Multimodality treatment of nongalenic arteriovenous malformations in pediatric patients

OBJECTIVE: Previously reported series of arteriovenous malformations (AVMs) in pediatric patients have primarily used a single-modality treatment approach of either surgery, radiosurgery, or embolization, with significant treatment-related morbidity and mortality. At our institution, we have used a combined multidisciplinary team approach of all three treatment modalities, alone or in combination, to minimize complications and to maximize efficacy in the management of these lesions. METHODS: We retrospectively reviewed 40 consecutive pediatric patients with AVMs seen at our institution from 1991 to 1999. A multidisciplinary team planned the treatment for each AVM. The treatment modality consisted of the following approaches: surgery alone in 14 patients, a combination of endovascular embolization and surgery in 6 patients, radiosurgery alone in 11 patients, a combination of endovascular embolization and radiosurgery in 2 patients, and a combination of radiosurgery and surgery in 2 patients. Four patients are receiving ongoing multistaged treatment for reduction of the nidus size for eventual surgical resection or radiosurgical obliteration of large, complex lesions. In one patient, no treatment was recommended. RESULTS: The clinical outcomes for the overall series were 95.0% excellent or good (Glasgow Outcome Scale score 5 or 4), 2.5% fair (Glasgow Outcome Scale score 3), and 2.5% dead. Radiographic efficacy in the patients who have completed treatment was 92.9% complete obliteration of their AVMs and 7.1% incomplete obliteration. Of the 10 patients who had seizures, 9 are seizure-free. CONCLUSION: A combined multimodality approach of surgery, radiosurgery, and embolization in managing AVMs in pediatric patients can improve outcomes and minimize morbidity and mortality.     

Radioactive seed embolization to the lung following prostate brachytherapy

Over the past decade, prostate brachytherapy has been increasingly utilized as definitive management for early stage carcinoma of the prostate gland. One risk of the procedure is pulmonary seed embolization. In this article we report the incidence and timing of seed migration. Pulmonary embolization of radioactive seeds occurs in approximately 20% of patients undergoing prostate brachytherapy. To date, no acute or delayed detrimental effects have been reported which are attributable to the pulmonary embolization of the seeds; nevertheless, it is imperative that patients and health care providers be cognizant of this possible event.     

Perspectives of those impacted: airline pilot's perspective

The airline pilot operates within an environment that consists of circadian dysrhythmia, reduced atmospheric pressure, mild hypoxia, low humidity, and exposure to sound, vibration, cosmic-radiation, and magnetic-field exposure. These occupational exposures present physiological challenges to the long term health of the airline pilot. In particular, exposure to cosmic radiation and its carcinogenic potential have recently received considerable attention. Given the complexity of the environment and possible synergistic exposures, there is an immediate requirement for comprehensive research into both cosmic-radiation and magnetic-field exposures in airline pilots. In response, the Airline Pilots Association International in conjunction with the Medical University of South Carolina (Department of Biometry and Epidemiology) has initiated an extensive research program into these occupational exposures. These investigations include ground based calculations, flight-dose estimates, epidemiological survey and exposure assessment, and biological marker analysis.     

Isolation and characterization of propagable cell lines (HUNC) from the androgen-sensitive Dunning R3327H rat prostatic adenocarcinoma

The Dunning H rat prostate tumor (R3327H) is a widely used experimental model of human prostatic adenocarcinoma (CaP). The Dunning H tumor has been characterized as androgen-sensitive, androgen-receptor (AR) positive, prostate-specific antigen and prostatic acid phosphatase (PAP) positive. To date, the tumor has been maintained by serial passage in vivo because of the lack of an in vitro cell line that retains the characteristics of the in vivo tumor. The objective of the present study was to establish a propagable cell line from R3327H adenocarcinoma that maintained androgen sensitivity and expression of AR, PSA and PAP. Tissue harvested from an in vivo R3327H tumor was dissociated with collagenase and placed into Richter's improved media (with supplements). A cytokeratin-positive epithelial cell line (HUNC- E) and a vimentin-positive stromal cell line (HUNC-S) were generated from the primary culture, subcultured continuously for >300 days, and passaged >50 times. Survival of the HUNC-E cell line in vitro depended on several media supplements, including nicotinamide, insulin, transferrin, selenium and epidermal growth factor (EGF). HUNC-E cells expressed AR and produced PSA and PAP throughout the culture period, as confirmed by immunocytochemistry and Western blot analyses. Addition of 14 nM testosterone (T) or dihydrotestosterone (DHT) to HUNC-E cells, stimulated DNA synthesis as well as anchorage-independent growth and PSA production, which demonstrated the androgen-sensitive nature of the cells in vitro. When HUNC-E and HUNC-S cells were combined in a 3:1 ratio and introduced subcutaneously into syngeneic male hosts, tumors formed in 2/3 animals with an average latency of 7 months. RT-PCR and immunocytochemical characterization of the HUNC cell lines revealed that the cells expressed several growth factors and their cognate receptors, including HGF, TGF-alpha and the TGF-betas, indicating the establishment of potential autocrine loops in the neoplastic cells. The HUNC-E and HUNC-S CaP cell lines, which retain the characteristics of the epithelial and stromal components of the in vivo R3327H tumor, will allow a more thorough and informative molecular and biological analysis of prostatic adenocarcinoma.      

Resistance to the tubulin-binding agents in renal cell carcinoma: no mutations in the class I beta-tubulin gene but changes in tubulin isotype protein expression.

PURPOSE: The primary purpose of this study was to determine whether mutations of the class I beta-tubulin gene may be implicated in the inherent resistance to tubulin-binding agents (TBA) in renal cancer, with a small number of samples and cell lines also being examined for class I and III beta-tubulin isotype protein expression. EXPERIMENTAL DESIGN: DNA was extracted from 90 renal tumors and the class I beta-tubulin gene analyzed for mutations. For each sample, eight PCRs were used to cover the complete coding sequence with intronic primers ensuring highly homologous pseudogenes were not coamplified. Additionally, expression levels of class I and III beta-tubulin isotypes in 17 matched normal and malignant renal samples and a panel of renal cell carcinoma cell lines with differing intrinsic resistance to the TBAs was examined by Western blotting. RESULTS: Four polymorphic sequence changes of the class I beta-tubulin gene were identified with no mutations. Class I protein expression levels were higher in tumor tissue versus normal tissue, whereas class III expression showed no consistent change. In renal cancer cell lines, a significant correlation between class III isotype expression and vinblastine sensitivity was observed. CONCLUSIONS: These results do not support a role for mutations in the class I beta-tubulin gene in the intrinsic resistance of renal cancer to TBAs. Class III isotype expression may be implicated in resistance in vitro but in vivo, changes in class I isotype expression in renal cell carcinoma tissue may support a role in resistance to the TBAs and warrants further investigation.     

The three systems: a conceptual way of understanding nocturnal enuresis

Childhood nocturnal enuresis has traditionally been regarded as a multifaceted problem with a variety of treatment interventions. This paper proposes a model based on the notion that nocturnal enuresis arises through the ill functioning of one or more of the following three systems - a lack of vasopressin release during sleep; bladder instability; and/or an inability to arouse from sleep to bladder sensations. Clinical signs of each system are outlined and the appropriate treatment intervention for each is discussed. It is argued that addressing nocturnal enuresis in this way will enhance overall treatment effectiveness.     

The effect of the anthrapyrazole antitumour agent CI941 on rat liver microsome and cytochrome P-450 reductase mediated free radical processes. Inhibition of doxorubicin activation in vitro

The anthrapyrazole CI941 is one of a new series of DNA complexing drugs which displays high level broad spectrum antitumour activity in mice. In view of the proposed role of drug free radical formation, superoxide generation and lipid peroxidation in anthracycline and anthraquinone induced toxicities, the redox biochemistry of CI941 has been investigated. Studies have been performed in vitro using rat liver microsomes and purified cytochrome P-450 reductase. In addition, the ability of CI941 to undergo chemical reduction has been examined. Pulse radiolysis of CI941 demonstrated that the drug can undergo chemical reduction with a one electron reduction potential of E1(7) = -538 +/- 10 mV. However, electron spin resonance (ESR) spectroscopy studies using either NADPH fortified microsomes or cytochrome P-450 reductase, failed to detect a drug free radical signal. Unlike doxorubicin, CI941 (150 microM) inhibited basal rate microsomal NADPH consumption by 45%. Furthermore, CI941 (50-200 microM) antagonised doxorubicin stimulated (1.8-fold) NADPH oxidation by over 50%. CI941 also antagonised the formation of a doxorubicin free radical ESR signal in a concentration dependent manner. CI941 induced minimal superoxide generation in the presence of either microsomes or cytochrome P-450 reductase and inhibited doxorubicin induced (50 microM) superoxide formation by up to 80% (50-200 microM CI941). Importantly, CI941 inhibits both basal rate and doxorubicin (100 microM) stimulated lipid peroxidation (52% inhibition at 5 microM CI941). These data suggest that CI941 is unlikely to induce free radical mediated tissue damage in vivo. On the contrary, CI941 may have a protective role if used in combination with doxorubicin.     

In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus

Zika virus (ZIKV) causes significant human diseases without specific therapy. Previously we found erythrosin B, an FDA-approved food additive, inhibited viral NS2B−NS3 interactions, leading to inhibition of ZIKV infection in cell culture. In this study, we performed pharmacokinetic and in vivo studies to demonstrate the efficacy of erythrosin B against ZIKV in 3D mini-brain organoid and mouse models. Our results showed that erythrosin B is very effective in abolishing ZIKV replication in the 3D organoid model. Although pharmacokinetics studies indicated that erythrosin B had a low absorption profile, mice challenged by a lethal dose of ZIKV showed a significantly improved survival rate upon oral administration of erythrosin B, compared to vehicle control. Limited structure−activity relationship studies indicated that most analogs of erythrosin B with modifications on the xanthene ring led to loss or reduction of inhibitory activities towards viral NS2B−NS3 interactions, protease activity and antiviral efficacy. In contrast, introducing chlorine substitutions on the isobenzofuran ring led to slightly increased activities, suggesting that the isobenzofuran ring is well tolerated for modifications. Cytotoxicity studies indicated that all derivatives are nontoxic to human cells. Overall, our studies demonstrated erythrosin B is an effective antiviral against ZIKV both in vitro and in vivo.KEY WORDS: Flavivirus, Zika virus, Dengue virus, Antiviral, Protease inhibitor, Erythrosin B