Biomedical subjects
Publications and source records attributed to S Kelley.
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Two juvenile pigtailed macaques (animals 1 and 2) received total body irradiation (TBI) followed by autologous stem cell transplantation, by a procedure known to be well tolerated by baboons. In this procedure, the TBI consisted of treatment on two consecutive days with 255cGy on one side, followed after 1-2 min by a similar dose on the other side. The two pigtailed macaques showed rapid haematopoietic engraftment, but succumbed either to systemic cytomegalovirus (CMV) infection and necrotising colitis or to haemorrhagic cystitis and tubulointerstitial nephritis. For four further pigtailed macaques (animals 3-6) the radiation procedure was changed to four equal doses of 255cGy, given 6-12 h apart. Animals 4-6 all showed engraftment and survived for long periods (>218 days), with no, or only minor treatable, complications. Animal 3 failed to show engraftment and succumbed to radiation-induced vascular lesions and severe multiorgan haemorrhages. The results suggest that pigtailed macaques have a lower tolerance threshold than baboons, rhesus macaques or human beings to TBI, the adverse effects of TBI being indistinguishable from those seen in human patients. The results also suggest that a hyperfractionated radiation procedure can prevent radiation-induced morbidity and mortality in pigtailed macaques.
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Adolescents with and those without mental retardation participated in a negative priming procedure in two experiments. They identified letters to stimulus displays presented in pairs. Negative priming was observed as the slowing of response times when the distractor in the first display (prime) became the target in the second display (probe). In the standard procedure, all displays include one target and one distractor. In our modification, prime displays occasionally included a distractor without a target. Although adolescents with mental retardation typically do not exhibit negative priming when responding on the basis of stimulus identity, they did so with single letter primes in these experiments.
Acedb is one of the more venerable pieces of Genomics software. Acedb was originally created in 1992 by Richard Durbin and Jean Thierry-Mieg to manage the data from the Caenorhabditis elegans mapping project and subsequently the C. elegans sequencing project. From beginnings as a C. elegans-specific tool, it has been continuously developed into a flexible suite of data management, display and scripting tools providing facilities for managing and annotation mapping information and DNA and peptide sequences. This paper gives a basic overview of the Acedb suite, and step-by-step guidance on how to download and install Acedb. It is intended to take an Acedb novice to stage where they can begin to experiment and explore the facilities that are available.
BACKGROUND: Controversy exists regarding the lowest blood hemoglobin concentration that can be safely tolerated. The authors studied healthy resting humans to test the hypothesis that acute isovolemic reduction of blood hemoglobin concentration to 5 g/dl would produce an imbalance in myocardial oxygen supply and demand, resulting in myocardial ischemia. METHODS: Fifty-five conscious healthy human volunteers were studied. Isovolemic removal of aliquots of blood reduced blood hemoglobin concentration from 12.8 +/- 1.2 to 5.2 +/- 0.5 g/dl (mean +/- SD). Removed blood was replaced simultaneously with intravenous fluids to maintain constant isovolemia. Hemodynamics and arterial oxygen content (Cao2) were measured before and after removal of each aliquot of blood. Electrocardiographic (ECG) changes were monitored continuously using a Holter ECG recorder for detection of myocardial ischemia. RESULTS: During hemodilution, transient, reversible ST-segment depression developed in three subjects as seen on the electrocardiogram during hemodilution. These changes occurred at hemoglobin concentrations of 5-7 g/dl while the subjects were asymptomatic. Two of three subjects with ECG changes had significantly higher heart rates than those without ECG changes at the same hemoglobin concentrations. When evaluating the entire study period, the subjects who had ECG ST-segment changes had significantly higher maximum heart rates than those without ECG changes, despite having similar baseline values. CONCLUSION: With acute reduction of hemoglobin concentration to 5 g/dl, ECG ST-segment changes developed in 3 of 55 healthy conscious adults and were suggestive of, but not conclusive for, myocardial ischemia. The higher heart rates that developed during hemodilution may have contributed to the development of an imbalance between myocardial supply and demand resulting in ECG evidence of myocardial ischemia. However, these ECG changes appear to be benign because they were reversible and not accompanied by symptoms.
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OBJECTIVE: Our experiments were designed to test the hypothesis that tendon cells might respond differently to applied strain in vitro than in vivo. DESIGN: We tested cells in whole tendons from exercised chickens and from isolated surface (TSC) and internal tendon (TIF) in vitro that were subjected to mechanical strain. We hypothesized that tendon cells differentially express genes in response to mechanical loading in vivo and in vitro. METHODS: We utilized an in-vivo exercise model in which chickens were run on a treadmill in an acute loading regime for 1 h 45 min with the balance of time at rest to 6 h total time. Gene expression was analyzed by a differential display technique. In addition, isolated avian flexor digitorum profundus TSC and TIF cells were subjected to cyclic stretching at 1 Hz, 5% average elongation for 6 h, +/- PDGF-BB, IGF-I, TGF-beta 1, PTH, estrogen, PGE2, or no drug and/or no load. mRNA was then collected and samples were subjected to differential display analysis. CONCLUSIONS: Load with or without growth factor and hormone treatments induced expression of novel genes as well as some known genes that were novel to tendon cells. We conclude that the study of gene expression in mechanically loaded cells in vivo and in vitro will lead to the discovery of novel and important marker proteins that may yield clues to positive and negative cell strain responses that are protective under one set of conditions and destructive under another.
CONTEXT: Although concern over the risks of red blood cell transfusion has resulted in several practice guidelines for transfusion, lack of data regarding the physiological effects of anemia in humans has caused uncertainty regarding the blood hemoglobin (Hb) concentration requiring treatment. OBJECTIVE: To test the hypothesis that acute isovolemic reduction of blood Hb concentration to 50 g/L in healthy resting humans would produce inadequate cardiovascular compensation and result in tissue hypoxia secondary to inadequate oxygen transport. DESIGN: Before and after interventional study. SETTING: Academic tertiary care medical center. PARTICIPANTS: Conscious healthy patients (n =11) prior to anesthesia and surgery and volunteers not undergoing surgery (n=21). INTERVENTIONS: Aliquots of blood (450-900 mL) were removed to reduce blood Hb concentration from 131 (2) g/L to 50 (1) g/L [mean (SE)]. Isovolemia was maintained with 5% human albumin and/or autologous plasma. Cardiovascular parameters, arterial and mixed venous oxygen content, oxyhemoglobin saturation, and arterial blood lactate were measured before and after removal of each aliquot of blood. Electrocardiogram and, in a subset, Holter monitor were monitored continuously. MAIN OUTCOME MEASURES: "Critical" oxygen delivery (TO2) as assessed by oxygen consumption (VO2), plasma lactate concentration, and ST changes on electrocardiogram. RESULTS: Acute, isovolemic reduction of Hb concentration decreased systemic vascular resistance and TO2 and increased heart rate, stroke volume, and cardiac index (each P<.001). We did not find evidence of inadequate oxygenation: VO2 increased slightly from a mean (SD) of 3.07 (0.44) mL of oxygen per kilogram per minute (mL O2 x kg(-1) x min[-1]) to 3.42 (0.54) mL O2 x kg(-1) x min(-1) (P<.001) and plasma lactate concentration did not change (0.81 [0.11] mmol/L to 0.62 [0.19] mmol/L; P=.09). Two subjects developed significant ST changes on Holter monitor: one apparently related to body position or activity, the other to an increase in heart rate (at an Hb concentration of 46-53 g/L); both occurred in young women and resolved without sequelae. CONCLUSIONS: Acute isovolemic reduction of blood Hb concentration to 50 g/L in conscious healthy resting humans does not produce evidence of inadequate systemic TO2, as assessed by lack of change of VO2 and plasma lactate concentration. Analysis of Holter readings suggests that at this Hb concentration in this resting healthy population, myocardial ischemia would occur infrequently.
Predictions that infectious diseases would be eliminated as a major threat to human health have been shattered by emerging and reemerging infections, among them acquired immunodeficiency syndrome (AIDS), hemorrhagic fevers, marked increases in infections caused by antimicrobial-resistant bacteria, and the resurgence of tuberculosis and malaria. Understanding the dynamics of emerging and reemerging infections is critical to efforts to reduce the morbidity and mortality of such infections, to establish policy related to preparedness for infectious threats, and for decisions on where to use limited resources in the fight against infections. In order to offer a multidisciplinary perspective, 23 infectious disease specialists, epidemiologists, geneticists, microbiologists, and population biologists participated in an open forum at Emory University on emerging and reemerging infectious diseases. As summarized below, the group addressed questions about the definition, the identification, the factors responsible for, and multidisciplinary approaches to emerging and reemerging infections.
To establish the extent of cross-cultural content contained in the 224 psychiatric residency training programs, the Directors of Residency Training were surveyed by mail. Thirty-seven percent (N = 83) of Directors responded; 92% (N = 76) had cross-cultural content, 99% (N = 82) had opportunities to work with minority patients, and 77% (N = 64) had supervision by some minority faculty. Responding programs reported a need for teaching videotapes (85%, N = 71), cross-cultural references (78%, N = 65), academic psychiatrists familiar with different cultural groups (76%, N = 63), and cross-cultural supervision (75%, N = 62).
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Nine strains of Streptococcus oralis, isolated from blood cultures of patients with infective endocarditis or from the oral cavity as part of the normal flora, were examined for their ability to elaborate sialidase (neuraminidase) and N-acetylglucosaminidase, enzymes which are involved in the degradation of glycoproteins. Both glycosidases were induced when bacteria were grown in a minimal medium supplemented with porcine gastric mucin, a model glycoprotein, and repressed when growth occurred in the presence of glucose. Cell-free extracts mucin-grown cultures expressed elevated levels of N-acetylneuraminate pyruvate-lyase (the first intracellular enzyme in the pathway of N-acetylneuraminate catabolism), N-acetylglucosamine (glcNAc)-6-phosphate deacetylase and glucosamine-6-phosphate deaminase (enzymes involved in the intracellular catabolism of GlcNAc 6-phosphate); activity of each of these intracellular enzymes was markedly repressed when bacteria were grown in media supplemented with alpha 1-acid glycoprotein, a major component of human plasma. Cells from these cultures expressed high levels of sialidase, N-acetylglucosaminidase, and the intracellular enzymes involved in the catabolism of N-acetyl-sugars released by action of these glycosidases. High-resolution 1H-NMR spectroscopy of spent culture supernatants revealed that sialic acid and GlcNAc residues of the molecularly mobile oligosaccharide side-chains of alpha 1-acid glycoprotein had been hydrolysed and the released sugars internalized by the bacteria. These data indicate that S. oralis has the ability to hydrolyse constituents of oligosaccharide side-chains of host-derived glycoproteins and to utilize simultaneously these released carbohydrates. The biochemical characteristics induced by the growth of S. oralis on glycoproteins may play a role in the survival and persistence of these bacteria at the infection site in vivo.
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We prospectively studied the use of either aspirin or intermittent pneumatic compression (IPC) as prophylaxis against thromboembolism after 330 consecutive total hip arthroplasties. Duplex ultrasonography of the veins of both lower extremities and ventilation-perfusion lung scans were done preoperatively and 7 to 14 days postoperatively. Eight patients in the IPC group (5%) had asymptomatic deep vein thrombosis; there were no symptomatic thrombi. In the aspirin group, 10 patients (7%) had asymptomatic deep vein thrombosis and two patients (1%) had symptomatic deep vein thrombosis. This difference was not statistically significant. There were no fatal pulmonary emboli in either group. In the IPC group, only one patient had symptomatic pulmonary embolism and 20 patients (22 hips [12%]) had asymptomatic pulmonary embolism. In the aspirin group, two patients (1%) had symptomatic pulmonary embolism and 26 patients (18%) had asymptomatic pulmonary embolism. This difference in asymptomatic pulmonary embolism between the two groups was statistically significant. Both groups had a low incidence of deep vein thrombosis, as shown by Duplex ultrasonography, but IPC was more effective than aspirin in preventing asymptomatic pulmonary embolism after total hip arthroplasty.
Development of human antimouse antibody (HAMA) is a major limiting factor in the application of murine mAb for clinical use. A novel immunomodulatory drug, deoxyspergualin (DSG), has shown potential to suppress antimouse antibody response in preclinical model systems. We conducted a Phase I trial to determine the effect of DSG on HAMA response to murine mAb L6 administered to patients with advanced cancers (in previous trials, this antibody elicited HAMA in two-thirds of the treated patients). L6 mAb was administered at a fixed dose of 200 mg/m2 on days 1-5. DSG was administered at doses of 50 mg/m2 [dose level (dl) 1] or 150 mg/m2 (dls II and III) on days 1-7. Treatment courses were repeated every 6 weeks (dls I and II) or every 3 weeks (dl III). HAMAs were quantitated by a commercially available ELISA assay (ImmuSTRIP; anti-isotypic antibodies) and a radiometric assay (antiisotypic and anti-idiotypic antibodies). Pharmacokinetics of L6 and DSG was also studied in all consenting patients. Among 24 evaluable patients, 2 patients developed detectable HAMAs using the ELISA (one each at dls I and II) after a median follow-up of 122 days (P = 0.0001 as compared to historical controls). Even in the two patients who developed HAMA, the HAMA levels were quite low (160 and 181 ng/ml; historical experience, 70-38,744 ng/ml). The radiometric assay detected anti-L6 antibodies in 13 patients (4, 6, and 3 at dls I-III, respectively) after a median of 82 days. The median highest anti-L6 antibody level was 129 ng/ml (range, 21-2150). The highest anti-L6 antibody level at dl III was only 44 ng/ml. The results suggest suppression of anti-idiotypic response also. No clinical antitumor activity was observed, and no significant changes in T4/T8 subsets or immunoglobulins occurred (suggesting a lack of generalized immunosuppression). We conclude that DSG can suppress HAMA response to L6. A starting dose of 150 mg/m2/day is recommended for Phase II trials to confirm this observation.
BACKGROUND: Total vascular exclusion (TVE) of the liver has been used to increase the safety of hepatectomy and the feasibility of difficult resections. Until recently, however, concern about the detrimental effect of warm ischemia has limited the use of this technique to patients with normal liver parenchyma. OBJECTIVE: To compare surgical outcomes of 12 patients with abnormal livers (group 1) with outcomes of 48 patients with normal parenchyma (group 2), based on the hypothesis that uncontrolled bleeding may be more detrimental than planned hepatic ischemia. DESIGN AND SETTING: Retrospective analysis of 60 consecutive patients undergoing liver resection under TVE in a university medical center. PATIENTS: All 10 patients with cirrhosis had albumin levels of 30 g/L or higher and normal prothrombin times preoperatively; none had ascites. Two patients with cholestasis (one with cholangiocarcinoma and one with hepatocellular carcinoma) are included in group 1. INTERVENTION: All 12 group 1 patients and 44 of 48 group 2 patients underwent total or extended lobectomy, with TVE induced by clamping the hilum and the vena cava above and below the liver during parenchyma division. MAIN OUTCOME MEASURES: Hospital survival and selected surgical and laboratory parameters. RESULTS: Operative times, ischemic times, and blood loss (1975 +/- 1601 vs 1255 +/- 1291 mL) (P = .10) were comparable in both groups. Sixty-day operative mortality was zero in both groups. There was an increased rate of complications in group 1 (44% vs 17% [P = 0.06]). Transient abnormal liver function was observed in both groups. However, significant delay in restoration of normal function was observed in group 1 with respect to bilirubin levels and prothrombin time. CONCLUSIONS: Patients with cirrhosis can undergo successful resection using TVE. This conclusion must be limited to cirrhotic patients with good liver function. The trend toward increased blood loss may reflect greater difficulties in establishing hemostasis after reperfusion in group 1. While this group appears to have a higher risk for hepatic insufficiency, successful outcomes were achieved in all cases. Prospective study will be required to define the parameters for use of TVE in cirrhosis.
The interaction between long-term potentiation (LTP) and the action of a peptide transmitter was examined with evoked field potential recording in the CA1 region of the hippocampus in anesthetized male rats. The peptide transmitter transiently reversed and opposed the effects of LTP, and LTP reversed the action of the peptide transmitter. Because the peptide transmitter is released and has action particularly during sexual behaviors, the results are interpreted to mean that any memory trace encoded by potentiating mechanisms in the rat hippocampus is probably not accessible in the 20-30-min period of time surrounding reproductive activity in male rats.