New approaches to hematopoietic cell transplantation in oncology

The use of high-dose chemotherapy followed by autologous HCT and the use of allogeneic HCT in children and adolescents with high-risk ALL, AML, and NBL has successfully improved outcomes. For other diseases, however, the role of HCT in treatment remains a subject of further research. The availability of HCT was significantly expanded by developing alternative graft sources that currently include BM, peripheral blood, and UCB from autologous and allogeneic related or unrelated donors. Progress in autologous HCT has been achieved by the identification of more effective and less toxic preparative regimens and by ex vivo purging of stem cell products. In allogeneic HCT, graft-versus-leukemia or graft-versus-tumor effects are being exploited increasingly to lower relapse rates. In addition, immunomodulation to promote tolerance, as well as allogeneic antitumor reactions have been achieved by antibody therapy, cytokine therapy, or cell-based immunotherapy. Future improvements are likely, as evidenced by promising preliminary results in the development of stem cell collection techniques, in vitro stem cell expansion, and purging techniques of stem cell grafts. The development of less intensive or nonmyeloablative preparative regimens may further reduce regimen-related morbidity and mortality Specific immunotherapy may facilitate tolerance induction in mismatched allogeneic HCT and support allogeneic HCT in the setting of donor-host HLA disparity. Ultimately, advances in cytokine therapy, tumor-specific vaccines, and gene therapy may decrease or even eradicate recurrence of the malignant disease after HCT.     

Implementation and evaluation of an undergraduate Sociocultural Medicine Program.

PURPOSE: To demonstrate an effective model for designing, implementing, and evaluating the Sociocultural Medicine Program (SMP), part of a comprehensive sociocultural medicine curriculum at the University of Michigan Medical School. METHOD: This study followed a cross-sectional, pre- and post-intervention survey design. A total of 167 medical students completed a measure of attitudes toward sociocultural issues in medicine prior to and following participation in the SMP. Students' attitudes were assessed in the domains of "exposure to sociocultural issues," "sociocultural factors in clinical scenarios," and "sociocultural background in patient/physician/health status issues." RESULTS: Paired t-tests of the pre- and post-intervention responses revealed significant positive changes for items in the domain of exposure to sociocultural issues in medicine: experience with sociocultural issues in a clinical setting (p <.01), understanding of relationship among sociocultural background, health, and medicine (p <.001), and importance of sociocultural background in students' future patient populations (p <.01). Significant changes were also found for the impact of sociocultural background in patient/physician/health status issues: physician-patient relationship (p <.001) and patients' health behavior (p <.001). CONCLUSIONS: The SMP had a significant educational impact on students' attitudes towards sociocultural issues in medicine. Students reported greater exposure to these issues conceptually and clinically, and greater influence of sociocultural factors in patients' behaviors and patient- physician relationships. Critical components of this SMP were faculty development, multiple teaching approaches, and pre- and post-intervention evaluation.     

T-lineage specification and commitment: a gene regulation perspective

T lymphocytes originate from pluripotent precursors and undergo lasting commitment to the T cell developmental fate during their processing in the thymus. Commitment includes both the acquisition of essential T cell characteristics and the foreclosing of other developmental options. Gain of T cell characteristics is probably mediated by separate mechanisms, at least in detail, from loss of alternative developmental potentials. Programmed shifts in survival requirements make changes irreversible. Here we review the current evidence identifying the regulatory components of this commitment pathway, and the first hints of how they work together. Roles for PU.1, GATA-3, and their target genes are highlighted.     

Wild-type and A328W mutant human butyrylcholinesterase tetramers expressed in Chinese hamster ovary cells have a 16-hour half-life in the circulation and protect mice from cocaine toxicity

Human butyrylcholinesterase (BChE) hydrolyzes cocaine to inactive metabolites. A mutant of human BChE, A328W, hydrolyzed cocaine 15-fold faster compared with wild-type BChE. Although the catalytic properties of human BChE secreted by Chinese hamster ovary (CHO) cells are identical to those of native BChE, a major difference became evident when the recombinant BChE was injected into rats and mice. Recombinant BChE disappeared from the circulation within minutes, whereas native BChE stayed in the blood for a week. Nondenaturing gel electrophoresis showed that the recombinant BChE consisted mainly of monomers and dimers. In contrast, native BChE is a tetramer. The problem of the short residence time was solved by finding a method to assemble the recombinant BChE into tetramers. Coexpression in CHO cells of BChE and 45 residues from the N terminus of the COLQ protein yielded 70% tetrameric BChE. The resulting purified recombinant BChE tetramers had a half-life of 16 h in the circulation of rats and mice. The 16-h half-life was achieved without modifying the carbohydrate content of recombinant BChE. The protective effect of recombinant wild-type and A328W mutant BChE against cocaine toxicity was tested by measuring locomotor activity in mice. Pretreatment with wild-type BChE or A328W tetramers at a dose of 2.8 units/g i.p. reduced cocaine-induced locomotor activity by 50 and 80%. These results indicate that recombinant human BChE could be useful for treating cocaine toxicity in humans.     

Occurrence of newer beta-lactamases in Klebsiella pneumoniae isolates from 24 U.S. hospitals

Despite the discovery of novel beta-lactamases such as extended-spectrum beta-lactamases (ESBLs), imported AmpC, and carbapenem-hydrolyzing beta-lactamases at least a decade ago, there remains a low level of awareness of their importance and how to detect them. There is a need to increase the levels of awareness of clinical laboratories about the detection of newer beta-lactamases. Therefore, a study was conducted in 2000 to investigate the occurrence of these beta-lactamases in Klebsiella pneumoniae isolates at 24 U.S. medical centers. To enhance the likelihood of detecting imported AmpC and carbapenem-hydrolyzing beta-lactamases, participating laboratories were permitted to include archived strains (1996 to 2000) that were intermediate or resistant to either cefoxitin or imipenem. The beta-lactamase production of 408 isolates positive by screening of 1,123 isolates was investigated by ESBL phenotypic confirmation tests; and for AmpC and carbapenem-hydrolyzing beta-lactamases, three-dimensional tests, isoelectric focusing, beta-lactamase inhibitor studies, spectrophotometric assays, induction assays, and molecular tests were used. ESBL-producing isolates were detected at 18 of the 24 sites (75%), imported AmpC-producing isolates were detected at 10 sites (42%), inducible imported AmpC-producing isolates were detected at 3 sites (12.5%), and a molecular class A carbapenem-hydrolyzing enzyme was detected at 1 site (4%). No class B or D carbapenem-hydrolyzing enzymes were detected. ESBLs and imported AmpC beta-lactamases were detected at a significant number of sites, indicating widespread penetration of these enzymes into U.S. medical institutions. Because these enzymes may significantly affect therapeutic outcomes, it is vital that clinical laboratories be aware of them and be able to detect their occurrence.     

New syndrome of simplified gyral pattern,micromelia, dysmorphic features and early death

We report two sisters with a new syndrome of simplified gyral pattern, normal head circumference at birth but with subsequent development of microcephaly, intractable seizures, and early death. Dysmorphic features included coarse face, hypertrichosis, short nose, paranasal widening, long philtrum, short neck, upper limb micromelia, single transverse palmar lines, and clasp thumbs. The proband had repeated convulsions from shortly after birth and she required continuous artificial ventilation. Neurological examination showed absent sucking, rooting, Moro and grasping reflexes. MRI revealed a diffuse simplified gyral pattern with apparent agyria over the frontal lobes. Biochemical screening gave normal results. Her older sister had bilateral renal pelvic dilatation on prenatal ultrasound. She also developed severe convulsions on the first day of life, and she had to be artificially ventilated for 38 days. She had severe developmental retardation and neurological examination showed absence of spontaneous movements and Moro reflex, weak sucking reflex, and hypertonicity. CT scan of the brain showed a simplified gyral pattern. At 3 months, she developed hypocalcemia and hyperphosphatemia with normal levels of vitamin D and alkaline phosphatase, and parathyroid hormone level was low. Other biochemical tests gave normal results. She died at 5 months due to a massive aspiration event. Based on the unique clinical and radiological features found in our patients, we propose that this is a new syndrome.