Kinetics of the biosynthesis of complement subcomponent C1q by murine macrophages: LPS, immune complexes, and zymosan alone and in combination with interferon-gamma.

We investigated the effects of bacterial lipopolysaccharide (LPS), immune complexes (IC), and C3b opsonized zymosan (AZ) alone and in combination with interferon-gamma (IFN-gamma) priming on macrophage synthesis and secretion of C1q. Our results indicated that LPS, IC, and AZ alone stimulated C1q mRNA and secretion in the absence of IFN-gamma. The increase in mRNA accumulation was detectable after 3 h, peaked at 6 h and was maintained at constitutive levels for 24 h. There was a corresponding early burst of increased secretion of functional C1q after 3 to 6 h which declined rapidly after 9 to 24 h culture of LPS-stimulated macrophages. Priming of macrophages with IFN-gamma and simultaneous triggering with LPS, IC, or AZ produced additive rather than synergistic increases in C1q mRNA accumulation. These same agents inhibited constitutive secretion of C1q in the absence of IFN-gamma priming as determined by autoradiographic analysis of metabolically radiolabeled secretory C1q. Triggering of IFN-gamma primed macrophages with LPS, IC, or AZ also markedly suppressed the increased rate of C1q secretion induced by IFN-gamma in a dose-related fashion. A corresponding dose-dependent increased accumulation of endogenous C1q in cell lysates was detected by Western blot analysis of macrophages which had been stimulated by LPS, IC, or AZ alone or in combination with IFN-gamma. Our findings indicate that LPS as well as FcR and C3bR triggering agents stimulate early and sustained C1q synthesis accompanied by an early and short-lived burst of C1q secretion which rapidly diminished and results in an increased intracellular accumulation of C1q due to ongoing synthesis. IFN-gamma appeared to further amplify the same kinetics of increased C1q mRNA accumulation and decreased extracellular accumulation mediated by LPS, IC, and ZM. Our results suggest that LPS, IC, and AZ alone or in combination with IFN-gamma stimulate early C1q production to modulate macrophage effector functions followed by an inhibition of C1q secretion when the activation process has been culminated.     

A sequence-specific polymerase chain reaction assay for mitochondrial DNA polymorphisms in human platelets and white cells

BACKGROUND: Because mitochondria are abundant in white cells and are also present in platelets, polymorphic sequences in mitochondrial DNA (mtDNA) represent a unique target for polymerase chain reaction (PCR)- based detection of donor material. STUDY DESIGN AND METHODS: A PCR assay was developed that uses sequence-specific primers (SSP) focused on two continent-specific mtDNA polymorphisms. Results were validated by the use of informative restriction endonucleases. Three commercially available methods to extract mtDNA from white cell-reduced human platelets was compared. In preparation for in vivo studies, in vitro mixing studies designed to mimic transfusion were conducted to investigate the performance of the SSP-PCR assay. RESULTS: The gene sequences of two representative examples of amplicons obtained with the new SSP-PCR matched the sequence expected from the published genetic code. Fifteen individuals were classified as either positive (n = 6) or negative (n = 9) for the Asian polymorphism by the use of published primers known to flank the polymorphic site followed by digestion with appropriate restriction enzymes. Results with SSP-PCR were nearly perfectly concordant with those of restriction enzyme analysis. Although the use of three DNA extraction methods allowed the preparation of mtDNA that was suitable for PCR, large and consistent differences (ranging from 10- to 1000-fold) in endpoint sensitivity were found. In vitro mixing studies reproducibly documented that the SSP-PCR assay could detect as little as 1 percent of donor platelets mixed with recipient blood. CONCLUSION: PCR-SSP can be reliably used to identify human mtDNA polymorphisms. By optimization of the method of mtDNA extraction, the sensitivity of PCR-SSP assay was greatly increased. This assay should prove useful in investigations of allogeneic platelet transfusions without cell labeling. It may also be applied to studies of the donor cell microchimerism that follows transfusion or transplantation.     

Roxatidine versus ranitidine in the treatment of duodenal ulcers: A randomized double-blind controlled multicentre study in Singapore

Roxatidine acetate, a new H₂ receptor antagonist, was compared with ranitidine in the treatment of duodenal ulcers in a double-blind multicentre study. Eighty-four patients with endoscopically proven duodenal ulcer were randomized to receive 150 mg roxatidine acetate or 300 mg ranitidine at bedtime. Repeat endoscopy was performed after 4 weeks (25–33 days) and if the ulcer had not healed, another endoscopy was performed after a further 4 weeks of treatment. Using per protocol analysis 73.6% of ulcers treated with roxatidine healed at 4 weeks compared to 72.2% of ulcers treated with ranitidine (P=NS). The healing rates at 8 weeks were 92% with roxatidine and 83.3% with ranitidine (P=NS). Using equivalence tests, the healing rate of roxatidine was found to be equivalent to that of ranitidine within a 20% region. Roxatidine users took significantly less antacids than ranitidine users (P < 0.05). There were no significant adverse effects due to roxatidine or ranitidine. Roxatidine is a safe effective drug in the treatment of duodenal ulcers with a healing rate comparable to that of ranitidine.     

Properties of molten magnesium oxide

The Significant Structure Theory of Liquids has been used to calculate the thermodynamic properties, viscosity, self-diffusion coefficient, and specific conductance of molten magnesium oxide, taking account of the decomposition of MgO to Mg and O₂ species in the gas-like part of the partition function.     

Effect of adenovirus-mediated transfer of the CTLA4IG gene in hamster-to-rat xenotransplantation

BACKGROUND: Costimulatory molecules such as CD28 and B7 are essential for T cell activation, as well as playing a role in the T cell receptor and major histocompatibility complex pathway. It is well known that rejection in allotransplantation is diminished by treatment with CTLA4Ig, but whether a similar effect occurs in xenotransplantation remains to be determined. METHODS: In this study, we investigated whether adenovirus-mediated gene transfer with CTLA4Ig cDNA by intravenous injection to the recipient is effective in suppression in hamster-to-rat cardiac xenotransplantation. RESULTS: With CTLA4Ig gene transfer, the duration of gene expression was clearly prolonged, based on reduced production of antiadenovirus antibody and shrinkage of the spleen. The survival of cardiac xenografts was significantly prolonged with CTLA4Ig gene transfer compared to the control graft, and survival with combination use of FK506 and CTLA4Ig gene transfer in xenotransplantation was also significantly prolonged compared to that with CTLA4Ig gene transfer alone. Cessation of the cardiac graft in the combination treatment occurred in parallel with the elevation of antihamster IgM antibodies in rat sera. CONCLUSIONS: These results suggest that adenovirus-mediated CTLA4Ig gene transfer is effective for immunosuppression in hamster-to-rat xenotransplantation.     

Effects on function and quality of life of postoperative home-based physical therapy for patients with hip fracture

OBJECTIVE: To evaluate the effects of a 3-month home-based physical therapy (PT) program for patients with hip fracture after surgery. DESIGN: Randomized controlled trial. SETTING: Home. PARTICIPANTS: Twenty-five patients recently discharged from an acute orthopedic department. INTERVENTIONS: Patients were randomized to the home-based PT group (n=13), where they received home-based PT 8 times from discharge to month 3 postdischarge, or to the control group (n=12). The home-based PT program included exercises for muscle strengthening, range of motion (ROM), balance, and functional training. Patients in the control group were instructed to practice the exercise program given at bedside before discharge. MAIN OUTCOME MEASURES: Patients were evaluated for hip ROM, strength, walking velocity, Harris hip score, and health-related quality of life (HRQOL) at the week of discharge and at 1, 3, and 6 months after discharge. RESULTS: The baseline characteristics showed no difference between the 2 groups. Harris score of the home-based PT group progressed from 58.6+/-8.5 to 90.1+/-5.4 at month 3, whereas Harris score of the control group progressed from 54.6+/-14.5 to 77.4+/-10.0 (P<.01). Scores of the psychologic domain of HRQOL for the home-based PT group were significantly better at month 1 (P<.05) and month 3 (P<.01) after discharge. Moreover, the physical domain score of the home-based PT group was also significantly better (P<.05) at 3 months after discharge. CONCLUSIONS: Home-based PT programs could help patients regain function and HRQOL earlier.     

Thoracic wall involvement by Hodgkin disease and non-Hodgkin lymphoma: CT evaluation

Thoracic computed tomographic (CT) scans of 250 patients with newly diagnosed or recurrent lymphoma revealed thoracic wall involvement in 24 patients (11 with Hodgkin disease, 13 with non-Hodgkin lymphoma). Thoracic wall involvement occurred without contiguous mediastinal or parenchymal involvement in 17 patients. Of these, 13 patients had masses beneath the pectoralis muscles or within the breast, and four had masses arising from the ribs. Five additional patients had mediastinal masses with thymic involvement and parasternal extension through the thoracic wall. Pulmonary parenchymal lymphoma with thoracic wall invasion was noted in the remaining two patients. In five of nine patients receiving radiation therapy, treatment plans were modified by CT demonstration of thoracic wall lymphoma.     

Nonpeptide alphavbeta3 antagonists. Part 11: discovery and preclinical evaluation of potent alphavbeta3 antagonists for the prevention and treatment of osteoporosis

3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.