Biomedical subjects
Publications and source records attributed to M Doyle.
An extremely difficult contract negotiation between a collective bargaining unit and a hospital resulted in a vote to strike by the nursing staff before reaching a final agreement. The authors describe the factors that led up to the strike vote. Realistic yet optimistic strategies for developing a working relationship with the bargaining unit leadership and the nursing staff are described.
BACKGROUND AND OBJECTIVES: Limited prospective data are available on sexually transmitted infections (STIs) among HIV-infected patients. The incidence and predictors of STIs were assessed among HIV-infected women enrolled in a clinical trial. STUDY DESIGN: Prospective cohort of 323 women. RESULTS: Sixty-five percent had at least one STI based on history and/or examination at baseline. Most conditions identified at baseline were based on patient history; only 10 of 123 women with no history of an STI (8.1%) had one identified upon examination. During a median follow-up of 2.1 years, 25% developed a new/recurrent STI. Being African-American (odds ratio [OR] = 4.22, 95% confidence interval [CI]: 1.45-12.26), reporting sex with an intravenous drug user as an HIV risk behavior (OR = 2.29, 95% CI: 1.34-3.92), and a history/presence of STIs at baseline (OR = 1.79, 95% CI: 1.01-3.19) were factors associated with significantly increased risk of STI's. CONCLUSIONS: A substantial proportion of women developed new STIs during the course of the clinical trial. Prevention efforts should be emphasized among high risk HIV-infected patients.
A variety of variable and constant rate, sparse sampling strategies have previously been proposed to rapidly image dynamically changing objects. The majority of these strategies compile a k-space data set for any given time point by substituting k-space data from the most recently sampled time positions (extracted from the sparsely sampled set). The BRISK technique, is a variable rate, sparse sampling technique which additionally incorporates an interpolation scheme to more accurately represent k-space data at positions which were not directly sampled. Here, strategies are introduced that allow tubo concepts to be incorporated with BRISK. Simulations are conducted to compare the efficacy of the turbo BRISK acquisition and processing strategy against a constant rate, sparse sampling strategy with direct substitution of the most recently acquired k-space lines. It is shown that turbo BRISK generates images of similar quality in approximately half the time as the uniform sampling rate, sparse sampling strategy. Data from turbo BRISK acquisitions of multicardiac phase image sets, obtained on a normal volunteer and cardiac patients are presented.
A current limitation of many myocardial tag acquisitions employing SPAMM encoding is the relatively rapid loss of tag contrast over the cardiac cycle. Acquisition schemes that apply line tags produce prolonged tag contrast compared with directly excited grid tags. However, a grid-tag series can be generated by combining two orthogonal line-tag series. To be time efficient, each line-tag series can be acquired with the read gradient oriented perpendicular to the line-tag direction. There are several disadvantages associated with this approach, including the requirement to avoid signal fold-over and that fat shift artifacts appear in different directions in each line-tag series. Presented here is a method of applying separate line tags that does not require interchanging the read and phase encoding gradients and does not extend the scan time compared with a conventional grid-tag acquisition. Additionally, the means of generating grid tags results in a doubling of the tag contrast to noise ratio compared a line-tag set. Computer simulations are presented along with phantom and volunteer scans.
Explore the source record for details and available documents.
While in-vitro fertilization (IVF) was initially developed in women with tubal factor infertility, recent clinical studies have suggested that the presence of hydrosalpinges lowers implantation and pregnancy rates. We postulated that these hydrosalpinges cause impaired endometrial receptivity. A total of 103 women with hydrosalpinges were prospectively evaluated, and compared with 55 infertile and 44 fertile controls. All women had endometrial biopsies during the window of implantation, analysed by conventional histological criteria, and also stained for three integrin markers of endometrial receptivity (alpha1beta1, alpha4beta1 and alpha vbeta3). Women with hydrosalpinges (cases) expressed significantly less of the alpha vbeta3 integrin compared with controls. There was no difference in expression of alpha1beta1 or alpha4beta1 among groups. A significantly greater number of cases had out of phase histology and missing alpha vbeta3 (type I defects) and absent integrin expression despite normal histological maturation (type II) defects, compared with controls. Of 20 women with impaired endometrial receptivity who were also biopsied after hydrosalpinx surgery, 70% demonstrated increased alpha vbeta3 expression. Seventy-seven percent of type I and 57% of type II defects were corrected postoperatively. Using markers of endometrial receptivity, this study demonstrates that inflammatory hydrosalpinges have an adverse effect on endometrial receptivity, which in some cases may be overcome by surgical treatment of the hydrosalpinx.
The inflammatory cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) have been associated with increased human immunodeficiency virus (HIV) expression and enhanced lymphocyte adhesion to trophoblastic cells in experimental systems. To determine if there is a correlation between the expression of these cytokines and the levels of HIV transcripts in trophoblasts of term placentas from HIV-infected women, we studied the placentae of 30 HIV-positive and 13 control gravidae. Twenty-three of the HIV-positive women received zidovudine (ZDV) as prophylaxis against HIV vertical transmission; only one of the seven women who did not receive ZDV was a transmitter, for an overall vertical transmission rate of 3.8%. Cytokine production was measured by enzyme-linked immunosorbent assay in the supernatants of trophoblastic cell cultures. Additionally, cytokine transcripts and HIV gag sequences were determined by a quantitative reverse transcription-PCR assay. In general, trophoblastic cells of HIV-positive placentas expressed significantly higher levels of IL-1beta, IL-6, and TNF-alpha than those of control placentas. All placentas from HIV-positive women expressed HIV gag transcripts at either a low (<156 copies per microg of total RNA) or a high (>156 copies per microg of total RNA) level. There was a statistically significant positive association between the basal level of TNF-alpha production and the level of HIV gag transcripts of HIV-positive placental trophoblastic cells. Nevertheless, these data, coupled with a low transmission rate, would indicate that some other factors, perhaps working in concert with cytokines, are necessary for vertical transmission of HIV from mother to infant.
Placental mononuclear cells (PMC) are susceptible to infection with the human immunodeficiency virus (HIV). PMC secreted tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta), and IL-6 among other factors, which, in turn, regulate HIV replication in latently infected cells. We assessed the induction of these cytokines in PMC from HIV-infected (HIV+) and uninfected (control) gravidae following exposure to lipopolysaccharide (LPS), HIV lysate (iHIV), recombinant HIV env (GP160) and HIV gag (gag55), and synthetic HIV p17 (HGP30) antigens. In comparison to control PMC, HIV+ PMC constitutively secreted higher levels of IL-1beta and IL-6 and were refractory to stimulation by iHIV, GP160, gag55, and HGP30. Control PMC IL-1 beta levels were boosted by LPS; gag55 and HGP30 augmented IL-6 but not IL-1 beta. Both groups exhibited low basal TNF-alpha production that was augmented by LPS. HIV+ PMC exhibited higher constitutive levels of IL-1 beta, IL-6, and TNF-alpha gene transcription than control PMC. These levels could be further augmented by LPS, yet the incremental levels were lower than those obtained from PMC of uninfected women. The high basal constitutive secretion of cytokines by HIV+ PMC and their refractoriness to activation may reflect a virus-mediated dysregulation of cytokine expression culminating in compromised host defenses against secondary opportunistic infections associated with AIDS.
OBJECTIVES: To determine the rate of in utero transmission of cytomegalovirus (CMV) in perinatally HIV-exposed infants and to determine whether coinfection with CMV in early life affects outcome. METHODS: Infants born to HIV-infected women between March, 1988, and March, 1995, were evaluated (n = 206). Congenital or in utero CMV infection was defined as a positive CMV culture or shell vial assay on urine obtained in the first 3 weeks of life. HIV-infected infants either had positive serology beyond 18 months of age or, for an infant younger than 18 months, had a positive HIV PCR or HIV culture on at least two separate occasions. RESULTS: There were 30 HIV-infected and 171 uninfected infants (144 who seroreverted and 27 infants with at least 2 negative HIV PCR or culture results and normal immunologic studies during the first 6 months of age). Urine culture for CMV was obtained during the first 3 weeks of life on 154 infants: 24 of 30 (80%) HIV-infected infants; and 130 of 171 (76%) HIV-uninfected infants. Overall 10 of 154 (6.5%) infants were infected with CMV: 5 of 24 (21%) HIV-infected and 5 of 130 (3.8%) HIV-uninfected infants. The rate of in utero CMV infection was significantly higher in HIV-infected infants (P = 0.008). Dually infected infants were more immunosuppressed than their CMV-negative counterparts. At 3 months of age the percentage of CD4+ T lymphocytes (P = 0.0021) and CD4:CD8 ratios (P = 0.0018) were significantly lower in the CMV-infected infants than in the CMV-uninfected infants. At 6 months of age the absolute CD4+ T lymphocyte counts (P = 0.0038), percentage of CD4+ T lymphocytes (P = 0.044) and CD4:CD8 ratios (P = 0.037) were significantly lower in the CMV-infected infants. The mean survival of HIV-infected infants who were coinfected with CMV in early life (5 in utero and 1 perinatally infected infant identified at 7 weeks) was 24.77 months. Kaplan-Meier survival analysis indicated a trend toward decreased survival in the infants who were coinfected with CMV in early life (P = 0.088). CONCLUSIONS: Congenital CMV infection is more common in HIV-infected infants than in HIV-uninfected infants. Infection with CMV in early life is associated with greater immunosuppression and may be associated with a more rapid progression of HIV infection in infants.
In human immunodeficiency virus (HIV)-infected adults, cytokine production profiles switch from predominantly type 1 (interleukin-2 [IL-2] and gamma interferon [IFN-gamma]) to type 2 (IL-4 and IL-10) cytokines with disease progression. To test this hypothesis in vertically HIV-infected children, we measured cytokine transcription and production in rapid progressors (RPs), seroreverters (SRs), and those children exposed to HIV in utero (P0s). Production of type 1 and type 2 cytokines was measured in peripheral blood mononuclear cell cultures of 8 SR, 25 P0, and 11 RP children. Unstimulated cultures, irrespective of infection and stage of disease, produced similar levels of IL-2, IFN-gamma, IL-4, and IL-10. Upon stimulation with phytohemagglutinin (PHA) plus phorbol-12-myristate-13-acetate (PMA), RP children produced less IL-2 (P < 0.01) and IFN-gamma (P < 0.02) than SR children and also expressed significantly less IFN-gamma mRNA (P < 0.01) than SR children. RP children expressed significantly higher levels of IL-4 mRNA than P0 children (P < 0.03). There were no differences in the production of IL-10 by PHA-PMA-stimulated peripheral blood mononuclear cell cultures among the three groups of children. Our data with these pediatric patients suggest that a deficiency in mitogen-stimulated type 1 cytokine production and excess type 2 cytokine (IL-4) transcription correlate with disease progression. Additional studies with larger sample sizes are needed to test further the hypothesis of the type 1-to-type 2 cytokine switch in children infected with HIV.
Explore the source record for details and available documents.
BACKGROUND: Contrast agent-enhanced magnetic resonance imaging (MRI) has the potential to visualize myocardial ischemia. To date, however, no agent has been found that has a sustained effect that allows MRI detection for the entire duration of ischemia and reperfusion and thus is useful in conjunction with stress test MRI. In this article, we introduce the gadolinium complex of N3,N6-bis(2'-myrisotyloxyethyl)-1,8-dioxo-triethylene- tetraamine-N,N,N1,N1-tetraacetic acid [Gd(BME-DTTA)], an agent potentially useful for such a purpose. METHODS AND RESULTS: Four protocols were carried out. ECG-triggered, partially T1-weighted, spin-echo MRI was used in protocols A through C. In protocol A, in nonischemic ferrets, 50 mumol/kg Gd(BME-DTTA) induced a 70 +/- 5% intensity enhancement lasting 3 hours. In protocol B, the left anterior descending coronary artery was occluded, and a 99mTc-sestamibi-induced autoradiographic contrast verified (r = .87, P < .01) a Gd(BME-DTTA)-induced (n = 5) or Gd(DTPA)-induced (n = 4) MRI contrast. In the Gd(BME-DTTA) group a sustained contrast and in the Gd(DTPA) group a short-lived contrast were observed. In protocol C (n = 11), during ischemia, a 31 +/- 3.3% (P < .02) contrast was evident between the ischemic and nonischemic myocardial regions. Upon reperfusion, a contrast of 19 +/- 3% (P < .05) and 13 +/- 4.5% (P < .05) persisted for 5 and 15 minutes, respectively. Beyond 15 minutes, the contrast continued to diminish gradually. Nonradioactive microspheres verified (r = .87, P < .05) ischemia and reperfusion in this model. In protocol D (n = 4), blood delta R1 data showed that the blood pool retained Gd(BME-DTTA) for the entire time frame of the experiment at high enough concentration to provide an appropriate wash-in effect during the initial contrast enhancement and during reperfusion. CONCLUSIONS: This study demonstrates that Gd(BME-DTTA) induces a sustained MRI contrast between regions of normal versus ischemic myocardium, showing the potential of this agent for the diagnosis of ischemic heart disease in conjunction with stress tests.
Explore the source record for details and available documents.
Human interleukin 5 (hIL5) and soluble forms of its receptor alpha subunit were expressed in Drosophila cells and purified to homogeneity, allowing a detailed structural and functional analysis. B cell proliferation confirmed that the hIL5 was biologically active. Deglycosylated hIL5 remained active, while similarly deglycosylated receptor alpha subunit lost activity. The crystal structure of the deglycosylated hIL5 was determined to 2.6-A resolution and found to be similar to that of the protein produced in Escherichia coli. Human IL5 was shown by analytical ultracentrifugation to form a 1:1 complex with the soluble domain of the hIL5 receptor alpha subunit (shIL5R alpha). Additionally, the relative abundance of ligand and receptor in the hIL5.shIL5R alpha complex was determined to be 1:1 by both titration calorimetry and SDS-polyacrylamide gel electrophoresis analysis of dissolved cocrystals of the complex. Titration microcalorimetry yielded equilibrium dissociation constants of 3.1 and 2.0 nM, respectively, for the binding of hIL5 to shIL5R alpha and to a chimeric form of the receptor containing shIL5R alpha fused to the immunoglobulin Fc domain (shIL5R alpha-Fc). Analysis of the binding thermodynamics of IL5 and its soluble receptor indicates that conformational changes are coupled to the binding reaction. Kinetic analysis using surface plasmon resonance yielded data consistent with the Kd values from calorimetry and also with the possibility of conformational isomerization in the interaction of hIL5 with the receptor alpha subunit. Using a radioligand binding assay, the affinity of hIL5 with full-length hIL5R alpha in Drosophila membranes was found to be 6 nM, in accord with the affinities measured for the soluble receptor forms. Hence, most of the binding energy of the alpha receptor is supplied by the soluble domain. Taken with other aspects of hIL5 structure and biological activity, the data obtained allow a prediction for how 1:1 stoichiometry and conformational change can lead to the formation of hIL5.receptor alpha beta complex and signal transduction.
We introduce an acquisition method, "block regional interpolation scheme for k-space" (BRISK), to reduce the acquisition time for cardiac imaging. The method exploits the high degree of correlation that exists between time-resolved cardiac images. For representative k-space data sets, Fourier analysis was applied along the cardiac phase dimension to reveal that different regions of k-space can be effectively sampled at different rates. A reduced sampling strategy was implemented, and unsampled points were generated by Fourier interpolation. Time savings of up to 75% are quite feasible and 25% BRISK scans compare well with 100% scans. Simulations and acquisitions using a normal volunteer and patients are presented.
A technique is demonstrated for the acquisition and processing of multislice, first-pass contrast-enhanced perfusion images in the myocardium. The acquisition is a modification of "keyhole" imaging in which time series images are acquired by sampling a limited segment of k-space, corresponding to the low spatial frequencies. In the modification demonstrated here, keyhole samples are divided into two groups that are sampled on alternate cardiac cycles. The alternate "missing" k-space portions are synthesized by Fourier interpolation. Visualization of contrast agent accumulation by image subtraction is demonstrated. A motion artifact reduction process using time domain Fourier filtering is used to reduce artifacts from respiration. Studies were performed on 46 patients at 1.5 T using gadoteridol (0.05-0.1 mmol/kg) injected into the right antecubital vein in conjunction with radionuclide imaging. Fully concordant studies were noted in 27 of these patients. Remaining studies were either partially or completely discordant for reasons relating to the differing natures of radionuclide versus MR contrast agent characteristics.
To test the hypothesis that the laryngeal mask airway (LMA) predisposes patients to gastroesophageal reflux, we randomly assigned 55 patients having elective surgery to receive standardized anesthesia with the LMA or with conventional face mask (FM) plus airway. A pH-sensitive probe with two electrodes, 10 cm apart, was passed nasally into the esophagus 1 h before induction of anesthesia, and recordings were made continuously until 30 min after surgery. At the distal electrode, 30 cm from the anterior nares, there was a significant difference in the incidence of reflux: 53.6% with the LMA versus 22.2% with the FM (P < 0.05). At the level of the proximal electrode, 20 cm from the anterior nares, there was no difference between groups. Multiple reflux events, defined as two or more reflux events before, during, or after anesthesia, were significantly more frequent in the LMA group (P < 0.05). Reflux events continued in the postanesthesia care unit (PACU) in both groups with no significant difference between groups. There was no clinical evidence of aspiration of gastric contents in either group. Use of the LMA appears to result in increased reflux to the level of the mid to upper esophagus, and is associated with a more frequent incidence of multiple reflux events than use of the FM.
The postischemic generation of oxygen-derived free radicals may contribute to myocardial reperfusion injury by affecting sarcolemmal ion transport. Recent evidence indicates that exposure to reactive oxygen intermediates induces rapid increases in myocardial cytosolic free Ca2+ (Ca2+i). The mechanism is undetermined but may involve disturbances in Na+ homeostasis. We tested this hypothesis by interleaving 23Na and 31P nuclear magnetic resonance (NMR) measurements of Na+i and high-energy phosphates in glucose-perfused rat hearts exposed to hydroxyl radicals generated from H2O2 and Fe3+. In separate experiments, K+i and Ca2+i were measured with 39K and 19F NMR, respectively. The hearts rapidly exhibited contracture. Threefold Na+i increases and substantial K+i depletion were observed. Glycolytic inhibition was indicated by rapid sugar phosphate accumulation and cellular energy depletion. Notably, however, severe functional and energetic deterioration and substantial elevation of Ca2+i occurred before substantial Na+i accumulation or K+i depletion was observed. Further experiments investigated the ability of pyruvate to scavenge H2O2 and to protect the myocardium from oxidant stress. Pyruvate (1 or 2.5 mmol/L) dramatically attenuated functional and energetic alterations and alterations in Na+i and K+i, whereas acetate (2.5 mmol/L) offered no protection. Unlike pyruvate, lactate (5 mmol/L) has little or no capacity to scavenge H2O2 but has similar protective effects. In conclusion, pyruvate effectively protects against H2O2/Fe3+, largely by direct H2O2 scavenging. Protection with lactate may involve intracellular pyruvate augmentation. Without exogenous pyruvate or lactate, myocardial Na+ homeostasis can be substantially altered by oxidant stress, possibly via cellular energy depletion. Excess Na+i accumulation may, in turn, hasten metabolic and functional deterioration, but a causal link with the initial alterations in function or Ca2+i was not supported.