BB-10010: an active variant of human macrophage inflammatory protein-1 alpha with improved pharmaceutical properties

The stem cell inhibitor, macrophage inflammatory protein-1 alpha (MIP-1 alpha) or LD78, protects multipotent hematopoietic progenitors in murine models from the cytotoxic effects of chemotherapy. Clinical use of human MIP-1 alpha during chemotherapy could therefore lead to faster hematologic recovery and may allow dose intensification. We have also shown that human MIP-1 alpha causes the rapid mobilization of hematopoietic cells, suggesting an additional clinical use in peripheral blood stem cell transplantation. However, the clinical evaluation of human MIP-1 alpha is complicated by its tendency to associate and form high molecular weight polymers. We have produced a variant of rhMIP-1 alpha, BB-10010, carrying a single amino acid substitution of Asp26 > Ala, with a reduced tendency to form large polymers at physiologic pH and ionic strength. This greatly increases its solubility, facilitating its production and clinical formulation. We confirmed the potency of BB-10010 as a human MIP-1 alpha-like agonist in receptor binding, calcium mobilization, inhibition of colony formation, and thymidine suicide assays. The myeloprotective activity of BB-10010 was shown in a murine model of repeated chemotherapy using hydroxyurea. BB-10010 is therefore an ideal variant with which to evaluate the therapeutic potential of recombinant human MIP-1 alpha.     

Posttraumatic stress disorder and work-related injury

This study examined whether fecal cortisol could be used as an index of stress responses. The stress responsiveness of fecal cortisol was tested with a stressor known to stimulate adrenal activity, the stress of anesthesia. Daily fecal and urine samples were collected from four captive chimpanzees (Pan troglodytes) before and after anesthetizations with Telazol/Ketasat. Tests of assay validity indicated that cortisol was measurable in chimpanzee fecal extracts. Fecal cortisol concentrations were significantly elevated 2 days after anesthetization, with elevations in seven of the eight treatments. The posttreatment peak was significantly greater than baseline values in three of the four subjects. Both fecal concentrations and proportionate increases in responses to stress were significantly correlated with the corresponding values in urinary cortisol, confirming the stressfulness of these procedures and the stress responsiveness of fecal cortisol. These findings provide evidence for the application of fecal cortisol as a noninvasive index of physiologic stress in nonhuman primates.     

Parasympathetic neurons in the cranial medial ventricular fat pad on the dog heart selectively decrease ventricular contractility

The present study examined the performance of rats with neurotoxic lesions centred in the thalamic nucleus medialis dorsalis on standard and modified versions of the eight arm radial maze test. In Experiment 1, the thalamic lesions produced a borderline deficit in acquisition of the standard task, but subsequently had no effect when a delay was interposed after the first four arms had been entered. The same lesions had no effect on T-maze alternation, but they did impair radial-arm maze performance when intramaze and extramaze cues were set against each other. In Experiment 2, lesions of the dorsomedial thalamus impaired acquisition of the standard radial-arm maze task, but combining the results from Experiments 1 and 2 showed that this acquisition deficit was confined to those animals in which bilateral damage extended into the adjacent anterior thalamic nuclei. In addition, lesions of the dorsomedial thalamus disrupted radial-arm maze performance when the task was modified to compare working memory and reference memory and increased activity and exploration. These changes were not associated with anterior thalamic damage. Finally, the thalamic lesions did not affect performance on a test of spontaneous object recognition. It is concluded that lesions of medialis dorsalis do not disrupt spatial memory but do affect other processes that can interact with task performance. These include a failure of extramaze cues to overshadow intramaze cues, a change in activity and exploration levels and deficits in with-holding spatial responses.     

drp, a novel protein expressed at high cell density but not during growth arrest

In this study the disposition of 1,2-[14C]dibromoethane (1, 2-[14C]DBE) was investigated in male Wistar rats. 1,2-DBE is a cytotoxic and carcinogenic compound that has been used as an additive in leaded gasoline and as a fumigant. 1,2-[14C]DBE was administered orally or iv. Radioactivity was recovered (mostly within 48 hr after administration) in urine (75-82% of the dose), feces (3.2-4% of the dose), and expired air (0.53-7.2% of the dose). One hundred-sixty-eight hours after administration of 1,2-[14C]DBE, most of the radioactivity in tissues was found in the liver, lungs, and kidneys (<1% of the dose) and the red blood cells (0.3% of the dose). Identified urinary metabolites were S-(2-hydroxyethyl)mercapturic acid, thiodiacetic acid, and thiodiacetic acid sulfoxide, together accounting for, on average, 78% of the total amount of radioactivity in urine. In addition to S-(2-hydroxyethyl)mercapturic acid, thiodiacetic acid, and thiodiacetic acid sulfoxide, several compounds were anticipated as potential urinary metabolites of 1,2-DBE, i.e. S-(carboxymethyl)mercapturic acid, S-(2-hydroxyethyl)thioacetic acid, S-(2-hydroxyethyl)thiopyruvic acid, S-(carboxymethyl)thiopyruvic acid, S-(2-hydroxyethyl)thiolactic acid, and S-(carboxymethyl)thiolactic acid. All of the postulated urinary metabolites were synthesized and searched for in urine samples. None of these metabolites could be detected in urine, however. The data obtained in the present study might be useful for risk assessment and biomonitoring studies of 1,2-DBE and will also be used to further validate a physiologically based pharmacokinetic model for 1, 2-DBE in rats and humans that was recently developed.     

The challenge to meet the mental health and biopsychosocial needs of the poor: expanded roles for hospital social workers in a changing healthcare environment

Despite the absence of coordinated federal health care reform, social workers in hospital settings have opportunities to identify, develop, advocate for, and facilitate access to innovative health care services, resulting in improved capacity to meet the mental health and biopsychosocial needs of the poor and, potentially, reduced hospital costs over time. There are opportunities for expanded roles for social workers in forging better linkages between hospital services and the community, developing an integrated biopsychosocial healthcare delivery system within hospitals and primary care settings, utilizing information systems as tools in an integrated system, and advocating for a client-centered approach to mental health services.