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Biomedical subjects

Andrew Lee

Publications and source records attributed to Andrew Lee.

At least 19 recordsLinked to original sources
PubMed2006

Recognition of the tumor suppressor protein p53 and other protein targets by the calcium-binding protein S100B.

S100B is an EF-hand containing calcium-binding protein of the S100 protein family that exerts its biological effect by binding and affecting various target proteins. A consensus sequence for S100B target proteins was published as (K/R)(L/I)xWxxIL and matches a region in the actin capping protein CapZ (V.V. Ivanenkov, G.A. Jamieson, Jr., E. Gruenstein, R.V. Dimlich, Characterization of S-100b binding epitopes. Identification of a novel target, the actin capping protein, CapZ, J. Biol. Chem. 270 (1995) 14651-14658). Several additional S100B targets are known including p53, a nuclear Dbf2 related (NDR) kinase, the RAGE receptor, neuromodulin, protein kinase C, and others. Examining the binding sites of such targets and new protein sequence searches provided additional potential target proteins for S100B including Hdm2 and Hdm4, which were both found to bind S100B in a calcium-dependent manner. The interaction between S100B and the Hdm2 and/or the Hdm4 proteins may be important physiologically in light of evidence that like Hdm2, S100B also contributes to lowering protein levels of the tumor suppressor protein, p53. For the S100B-p53 interaction, it was found that phosphorylation of specific serine and/or threonine residues reduces the affinity of the S100B-p53 interaction by as much as an order of magnitude, and is important for protecting p53 from S100B-dependent down-regulation, a scenario that is similar to what is found for the Hdm2-p53 complex.

Amino Acid Sequence↗
PubMed2006

Late gastrointestinal toxicity after radiation for prostate cancer.

BACKGROUND: The current study was designed to determine rates and predictors of late, lower gastrointestinal toxicity after radiation therapy in a population-based cohort of older men with prostate cancer. METHODS: The study population consisted of men with localized or regional stage prostate cancer who were age > or =66 years and were diagnosed between 1992 and 1999 who were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Gastrointestinal diagnoses were ascertained through claims from 6 to 60 months after diagnosis. The relative rates of diagnoses in the radiation group versus the nonradiation group were used as a means of estimating toxicity from radiotherapy. Cox modeling was used to determine factors associated with gastrointestinal diagnoses. RESULTS: A total of 57,955 men were included, 24,130 of whom were treated with radiation therapy. Among patients with 5 years of follow-up, the rates of gastrointestinal diagnoses were 19.4% higher in irradiated patients than among patients who did not have local therapy. Hemorrhage was the most common diagnosis, and was increased by 18.9% among patients treated with radiation (39.6% of irradiated patients vs. comparison rates of 18.2% in patients treated with radical prostatectomy and 20.7% in patients with no local therapy). Diagnostic lower endoscopies were performed in an additional 20.9% of men (32.4% of men treated with radiation vs. 12.7% of men who underwent prostatectomy). In all, 4.4% of irradiated men were hospitalized with a gastrointestinal diagnosis versus comparison rates of 3.2% among men with no local therapy. In multivariate models, increasing patient age, hormonal therapy, comorbidity, diabetes, peripheral vascular disease, and hemorrhoids were all associated with gastrointestinal diagnoses consistent with toxicity, whereas tumor stage and grade were not predictors. CONCLUSIONS: Lower gastrointestinal toxicity after radiation therapy for prostate cancer continues for at least 5 years and may be more common than previously reported.

Adult↗
PubMed2006

Inhibition of RhoA GTPase activity enhances hematopoietic stem and progenitor cell proliferation and engraftment.

Ras-related Rho GTPases regulate actin cytoskeletal organization, adhesion, gene transcription, and cell-cycle progression. The Rac subfamily of Rho GTPases and Cdc42 has been shown to play essential roles in hematopoietic stem cell (HSC) engraftment and mobilization. Here, we study the role of RhoA, a related Rho GTPase, in HSC functions. Using retrovirus-mediated gene transfer of a dominant-negative (DN) mutant of RhoA (RhoAN19), we demonstrate that down-regulation of RhoA activity resulted in increased HSC engraftment and self-renewal as measured by competitive repopulation and serial transplantation assays. However, overexpression of RhoAN19 resulted in decreased migration toward SDF-1alpha and alpha(4)beta(1)- and alpha(5)beta(2)-integrin-mediated adhesion of hematopoietic progenitor cells in vitro. Low RhoA activity was associated with higher proliferation rate of hematopoietic progenitor cells and increased cells in active phases of cell cycle, most likely via decreasing p21Cip/Waf expression and increasing cyclin D1 levels. Thus, reducing RhoA activity by optimizing the balance between adhesion/migration and proliferation/self-renewal results in a net increase in HSC engraftment. This mechanism could provide a novel therapeutic target to enhance HSC therapies.

Animals↗
PubMed2006

Plasma nitrite reserve and endothelial function in the human forearm circulation.

Attenuation of endothelium-derived nitric oxide (NO) synthesis is a hallmark of endothelial dysfunction. Early detection of this disorder may have therapeutic and prognostic implications. Plasma nitrite mirrors acute and chronic changes in endothelial NO-synthase activity. We hypothesized that local plasma nitrite concentration increases during reactive hyperemia of the forearm, reflecting endothelial function. In healthy subjects (n = 11) plasma nitrite and nitrate were determined at baseline and during reactive hyperemia of the forearm using reductive gas-phase chemiluminescence and flow-injection analysis, respectively. Endothelium-dependent dilation of the brachial artery was measured as flow-mediated dilation (FMD) using high-resolution ultrasound. Results were compared to patients with endothelial dysfunction as defined by reduced FMD (n = 11). Reactive hyperemia of the forearm increased local plasma nitrite concentration from 68 +/- 5 to 126 +/- 13 nmol/L (p < 0.01), whereas in endothelial dysfunction nitrite remained unaffected (116 +/- 12 to 104 +/- 10 nmol/L; n.s.), corresponding to nitrite reserves of 94 +/- 21 and -8 +/- 4%. This was accompanied by a significantly greater increase in brachial artery diameter (FMD: 8.5 +/- 0.4% vs 2.9 +/- 0.5%, for healthy subjects and endothelial dysfunction, respectively; p < 0.001). This observation suggests that nitrite changes reflect endothelial function. Assessment of local plasma nitrite during reactive hyperemia may open new avenues in the diagnosis of vascular function.

Adult↗
PubMed2006

The contribution of neuroimaging to the study of language and aphasia.

New structural and functional imaging methods continue to be developed at a rapid pace. In the last 25 years, advanced imaging techniques have provided insights into how language is represented and processed in the brain and how it can be disrupted by damage to, or dysfunction of, various parts of the brain. Imaging studies have also yielded new information regarding how individuals recover language after stroke. We briefly review the strengths and weaknesses of the various radiological methods currently used to study language and aphasia.

Aphasia↗
PubMed2006

Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting.

BACKGROUND: Hemostatic drugs are widely thought to be unnecessary and potentially detrimental in off-pump coronary artery bypass graft surgery (OPCABG), despite well-established use in on-pump surgery. In a randomized, prospective OPCABG trial, we assessed efficacy and safety of aprotinin through a comprehensive assessment of graft patency and hematologic function. METHODS: Sixty patients were randomly assigned to full-dose aprotinin or placebo. Heparin was titrated to a kaolin-based activated clotting time of greater than 300 seconds. Exclusionary criteria included creatinine greater than 2 mg/dL, conversion to on-pump CABG, and preoperative GPIIb/IIIa inhibition. Hematologic assessments were obtained preoperatively, at the end of surgery, and on days 1 and 3: mean platelet volume, thrombin generation (prothrombin fragment 1.2 assay), and aspirin resistance using a modified thrombelastography, whole blood aggregometry, 11-dehydro-thromboxane B2 levels, and flow cytometry. Thrombotic events were defined as postoperative myocardial infarction by electrocardiography or elevated troponin I, clinical stroke by examination and head computed tomography, and bypass graft failure by multichannel computed tomography angiography on day 5. RESULTS: Aprotinin was associated with a significant reduction in intraoperative and postoperative blood loss compared with placebo but had no effect on transfusion rates. Patients treated with aprotinin had significantly fewer thrombotic events (3% versus 23%, p < 0.05, Fisher's exact test) and less postoperative aspirin resistance (20% versus 46%, respectively, p < 0.05, Fisher's exact test). Postoperative prothrombin fragment 1.2 level was reduced by aprotinin use. CONCLUSIONS: Aprotinin reduced perioperative bleeding after OPCABG. Preserved aspirin sensitivity in the aprotinin group may explain the observed reduction in thrombotic events and might be related to the suppression of perioperative and transmyocardial thrombin formation.

Aprotinin↗
PubMed2006

Accidental seizure with repetitive transcranial magnetic stimulation.

Accidental induction of convulsions by using repetitive transcranial magnetic stimulation (rTMS) has been reported to have occurred in 6 normal voluntary subjects, in 1 patient with depression and in 1 patient who had temporal lobe epilepsy, with secondary generalization. In addition, 3 other cases have been published relating its use with seizure induction and in 1 case, using 1-Hz stimulation. In this paper, we report a patient who was participating in a protocol for the use of rTMS in chronic pain, with stimulation in the motor cortex, who developed a generalized seizure in the fifth application. Intertrain interval was within safety guidelines, but the combination of 10 Hz for 10 seconds was excessive and must be considered the main cause for the episode. No further complication has been noted after she was withdrawn from the study protocol.

Adult↗
PubMed2005

Torque-actuated valves for microfluidics.

This paper describes torque-actuated valves for controlling the flow of fluids in microfluidic channels. The valves consist of small machine screws (> or =500 microm) embedded in a layer of polyurethane cast above microfluidic channels fabricated in poly(dimethylsiloxane) (PDMS). The polyurethane is cured photochemically with the screws in place; on curing, it bonds to the surrounding layer of PDMS and forms a stiff layer that retains an impression of the threads of the screws. The valves were separated from the ceiling of microfluidic channels by a layer of PDMS and were integrated into channels using a simple procedure compatible with soft lithography and rapid prototyping. Turning the screws actuated the valves by collapsing the PDMS layer between the valve and channel, controlling the flow of fluids in the underlying channels. These valves have the useful characteristic that they do not require power to retain their setting (on/off). They also allow settings between "on" and "off" and can be integrated into portable, disposable microfluidic devices for carrying out sandwich immunoassays.

Immunoassay↗
PubMed2005

Bacterial printing press that regenerates its ink: contact-printing bacteria using hydrogel stamps.

This paper describes the use of micropatterned agarose stamps prepared by molding against PDMS masters to print patterns of bacteria on agar plates. Topographically patterned agarose stamps were inked with suspensions of bacteria; these stamps generated patterns of bacteria with features as small as 200 microm over areas as large as 50 cm2. Stamps with many small features (>200 microm) were used to study patterns of bacteria growing on media containing gradients of small molecules; stamps with larger features (>750 microm) were used to print different strains of bacteria simultaneously. The stamp transfers only a small percentage of cells that are on its surface to the agar at a time; it is thus possible to replica-pattern hundreds of times with a single inking. The use of soft stamps provides other useful functions. Stamps are easily customized to provide a range of patterns. When culture media is included in the agarose stamp, cells divide and thrive on the surface. The resulting "living stamp" regenerates its "ink" and can be used to pattern surfaces repetitively for a month. This method is rapid, reproducible, convenient, and can be used to control the pattern, spacing, and orientation between colonies of different bacteria.

Aliivibrio fischeri↗
PubMed2005

Sixth and tenth nerve palsy secondary to pseudomonas infection of the skull base.

PURPOSE: To describe skull base osteomyelitis, an uncommon complication of chronic otitis media in the post-antibiotic era, as a cause for diplopia. DESIGN: Case report. METHODS: The records of a patient with skull base osteomyelitis were reviewed. RESULTS: A patient presented with a sixth nerve palsy and tenth nerve palsy. Magnetic resonance imaging, bone scan, and gallium scan were helpful in establishing the diagnosis. Cultures grew Pseudomonas. The treatment required long-term intravenous antibiotics. CONCLUSIONS: Pseudomonas skull-based osteomyelitis can produce a sixth nerve palsy as a result of the involvement of the clivus. Although uncommon in the post-antibiotic era, early recognition, appropriate diagnostic testing, and aggressive systemic antibiotic treatment might prevent permanent neurologic sequel.

Abducens Nerve Diseases↗
PubMed2005

Platelet function tests predict bleeding and thrombotic events after off-pump coronary bypass grafting.

OBJECTIVE: A balanced coagulation system after cardiac surgery minimizes bleeding and thrombotic events. However, the best method to monitor this balance has not been established. We used a series of tests of coagulation and platelet function to define the risk of bleeding and thrombotic events after OPCAB. METHODS: In 76 patients, routine coagulation tests (i.e. prothrombin time, fibrinogen level, d-dimer, and platelet count), thrombelastography, and whole blood aggregometry were obtained perioperatively and on days 1 and 3 after OPCAB. Intra- and postoperative blood loss was determined. Early patency of venous bypass grafts was determined using CT angiography (Philips Medical, Corp.). RESULTS: Chest tube output and red cell volume loss at 24 h were 952+/-475 and 190+/-115 ml, respectively. Early graft failure developed in eight patients. Perioperative changes in routine coagulation tests showed no correlation with either bleeding or thrombosis. However, perioperative decline in platelet function as assessed by the area under the impedance curve for whole blood aggregometry correlated with intraoperative blood loss (R=0.42, P<0.05). A perioperative decline in the maximum amplitude of the thrombelastography trace showed a significant correlation with 24h hemoglobin loss (R=0.45, P<0.05). Compared to those with all patent grafts, patients with early graft failure demonstrated a reduction in platelet sensitivity to aspirin by both thrombelastography and aggregometry on day 3. CONCLUSIONS: In contrast to standard coagulation testing, platelet function predicted both bleeding and thrombosis after OPCAB. Titration of perioperative platelet function according to these tests may minimize thrombosis without increasing bleeding.

Aged↗
PubMed2005

Magnetic resonance criteria for future trials of cardiac resynchronization therapy.

Current patient selection criteria for Cardiac Resynchronization Therapy (CRT), an efficacious treatment for heart failure, include no measure of disconjugate cardiac contractility other than prolonged QRS on electrocardiogram. Using cardiac magnetic resonance imaging, we examined the roles of cardiac asymmetry, asynchrony, and circumferential strain in DCC with the principal aim of generating a robust numerical index for use in future trials of CRT. Standard cardiac magnetic resonance imaging was done on a GE 1.5 Tesla Signa LX MRI clinical scanner (GE Healthcare, Milwaukee, WI, USA) and analyzed by MASS Analysis (MEDIS, Leiden, The Netherlands). The methods were evaluated in eleven patients with advanced heart failure due to ischemic and non-ischemic cardiomyopathy, who did not qualify under current criteria for CRT, five CRT candidates pre-op and eleven normal subjects. Using t-test and standardized differences (SD = sd/diff, Power (N) = number of patients to reach p < .05) we determined efficacy. Indices of asymmetry and asynchrony (Ism and Isn, respectively) could be measured with accuracy and provided excellent statistical power when used as surrogate markers to delineate heart failure and CRT patients from control subjects. Asymmetry and asynchrony in heart contraction are both critical components of dilated cardiomyopathy that can be improved by CRT. Magnetic resonance asynchrony is efficacious in screening patients and should now be compared with recently published echocardiography data to improve outcome for this costly but valuable therapy.

Adult↗
PubMed2004

Potential efficacy of p16 gene therapy for EBV-positive nasopharyngeal carcinoma.

The p16 cell cycle inhibitory gene is a potentially critical molecular abnormality in nasopharyngeal carcinoma (NPC). Its expression is silenced through either deletion or promoter methylation in the vast majority of NPC. This in turn is associated with absent or reduced protein expression, which has been previously demonstrated by our group to correlate with inferior clinical outcome. Therefore, we were interested in evaluating the potential of adenoviral mediated p16 gene therapy (adv.p16) in an EBV-positive NPC model (C666-1). We confirm that under basal conditions, p16 protein is undetectable in C666-1 cells, which, in turn, is associated with retention of retinoblastoma protein (pRb) expression. P16 expression was observed as early as 4 hr after infection of C666-1 cells with adv.p16 (10 pfu/cell) with no discernible perturbation in pRb for up to 24 hr. At 48 hr post-infection, p16 expression continued to increase, but at this point, pRb expression started to decline significantly. Cell viability decreased in a dose-dependent manner, down to 20% using 50 pfu/cell of adv.p16. The addition of radiation therapy (RT) administered 24 hr post-infection achieved only a slightly additive cytotoxicity. Adv.p16 therapy resulted in multiple mechanisms of cytotoxicity, including cell cycle arrest at the G0/G1 phase, induction of senescence, along with apoptosis. Ex vivo infection of C666-1 cells with adv.p16 (25 pfu/cell) with subsequent implantation into scid mice completely prevented tumor formation, followed for up to 51 days. Our study demonstrates the potential efficacy of adv.p16 gene therapy for NPC, mediated through multimodal mechanisms of cytotoxicity. Future evaluations will examine strategies to increase in vivo tumor transduction with a view towards future clinical applications.

Adenoviridae↗
PubMed2004

Linguistic and location effects in compliance with pesticide warning labels for amateur and professional users.

Three studies explored amateur and professional users' compliance with pesticide warning labels. Professionals were classified as people working in a profession in which the use of pesticides is a necessary part of their job. Amateurs used pesticides only in their leisure time. The first study showed that the wording used affected perception of the appropriateness of hazard statements, one of the most effective variations being the use of the personal pronoun (statements beginning "You should..."). The location of warning information was also found to affect actual compliance: Compliance increased when warning information was presented in the directions for use section. A supplemental directive increased compliance only for professional users. In a final study, "best-case" and "worst-case" linguistic variations were combined with best-case and worst-case locations for safety information. Instruction statements using the personal pronoun and presented in the directions for use section resulted in the highest levels of compliance. The differences in compliance between amateur and professional users are interpreted within the framework of Rasmussen's (1986) distinction among skill-, rule-, and knowledge-based behavior. Actual or potential applications of this research include the design of warning labels and safety information.

Adolescent↗
PubMed2004

Virchow triad, but not use of an aortic connector device, predicts early graft failure after off-pump coronary bypass.

The risk of early thrombosis of coronary artery bypass (CAB) grafts may be increased after off-pump CAB, particularly after the use of an aortic connector device (ACD) to perform the proximal aortosaphenous anastomosis. We have been investigating tools that quantify the risk of early vein graft thrombosis after off-pump CAB on the basis of the Virchow triad of hypercoagulability, endothelial disease, and low conduit flow. These tools were applied in this prospective trial of a heterogeneous group of patients with varying degrees of aortic disease and who received the Symmetry ACD. After controlling for the Virchow risk factor triad, we hypothesized that the ACD does not independently influence graft thrombosis. There was no statistically significant difference in the early thrombosis rates of vein grafts connected with an ACD versus hand-sewn grafts (6.7% versus 6.5%). We found a wide range of graft flow measurements, platelet function, and vein endothelial phenotypes in patients with traditionally hand-sewn vein grafts and with grafts connected with an ACD in patients with a wide range of ascending aortic atherosclerosis. The perioperative combination of platelet hyperreactivity, marginal graft flow, and endothelial disease proved to be highly predictive of early graft failure as seen with postoperative computed tomographic angiography.

Aorta↗