Characterization of bortezomib-adapted I-45 mesothelioma cells

Background  

Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. However, development of resistance to bortezomib may pose a challenge to effective anticancer therapy. Therefore, characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy.     

Endocrine and amine responses to D,L-fenfluramine in normal subjects.

To investigate indirectly the central neurotransmitter mechanisms of D,L-fenfluramine-induced hormone release, prolactin, adrenocorticotropic hormone, cortisol, growth hormone, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) responses to D,L-fenfluramine (60 mg, oral) were examined in a single-blind, placebo-controlled trial in 14 normal subjects. As compared with placebo, D,L-fenfluramine significantly increased both prolactin and cortisol. There was a significant correlation between the cortisol and prolactin responses. HVA levels were also significantly increased, but there were no changes in MHPG or 5HIAA. The elevation in HVA significantly correlated with increases in both prolactin and cortisol. These findings are consistent with recent animal studies suggesting that D,L-fenfluramine-induced prolactin and cortisol release may be mediated, at least in part, by catecholaminergic systems.     

Patient-controlled analgesia: a review.

The patient-activated analgesic system was introduced in 1968. Early trials, although uncontrolled, supported the safety and efficacy of patient-controlled analgesia (PCA) in several kinds of pain, such as that relating to surgery, cancer, trauma, and obstetric procedures. In the past decade, prospective, randomized trials have reported several advantages of PCA over conventional analgesia in the early postoperative period. Although not supported by all controlled trials, they include improved pain relief, less sedation, lower level of narcotic consumption, fewer postoperative complications, greater patient satisfaction, and improved pulmonary function. Preliminary results in the management of chronic pain indicate that PCA can lead to significant lifestyle improvements in ambulatory patients with cancer. The most significant, although infrequent, adverse effect is respiratory depression, the majority of cases occurring in patients predisposed secondary to concomitant illness or as a result of human error. The clinical use of PCA will likely see a significant increase among persons with cancer, and an increase in epidural administration. The cost benefit of PCA has yet to be assessed in inpatient and outpatient settings.     

Pulmonary granuloma caused by Pseudomonas andersonii sp nov

Pulmonary granuloma is a common lesion for which gram-negative bacteria are rarely implicated as a cause. Hence, most physicians are unaware of this etiology. We isolated a gram-negative bacterium from a surgically resected pulmonary granuloma in a 42-year-old, nonimmunocompromised woman. Within the necrotizing granuloma, numerous organisms also were demonstrated by Gram stain, suggesting a cause-disease relationship. Characterization of the bacterium by sequence analysis of the 16S ribosomal gene, cellular fatty acid profiling, and microbiologic studies revealed a novel bacterium with a close relationship to Pseudomonas. We propose a new species for the bacterium, Pseudomonas andersonii. These results suggest that the differential diagnosis of a lung granuloma also should include this gram-negative bacterium as a potential causative agent, in addition to the more common infections caused by acid-fast bacilli and fungi. This bacterium was shown to be susceptible to most antibiotics that are active against gram-negative bacteria.     

Adeno-associated virus-mediated vascular endothelial growth factor gene therapy in skeletal muscle before transplantation promotes revascularization of regenerating muscle

Successful clinical transplantation of whole skeletal muscles can be limited by impaired muscle revascularization and regeneration. The aim of this study was to enhance the revascularization (and hence speed of regeneration) of transplanted whole muscles by transducing muscles with the vascular endothelial growth factor (VEGF) gene before transplantation, using a recombinant adeno-associated virus (rAAV). The rAAV encoding VEGF and green fluorescent protein (GFP) (rAAV.VEGF.GFP) was injected into the tibialis anterior muscles of adult BALB/c mice. One month after injection whole muscle autotransplantation was performed. Muscles were sampled 7 days after autografting. GFP expression was examined as an indicator of persistent transgene expression after grafting, and immunohistochemistry was used to identify VEGF, blood vessels, and newly formed myotubes. After grafting, GFP expression persisted only in a few surviving myofibers in the periphery of rAAV.VEGF.GFP-pretreated muscles, although abundant VEGF expression was seen in myogenic cells in all grafted muscles. Quantitative analysis demonstrated that, although only small numbers of rAAV.VEGF.GFP-transduced myofibers were present, whole muscle grafts preinjected with rAAV.VEGF.GFP were significantly more vascular than saline-injected and uninjected control muscle grafts. Furthermore, rAAV.VEGF.GFP-injected whole muscle transplants were further advanced in terms of regeneration (myotube formation) compared with the uninjected control muscle transplants. This study clearly shows that rAAV-mediated VEGF expression persists only in myofibers that survive the necrosis induced by muscle transplantation; however, this amount of VEGF results in significantly increased revascularization and regeneration of whole muscle transplants.     

Prospective patient-controlled analgesia quality assurance: one year's experience

The goal of this project was to develop a prospective patient-controlled analgesia (PCA) quality assurance (QA) program and evaluate its impact on patient care. Initial elements selected for inclusion into the QA were: patient satisfaction, pain relief, clarity of instructions, respiratory rate, and nausea and vomiting. Standards were initially set at 100% with the exception of nausea and vomiting, which was 90%. Preliminary evaluation in 26 patients indicated initial standards were unrealistically high. Standards were revised to 90% for all elements except respiratory rate, which was left at 100%. Nausea and vomiting were eliminated from the QA because it was difficult to establish a cause and effect relationship with narcotic. Data were collected through patient interviews and chart reviews on a bimonthly basis. Cumulative data on 297 patients revealed standards were met in all categories. Two systematic problems identified early in the QA were that there was no recording of respiratory rate and there was a high incidence of unclear instructions. As a result of pharmacist interventions, outcomes improved. Patient outcomes with PCA therapy can be improved using a prospective PCA QA program. Pharmacy Department's without resources for daily monitoring of PCA patients should consider implementing a prospective PCA QA program.     

The effect of temazepam on melatonin secretion and light sensitivity

Seven healthy male volunteers had their light sensitivity (melatonin suppression) and melatonin phase measured before and after treatment with temazepam (20 mg) for 7 days. Temazepam did not alter the circadian phase of melatonin secretion (the Dim Light Melatonin Onset, the timing of the peak of secretion), the total melatonin secretion nor the sensitivity of melatonin secretion to suppression by full spectrum light. This is an important negative finding which suggests that the short half-life benzodiazepine hypnotic temazepam does not confound tests of light sensitivity or melatonin phase.     

Levels of messenger-RNA coding for DNA topoisomerase-ii isoforms do not correlate with in-vitro drug-sensitivity

The relationship between cellular levels of mRNA coding for DNA topoisomerase II, both the alpha and beta isoforms, and in vitro sensitivity to anticancer drugs were evaluated. Using a sensitive RNA-polymerase chain reaction technique, the levels of mRNA coding for the alpha and beta isoforms of topoisomerase II were estimated relative to beta-actin mRNA. A relatively narrow range of expression was observed across a broad range of approximately 60 human tumor cell lines representing eight major histological types which have been characterized in detail with respect to their in vitro sensitivity to standard anticancer drugs. No significant correlations were observed between mRNA level and cellular response to drugs thought to inhibit topoisomerase II or any of the other drugs studied. These results suggest that predictive tests for response to topoisomerase II-related drugs can not be based on estimation of levels of mRNA.     

In vivo intrahippocampal microinfusion of carbachol and bicuculline induces theta-like oscillations in the septally deafferented hippocampus.

In their laboratory the authors have previously demonstrated that hippocampal slices could be induced to generate trains of "theta-like" oscillations by whole-bath perfusions of carbachol. Until recently, it has not been possible to generate similar activity in the septally deafferented hippocampus of an otherwise intact brain by microinfusions of carbachol. This study presents a full report of the first demonstration of a theta-like oscillation in the in vivo, septally deafferented hippocampal formation. Rats were anesthetized with urethane and implanted with microinfusion cannulae in the region of the medial septum/vertical limb of the diagonal band of Broca (MS/vDBB) and at single or multiple sites in the stratum moleculare of the fascia dentata. The MS/vDBB was microinfused with procaine hydrochloride to produce a reversible suppression lasting for approximately 20 minutes. Intrahippocampal microinfusions of carbachol or bicuculline alone (in the postprocaine condition of the MS/vDBB) failed to produce any theta-like oscillations. The combination of carbachol and bicuculline produced trains of theta-like oscillations during suppression of the MS/vDBB very similar to those seen in the slice preparations. The oscillations were blocked by intravenous administration of atropine sulfate, and they had the same depth profile as that of theta. Theta-on cells were shown to discharge in rhythmic bursts in synchrony with the oscillations. Thus, it would appear that the essential nature of the medial septal input to the hippocampal formation, for the generation of theta field activity in the intact brain, consists of a critical balance between cholinergic and GABAergic circuitry.