Discovery of novel non-peptide CCR1 receptor antagonists

Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.     

Detection of migrated allogeneic oligodendrocytes throughout the central nervous system of the galactocerebrosidase-deficient twitcher mouse

Summary Galactocerebrosidase-deficient oligodendrocytes of twitcher (twi/twi) mice degenerate prematurely. Transplantation of normal bone marrow cells has been shown to alleviate symptoms and to prolong survival time. However, characteristic ataxia (twitching) is not cured. In an attempt to improve further the condition of twitcher mice, allogeneic foetal liver cells were transplanted as a source of normal haemopoietic stem cells and supplemented with intracerebral transplantation of foetal brain cells. A reliable method was developed to detect donor-type cells in brain tissue. Bacteriophage . transgenic foetal mice were used as donors of both foetal liver and brain cells. Integrated copies of . DNA in donor cells were detected byin situ hybridization with biotinylated probes, which were then stained using streptavidin alkaline phosphatase. This technique was combined with immunohistochemistry to distinguish donor-type oligodendrocytes from macrophages. Immunoperoxidase staining with an antiserum to carbonic anhydrase-II produced dark perikarya of oligodendrocytes. The results demonstrated that local foetal brain cell grafts resulted in a wide dissemination of donor-type oligodendrocytes throughout the twitcher brain. The addition of a foetal brain cell graft to haemopoietic cell transplantation resulted in significantly prolonged survival of twitcher mice.     

Simple pressure bandage technique for free skin grafts.

We applied sterile packed cellulose sponges in the dehydrated state as a pressure dressing from skin grafts by using the classic "tie-over" technique. At the end of the procedure, the sponges were hydrated, and provided flat, even pressure to a localized area. By using this simple technique, we obtained 26 of 27 successful free skin grafts with flat apposition.     

Premarital sexual attitudes of unmarried university students: 1968 vs. 1972

Information on premarital sexual attitudes of unmarried undergraduates was obtained from random samples on the same campus in 1968 and 1972. Students in 1972, compared with those in 1968, reported (1) more permissive attitudes toward premarital sexual behavior (both men and women), (2) fewer differences in attitudes between men and women, and (3) less adherence to the double standard. In contrast to earlier research on premarital sexual attitudes, these differences need not be due to the markedly different populations compared, or generalizable only to sociology and psychology students, or indicative of only those who chose to volunteer for study (volunteer bias).This research received support from the Institute for Research in Social Science and the University Research Council, University of North Carolina at Chapel Hill.     

Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial.

PURPOSE: To prospectively compare standard radiation therapy (RT) with an abbreviated course of RT in older patients with glioblastoma multiforme (GBM). PATIENTS AND METHODS: One hundred patients with GBM, age 60 years or older, were randomly assigned after surgery to receive either standard RT (60 Gy in 30 fractions over 6 weeks) or a shorter course of RT (40 Gy in 15 fractions over 3 weeks). The primary end point was overall survival. The secondary end points were proportionate survival at 6 months, health-related quality of life (HRQoL), and corticosteroid requirement. HRQoL was assessed using the Karnofsky performance status (KPS) and Functional Assessment of Cancer Therapy-Brain (FACT-Br). RESULTS: All patients had died at the time of analysis. Overall survival times measured from randomization were similar at 5.1 months for standard RT versus 5.6 months for the shorter course (log-rank test, P =.57). The survival probabilities at 6 months were also similar at 44.7% for standard RT versus 41.7% for the shorter course (lower-bound 95% CI, -13.7). KPS scores varied markedly but were not significantly different between the two groups (Wilcoxon test, P =.63). Low completion rates of the FACT-Br (45%) precluded meaningful comparisons between the two groups. Of patients completing RT as planned, 49% of patients (standard RT) versus 23% required an increase in posttreatment corticosteroid dosage (chi(2) test, P =.02). CONCLUSION: There is no difference in survival between patients receiving standard RT or short-course RT. In view of the similar KPS scores, decreased increment in corticosteroid requirement, and reduced treatment time, the abbreviated course of RT seems to be a reasonable treatment option for older patients with GBM.