Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours

Topotecan is a specific inhibitor to topoisomerase I. An oral formulation of topotecan is available with a bioavailability of 32-44% in humans. A phase I and pharmacological study of the oral formulation of topotecan administered daily for 5 days every 21 days was performed in adult patients with solid tumours to determine the maximum tolerated dose (MTD). Adult patients with a WHO performance status < or = 2 adequate haematological, hepatic and renal functions, with malignant solid tumours refractory to standard forms were entered into the study. Pharmacokinetics were performed on days 1 and 4 of the first course using a validated high performance liquid chromatographic assay. 29 patients entered the study, all patients were evaluable for toxicity and response. The doses studied in the 29 patients were 1.2, 1.8, 2.3, 2.7 mg/m2/day and a fixed dose of 4 mg/day without surface area adjustment. A total of 109 courses were given. Dose limiting toxicity (DLT) was reached at a dose of 2.7 mg/m2/day and consisted of CTC (NCI-Common Toxicity Criteria) grade IV granulocytopenia. The regimen was well tolerated. Non-haematological toxicities were mild, including fatigue, anorexia, nausea, vomiting and diarrhoea. A significant correlation was observed between the percentage decrease in white blood cells versus the area under the curve (AUC(t)) of topotecan lactone (R = 0.76 P < 0.01) which was modelled by a sigmoidal Emax function. The correlation coefficient between the absolute topotecan dose administered and the AUC(t) was R = 0.52 (P = 0.04). Pharmacokinetics of the fixed dose of 4 mg/day were comparable to the 2.3 mg/m2/day dose. DLT in this phase I study of five daily doses of oral topotecan every 21 days was granulocytopenia. The recommended dose for phase II studies is 2.3 mg/m2/day or alternatively, a fixed dose of 4 mg/day.     

Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase

Recycling of ascorbic acid from its oxidized forms is required to maintain intracellular stores of the vitamin in most cells. Since the ubiquitous selenoenzyme thioredoxin reductase can recycle dehydroascorbic acid to ascorbate, we investigated the possibility that the enzyme can also reduce the one-electron-oxidized ascorbyl free radical to ascorbate. Purified rat liver thioredoxin reductase catalyzed the disappearance of NADPH in the presence of low micromolar concentrations of the ascorbyl free radical that were generated from ascorbate by ascorbate oxidase, and this effect was markedly stimulated by selenocystine. Dehydroascorbic acid is generated by dismutation of the ascorbyl free radical, and thioredoxin reductase can reduce dehydroascorbic acid to ascorbate. However, control studies showed that the amounts of dehydroascorbic acid generated under the assay conditions used were too low to account for the observed loss of NADPH. Electron paramagnetic resonance spectroscopy directly confirmed that the reductase decreased steady-state ascorbyl free radical concentrations, as expected if thioredoxin reductase reduces the ascorbyl free radical. Dialyzed cytosol from rat liver homogenates also catalyzed NADPH-dependent reduction of the ascorbyl free radical. Specificity for thioredoxin reductase was indicated by loss of activity in dialyzed cytosol prepared from livers of selenium-deficient rats, by inhibition with aurothioglucose at concentrations selective for thioredoxin reductase, and by stimulation with selenocystine. Microsomal fractions prepared from rat liver showed substantial NADH-dependent ascorbyl free radical reduction that was not sensitive to selenium depletion. These results suggest that thioredoxin reductase can function as a cytosolic ascorbyl free radical reductase that may complement cellular ascorbate recycling by membrane-bound NADH-dependent reductases.     

Effects of nicotine dose and administration method on withdrawal symptoms and side effects during short-term smoking abstinence.

The effects of using several different nicotine replacement treatments on self-reported withdrawal symptoms and side effects during 2-day periods of smoking cessation, with 5 days of ad lib smoking between cessation days, were evaluated. Participants (N ?=?18) experienced the following conditions: nicotine gum, 24-hr patch, 16-hr patch, 24-hr patch plus gum, double 24-hr patch, and no nicotine replacement. The present study found morning urge to smoke was greater during the 16-hr than during the 24-hr patch condition. Double-patch use resulted in significantly greater insomnia than the smoking baseline and 16-hr patch conditions. The no medication and gum alone conditions resulted in similar withdrawal symptoms, and both tended to result in greater reported withdrawal symptoms than the smoking baseline condition. There were no significant withdrawal symptom differences between the 24-hr, patch-gum, and double-patch conditions. The 24-hr and double-patch conditions were preferred by two thirds of the participants (6 each). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sexual attraction toward clients, use of supervision, and prior training: A qualitative study of predoctoral psychology interns.

Interviews were conducted with 13 predoctoral psychology interns about an experience of sexual attraction toward a client, use of supervision to address the sexual attraction, and prior training regarding sexual attraction. Results indicated that sexual attraction to clients consisted of physical and interpersonal aspects. Therapists believed they were more invested and attentive than usual to clients to whom they were sexually attracted, and they indicated that sexual attraction created distance, distraction, and loss of objectivity. In terms of supervision, only half of the participants disclosed their sexual attraction to supervisors, and supervisors seldom initiated the discussion. Furthermore, trainees found it helpful when supervisors normalized the sexual attraction and provided the opportunity to explore feelings in supervision. Finally, trainees believed their training programs did not adequately address therapist sexual attraction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cost-effectiveness of detecting breast cancer in lower socioeconomic status African American and Hispanic women through mobile mammography services

A new method based on jackknifing is presented for measuring the difference between two conditions in the onset latencies of the lateralized readiness potential (LRP). The method can be used with both stimulus- and response-locked LRPs, and simulations indicate that it provides accurate estimates of onset latency differences in many common experimental conditions.     

Anxiety responses of parents during and after the hospitalization of their 5- to 11-year-old children

Pemphigus vulgaris (PV) is an autoimmune disease of the skin and mucous membranes characterized by an autoantibody response against an epidermal cadherin. We performed high resolution HLA class II typing in 19 patients with PV from Rawalpindi, Pakistan and 19 non-Jewish European PV patients from Boston by sequence-specific oligonucleotide probe hybridization. The results were compared with two separate ethnically matched control populations. WE found that PV patients from Pakistan had significantly increased frequencies of DRB1*1404 (p = 0.01), DQA1*0101 (p = 0.02), and DQB1*0503 (p = 0.01). Among the patients of non-Jewish European ancestry, DRB1*1401 (p < 10(-6)), DQA1*0101 (p < 10(-5)) and DQB1*0503 (p < 10(-6)), were increased in PV patients. Formal linkage analysis between the major histocompatibility complex and the PV antibody was performed in 67 relatives of the 19 Pakistani patients. The results showed strong evidence for linkage of HLA-DRB1*1404, DQA1*0101, DQB1*0503, with the presence of PV antibody in relatives' families with a significant logarithm of the odds score of 6.06. Based on the three dimensional structure of class II molecules, we propose that HLA-DQA1*0101 and DQB1*0503, encode a negatively charged P9 peptide binding pocket of the DQ molecule and are significantly associated with susceptibility to PV in non-Jewish populations.     

Beyond relevance--characteristics of key papers for clinicians: an exploratory study in an academic setting

OBJECTIVE: The purpose of this study was to determine what factors beyond relevance influence a clinician's decision to choose to read one journal article over another in satisfying an information need. DESIGN: Seventeen health care providers were interviewed and then surveyed regarding the characteristics of key articles (those they would not want to miss). On a Likert scale, the clinicians graded forty-two characteristics for importance in the decision process. Relevance was assumed and not at issue. SETTING: The study took place in an academic health science center. SUBJECTS: The subjects were seventeen clinicians, all with patient care responsibilities. There were four internists, four surgeons, three family practitioners, three pediatricians, two psychiatrists, and one clinical psychologist. RESULTS: Factors beyond relevance that most often influenced the decision process pertained to methodological rigor, authors and their institutional affiliations, document types, and population studied. CONCLUSIONS: Among the clinicians surveyed, factors beyond topicality influenced judgments as to what constitutes an important article. The emphasis respondents gave to certain attributes is echoed in other published work and highlights the need for more intensive investigation of these non-subject indicators as search parameters. Improved searching capabilities might well lead to a significant reduction in the clinician's information overload.     

High-level expression of a novel epitope of CD59 identifies a subset of CD34+ bone marrow cells highly enriched for pluripotent stem cells

To further define the hierarchy of human hematopoietic progenitor cells, we have attempted to identify antibodies to cell-surface molecules expressed on CD34+ progenitor cell subsets. Herein we describe the utility of a new monoclonal antibody, HCC-1, which binds to a novel epitope of CD59 differentially expressed among CD34+ progenitor cells. HCC-1 subdivides the adult marrow CD34+ population into HCC-1high and HCC-1low/- fractions of approximately equal size. Cobblestone area-forming cells (CAFC) in long-term bone marrow culture were enriched 10-30-fold in CD34+HCC-1high cells compared with CD34+HCC1-low/- cells and two-fold compared with CD34+ cells. When injected into fetal human bone fragments implanted in SCID mice, the CD34+HCC-1high population showed potent engrafting activity leading to the production of myeloid, lymphoid, and erythroid elements, as well as the retention of progenitor cell phenotype. These studies demonstrate that the CD34+HCC-1high population contains primitive pluripotent hematopoietic stem cells. No hematopoietic engrafting activity was detected in the CD34+HCC-1low/- population. Consistent with this finding, simultaneous five-color flow cytometric analysis revealed that HCC-1high cells include virtually all CD34+Thy-1+Lin- cells, a cell population previously characterized as highly enriched for primitive pluripotent hematopoietic stem cells. The ability of CD34+ cells divided into subsets by HCC-1 to produce T cells was assessed by transplantation of sorted cells into human fetal thymus implanted into SCID mice. A higher frequency of thymus-engrafting activity was observed in the CD34+HCC-1high than in the CD34+HCC-1low/- population. Consistent with the limited ability to engraft in the SCID-hu thymus model, the CD34+HCC-1low/- population was shown to contain a low frequency of CD34+CD10+ lymphoid progenitor cells. We conclude that the HCC-1 epitope is expressed at high levels on a subset of CD34+ cells that contain virtually all primitive pluripotent hematopoietic stem cells and that the population of CD59 molecules expressed on CD34+ cells is not homogeneous.     

A single glucose transporter configuration in normal primate brain endothelium: comparison with resected human brain

Cellular distribution of the Glut1 glucose transporter in normal primate brains was analyzed by immunogold electron microscopy. Two configurations of endothelial Glut1 glucose transporter (high and low density capillaries) have been found in resections of traumatically injured and epileptogenic human brain; the objective of the present study was to ascertain whether these same 2 capillary populations, expressing high and low glucose transporter densities, were the common configuration in normal brain. The relative numbers of Glut1 glucose transporter-associated gold particles on luminal and abluminal endothelial cell membranes were determined within the cerebral cortex of several normal, nonhuman primates. Low Glut1 densities were seen in brain endothelia of both the rhesus and squirrel monkey cortex, with slightly greater quantities of Glut1 in vervet monkey cortices. The Glut1 transporter was most highly expressed in the baboon cortex, approaching the concentrations seen in human brains. In the rhesus, squirrel, and vervet monkeys, Glut1 concentrations were greater on the abluminal than luminal capillary membranes. In contrast, mean luminal membrane Glut1 concentrations were greater in baboons, resembling the distribution seen in the human brain. Brain regional differences in transporter concentration were seen in comparing membrane densities in the baboon cortex (approximately 15 Glut1-gold particles per micrometer), hippocampus (approximately 12 Glut1 gold particles per micrometer), cerebellum (approximately 6 Glut1-gold particles per micrometer), and retinal microvasculature (approximately 20 Glut1-gold particles per micrometer). We conclude that a single, uniform Glut1 distribution characterizes brain capillaries of normal nonhuman primates, and hypothesize that the presence of high and low density glucose transporter endothelial cells (seen in human traumatic injury and seizure resections) represents a pathologic response to brain insult.