Application of a macromolecular contrast agent for detection of alterations of tumor vessel permeability induced by radiation.

Permeability of tumor vasculature can be a major barrier to successful drug delivery, particularly for high molecular weight agents such as monoclonal antibodies and their diagnostic or therapeutic conjugates. In this study, changes in permeability of SCCVII tumor vessels after radiation treatment were evaluated by dynamic magnetic resonance imaging as a function of time after irradiation using a generation-8 polyamidoamine dendrimer (G8-Gd-D)-based magnetic resonance imaging contrast agent shown previously to be confined to tumor blood vessels. Tumor irradiation consisted of either single doses (2-15 Gy) or various daily fractionated doses (5 days). A single radiation dose of 15 Gy resulted in significant transient image enhancement of the tumor tissue with a maximum occurring between 7 and 24 hours after radiation treatment. No observable enhancement was recorded for fractionated radiation doses. Use of dynamic magnetic resonance imaging coupled with G8-Gd-D provides an exquisite methodology capable of defining the timing of enhanced permeability of macromolecules in tumors after irradiation. Such information might be applied to optimize the efficacy of subsequent or concurrent therapies including radiolabeled antibodies or other anticancer agents in combination with external beam therapies.     

Publication rates of abstracts presented at annual scientific meetings: How does the Royal Australian and New Zealand College of Radiologists compare?

The abstract to publication ratio (APR) is a measure of the quality of scientific meetings. The aim of the present study was to determine the publication rate of abstracts presented at annual Royal Australian and New Zealand College of Radiologists (RANZCR) conferences, and to identify the publishing journals. All free paper research abstracts (oral or poster) presented by RANZCR radiologists, radiation oncologists and trainees at the four consecutive meetings between 1996 and 1999 were identified retrospectively from conference programmes. The PubMed database ( http:www.ncbi.nlm.nih.govPubMed ) was searched to determine whether or not the abstract had been published as a full paper. Of the 480 free paper research abstracts, 168 (35%) had been published as full articles. The overall abstract to publication ratio for radiology was 29% and for radiation oncology was 41%. Papers were published in a variety of journals but Australasian Radiology accounted for 27%. The mean time between presentation and publication was 16.5 months (median 17 months). These overall abstract to publication ratios are lower than those reported for overseas‐based meetings in each respective area. Guidelines to scientific committees could increase the APR by more rigorous selection of abstracts. Future research should look at barriers to the publication of research findings, and identify ways to assist the publication process.     

Targeted liposomal c-myc antisense oligodeoxynucleotides induce apoptosis and inhibit tumor growth and metastases in human melanoma models.

PURPOSE: Melanoma is a highly malignant and increasingly common tumor. Because the cure rate of metastatic melanoma by conventional treatment is very low, new therapeutic approaches are needed. We previously reported that coated cationic liposomes (CCL) targeted with a monoclonal antibody against the disialoganglioside (GD(2)) and containing c-myb antisense oligodeoxynucleotides (asODNs) resulted in a selective inhibition of the proliferation of GD(2)-positive neuroblastoma cells in vitro. EXPERIMENTAL DESIGN: Here, we tested the in vivo antitumor effects of this novel antisense liposomal formulation by targeting the c-myc oncogene on melanoma, a neuroectodermal tumor sharing with neuroblastoma the expression of GD(2). RESULTS: Our methods produced GD(2)-targeted liposomes that stably entrapped 90% of added c-myc asODNs. These liposomes showed a selective binding for GD(2)-positive melanoma cells in vitro. Melanoma cell proliferation was inhibited to a greater extent by GD(2)-targeted liposomes containing c-myc asODNs (aGD(2)-CCL-myc-as) than by nontargeted liposomes or free asODNs. The pharmacokinetic results obtained after i.v. injection of [(3)H]-myc-asODNs, free or encapsulated in nontargeted CCLs or GD(2)-targeted CCLs, showed that free c-myc-asODNs were rapidly cleared, with less than 10% of the injected dose remaining in blood at 30 min after injection. c-myc-asODNs encapsulated within either CCL or aGD(2)-CCL demonstrated a more favorable profile in blood, with about 20% of the injected dose of each preparation remaining in vivo at 24 h after injection. In an in vivo melanoma experimental metastatic model, aGD(2)-CCL-myc-as, at a total dose of only 10 mg of asODN per kilogram, significantly inhibited the development of microscopic metastases in the lung compared with animals treated with myc-asODNs, free or entrapped in nontargeted liposomes, or aGD(2)-CCL encapsulating scrambled asODNs (P < 0.01). Moreover, mice bearing established s.c. human melanoma xenografts treated with aGD(2)-CCL-myc-as exhibited significantly reduced tumor growth and increased survival (P < 0.01 versus control mice). The mechanism for the antitumor effects appears to be down-regulation of the expression of the c-myc protein and interruption of c-myc-mediated signaling: induction of p53 and inhibition of Bcl-2 proteins, leading to extensive tumor cell apoptosis. CONCLUSION: These results suggest that inhibition of c-myc proto-oncogene by GD(2)-targeted antisense therapy could provide an effective approach for the treatment of melanoma in an adjuvant setting.     

Pilot study of abuse of asthma inhalers by middle and high school students

During a school-based survey, middle and high school students (n = 1536) reported on their nonprescribed, lifetime use of asthma inhalers. Approximately 15% of 8th and 9th graders reported using nonprescribed asthma inhalers; the odds for this behavior were significantly higher for these students (2.25 and 2.30, respectively) and the nonprescribed use of asthma inhalers was significantly associated with higher rates of other drug use.     

Nasal carriage of methicillin-resistant Staphylococcus aureus in an American Indian population.

BACKGROUND AND OBJECTIVE: Although reports of methicillin-resistant Staphylococcus aureus (MRSA) infections without healthcare exposure are increasing, population-based data regarding nasal colonization are lacking. We assessed the prevalence of and risk factors for community-associated MRSA nasal carriage in patients of a rural outpatient clinic. DESIGN: A cross-sectional population survey was conducted through random sample and stratification by community of residence. Recent healthcare exposure (ie, hospitalization, dialysis, or healthcare occupation) and other risk factors for MRSA carriage were assessed. Cultures of the nares were performed. Community-associated MRSA was defined as MRSA carriage without healthcare exposure. SETTING: A predominantly American Indian community in Washington. PATIENTS: Those receiving healthcare from an Indian Health Service clinic. RESULTS: Of 1,311 individuals identified for study, 475 (36%) participated. Unsatisfactory culture specimens resulted in exclusion of 6 participants. In all, 128 (27.3%) of 469 participants had S. aureus. Nine (1.9%) of 469 had MRSA carriage; of these, 5 had community-associated MRSA (5 of 469; overall community-associated MRSA carriage rate, 1.1%). MRSA carriage was associated with antimicrobial use in the previous year (risk ratio [RR], 7.2; P = .04) and residence in a household of more than 7 individuals (RR, 4.5; P = .03). Pulsed-field gel electrophoresis indicated that 5 (55%) of 9 MRSA carriage isolates were closely related, including 3 (60%) of 5 that were community associated. CONCLUSIONS: Prevalence of community-associated MRSA colonization was approximately 1% in this rural, American Indian population. Community-associated MRSA colonization was associated with recent antimicrobial use and larger household.     

Central allopregnanolone is increased in rat pups in response to repeated, short episodes of neonatal isolation

This experiment investigated whether neonatal isolation stress alters central concentrations of progestins. Whole brain progesterone (P), dihydroprogesterone (DHP), and allopregnanolone (3alpha, 5alpha-THP) were measured in pups that were isolated from the nest, dam, and siblings for 1 h on postnatal days (PND) 2-9 and were compared to control litters of pups that were not isolated. Isolated 2-day-old pups had significantly lower central P and higher P to DHP and 3alpha, 5alpha-THP metabolism ratios. On PND 9, pups that had been repeatedly isolated (PND 2-8), had significantly lower whole brain DHP and significantly greater whole brain 3alpha, 5alpha-THP compared to controls. Thus, the biosocial stress of isolation in neonatal rats alters central pregnane steroids.     

Diagnosis and management of salivary fistula after surgery for congenital aural atresia.

OBJECTIVE: Salivary fistula is an uncommon and unreported yet meaningful complication associated with the repair of congenital aural atresia. The capsule of the parotid gland may be violated during two steps of the operation: the initial dissection around the glenoid fossa or while aligning the auricle with the bony canal at the end of the procedure. We present the first described series of patients with salivary fistula after repair of congenital aural atresia. STUDY DESIGN: Retrospective case review from 1985 to 2004. SETTING: Tertiary referral center. PATIENTS: We included all patients who were diagnosed with a salivary fistula after congenital aural atresia repair. MAIN OUTCOME MEASURE: The diagnosis of a salivary fistula or salivary tissue in the external auditory canal after atresia repair was based on one of the following criteria: 1) identification of a fistula tract or salivary tissue in the external auditory canal, 2) otorrhea positive for amylase, or 3) intermittent otorrhea associated with eating. RESULTS: Of 1,500 patients operated on for aural atresia, we identified 6 with salivary fistula after atresia repair. Salivary fistulas were diagnosed from 15 days to 10 years postoperatively, and the duration ranged from 6 months to 14 years. Treatment included observation, medical management, and surgical intervention. CONCLUSION: Salivary fistulas in the external auditory canal may present with granulation tissue, persistent crusting, or persistent otorrhea; it is therefore necessary to consider salivary fistula when managing these findings in postoperative congenital aural atresia patients. Salivary fistula secondary to repair of congenital aural atresia may be managed conservatively or surgically.