Human papillomavirus and survival of patients with oropharyngeal cancer.

BACKGROUND: Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown. METHODS: We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer. RESULTS: The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P<0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional pack-year of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage. CONCLUSIONS: Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.)

Successful combination therapy of a proximal haemophilic pseudotumour with surgery, radiation and embolization in a child with mild haemophilia A.

We describe the management of a young boy with mild haemophilia A and a massive iliac pseudotumour with a multi modality approach involving factor replacement, radiation therapy, embolization and surgery. The patient was initially treated with recombinant factor VIII and radiation therapy. Because of inadequate response and worsening of bony erosion, the patient had a preoperative embolization followed by surgical excision. The surgical procedure was associated with minimal blood loss and the patient had a relatively smooth postoperative course with no physical morbidity. This case illustrates successful aggressive management of a large, proximally located pelvic pseudotumour, which resulted in an excellent outcome despite the need for a normally morbid operation.

B-type natriuretic peptide levels are not a surrogate marker for invasive hemodynamics during management of patients with severe heart failure.

BACKGROUND: We sought to assess the utility of serial BNP measurements in patients with severe heart failure and attempted to correlate values with invasively derived data. METHODS: In a retrospective study, we analyzed serial BNP levels in patients receiving hemodynamically guided therapy for severe heart failure and sought correlation with invasively derived data. RESULTS: Thirty-nine patients with New York Heart Association Class III-IV, with an ejection fraction of 35% or less, who had a pulmonary artery catheter inserted for hemodynamically tailored heart failure therapy, were identified and serial BNP measurements reviewed. BNP was estimated on admission, at 12 and 36 hours. Normally distributed variables are expressed as mean +/- SD and otherwise as median +/- interquartile range. Mean ejection fraction was 16% +/- 6%. Mean pulmonary artery occlusion pressures (PAOP) fell with therapy and were 25 +/- 7 mmHg, 18 +/- 7 mmHg and 19 +/- 7 mmHg at admission, 12 hours and 36 hours respectively ( P < 0.05). Median BNP levels fell from 1200 +/- 641 to 771 +/- 803 at 12 hours and to 805 +/- 771 at 36 hours (P < .001). There was no correlation between BNP and any hemodynamically derived variable. A change in BNP was not associated with a change in PAOP in any individual patient. Only 42% remained alive on medical therapy at 30 days. CONCLUSIONS: In patients with severe heart failure, BNP levels do not accurately predict serial hemodynamic changes and do not obviate the need for pulmonary artery catheterization.

Survival beyond 10 years following heart transplantation: The Cleveland Clinic Foundation experience.

BACKGROUND: Long-term survival after heart transplantation is a desirable although challenging goal. METHODS: We analyzed clinical outcomes in the cohort of 170 patients who have undergone heart transplantation at The Cleveland Clinic Foundation and survived >10 years. RESULTS: We found 10-year and 15-year survival rates of 54% and 41%, respectively, in these patients, but there was also a high incidence of complications, such as hypertension, renal dysfunction, transplant vasculopathy, and malignancy. CONCLUSIONS: Long-term survival following cardiac transplantation is possible although complications are frequent. Beyond 10 years, malignancy is a major cause of death.

Donor intracranial bleeding is associated with advanced transplant coronary vasculopathy: evidence from intravascular ultrasound.

OBJECTIVES: We evaluated the impact of spontaneous intracranial bleeding (ICB) in the donor on transplant coronary vasculopathy using serial intravascular ultrasound examinations. MATERIALS AND METHODS: Between January 1995 and December 2000, 72 recipients underwent cardiac transplantation from donors who had experienced spontaneous ICB (ICB group). Their findings using serial intravascular ultrasound analysis at baseline (within 1 month) and 1 year after transplantation were compared with 90 recipients who had undergone transplantation from trauma donors (trauma group). RESULTS: Compared with the Trauma group, the ICB group showed increased coronary intimal thickness (0.55 +/- 0.33 vs 0.39 +/- 0.3 mm; P = .034), plaque volume (3.84 +/- 2.5 vs 2.28 +/- 1.65 mm(3); P = .015) and plaque burden (7.4 vs 2%) at 1 year after transplantation. CONCLUSIONS: Donor spontaneous ICB is associated with significantly increased coronary vasculopathy.

The influence of donor gender on allograft vasculopathy: evidence from intravascular ultrasound.

BACKGROUND: Allograft vasculopathy is a major risk factor for mortality following cardiac transplantation. Several immune and nonimmune factors have been evaluated as risk factors for the development of coronary vasculopathy. OBJECTIVE: We evaluated the influence of donor gender on the progression of coronary vasculopathy in heart transplant recipients. METHODS: Eighty-nine heart transplant recipients (67 men, 22 women of mean age: 56 +/- 12 years) underwent serial volumetric intravascular ultrasound analysis (IVUS) at baseline (within 1 month) and at 1 year after transplantation. Patients were divided into four groups in relation to the donor-recipient gender status: female-female, n=17; female-male, n=28; male-female, n=5; male-male, n=39. Ultrasound images were recorded during an automated pullback and with an equal number of slices (average=22 per coronary vessel). The measured IVUS indices for the left anterior descending artery were: change in maximal intimal thickness, average intimal area, total plaque volume, and intimal index. RESULTS: Patients were similar in baseline characteristics. At 1 year after transplantation, IVUS indices of coronary vasculopathy were significantly increased among recipients of female allografts (P <.05). CONCLUSION: Heart transplant recipients of female allografts display increased coronary vasculopathy progression.

Determination of carbohydrate structures N-linked to soluble CD154 and characterization of the interactions of CD40 with CD154 expressed in Pichia pastoris and Chinese hamster ovary cells.

CD40-CD154 (CD40 ligand) interactions are essential for the development of protective immunity. Previous studies have described the CD40 binding site as a shallow groove formed between two monomers of CD154. However, these studies have not examined the structure or biological function of the carbohydrate on CD154. Human CD154 contains a single N-linked glycosylation site at asparagine 240. We have characterized the interactions between CD40 and soluble (s) CD154 in which sCD154 contains different types of carbohydrates. Detailed carbohydrate analysis revealed high-mannose structures on sCD154 purified from Pichia pastoris, whereas CD154 purified from Chinese hamster ovary E1A contained heterogeneous populations of complex carbohydrates. sCD154 purified from either system was trimeric, it bound to CD40 with similar affinities of 10-30 nM, and it functionally induced CD69 and CD95 expression on primary B cells. Together, these results indicate that the presence of varied types of N-linked glycans on asparagine 240 of CD154 does not play a significant role in the CD40-CD154 interactions.

Identification, substrate specificity, and inhibition of the Streptococcus pneumoniae beta-ketoacyl-acyl carrier protein synthase III (FabH).

In the bacterial type II fatty acid synthase system, beta-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) catalyzes the condensation of acetyl-CoA with malonyl-ACP. We have identified, expressed, and characterized the Streptococcus pneumoniae homologue of Escherichia coli FabH. S. pneumoniae FabH is approximately 41, 39, and 38% identical in amino acid sequence to Bacillus subtilis, E. coli, and Hemophilus influenzae FabH, respectively. The His-Asn-Cys catalytic triad present in other FabH molecules is conserved in S. pneumoniae FabH. The apparent K(m) values for acetyl-CoA and malonyl-ACP were determined to be 40.3 and 18.6 microm, respectively. Purified S. pneumoniae FabH preferentially utilized straight short-chain CoA primers. Similar to E. coli FabH, S. pneumoniae FabH was weakly inhibited by thiolactomycin. In contrast, inhibition of S. pneumoniae FabH by the newly developed compound SB418011 was very potent, with an IC(50) value of 0.016 microm. SB418011 also inhibited E. coli and H. influenzae FabH with IC(50) values of 1.2 and 0.59 microm, respectively. The availability of purified and characterized S. pneumoniae FabH will greatly aid in structural studies of this class of essential bacterial enzymes and facilitate the identification of small molecule inhibitors of type II fatty acid synthase with the potential to be novel and potent antibacterial agents active against pathogenic bacteria.

Bone conduction impairment in chronic ear disease.

The preoperative and postoperative bone conduction (BC) thresholds were prospectively investigated in 24 patients with chronic ear disease in the form of cholesteatoma, chronic suppurative otitis media, or adhesive otitis media. All underwent tympanoplasty with mastoidectomy. Ossicular reconstruction was performed in 14, and the remaining 10 were still awaiting second-stage ossicular reconstruction at the time of this investigation. In each group, the postoperative results were compared with the preoperative results by the paired-samples t-test. In the ossicular reconstruction group, the results revealed a significant improvement in the postoperative BC thresholds, as compared with the preoperative BC thresholds, at 250, 1,000, and 2,000 Hz, with the largest mean improvement observed at 2,000 Hz. No significant improvement was observed at any frequency for the group without ossicular reconstruction. Postoperative improvement of at least 10 dB at 2 or more frequencies was observed in 71% of the ossicular reconstruction group, as compared with 0% of the group that did not undergo ossicular reconstruction. The results support the theory that the elevated BC thresholds of patients with chronic ear disease result from the elimination, due to disease, of the middle ear contribution (from the inertial ossicular component and ossicular resonance) to the BC response. The results also suggest that the middle ear contribution to the BC response is restored with ossicular reconstruction.

Cellular rejection and rate of progression of transplant vasculopathy: a 3-year serial intravascular ultrasound study.

Intravascular ultrasound (IVUS) is established as the optimal method for early detection of transplant vasculopathy. The association between cellular rejection and development of transplant vasculopathy remains controversial. This study attempts to determine the rate of progression of transplant vasculopathy lesions and its relationship with cellular rejection in a long-term (> 1 year) IVUS serial follow-up.A study cohort of 47 patients undergoing heart transplantation from 1993 to 1995 was evaluated. Intravascular ultrasound was performed at baseline (within 8 weeks) and annually for a period of 3 years to determine maximum intimal thickness and maximum plaque area in each coronary segment. Significant allograft vasculopathy was defined as a site with intimal thickness > 0.5 mm not present at baseline. Biopsy results were scored by assigning a numerical weight to each ISHLT grade during the first year. Donor lesions ranged from 0.86 to 1.1 mm, showing no evidence of progression at serial follow-up. De novo lesions were identified in 30 patients. These lesions appeared yearly but progressed slowly. The average biopsy score in the entire cohort was 1.1 +/- 0.8. Average biopsy score was > 1.0 in 35 patients with significant linear correlation between the rate of intimal progression and biopsy score (r = 0.42, p = 0.01). Multivariate analysis demonstrated that only the biopsy score correlated with the rate of progression. Lesions of donor atherosclerosis do not change significantly after transplantation. However, de novo lesions continue to develop every year. In patients with evidence of rejection, the rate of progression of transplant vasculopathy correlates with the severity of rejection.

Eustachian tube endoscopy in patients with chronic ear disease.

OBJECTIVES/HYPOTHESIS: A paucity of research exists on trans-eustachian tube endoscopy to evaluate the status of the eustachian tube. Fuller examination of the role of the eustachian tube in chronic ear disease is needed, particularly because the eustachian tube has been implicated in the chronicity and pathogenesis of chronic ear disease. Therefore the purpose of this study was to evaluate the eustachian tube, based on observations from trans-eustachian tube endoscopy. STUDY DESIGN: Twenty-two adult patients with chronic ear disease gave informed consent to participate in a prospective, trans-eustachian tube endoscopic investigation. METHODS: Flexible, fiberoptic, nonarticulating (outside diameter of 0.5 mm) and articulating (outside diameter of 1.0 mm) endoscopes (coherent fused bundle of 3,000 pixels) were employed. The eustachian tube endoscopy was performed under general endotracheal anesthesia as the initial part of a larger, otological surgical procedure for chronic ear disease. The endoscope was passed from the middle ear (transtympanic approach) to the nasopharynx. RESULTS: The 0.5-mm endoscope passed entirely through the eustachian tube from the tympanic orifice into the pharyngeal orifice in 16% of the cases. Stenotic blockage occurred at the infundibulum in 37%, isthmus in 42%, and fossa of Rosenmuller in 5% of cases. The eustachian tube mucosa was abnormal in 64% of cases. The risk for abnormal eustachian tube mucosa was four times greater for persons with long-standing disease (> or = 20 y) than for persons without long-standing disease (<20 y). The mean therapeutic efficiency of ossicular reconstruction was higher for the subgroup with normal than for the subgroup with abnormal eustachian tube mucosa. CONCLUSIONS: The findings of trans-eustachian tube endoscopy provide objective evidence concerning eustachian tube status in persons with chronic ear disease and have implications for the timing of surgical intervention (ossicular reconstruction).

Analysis of small amines in pharmaceuticals by capillary ion electrophoresis with conductivity detection.

Capillary ion electrophoresis (CIE) with direct conductivity detection is a simple, fast, and versatile method for analysis of ions. In this study CIE with conductivity detection was used to analyze for hydroxylamine which is often used in the synthesis of pharmaceutical intermediates and drug substances. The conductivity response of hydroxylamine was investigated by using different buffer types and buffer concentrations. Other small amines were also studied with this method and were correlated with the molecular weight of the amines. The response of hydroxylamine increased significantly with MES glycylglycine buffer as compared to MES-histidine buffer (LOD from 10 to 1 ppm). The detection of trace level of hydroxylamine in a drug substance proved to be possible with this method. The developed method was also tested for the linearity range, reproducibility, and selectivity with several small amines. The method developed in this study was demonstrated as a sensitive and reliable method for detection and quantification of small amines in pharmaceutical substances.

Measuring clients' satisfaction with self-help agencies.

OBJECTIVE: Clients' satisfaction with their involvement in treatment decisions has been largely overlooked in the formulation of satisfaction measures. The authors describe the development of a scale that assesses clients' satisfaction with services and with their involvement in treatment decisions. METHODS: Long-term users of four client-operated mental health self-help agencies were interviewed at baseline (N=310) and six months (N=248) using the 11-item Self-Help Agency Satisfaction Scale (SHASS). The scale was developed on the basis of consumers' input about their satisfaction with services and their involvement in treatment decisions. To explore the relationship between satisfaction as measured by the SHASS and outcomes, the six-month interview included four outcome measures-independent and assisted social functioning, symptom severity, and a sense of personal empowerment. Internal consistency, stability, and discriminant validity were evaluated. RESULTS: Factor analyses confirmed that the SHASS has two subscales, one assessing service satisfaction and the other assessing satisfaction with involvement in treatment decisions. The scale and its subscales showed high internal consistency, moderate stability, and discriminant validity. The SHASS subscales showed modest associations with two of four outcome measures-assisted and independent social functioning. CONCLUSIONS: The SHASS is a brief instrument that can be used to measure clients' satisfaction with their involvement in treatment in mental health self-help agencies.

Temperature-sensitive differential affinity of TRAIL for its receptors. DR5 is the highest affinity receptor.

TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines which induces apoptotic cell death in a variety of tumor cell lines. It mediates its apoptotic effects through one of two receptors, DR4 and DR5, which are members of of the TNF receptor family, and whose cytoplasmic regions contain death domains. In addition, TRAIL also binds to 3 "decoy" receptors, DcR2, a receptor with a truncated death domain, DcR1, a glycosylphosphatidylinositol-anchored receptor, and OPG a secreted protein which is also known to bind to another member of the TNF family, RANKL. However, although apoptosis depends on the expression of one or both of the death domain containing receptors DR4 and/or DR5, resistance to TRAIL-induced apoptosis does not correlate with the expression of the "decoy" receptors. Previously, TRAIL has been described to bind to all its receptors with equivalent high affinities. In the present work, we show, by isothermal titration calorimetry and competitive enzyme-linked immunosorbent assay, that the rank order of affinities of TRAIL for the recombinant soluble forms of its receptors is strongly temperature dependent. Although DR4, DR5, DcR1, and OPG show similar affinities for TRAIL at 4 degrees C, their rank-ordered affinities are substantially different at 37 degrees C, with DR5 having the highest affinity (K(D)

External beam irradiation as an adjunctive treatment in failing dialysis shunts.

PURPOSE: To evaluate the utility of low-dose irradiation as adjunctive treatment for failing dialysis shunts related to stenoses. MATERIALS AND METHODS: Thirty-one patients with 41 lesions in their dialysis shunts were successfully enrolled for this study. After imaging of the shunt and calculation of venous stenoses, each patient was randomized into one of two segments of the protocol: (i) angioplasty and/or stent placement alone, and (ii) angioplasty and/or stent placement followed by external beam irradiation. All patients with significant venous stenoses (> or =50%) were treated with appropriately sized PTA (percutaneous transluminal angioplasty) and Wallstents. Patients randomized to the external irradiation segment underwent localized irradiation via a Theratron cobalt unit of 7 Gy 0-24 hours and 24-48 hours after intervention. Those patients randomized to the control group received no additional treatment. Clinical follow-up included resumption of successful dialysis with appropriate hemodynamic parameters. Two follow-up shunt images were obtained, follow-up 1 (fu-1) from 90 to 179 days and follow-up 2 (fu-2) from 180 to 365 days. Percentages of significant recurrent stenoses, defined as greater than 50%, were recorded and re-treated as needed. RESULTS: Sixteen of the 31 patients underwent external beam irradiation. There were 21 lesions in the test group that underwent irradiation after intervention, and 20 lesions were treated with intervention alone. There were seven native arteriovenous fistulas and 24 Gore-tex grafts. All stenoses were either venous outflow stenoses (68%) or central stenoses (32%). The authors utilized chi2 analysis to compare restenoses rates between the control and irradiated groups at fu-1 (P<.99) and fu-2 (P<.10). CONCLUSIONS: Although the results show that external beam irradiation has minimal effects on the restenoses of dialysis grafts when used in conjunction with PTA and stent placement, further studies with a larger, more homogenous population are needed to assess the trend of improving patency rates after external beam irradiation.

Expression, purification, and crystallization of the Escherichia coli selenomethionyl beta-ketoacyl-acyl carrier protein synthase III.

Bacterial beta-ketoacyl-acyl carrier protein (ACP) synthase III (KAS III, also called FabH) catalyzes the condensation and transacylation of acetyl-CoA with malonyl-ACP. In order to understand the mode of enzyme/substrate interaction and design small molecule inhibitors, we have expressed, purified, and crystallized a selenomethionyl-derivative of E. coli KAS III. Several lines of evidence confirmed that purified selenomethionyl KAS III was homogenous, stably folded, and enzymatically active. Dynamic light scattering, size exclusion chromatography, and mass spectrometry results indicated that selenomethionyl KAS III is a noncovalent homodimer. Diffraction quality crystals of selenomethionyl KAS III/acetyl-CoA complex, which grew overnight to a size of 0.2 mm(3), belonged to the tetragonal space group P4(1)2(1)2.

Intravascular ultrasound imaging after cardiac transplantation: advantage of multi-vessel imaging.

BACKGROUND: Intravascular ultrasound is a sensitive tool to study transplant vasculopathy. However, there is no consensus regarding the methodology for imaging protocol. The impact of single versus multiple epicardial vessel imaging in determining the prevalence of transplant vasculopathy has not been determined. This study examines the benefit of three-vessel imaging versus one-vessel imaging in detecting transplant vasculopathy. METHODS AND RESULTS: One hundred eleven transplant recipients with intravascular ultrasound imaging at baseline (within 2 months of transplantation) were studied: 107 at 1-year, 53 at 2-year and 41 at 3-year follow-up. A total of 222 arteries, 519 segments and 772 sites were analyzed (94 LAD, 65 LCX and 65 RCA). The prevalence of transplant vasculopathy lesions was 27%, 41% and 58% at 1 year, 39%, 55% and 71% at 2 years and 39%, 55% and 74% at 3 years for patients with one-, two- and three-vessel imaging, respectively. Single- or two-vessel disease was present in 23% (7) and 32% (10) patients with three-vessel imaging, leading to the potential mislabeling of these 17 (55%) patients as "disease free" if they underwent only single-vessel imaging. CONCLUSIONS: Multivessel imaging is more sensitive in detecting the transplant vasculopathy lesions compared to single-vessel imaging. This important variable should be considered when designing and interpreting trials utilizing intravascular imaging derived end-point.

Central auditory processing disorders and reduced motivation: three case studies.

The central auditory test results for three normal-hearing children who were initially diagnosed as having a central auditory processing disorder and learning disability are presented. They were referred to the authors for second-opinion consultations. Central auditory processing retesting was performed by the authors under the condition of no reinforcement and then the condition of reinforcement with the child's favorite food, hobby, or toy. For all three cases, the central auditory test scores improved markedly bilaterally under the condition of reinforcement as compared with the condition of no reinforcement. We hypothesize that the improvement was related to increased motivation associated with the reinforcement and that these children represented false-positive results on the central auditory test battery. Large-sample studies are needed to investigate the effect of reinforcement on test performance in children with reduced central auditory test scores.

Facial-motion analysis with a video and computer system: a preliminary report.

HYPOTHESIS: To investigate the feasibility of a video and computer-assisted system for evaluating the temporal and spatial aspects of facial motion during selected facial expressions in a pilot group of six normal adults. Evaluation of the diverse medical and surgical treatments for facial paralysis and paresis cannot occur until objective, reliable, and sensitive measures of the spatial and temporal aspects of facial function at specific facial landmarks are developed. METHODS: Facial motion at predetermined facial locations was assessed using a commercially available computer-interactive motion analysis system, which is based on videography principles. The displacement, velocity, and acceleration data were averaged across all trials and subjects. Time plots also were obtained for the left versus right side. RESULTS: The greatest mean maximum displacement (resultant vector) occurred during the eyebrow lift expression, reaching 1.2 cm in magnitude. The mean maximum velocity (resultant vector), which ranged from 4.5 to 8.5 cm/s for the dynamic facial expressions, was greatest for the eyes closed tight expression. The mean maximum acceleration (resultant vector), which ranged from 193 to 465 cm/s/s, was greatest for the eyebrow lift expression. Symmetrical time plots were obtained. The system documented synkinesis by revealing substantial left upper eyelid motion during the nose-wrinkle expression in an illustrative case with slight left facial dysfunction. CONCLUSION: This approach to facial motion analysis is feasible for the simultaneous, multiregional, spatial-temporal assessment of facial expressions. Because motion at relatively remote regions could be quantified, this approach is potentially useful for the evaluation of synkinesis.