A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have
great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor
and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited,
and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels.
Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with
myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered
once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic
studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule
only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose
studied (1000 μg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing
doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77–1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase
63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were
<1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent
activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no
demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained
by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase
in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either
extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling
circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the
systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.
Received: 29 January 1997 / Accepted: 9 May 1997 相似文献
The Authors for the Live Organ Donor Consensus Group
JAMA. 2000;284:2919-2926.
Objective To recommend practice guidelines for transplantphysicians, primary care providers, health care planners, andall those who are concerned about the well-being of the liveorgan donor.
Participants An executive group representing the NationalKidney Foundation, and the American Societies of Transplantation,Transplant Surgeons, and Nephrology formed a steering committeeof 12 members to evaluate current practices of living donortransplantation of the kidney, pancreas, liver, intestine, andlung. The steering committee subsequently assembled more than100 representatives of the transplant community (physicians,nurses, ethicists, psychologists, lawyers, scientists, socialworkers, transplant recipients, and living donors) at a nationalconference held June 1-2, 2000, in Kansas City, Mo.
Consensus Process Attendees participated in 7 assignedwork groups. Three were organ specific (lung, liver, and kidney)and 4 were focused on social and ethical concerns (informedconsent, donor source, psychosocial issues, and live organ donorregistry). Work groups' deliberations were structured by a seriesof questions developed by the steering committee. Each workgroup presented its deliberations to an open plenary sessionof all attendees. This information was stored and shaped intoa statement circulated electronically to all attendees for theircomments, and finally approved by the steering committee forpublication. The term consensus is not meant to convey universalagreement of the participants. The statement identifies issuesof controversy; however, the wording of the entire statementis a consensus by approval of all attendees.
Conclusion The person who gives consent to be a live organdonor should be competent, willing to donate, free from coercion,medically and psychosocially suitable, fully informed of therisks and benefits as a donor, and fully informed of the risks,benefits, and alternative treatment available to the recipient.The benefits to both donor and recipient must outweigh the risksassociated with the donation and transplantation of the livingdonor organ.
Objectives: Trends in first-time and later PSA procedure rates are ascertained using longitudinal data from a population-based cohort. These trends are compared to trends in prostate cancer incidence to determine the role of PSA in the recent decline in prostate cancer incidence.Methods: Medicare data were linked with tumor registry data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. A 5 percent random sample (n=39985) of Medicare beneficiaries from the SEER areas without a previous diagnosis of prostate cancer as of January 1, 1988 was followed through 1994. Trends in first-time PSA use were distinguished from those of second or later for men without diagnosed prostate cancer.Results: Trends in the rate of first-time PSA procedures track closely with trends in prostate cancer incidence rates, increasing until 1992 and decreasing thereafter. Similar patterns were observed by race and age group. Geographic variability in the dissemination of PSA screening was observed, yet the association between testing and incidence remained. Men in the cohort had a 4.7 percent chance of being diagnosed within three months of an initial PSA test, with the percentage falling for subsequent tests.Conclusions: It is informative to distinguish first from later tests when assessing the effect of the diffusion of a test in a population. Taking this approach was useful in illuminating the role of PSA testing in a reversal of a long-term increase in prostate cancer incidence rates. 相似文献
Children with cerebral palsy frequently walk with excessive internal rotation of the hip. Spastic medial hamstrings or adductors are presumed to contribute to the excessive internal rotation in some patients; however, the capacity of these muscles to produce internal rotation during walking in individuals with cerebral palsy has not been adequately investigated. The purpose of this study was to determine the hip rotation moment arms of the medial hamstrings and adductors in persons who walk with a crouched, internally-rotated gait. Highly accurate computer models of three subjects with cerebral palsy were created from magnetic resonance images. These subject-specific models were used in conjunction with joint kinematics obtained from gait analysis to calculate the rotational moment arms of the muscles at body positions corresponding to each subject’s internally-rotated gait. Analysis of the models revealed that the medial hamstrings, adductor brevis, and gracilis had negligible or external rotation moment arms throughout the gait cycle in all three subjects. The adductor longus had an internal rotation moment arm in two of the subjects, but the moment arm was small (<4 mm) in each case. These findings indicate that neither the medial hamstrings nor the adductor brevis, adductor longus, or gracilis are likely to be important contributors to excessive internal rotation of the hip. This suggests that these muscles should not be lengthened to treat excessive internal rotation of the hip and that other factors are more likely to cause internally-rotated gait in these patients. 相似文献
OBJECT: Unilateral resection of the hippocampus and amygdala can be used to treat medically intractable mesial temporal lobe seizures. To date seizure outcome and the extent of cognitive morbidity have been unknown in children following the transparahippocampal variation of selective amygdalohippocampectomy (TSA), which prompted the present prospective study. METHODS: Preoperative examinations and outcomes in 22 consecutive children and adolescents who underwent TSA were studied. Cognitive and psychological morbidity were assessed using standard neuropsychological instruments. The authors evaluated relationships between seizure control and cognitive morbidity and 13 and nine clinical variables, respectively. Seizure control was achieved in 11 (65%) of 17 patients (>2 years follow up). Among 13 clinical variables, the only preoperative finding that had a significant bearing on seizure control was the presence of unilateral hypometabolism, which could be observed on [18F]fluorodeoxyglucose-positron emission tomography scans (p<0.001). Patients with seizure control showed significant improvements in verbal and full scale intelligence quotients (both p = 0.05). Patients with longer preoperative durations of seizures exhibited more cognitive impairment that persisted postoperatively. Cognitive outcome analysis based on nine clinical factors revealed no significant difference in cognitive parameters postoperatively, except that significant improvement occurred in rote verbal memory scores among patients who underwent right-sided TSA (p = 0.01). Individually, 81% of the children achieved significant improvement in at least one of seven cognitive parameters, and 52% had stable or improved scores in all parameters. CONCLUSIONS: The results indicate that TSA is a safe effective approach for the treatment of medically intractable mesial temporal lobe seizures in children with minimum effect on cognitive morbidity. Given that the literature suggests that children suffer progressive cognitive morbidity from persistent seizures, the results of this study support early surgical intervention for this group of children. 相似文献
We compared three angiographic methods for grading of carotid stenosis and examined the correlation between angiographic
and ultrasound findings. Two observers independently measured 111 carotid stenoses on arteriographic films of 84 patients.
The stenoses were graded according to the European Carotid Surgery Trial (ECST), North American Symptomatic Carotid Endarterectomy
Trial (NASCET), and Common Carotid (CC) methods. The results obtained by these methods were compared, and the interobserver
reproducibility of the measurements was calculated. In addition, all angiographic results were compared to ultrasound findings
obtained before angiography. Measurements using the CC method were the most reproducible and those using the NASCET method
the least. The NASCET method underestimated the degree of stenosis compared to the other methods. The ECST and CC methods
yielded almost identical results (97% agreement). Ultrasound provided an accuracy of 94% compared to ECST and CC methods and
84% compared to the NASCET method. Interobserver reproducibility of angiographic quantification of carotid stenoses was best
for the CC and ECST methods and least for the NASCET method. Ultrasound demonstrated better accuracy than the ECST and CC
methods.
Received: 7 April 1999/Received in revised form: 5 October 1999/Accepted: 11 April 2000 相似文献
The present experiment tested whether previous exposure to amphetamine would enhance rats' predisposition to self-administer a high dose of the drug under fixed (FR) and progressive ratio (PR) schedules of reinforcement. Rats in different groups were given five injections of either amphetamine (1.5 mg/kg, i.p.) or saline (1.0 ml/kg, i.p.), one injection administered every third day and, starting 10 days later, given the opportunity to lever press for amphetamine (200 microg/kg/infusion, i.v.) on each of several 4 h sessions. When allowed to self-administer up to 10 infusions under first an FR-1 and then an FR-2 schedule, amphetamine and saline pre-exposed rats were indistinguishable and readily acquired the lever press response. However, when tested under the PR schedule of reinforcement, rats previously exposed to amphetamine achieved higher break points than saline pre-exposed rats across six consecutive PR sessions. This difference between groups was long lasting and durable. When compared to saline pre-exposed rats on three separate tests conducted 10, 14 and 21 days following the last PR session, rats pre-exposed to amphetamine also showed (i) greater nucleus accumbens dopamine reactivity to amphetamine (1.0 mg/kg, i.p.), (ii) higher break points when retested on the PR schedule, and (iii) a greater locomotor response to amphetamine (1.0 mg/kg, i.p.). On the last test, both groups showed higher levels of locomotion than no drug control animals that received amphetamine for the first time on this test. These findings suggest that previous exposure to amphetamine produces a long lasting enhancement in the incentive motivation animals will exhibit in their effort to obtain the drug. This enhancement appears to parallel sensitization of the drug's locomotor and nucleus accumbens dopamine activating effects. It may very well be exacerbated by continued exposure to self-administered amphetamine. 相似文献
Previous studies have revealed that hematological disorders associated with trichothecenes intoxication in humans could result from hematopoiesis inhibition. The most frequent and potent trichothecene mycotoxins are T-2 toxin and deoxynivalenol (DON), respectively. Apoptosis induction by these two toxins was investigated in vitro on human hematopoietic progenitors (CD34+ cells). Hoechst coloration, DNA fragmentation and annexin-V/PI labeling in flow cytometry showed that T-2 toxin, in contrast to DON, induced apoptosis in CD34+ cells. T-2 toxin effect was dose- and time-dependent with a significant increase of apoptotic cells as early as 3 h after incubation at 10−7 M and a maximum reached at 12 h. This observation evidenced the high sensitivity of hematopoietic progenitors to T-2 toxin. The inhibition of T-2 toxin-induced apoptosis by a pan-caspase inhibitor (Z-VAD-fmk) suggested the involvement of caspases. The proportional increase of caspase-3 specific activity (DEVDase) with T-2 toxin concentration confirmed its role in the process. After incubation of CD34+ cells with T-2 toxin, in conditions that induced apoptosis, clonal expansion of granulo-monocytes, erythrocytes and megakaryocytes precursors was dose-dependently inhibited. The hematological effects observed in T-2 toxin mycotoxicosis could then be assigned to hematopoiesis inhibition by apoptosis. Different mechanisms that need to be further elucidated are involved in DON myelotoxicity. 相似文献