Tissue factor expression in mesothelial cells: induction both in vivo and in vitro

Docking algorithms play an important role in the process of rational drug design and in understanding the mechanism of molecular recognition. An important determinant for successful docking is the extent to which the configurational space (including conformational changes) of the ligand/receptor system is searched. Here we describe a new, combinatorial method for flexible docking of peptides to proteins that allows full rotation around all single bonds of the peptide ligand and around those of a large set of receptor side chains. We have simulated the binding of several viral peptides to murine major histocompatibility complex class I H-2Kb. In addition, we have explored the limits of our method by simulating a complex between calmodulin and an 18-residue long helical peptide from calmodulin-dependent protein kinase IIalpha. The calculated peptide conformations generally matched well with the X-ray structures. Essential information about local flexibility and about residues that are responsible for strong binding was obtained. We have frequently observed considerable side-chain flexibility during the simulations, showing the need for a flexible treatment of the receptor. Our method may also be useful whenever the receptor side-chain conformation is not available or uncertain, as illustrated by the docking of an H-2Kb binding nonapeptide to the receptor structure taken from an octapeptide/H-2Kb complex.     

Ras-GRF activates Ha-Ras, but not N-Ras or K-Ras 4B, protein in vivo

Human cells contain four homologous Ras proteins, but it is unknown whether these homologues have different biological functions. As a first step in determining if Ras homologues might participate in distinct signaling cascades, we assessed whether a given Ras guanine nucleotide exchange factor could selectively activate a single Ras homologue in vivo. We found that Ras-GRF/Cdc25Mm activates Ha-Ras, but does not activate N-Ras or K-Ras 4B, protein in vivo. Moreover, our results suggested that residues within the C-terminal hypervariable domains of Ras proteins may dictate, at least in part, the specificity of Ras-GRF/CDC25Mm for Ha-Ras protein. Our studies represent the first biochemical evidence that a Ras GEF can selectively activate a single Ras homologue in vivo. Selective activation of a single Ras homologue by Ras-GRF/Cdc25Mm or other Ras guanine nucleotide exchange factors could potentially enable each of the Ras homologues to participate in different signal transduction pathways.     

Blastomycotic osteomyelitis of the pelvis: a case report

Blastomycosis dermatitis is an unusual fungal infection that can become a diagnostic dilemma if a high index of suspicion is not maintained in patients who present with a chronic granulomatous infection of bone and soft tissue. We present a patient with a long history of pain, systemic manifestations of chronic infection, a draining sinus, and lytic changes on plain films to illustrate the difficulty in establishing the diagnosis. Appropriate staging studies and a bone biopsy led to the correct diagnosis in the patient.     

Memory effects on piezoelectric InGaAs/GaAs MQW PIN diodes

Charge accumulation erects in piezoelectric multiple quantum well (MQW) InGaAs/GaAs PIN diodes grown on (111)B GaAs substrates have been studied regarding memory applications. Strain-induced piezoelectric fields allow new PIN structures with configurations of negative average electric field (NAF) active region. These new devices can store an electric dipole with spatially separated electrons and holes that have low recombination probability and thus long lifetimes. This produces a longrange screening of the field in the active region and hence a strong blue shift of the absorption band edge (maximum light transmission for reading purposes). Both a light pulse and a forward voltage pulse are able to create the dipole (data writing or charged device). The stored dipole can be removed by a reverse electrical pulse (data erasing or device discharge), resulting in a minimum light transmission across the device. Capacitance voltage and time resolved capacitance measurements, after single optical or electrical charging pulse at low temperature (20 K) have been used to determine the stored dipole behaviour. Capacitance transients analysis allowed study of the kinetics of the discharge process, which shows a non-exponential behaviour with storage times up to 10³ sec, suggesting very long time refresh cycles. Time resolved photocurrent has been used to check read and write capabilities giving on-off ratios up to 30.     

Comparison of the cumulative probability of pregnancy after in vitro fertilization-embryo transfer by infertility factor and age

OBJECTIVE: To compare the cumulative probability of pregnancy after multiple IVF cycles by age and cause of infertility. DESIGN: A prospective study was done in which patients were followed from the time they registered for their first IVF cycle until they achieved a clinical pregnancy, withdrew from treatment, or study was terminated. PATIENTS, SETTING, TREATMENTS: Infertile women undergoing IVF-ET at the Cooper Institute for In Vitro Fertilization were enrolled in this study if the luteal phase leuprolide acetate (LA) and hMG controlled ovarian hyperstimulation (COH) regimen was used. MAIN OUTCOME MEASURES: Clinical pregnancy, as determined by a positive beta-hCG level and ultrasonographic confirmation of a gestational sac, and delivery rates based on number of women with live births were compared by infertility factor and age. RESULTS: The 3-month cumulative probability of pregnancy based on life table analysis was 33% in women with tubal factor who were < or = 35 years of age, 25% in women with tubal factor who were > 35 years of age, 30% for women with multiple factors who were < or = 35 years of age, and 14% for women with multiple factors who were > 35 years of age. The rate for the older women with multiple factors was significantly lower than that for the other groups. The delivery rates were lower for the women with multiple factors than for women under 35 with tubal factor only. CONCLUSIONS: There is a significant effect of age and infertility factor on pregnancy and delivery rates. Physicians should consider these factors in evaluating their patients' prospects for success in IVF-ET.     

Single lung transplantation in patients with systemic disease

OBJECTIVE: To report functional results and survival in patients undergoing single lung transplantation (SLT) for pulmonary involvement associated with systemic disease or prior malignancy, criteria traditionally considered contraindications to SLT. DESIGN: Case series. SETTING: The University of Texas Health Science Center at San Antonio. PATIENTS: Nine patients who have undergone SLT for end-stage lung disease: four patients with sarcoidosis; two patients with limited scleroderma; and three patients with prior malignancies (two with prior lymphoma and bleomycin-induced pulmonary fibrosis and one who received two bone marrow transplants for acute lymphocytic leukemia and subsequently developed chemotherapy-induced pulmonary fibrosis). MEASUREMENTS: Pulmonary function testing, exercise oximetry, quantitative ventilation-perfusion lung scanning. Actuarial survival. RESULTS: All patients had marked improvement in pulmonary function, exercise oximetry, and quantitative ventilation perfusion to the SLT. One patient with scleroderma died 90 days postoperatively from Pseudomonas pneumonia with a sepsis syndrome. One patient with sarcoidosis died 150 days postoperatively from disseminated aspergillosis. At autopsy, there was no evidence of recurrent fibrosis or sarcoidosis in the transplanted lungs in either of these two patients. The seven surviving patients have returned to work or school and are conducting all activities of daily living without pulmonary disability. The 1- and 2-year actuarial survival rates in these nine patients is 68.6 percent as compared with the 1- and 2-year actuarial survival rates of 66.3 percent and 55.8 percent in the remainder of our SLT group as a whole (n = 49). Despite pharmacologic immunosuppression, there is no evidence of recurrent malignancy in the 3 patients with prior malignancies. CONCLUSIONS: We conclude that carefully selected patients with end-stage lung involvement related to systemic disease or chemotherapy-induced fibrosis may benefit from SLT.     

Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833

Mice lacking mdr1-type P-glycoproteins (mdr1a/1b [-/-] mice) display large changes in the pharmacokinetics of digoxin and other drugs. Using the kinetics of digoxin in mdr1a/1b (-/-) mice as a model representing a complete block of P-glycoprotein activity, we investigated the activity and specificity of the reversal agent SDZ PSC833 in inhibiting mdr1-type P-glycoproteins in vivo. Oral PSC833 was coadministered with intravenous [3H]digoxin to wild-type and mdr1a/1b (-/-) mice. The direct excretion of [3H]digoxin mediated by P-glycoprotein in the intestinal mucosa of wild-type mice was abolished by administration of PSC833. Hepatobiliary excretion of [3H]digoxin was markedly decreased in both wild-type and mdr1a/1b (-/-) mice by PSC833, the latter effect indicating that in vivo, PSC833 inhibits not only mdr1-type P-glycoproteins, but also other drug transporters. Upon coadministration of PSC833, brain levels of [3H]digoxin in wild-type mice showed a large increase, approaching (but not equaling) the levels found in brains of PSC833-treated mdr1a/1b (-/-) mice. Thus, orally administered PSC833 can inhibit blood-brain barrier P-glycoprotein extensively, and intestinal P-glycoprotein completely. These profound pharmacokinetic effects of PSC833 treatment imply potential risks, but also promising pharmacological applications of the use of effective reversal agents.