Biomedical subjects

C J Morgan

Publications and source records attributed to C J Morgan.

At least 19 recordsLinked to original sources

PubMed1999

Hypoxemia after coronary bypass surgery modeled by resistance to oxygen diffusion.

OBJECTIVE: To evaluate a model describing postoperative hypoxemia after cardiac surgery by using two variables, i.e., shunt and resistance to oxygen diffusion (Rdff). DESIGN: Estimation of these two variables in normal subjects and postoperative cardiac patients. SETTING: The pulmonary function laboratory for the normal subjects and the intensive care unit for the cardiac patients. PATIENTS/SUBJECTS: Nine postoperative cardiac patients and six healthy subjects. INTERVENTIONS: Inspired oxygen fraction was varied in normal subjects and in cardiac patients 3-6 hrs after surgery. This variation occurred in four to seven steps to achieve arterial oxygen saturations in the range 0.90-1.00. MEASUREMENTS AND MAIN RESULTS: Measurements were taken of arterial oxygen saturation, cardiac output, ventilation, and end-tidal gases at each inspired oxygen fraction. These measurements gave the following estimates for the normal subjects: shunt = 3.9+/-5.4% (mean +/- SD) and Rdiff = -5+/-16 torr/(L/min) [-0.7+/-2.2 kPa/(L/min)]; for the cardiac patients: shunt = 7.7+/-1.8% and Rdiff = 212+/-230 torr/(L/min) [28.2+/-30.6 kPa/(L/min)]. The increase in Rdiff (P = .01) was sufficient to explain the observed hypoxemia in these patients. The value for shunt was not significantly increased in the patients (p = .09). The two-variable model (shunt and Rdff) gave a better prediction of arterial oxygen saturation than a model with shunt as the only variable (p = .02). CONCLUSIONS: In cardiac patients requiring supplementary oxygen, the respiratory abnormality could, in our model, be best described by an increased Rdiff, not by an increased shunt value.

Adult↗

PubMed1999

Predicting DSM-III-R disorders from the Youth Self-Report: analysis of data from a field study.

OBJECTIVE: To predict DSM-III-R diagnoses from Youth Self-Report (YSR) scores. METHOD: The Diagnostic Interview Schedule for Children Version 2.1c (DISC-2.1c) and YSR were administered to 289 homeless adolescents. Stepwise discriminant analysis identified YSR scales contributing to predictions of DSM-III-R disorders. Paper-and-pencil prediction rules based on YSR "borderline" or "clinical" scores were evaluated. RESULTS: Statistically significant discriminant functions for disruptive disorders, depressive disorders, manic disorders, attention-deficit hyperactivity disorder, schizophrenia, and posttraumatic stress disorder, each based on a unique pair of YSR scales, produced overall hit rates of 0.66 to 0.90. Paper-and-pencil predictions produced comparable results. The weakest overall predictions were for the disruptive behaviors; the best rule ("IF Aggressive OR Delinquent is at least borderline THEN predict oppositional defiant disorder or conduct disorder") produced a 0.72 hit rate. The strongest overall predictions were for schizophrenia; the best prediction rule ("IF [Thought Problems AND Delinquent are at least borderline] AND [at least one is clinical] THEN predict schizophrenia") produced a 0.87 hlt rate. CONCLUSIONS: While the success rates reported here are specific to this sample, it appears that the YSR has good ability to predict DSM-III-R diagnoses as determined by the DISC. Furthermore, it was demonstrated that categorical diagnoses can be treated as locations or cluster sectors in a multidimensional space.

Adolescent↗

PubMed1998

Characterization of collapsed states in the early stages of the refolding of hen lysozyme.

Early conformational states in the refolding of hen lysozyme from guanidine hydrochloride have been characterized by measuring both the fluorescence and the solvent exchange properties of tryptophan side chains. The indole proton occupancies indicate that at pH 5.5, 25 degrees C, half the protection against pulse labeling occurs in the dead time (4 ms) of the experiment, with the remaining protection developing with a time constant of 55 ms. Comparison of these data with the protection kinetics of backbone amides and with the fluorescence data provides evidence for hydrophobic collapse involving incorporation of tryptophan residues in a solvent-excluded state in advance of stable secondary structure formation. Analysis of the pH dependence of the indole hydrogen exchange protection is consistent with two or more structurally distinct collapsed states, and indicates that the generation of a correctly folded compact hydrophobic core is a key precursor to the formation of persistent native-like structure during refolding.

Animals↗

PubMed1998

Reduced mortality in association with the acute respiratory distress syndrome (ARDS).

BACKGROUND: A study was undertaken to investigate possible reductions in mortality and/or changes in outcome predictive factors in patients with the acute respiratory distress syndrome (ARDS) managed in a single centre. METHODS: The study was a prospective observational cohort study of two patient populations with ARDS. Group 1 comprised 41 patients enrolled between May 1990 and April 1993, and group 2 consisted of 78 patients enrolled between June 1993 and March 1997. The end points of the study were mortality and various factors predictive of death. RESULTS: There was a marked reduction in mortality between groups 1 and 2 (66% versus 34%; relative risk 1.77; CI 1.23 to 2.55). There were no significant differences between the groups in terms of age (40.6 (3.3) versus 45.5 (2.2) years), APACHE score (14.5 (0.72) versus 13.6 (0.1)), lung injury score (2.95 (0.07) versus 2.8 (0.1)), incidence of multi-organ failure (29% versus 32%), incidence of sepsis (31% versus 39%), or PaO2/FIO2 (kPa) ratio (11.8 (0.67) versus 12.0 (0.6)). There was a significantly lower proportion of men in group 1 (51% versus 74%). The case mix of the two groups was closely matched: following elective surgery 48% versus 48%, trauma 17% versus 16%, primary lung injury 12% versus 24%. Patients in group 1 were supported using several ventilatory and other modes (volume preset, non-inverse ratio ventilation, n = 15; pressure controlled inverse ratio ventilation (PC-IRV), n = 11; ultra high frequency jet ventilation (UHFJV), n = 13; an intravascular oxygenation device (IVOX) and extracorporeal gas exchange (ECGE), n = 2). Within group 1 no significant difference in mortality was observed between the patients on volume controlled ventilation and the remainder. In group 2 all patients received PC-IRV (n = 78) but, in addition, some received other support techniques (UHFJV n = 4, ECGE n = 2). In group 1 only sepsis on admission (21% (survivors) versus 56% (non-survivors)) predicted death. In group 2 age of survivors and non-survivors (41.2 (2.6) versus 52.6 (3.5)), APACHE score (12.2 (0.6) versus 15.8 (0.9)), and PaO2/FIO2 (12.8 (0.86) versus 10.5 (0.72)) predicted survival, but not the incidence of sepsis or multi-organ failure. CONCLUSIONS: In recent years a highly significant reduction in mortality associated with ARDS has been observed between two groups of patients well matched for disease severity and case mix. Changes in ICU organisation rather than specific interventions may account for this reduction, although different ventilatory and other management strategies used in the two groups may also be relevant.

Adult↗

PubMed1997

No early effects of electroconvulsive therapy on tryptophan metabolism and disposition in endogenous depression.

The possibility that a single electroconvulsive therapy (ECT) could increase tryptophan (Trp) availability to the brain for 5-hydroxytryptamine (5-HT, serotonin) synthesis was examined in 10 depressed patients before and during the 1st hour following an ECT and in 4 control (minor ear, nose, and throat surgical) subjects receiving similar premedication. Trp availability to the brain, expressed as the serum Trp: competing amino acid ratio, and related aspects of Trp disposition were not significantly altered by ECT any differently than from preoperative stress and premedication. We suggest that Trp availability to the brain and, hence, cerebral 5-HT synthesis are not altered in depressed patients early after a single ECT.

Adult↗

PubMed1997

Hydrogen exchange properties of proteins in native and denatured states monitored by mass spectrometry and NMR.

The extent of deuterium labeling of hen lysozyme, its three-disulfide derivative, and the homologous alpha-lactalbumins, has been measured by both mass spectrometry and NMR. Different conformational states of the proteins were produced by varying the solution conditions. Alternate protein conformers were found to contain different numbers of 2H atoms. Furthermore, measurement in the gas phase of the mass spectrometer or directly in solution by NMR gave consistent results. The unique ability of mass spectrometry to distinguish distributions of 2H atoms in protein molecules is exemplified using samples prepared to contain different populations of 2H-labeled protein. A comparison of the peak widths of bovine alpha-lactalbumin in alternate solution conformations but containing the same average number of 2H atoms showed dramatic differences due to different 2H distributions in the two protein conformers. Measurement of 2H distributions by ESI-MS enabled characterization of conformational averaging and structural heterogeneity. In addition, a time course for hydrogen exchange was examined and the variation in distributions of 2H atom compared with simulations for different hydrogen exchange models. The results clearly show that exchange from the native state of bovine alpha-lactalbumin at 15 degrees C is dominated by local unfolding events.

Animals↗

PubMed1997

Leukotrienes are indicated as mediators of hyperoxia-inhibited alveolarization in newborn rats.

We investigated the role of leukotrienes (LT) in hyperoxia-induced changes in lung parenchyma in neonatal rat pups. Rat pups were exposed to 21% O(2) (air) or >95% O(2) from days 4 to 14 after birth and were administered the 5-lipoxygenase (5-LO) inhibitor and LTD4 receptor antagonist Wy-50295, 5-LO-activating protein inhibitor MK-0591, or vehicle from days 3 to 14. All measurements were done on days 12-14. There was a significant (P < 0.05) increase in peptido-LT output from lung slices of animals exposed to O(2) compared with air-exposed animals. Both Wy-50295 and MK-0591 significantly lowered (P < 0.05) peptido-LT output in O(2)-exposed animals. The 6-ketoprostaglandin F(1alpha) output was increased similarly in both vehicle- and drug-treated O(2)-exposed animals. O(2) exposure also caused a significant increase in bronchoalveolar lavage fluid protein and extravascular lung water that could not be ameliorated by Wy-50295 or MK-0591. Hyperoxia-induced inhibition of alveolarization, indicated by a significantly (P < 0.05) lower parenchymal tissue density, specific internal surface area, and airspace perimeter-to-area ratio, and a significantly (P < 0.05) higher mean linear intercept and airspace unit volume than air-exposed animals, was prevented by both Wy-50295 and MK-0591. Although hyperoxia had no effect on septal thickness, Wy-50295 caused significant thickening in both air- and O(2)-exposed pups. Our studies provide evidence that hyperoxia-induced peptido-LT may mediate O(2)-induced inhibition of alveolarization and that this is not caused by an arachidonic acid shunt to cyclooxygenase.

Acute Disease↗

PubMed1996

Defective transfer RNA-queuine modification in C3H10T1/2 murine fibroblasts transfected with oncogenic ras.

tRNA isoacceptors for aspartic acid, asparagine, histidine, and tyrosine are modified in the anticodon wobble position with the deazaguanine analogue queuine. Queuine modification is defective in many tumors and transformed cell lines, and the extent of hypomodification correlates with staging and outcome in numerous human tumors. The molecular role of queuine modification in normal cells and the mechanisms of queuine hypomodification in tumors are unknown. We have characterized nontransformed C3H10T1/2 murine fibroblasts (C3H) and their ras-transfected counterparts (RasC4) with respect to the causes and effects of queuine hypomodification. RasC4 cells are hypomodified for queuine compared with C3H cells, despite increase tRNA-guanine ribosyltansferase activity. Excess exogenous queuine can cause repletion of tRNA queuine levels in RasC4 cells. Queuine modification of both C3H and RasC4 cells can be decreased by treatment with 7-methylguanine. This treatment does not affect growth in monolayer culture but enhances anchorage-independent growth of RasC4 cells greatly. These cell lines may be useful systems for the study of queuine function in normal cells and the causes and consequences of hypomodification for queuine in tumors.

Animals↗

PubMed1996

Limitation of life support: frequency and practice in a London and a Cape Town intensive care unit.

OBJECTIVES: To examine the frequency of limiting (withdrawing and withholding) therapy in the intensive care unit (ICU), the grounds for limiting therapy, the people involved in the decisions, the way the decisions are implemented and the patient outcome. DESIGN: Prospective survey. Ethical approval was obtained. SETTING: ICUs in tertiary centres in London and Cape Town. PATIENTS: All patients who died or had life support limited. INTERVENTIONS: Data collection only. RESULTS: There were 65 deaths out of 945 ICU discharges in London and 45 deaths out of 354 ICU discharges in Cape Town. Therapy was limited in 81.5% and 86.7% respectively (p = 0.6) of patients who died. The mean ages of patients whose therapy was limited were 60.2 years and 51.9 years (p = 0.014) and mean APACHE II scores 18.5 and 22.6 (p = 0.19) respectively. The most common reason for limiting therapy in both centres was multiple organ failure. Both medical and nursing staff were involved in most decisions, which were only implemented once wide consensus had been reached and the families had accepted the situation. Inotropes, ventilation, blood products, and antibiotics were most commonly withdrawn. The mean time from admission to the decision to limit therapy was 11.2 days in London and 9.6 days in Cape Town. The times to outcome (death in all patients) were 13.2 h and 8.1 h respectively. CONCLUSIONS: Withdrawal of therapy occurred commonly, most often because of multiple organ failure. Wide consensus was reached before a decision was made, and the time to death was generally short.

APACHE↗

PubMed1996

Definition and detection of alarms in critical care.

Critical care medicine has developed enormously in complexity and even more so in cost over the past twenty years. There has been evidence of remarkable progress in improved outcomes from some conditions, particularly when severely ill patients are treated in well equipped and well managed intensive care units (ICU) which have clear directorship and comprehensive management guidelines and protocols (Zimmermann et al., Crit Care Med 1993; 21:1443-1451). Nevertheless, for some conditions such as severe acute respiratory failure and multiple organ failure, there is considerable debate as to whether there has been any improvement at all (Lee et al., Thorax 1994; 49:596-597. Artigas et al., Adult respiratory distress syndrome, Churchill Livingstone, Edinbugh, London, Madrid, Melbourne, New York, Tokyo, pp. 509-525). Developments in signal processing and monitoring and recording technology have resulted in a vast increase in the quantity of data that is available to clinicians trying to manage critically ill patients (Price, Bailliere's Clin Anaesthesiol 1987; 1:533-556) but there is little evidence that this apparent gain has lead to better clinical decisions or earlier warning of significant instability. One of the tasks of the European Union sponsored IMPROVE group was to attempt to identify significant downward trends in vital parameters sufficiently early to allow clinical intervention to be potent and effective and ultimately improve patient outcome from a wide range of life threatening conditions. The first stage of this task was to define examples of such life threatening deterioration and conduct a survey in representative intensive care units of the incidence of these conditions and the subsequent patient outcomes. This is a preliminary task, the next stage being the gathering of "real time' data from critically ill patients for 24-h sample periods to probe for deteriorating trends and to compile a comprehensive annotated data library of physiological data as a rich resource for future adaptations in signal processing technology and clinical decision support.

Bacterial Infections↗

PubMed1996

Effects of chronic administration and subsequent withdrawal of ethanol-containing liquid diet on rat liver tryptophan pyrrolase and tryptophan metabolism.

An investigation of the effects of chronic administration of ethanol by the liquid diet procedure and its subsequent withdrawal on tryptophan (Trp) metabolism and disposition was performed in rats. Treatment with the control liquid diet caused an enhancement of liver Trp pyrrolase activity and mRNA abundance. These effects are not due to the starvation associated with this feeding procedure, because they occur in rats maintained on the liquid diet ad libitum. Chronic ethanol administration in the liquid diet did not further influence the above increased expression of Trp pyrrolase mRNA but caused inhibition of pyrrolase activity in competition with the effects of the diet. The control liquid diet decreased liver Trp concentration, but exerted no significant effects on other aspects of Trp disposition. The most striking and robust finding was a highly significant elevation in both Trp pyrrolase activity and mRNA expression at 7 h following discontinuation of ethanol availability, at which time there were demonstrable behavioural signs of ethanol withdrawal. The increase in Trp pyrrolase mRNA during alcohol withdrawal may be caused by corticosterone, whose circulating concentration was also increased. The changes in Trp pyrrolase activity during ethanol withdrawal were associated with significant alterations in Trp disposition including decreased brain Trp concentration and 5-hydroxytryptamine synthesis and turnover. These alterations may play a pivotal role in the behavioural manifestations of ethanol withdrawal including the hyperexcitement underlying audiogenic seizures. We suggest that rat Trp pyrrolase gene regulation may be an important biological determinant of the ethanol withdrawal syndrome and requires further study, and that the use of the liquid diet procedure in Trp metabolic studies requires inclusion of adequate controls and special attention to the effects of the liquid diet itself.

Alcohol Withdrawal Delirium↗

PubMed1996

Prevention by cycloheximide of the audiogenic seizures and tryptophan metabolic disturbances of ethanol withdrawal in rats.

Cycloheximide (20 mg/kg body wt, given intraperitoneally at-1 and 3 h after withdrawal of an ethanol-containing liquid diet) prevents the activation of liver tryptophan pyrrolase, the consequent inhibition of synthesis of brain 5-hydroxytryptamine, and the audiogenic seizures observed at 7 h after alcohol withdrawal. We suggest that a rapidly-turning-over protein mediates the alcohol withdrawal syndrome and discuss the possible role of liver tryptophan pyrrolase.

Acoustic Stimulation↗

PubMed1996

The localisation and characterisation of insulin-like growth factor-I receptors and the investigation of melatonin receptors on the hair follicles of seasonal and non-seasonal fibre-producing goats.

To define the hormonal influences that are directly involved in the hair follicle cycles of animals with differing patterns of fibre growth and moulting, we have investigated the possible presence of IGF-I and melatonin receptors on the dermis and hair follicles of cashmere and Angora goats, sampled in February. March and June, using quantitative in vitro autoradiography. The presence of IGF-I receptors in the dermis of both breeds of goat was determined using cryostat sections incubated with 50 pM 125I-labelled IGF-I in the presence or absence of 50 nM IGF-I. Sections of the growing tip of deep antlers concerning the cartilaginous zone, a tissue known to contain high concentrations of specific IGF-I receptors, were used as a positive control. As the production of antler velvet uniquely involves the generation of hair follicles de novo, the presence of IGF-I receptors in the velvet-producing region was also investigated. In both breeds of goat, specific 125I-IGF-I binding was localised over the inner and outer root sheath, the matrix, the germinal matrix, the dermal papilla and the sebaceous glands and satisfied the basic kinetic criteria considered to be representative of a specific IGF-I receptor. Analysis of saturation isotherms using a one-site binding model revealed dissociation constants (Kd) in the range 0.1-0.9 nM and theoretical maximal numbers of binding sites (Bmax) between 21.4 and 45.6 fmol/mg tissue. Kd and Bmax values derived from cashmere and Angora goats sampled at different times of the year did not differ significantly between breeds or sampling times. Specific 125I-IGF-I binding was also localised to the developing follicles on the deer antler dermis. The presence of melatonin receptors within the goat dermis was also investigated. Sections were incubated with 100 pM 2-[125I]iodomelatonin with or without 0.1 microM melatonin, along with sections of sheep pars tuberalis which are known to contain high levels of high-affinity melatonin receptors. No displaceable 2-[125I]iodomelatonin binding was found on any sections of the cashmere or Angora skin analysed. It is therefore concluded that melatonin receptors are not present on the hair follicles or associated structures. IGF-I receptors are present on the hair follicle and sebaceous gland and may be involved in the growth of both seasonally and non-seasonally produced fibre and in the development of antler velvet.

Animals↗

PubMed1995

Decrease in circulating tryptophan availability to the brain after acute ethanol consumption by normal volunteers: implications for alcohol-induced aggressive behaviour and depression.

Acute ethanol consumption by fasting male volunteers decreases circulating trytophan (Trp) concentration and availability to the brain as determined by the ratio of (Trp) to the sum of its five competitors ([Trp]/[CAA]ratio). These effects of alcohol are specific to Trp, because levels of the 5 competitors are not increased. The decrease in circulating (Trp) is not associated with altered binding to albumin and may therefore be due to enhancement of hepatic Trp pyrrolase activity. It is suggested that, under these conditions brain serotonin synthesis is likely to be impaired and that, as a consequence, a possible strong depletion of brain serotonin in susceptible individuals may induce aggressive behaviour after alcohol consumption. The possible implications of these findings in the relationship between alcohol and depression are also briefly discussed.

Adult↗

PubMed1995

Expansion of mucin-reactive T-helper lymphocytes from patients with colorectal cancer.

The ability to identify and expand effector cells with reactivity against tumor-associated antigens (TAA) is critical for effective adoptive cellular therapy. The purpose of this study was to assess lymph node lymphocytes sensitized in vivo to the shed TAA TAG-72 as a potential source of cells for adoptive cellular therapy. Lymph nodes containing microscopic tumor and/or shed TAG-72+ mucin were localized using radiolabeled CC49 monoclonal antibody and a gamma detector at the time of exploratory colorectal surgery. Lymph nodes containing microscopic tumor and shed mucin exhibited approximately 40-fold expansion in short-term (< 21 days) cultures with either IL-2 or IL-1 plus IL-2; the combination of IL-2/anti-CD3 monoclonal antibody (mAb) resulted in significantly higher expansion. Cultures generated with IL-2 alone favored the expansion of CD8+ and CD56+ cells, whereas addition of IL-1 or anti-CD3 mAb to IL-2 promoted outgrowth of CD4+ T-cells. The IL-2/anti-CD3 expanded cells exhibited low levels of cytolytic activity in vitro against autologous and allogeneic colon tumor targets. However, CD4+ cells expanded in IL-2/anti-CD3 retained the ability to proliferate in response to TAG-72 mucin-expressing autologous tumor as well as bovine submaxillary mucin (BSM) a soluble TAG-72+ mucin. In addition, CD4+ cells expressed mRNA for IL-2, IL-4, tumor necrosis factor-beta and IFNg, and retained the ability to secrete IL-2 after expansion. Thus, noncytolytic, cytokine-secreting, mucin-reactive T- cells can be expanded from lymph nodes of patients with colorectal cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, Neoplasm↗

PubMed1995

Difficulties in predicting outcome in cardiac surgery patients.

OBJECTIVE: To evaluate a novel combination of preoperative, intraoperative, and postoperative variables (including the Parsonnet, and the Acute Physiology and Chronic Health Evaluation II and III [APACHE II and III] scores) in cardiac surgery patients in order to predict hospital outcome, complications, and length of stay. DESIGN: Prospective survey. SETTING: Adult intensive care unit (ICU) at a tertiary care cardiothoracic surgery center. PATIENTS: All cardiac surgery patients admitted to the ICU over a 1-yr period. INTERVENTIONS: Medical history, Parsonnet score, intraoperative data (including bypass and ischemic times), APACHE II and III scores, complications, and outcome were collected for each patient. MEASUREMENTS AND MAIN RESULTS: One thousand eight patients were entered into the study. The mean Parsonnet score was 7.8 (range 0 to 33), mean APACHE II score 11.8 (range 2 to 33), and mean APACHE III score 42.5 (range 9 to 132). ICU mortality rate was 2.7% and hospital mortality rate was 3.8%. The mean APACHE II predicted risk of dying was 5.31%, which gave a standardized mortality ratio of 0.71. The above scores were all statistically well correlated with hospital mortality. Further, a logistic regression model was developed for the probability of hospital death. This model (which included bypass time, need for inotropes, mean arterial pressure, urea, and Glasgow Coma Scale) had an area under the receiver operating characteristic curve of 0.87, while the Parsonnet score had an area of 0.82 and the APACHE II risk of dying had an area of 0.84. CONCLUSIONS: Cardiac surgery remains a difficult area for outcome prediction. A combination of intraoperative and postoperative variables can improve predictive ability.

APACHE↗

PubMed1994

6-Thioguanine-induced growth arrest in 6-mercaptopurine-resistant human leukemia cells.

The thiopurines 6-thioguanine (6TG) and 6-mercaptopurine (6MP) are cytotoxic to proliferating cells by a mechanism involving incorporation into DNA via the purine salvage pathway, and resistance to these agents can be conferred by lack of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase. However, human and murine hypoxanthine-guanine phosphoribosyltransferase-deficient leukemia cell lines have been shown to respond to 6TG by growth arrest and differentiation by a mechanism apparently not involving incorporation of 6TG into DNA. If so, leukemia cells resistant to 6MP should still respond to 6TG by growth arrest via an undescribed epigenetic mechanism. To test this, polyclonal 6MP-resistant variants were produced from three human leukemia cell lines, HL-60, U937, and CCRF-CEM. Treatment of both sensitive and resistant cells with 6TG induced growth arrest. The effect of 6TG in the 6MP-sensitive HL-60 and U937 cells was associated with significant loss of viability and DNA fragmentation. In contrast, the 6TG-treated 6MP-resistant cells exhibited a slower decline in viability and no DNA fragmentation. To identify the mechanism by which 6TG may induce growth arrest, tRNA was isolated from 6MP-resistant cells cultured for 48 h with 6TG. 6TG was found to be incorporated into tRNAs normally containing queuine in the anticodon wobble position. These studies may provide a basis for the development of new therapeutic regimens for the treatment of leukemia.

Apoptosis↗

PubMed1994

Transmission of hepatitis C by kidney transplantation--the risks.

The use of cadaveric organ donors with positive serologic tests for hepatitis C (HCV) has caused considerable debate. We have reviewed the clinical course of 43 EIA1 HCV-negative recipients who received kidney transplants from EIA1 HCV-positive donors (Study). We have attempted to define the rate of HCV-RNA transmission and to determine the frequency of HCV disease transmission as determined by abnormalities in liver function tests. Viral transmission was assessed using serologic assays for HCV antibody formation (EIA1, EIA2, and Matrix--an automated multiple antigen immunoblot assay) and with PCR testing for the presence of HCV-RNA on recipient sera. Liver function was followed longitudinally in the Study patients and compared with a group of 103 kidney recipients of organs from EIA1 HCV-negative donors (Control). Of the Study patients, 56% became PCR-positive for HCV-RNA, suggesting the transmission of HCV-RNA from the HCV-positive donor. Interpretation of serologic tests for HCV was complex. Currently available first (EIA1) and second (EIA2) generation serologic assays were always negative. The multiple antigen immunoblots assay (Matrix) had a high positive predictive value (93%) for the presence of HCV-RNA transmission, but one-third of Matrix-negative Study patients were PCR-positive (sensitivity = 66%). Currently, only 38% of recipients have HCV-RNA, suggesting that the virus may have been cleared by one-third of Study recipients who had circulating virus. Traditional tests of liver function (ALT, AST, AP, and GGT) were of limited use in predicting HCV-RNA transmission. Average AST, AP, and GGT were similar in the two groups. Average ALT was increased (93 I/U and 47 I/U) in Study and Control patients, respectively, but this difference was not significant. Episodes of abnormal liver function (ALT 60-99 IU for > or = 14 days) occurred in 22% of Study and 10% of Control patients (P = NS) and lasted longer in Study compared with Control patients (301 vs. 138 days; P < 0.02). Hepatitis (ALT > or = 100 IU for > 14 days) occurred with an equal frequency (6.5%) in both groups. The presence of HCV-RNA did not predict episodes of abnormal liver function. Fulminant hepatitis or rapidly progressive cirrhosis did not occur in the recipients of organs from HCV-positive donors. These data demonstrate a high efficiency of transfer of HCV-RNA by kidney transplantation from an HCV-positive donor to an HCV-negative recipient. A majority of the patients have asymptomatic HCV infection.(ABSTRACT TRUNCATED AT 400 WORDS)

Cadaver↗