Inverse relationship between human papillomavirus-16 infection and disruptive p53 gene mutations in squamous cell carcinoma of the head and neck.

PURPOSE: Squamous cell carcinomas of the head and neck (HNSCC) often harbor p53 mutations, but p53 protein degradation by the viral oncoprotein E6 may supercede p53 mutations in human papillomavirus 16 (HPV16)-positive tumors. The prevalence of p53 mutations in HPV-positive HNSCCs is indeed lower, but in some tumors these alterations coexist. The purpose of this study was to discern whether HNSCCs differ in the type of p53 mutations as a function of HPV16 status. EXPERIMENTAL DESIGN: The study was nested within a prospective multicenter study (ECOGE 4393/RTOG R9614) of patients with HNSCC treated surgically with curative intent. Tumors from one study center were used to construct a tissue microarray. The tumors were well characterized with respect to p53 mutational status. The tissue microarray was evaluated by HPV16 in situ hybridization. HPV16 analysis was also done on a select group of tonsillar carcinomas known to harbor disruptive p53 mutations defined as stop mutations or nonconservative mutations within the DNA binding domain. RESULTS: HPV16 was detected in 12 of 89 (13%) HNSCCs. By tumor site, HPV16 was detected in 12 of 21 (57%) tumors from the palatine/lingual tonsils, but in none of 68 tumors from nontonsillar sites (P < 0.00001). Both HPV16-positive and HPV16-negative HNSCCs harbored p53 mutations (25% versus 52%), but disruptive mutations were only encountered in HPV16-negative carcinomas. Of seven tonsillar carcinomas with disruptive p53 mutations, none were HPV16 positive, in contrast to HPV16-positive tonsillar carcinomas without disruptive p53 mutations (0% versus 57%; P = 0.008). CONCLUSIONS: Although HPV16 and mutated p53 may coexist in a subset of HNSCCs, HPV16 and disruptive p53 mutations seem to be nonoverlapping events. A less calamitous genetic profile, including the absence of disruptive p53 mutations, may underlie the emerging clinical profile of HPV16-positive HNSCC such as improved patient outcome.     

The Role of Cohort Studies in Drug Development: Clinical Evidence of Antiviral Activity of Serotonin Reuptake Inhibitors and HMG-CoA Reductase Inhibitors in the Central Nervous System

Background Effective antiretroviral therapy (ART) has reduced the incidence of HIV-associated neurocognitive impairment (HNCI) but its prevalence remains high. Clinical trials have yet to identify a consistently effective treatment for HNCI, other than ART, but in vitro data support that some drugs approved by the Food and Drug Administration (FDA) for other indications might benefit individuals with HNCI. Some of these drugs, such as serotonin reuptake inhibitors (SRIs) and HMG-CoA reductase inhibitors (statins), may do so by reducing HIV replication in the CNS and are already widely used by HIV-infected individuals. Methods Six-hundred fifty-eight HIV-infected participants of the CHARTER cohort had a baseline assessment, which included comprehensive neuropsychological (NP) testing and HIV RNA measurements in plasma and cerebrospinal fluid (CSF). Four-hundred sixty-seven (71%) subjects used ART, 195 (30%) used SRIs, and 63 (10%) used statins. Results SRI users were less likely to have HIV RNA levels in CSF above 50 copies (c)/mL (29 vs. 37% in non-SRI users, OR 0.69, p = 0.05). This association was most evident for three of the seven SRIs (citalopram, sertraline, and trazodone, or “antiviral” SRIs, combined 25 vs. 38% in non-SRI users, OR 0.56, p = 0.01) and was strongest in those not taking concomitant ART (61 vs. 83%, OR 0.31, p = 0.01). “Antiviral” SRI users also performed better on NP tests (median global deficit score 0.37 vs. 0.47, p = 0.04). Statin users were also less likely to have HIV RNA levels in CSF above 50 c/mL (16 vs. 37%, p < 0.001) but, in contrast to SRIs, the association was strongest in those taking ART (2 vs. 18%, p < 0.001). Statin use was not associated with better NP performance. Multivariate analyses indicated that the use of “antiviral” SRIs—but not statins—was associated with undetectable HIV RNA levels in CSF and better NP performance. Conclusions SRIs may reduce HIV replication in CSF and improve NP performance. This was particularly true for three SRIs—supporting differences in antiviral efficacy between drugs—in individuals who were not taking ART. In contrast, statins were not associated with lower HIV replication in CSF in multivariate analyses and were not associated with better NP performance. These analyses support the value of large observational cohort studies in identifying FDA-approved drugs that may be worth further investigation.     

An in vitro study of ceftazidime and vancomycin concentrations in various fluid media: implications for use in treating endophthalmitis

PURPOSE: To investigate the precipitation process of a mixture of vancomycin and ceftazidime by equilibrium dialysis and determine its subsequent effect on the level of free antibiotics for treatment of endophthalmitis. METHODS: Concentrations of vancomycin and ceftazidime in an equilibrium dialysis chamber were measured during the equilibrium process by high-performance liquid chromatography. Normal saline (NS), balanced salt solution (BSS), and vitreous were used separately as the medium of dialysis. RESULTS: Precipitation of ceftazidime occurred at 37 degrees C but not at room temperature and did not affect the pH of the medium. It formed precipitate on its own or when mixed with vancomycin in all the three media of NS, BSS, and vitreous. More precipitation was formed if ceftazidime was initially prepared in BSS than in NS. After 168 hours in the dialysis chambers, ceftazidime prepared in NS precipitated to 54% of that in vitreous, compared with 88% if prepared in BSS. At 48 hours, ceftazidime prepared in NS decreased from an initial concentration of 137.5 to 73.4 microg/mL in vitreous medium and to 6.3 microg/mL if prepared in BSS. Precipitation of vancomycin was negligible. CONCLUSIONS: Based on this in vitro investigation, ceftazidime precipitates in vitreous at body temperature, regardless of the presence of vancomycin. NS is preferred to BSS as a preparation medium for antibiotics for intravitreal injection, because the extent of ceftazidime precipitation is less. However, due to precipitation, the concentration of free ceftazidime in vitreous may not be sufficiently high for antibacterial activity against most common organisms.     

Infant bed-sharing among Pacific families in New Zealand

AIM: To describe infant bed-sharing among Pacific families in New Zealand. METHODS: The data were gathered as part of the Pacific Island Families: First Two Years of Life (PIF) Study in which 1376 mothers were interviewed when their infants were six-weeks-old. Maternal reports of infant bed-sharing practices were assessed by questions about infant sleep location and the number of people who usually shared a mattress with the infant. RESULTS: Over half of the mothers (54.9%) reported that their infants shared a mattress with other people, 44.2% sharing with one other person, the remainder sharing with two or more people. Of the bed-sharing infants, 4.7% slept on a mattress on top of the bed, and 4.7% only slept part of the night in the shared bed. CONCLUSIONS: Together with effective information delivery, the educational and housing issues that many Pacific families in New Zealand face need to be addressed so that parents can make informed decisions about infant care practices.     

Participation in home therapy programs for children with cerebral palsy: a compelling challenge

In this grounded theory study, the authors purposed to generate a conceptual model of the experience of parents and therapists involved in home therapy programs for children with cerebral palsy. There were 12 participants: 4 therapists and 8 parents. Through constant comparative method of analysis, a process emerged interpreted as the compelling challenge comprising two time-distinct phases that described the parents' journey of adjustment and their capacity to participate in activities to improve their child's abilities. Initially, parents were coming to grips with the diagnosis, and this precluded their full involvement in home activities. However, at a point of breakthrough, they entered a phase of high participation interpreted as striving to maximize. The authors discuss the implications of this process for service providers and therapists.     

Transthyretin Val122Ile,accumulated Abeta,and inclusion-body myositis aspects in cultured muscle

Cultured muscle fibers (CMF) from a patient with inclusion-body myositis (IBM) and cardiac amyloidosis associated with the transthyretin (TTR) Val122Ile mutation contained aspects of the IBM phenotype: vacuolation, congophilic inclusions, and clusters of immunocolocalizing amyloid beta-peptide (Abeta) and TTR accumulations. These abnormalities are never present in normal human CMF. These perturbations were greatly increased after Abeta precursor protein gene transfer. The TTR mutation may be a genetic predisposition factor for the patient's IBM.     

Causes of interscan variability of coronary artery calcium measurements at electron-beam CT

RATIONALE AND OBJECTIVES: The authors performed this study to investigate the causes of interscan variability of coronary artery calcium measurements at electron-beam computed tomography (CT). MATERIALS AND METHODS: Two sets of electron-beam CT scans were obtained in 298 consecutive patients who underwent electron-beam CT to screen for coronary artery calcium. Interscan variations of coronary artery calcium characteristics and the effects of heart rate, electrocardiographic (ECG) triggering method, image noise, and coronary motion on interscan variability were analyzed. RESULTS: The interscan mean variabilities were 21.6% (median, 11.7%) and 17.8% (median, 10.8%) with the Agatston and volumetric score, respectively (P < .01). Variability decreased with increasing calcification score (34.6% for a score of 11-50 and 9.4% for a score of 400-1,000, P < .0001). The absolute difference in Agatston score between scans was 44.1 +/- 95.6. The correlation coefficient between the first and second sets of scans was 0.99 (P < .0001). Lower interscan variability was found in younger patients (<60 years), patients with stable heart rates (heart rate changing less than 10 beats per minute during scanning), patients with no visible coronary motion, and those with an optimal ECG triggering method (P < .05 for all). Results of multivariate logistic analysis showed that changes in calcium volume, mean attenuation, and peak attenuation were significant predictors of interscan variability and caused the interscan variations of the coronary artery calcium measurements (r2 = 0.83, P < .0001). CONCLUSION: Coronary calcification at electron-beam CT varies from scan to scan. Volumetric scoring and optimal ECG triggering should be used to reduce interscan variability. Baseline calcium score and interscan variability must be considered in the evaluation of calcium progression.     

Graft Distortion After Endovascular Repair of Abdominal Aortic Aneurysm: Association with Sac Morphology and Mid-Term Complications

Purpose: To investigate the incidence, significance, and mechanism of stent-graft distortion after endovascular repair (EVR) of abdominal aortic aneurysm. Methods: EVR of abdominal aortic aneurysm was performed in 51 cases (49 modular, bifurcated; 2 tube). Thirty-two patients were followed for 6 or more months and had equivalent baseline and follow-up images which could be used to determine changes in graft configuration. Sac dimensions were measured using computed tomographic (CT) images and graft-related complications were recorded. Results: Amongst 32 patients evaluated on follow-up, there was graft distortion in 24. Distorted grafts were significantly (p= 0.002) associated with sac diameter reduction (mean 5 mm) and sac length reduction (mean 8.1 mm). All graft-related complications occurred in the limbs of eight distorted grafts, with a mean reduction of sac length in this group of 7.8 mm on reformatted CT images. Conclusion: There was a highly significant association between graft distortion and limb complications, and reduced sac dimensions.