia is defined as an enhanced tendency to form intravascular thrombi, which may be arterial or venous. Of the inherited thrombophilias, factor V Leiden and the prothrombin 20210 mutation have been associated with stroke, but this association is statistically significant only in children and adults under age 40. The risk of stroke in persons with these mutations is substantially increased by concomitant exposure to oral contraceptives. Hyperhomocystinemia is a major risk factor for stroke as well as Alzheimer's disease; persons with deficiencies of vitamin B12 or folic acid are especially vulnerable to these complications. Of the acquired thrombophilias, the antiphospholipid antibody syndrome is strongly associated with transient ischemic attacks, cerebral infarction, Sneddon syndrome, and dementia. The diagnosis of thrombophilia should be considered in stroke patients who are young, have a family history of thrombosis, suffer venous dural sinus thrombosis, or have recurrent strokes.

Contraceptives, Oral↗
PubMed2003

Hematologic findings in children with rotavirus-positive and -negative diarrhea.

The authors studied neutropenia in 101 children hospitalized for gastroenteritis between 1 December 2000 and 30 June 2001 and identified children tested for rotavirus by reviewing their laboratory records. Rotavirus-positive and rotavirus-negative subjects did not differ significantly in their white blood cell counts, absolute neutrophil counts, or frequency of neutropenia (defined as an absolute neutrophil count < 1.0 x 10(9)/L), which accompanied 8.6% of rotavirus-positive cases and 9.3% of rotavirus-negative cases of gastroenteritis. The authors conclude that mild neutropenia accompanying diarrhea does not require further evaluation unless it persists or is associated with other factors such as sepsis.

Black or African American↗
PubMed2002

Unique biochemical and behavioral alterations in Drosophila shibire(ts1) mutants imply a conformational state affecting dynamin subcellular distribution and synaptic vesicle cycling.

Dynamin is a GTPase protein that is essential for clathrin-mediated endocytosis of synaptic vesicle membranes. The Drosophila dynamin mutation shi(ts1) changes a single residue (G273D) at the boundary of the GTPase domain. In cell fractionation of homogenized fly heads without monovalent cations, all dynamin was in pellet fractions and was minimally susceptible to Triton-X extraction. Addition of Na(+) or K(+) can extract dynamin to the cytosolic (supernatant) fraction. The shi(ts1) mutation reduced the sensitivity of dynamin to salt extraction compared with other temperature-sensitive alleles or wild type. Sensitivity to salt extraction in shi(ts1) was enhanced by GTP and nonhydrolyzable GTP-gammaS. The shi(ts1) mutation may therefore induce a conformational change, involving the GTP binding site, that affects dynamin aggregation. Temperature-sensitive shibire mutations are known to arrest endocytosis at restrictive temperatures, with concomitant accumulation of presynaptic collared pits. Consistent with an effect upon dynamin aggregation, intact shi(ts1) flies recovered much more slowly from heat-induced paralysis than did other temperature-sensitive shibire mutants. Moreover, a genetic mutation that lowers GTP abundance (awd(msf15)), which reduces the paralytic temperature threshold of other temperature-sensitive shibire mutations that lie closer to consensus GTPase motifs, did not reduce the paralytic threshold of shi(ts1). Taken together, the results may link the GTPase domain to conformational shifts that influence aggregation in vitro and endocytosis in vivo, and provide an unexpected point of entry to link the biophysical properties of dynamin to physiological processes at synapses.

Animals↗
PubMed2002

Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors.

A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with but possessing improved solubility.

Alkylation↗
PubMed2002

Importance of cutaneous cooling during photothermal epilation: theoretical and practical considerations.

BACKGROUND AND OBJECTIVES: Sapphire contact cooling is widely used to prevent non-specific epidermal injury from occurring during selective laser treatment of unwanted hair and vascular lesions. This small study was performed to examine the clinical response of the skin to 800-nm laser irradiation with varying extent of cutaneous sapphire contact cooling. Observed clinical responses are compared to those predicted by theoretical analysis in an attempt to construct a more complete picture of sapphire contact cooling and its role in preventing non-targeted tissue devitalization during laser treatment of the skin using a wavelength, pulse duration, and radiant exposure commonly used for laser hair removal. STUDY DESIGN/MATERIALS AND METHODS: Three subjects each received a total of three pulses of laser light (800 nm) of equal radiant exposure (60 J/cm(2)), pulse duration (30 msec), and spot size (9 mm x 9 mm), but with varying extent of cutaneous cooling. One site was pre-cooled and heat-sinked with a chilled (5 degrees C) sapphire window in contact with the skin; another site was heat-sinked only with a room-temperature (20 degrees C) sapphire window in contact with the skin; and a third site received no pre-cooling or heat-sinking. Each site was examined immediately after treatment and at intervals throughout a 3-month period. The thermal response of the tissue was calculated in each case using a Monte Carlo model for light transport in multi-layered tissues coupled with an axisymmetric finite-difference heat diffusion model. Thermal injury was modeled as a first-order kinetic rate process using an Arrhenius expression. RESULTS: In all three subjects, the sites that were pre-cooled and heat-sinked showed no evidence of epidermal or dermal devitalization. The three sites that were heat-sinked only had a few patches of perifollicular epidermal devitalization and subsequent desquamation without any permanent epidermal or dermal injury, as would be evidenced by pigmentary alteration or textural change. In each subject, the site that received no pre-cooling or heat-sinking sustained epidermal and dermal devitalization, appearing as ulceration and resulting in sustained erythema and textural alteration. Clinical responses predicted by theoretical analysis agree with the clinical observations and show that the dominant effect of sapphire contact cooling for pulse durations of 30 msec or less is the reduction of fluence within the epidermis resulting from index matching at the skin surface. CONCLUSIONS: The results of this small study suggest that by judiciously selecting the laser pulse duration and pre-cooling and heat-sinking the epidermis in a manner that provides index matching and compression of the skin, epidermal damage can be avoided while administering the highest, most effective radiant exposures.

Aluminum Oxide↗
PubMed2002

Structural basis for activation of fibroblast growth factor signaling by sucrose octasulfate.

Sucrose octasulfate (SOS) is believed to stimulate fibroblast growth factor (FGF) signaling by binding and stabilizing FGFs. In this report, we show that SOS induces FGF-dependent dimerization of FGF receptors (FGFRs). The crystal structure of the dimeric FGF2-FGFR1-SOS complex at 2.6-A resolution reveals a symmetric assemblage of two 1:1:1 FGF2-FGFR1-SOS ternary complexes. Within each ternary complex SOS binds to FGF and FGFR and thereby increases FGF-FGFR affinity. SOS also interacts with the adjoining FGFR and thereby promotes protein-protein interactions that stabilize dimerization. This structural finding is supported by the inability of selectively desulfated SOS molecules to promote receptor dimerization. Thus, we propose that SOS potentiates FGF signaling by imitating the dual role of heparin in increasing FGF-FGFR affinity and promoting receptor dimerization. Hence, the dimeric FGF-FGFR-SOS structure substantiates the recently proposed "two-end" model, by which heparin induces FGF-FGFR dimerization. Moreover, the FGF-FGFR-SOS structure provides an attractive template for the development of easily synthesized SOS-related heparin agonists and antagonists that may hold therapeutic potential.

Animals↗
PubMed2002

A prospective, randomized study of preoperative autologous donation for hip replacement surgery.

BACKGROUND: Preoperative autologous blood donation is commonly performed to meet potential perioperative transfusion needs and is a common practice prior to total hip arthroplasty. Using standardized transfusion guidelines, we prospectively analyzed the effectiveness of preoperative autologous donation as a method for decreasing allogeneic transfusion among patients undergoing unilateral primary total hip replacement who were eligible to donate autologous blood. METHODS: Patients who were scheduled for primary total hip replacement surgery and who had a preoperative baseline hemoglobin level >or=120 g/L were randomized either to donate two units of blood (autologous donors) or not to donate any blood (nondonors). The donors and nondonors were compared with regard to demographic data, blood-loss volumes, hemoglobin measurements, and transfusion rates. Randomization continued until data were obtained from at least forty patients per treatment group. RESULTS: Of the ninety-six patients who completed the study, forty-two were autologous donors and fifty-four were nondonors. There were no significant differences between the donors and nondonors with regard to age, male:female ratio, estimated blood volume, baseline physical condition, or operative blood loss. The hemoglobin values at the time of enrollment (baseline), at the time of hospital discharge, and six weeks postoperatively were not significantly different between the two groups, although values at the time of admission (129 +/- 13 g/L versus 138 +/- 12 g/L) and in the recovery room (104 +/- 12 g/L versus 115 +/- 13 g/L) were significantly lower in the autologous donor group (p < 0.05). No patient in either group required an allogeneic transfusion. Twenty-nine (69%) of the forty-two donors received an autologous transfusion. Thirty-four (41%) of eighty-two autologous units were wasted. At a charge of $379 per autologous unit, there was an additional cost of $758 for each patient in the donor group. CONCLUSIONS: Preoperative autologous donation provided no benefit for nonanemic patients undergoing primary total hip replacement surgery. Preoperative autologous donation increased the likelihood of autologous transfusion, wastage of predonated units, and costs.

Aged↗