Search

Introduction: Artificial Intelligence (AI) chatbots are able to explain complex concepts using plain language. The aim of this study was to assess the accuracy of three AI chatbots answering common questions related to contact lens (CL) wear., Methods: Three open access AI chatbots were compared: Perplexity, Open Assistant and ChatGPT 3.5. Ten general CL questions were asked to all AI chatbots on the same day in two different countries, with the questions asked in Spanish from Spain and in English from the U.K. Two independent optometrists with experience working in each country assessed the accuracy of the answers provided. Also, the AI chatbots' responses were assessed if their outputs showed any bias towards (or against) any eye care professional (ECP)., Results: The answers obtained by the same AI chatbots were different in Spain and the U.K. Also, statistically significant differences were found between the AI chatbots for accuracy. In the U.K., ChatGPT 3.5 was the most and Open Assistant least accurate (p < 0.01). In Spain, Perplexity and ChatGPT were statistically more accurate than Open Assistant (p < 0.01). All the AI chatbots presented bias, except ChatGPT 3.5 in Spain., Conclusions: AI chatbots do not always consider local CL legislation, and their accuracy seems to be dependent on the language used to interact with them. Hence, at this time, although some AI chatbots might be a good source of information for general CL related questions, they cannot replace an ECP., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To describe the reliability and validity of the publicly reported facility-level quality measures Inpatient Rehabilitation Facility (IRF) Discharge Mobility Score for Medical Rehabilitation Patients ("Discharge mobility score") and IRF Discharge Self-Care Score for Medical Rehabilitation Patients ("Discharge self-care score")., Design: Observational study using standardized patient assessment data to examine facility-level split-half reliability and construct validity of quality measure scores., Setting and Participants: All IRFs (n = 1117) in the United States with at least 20 Medicare stays. Facility-level quality measure scores were calculated from 2017 data on 428,192 Medicare (fee-for-service and Medicare Advantage) IRF patient stays., Methods: Using clinician-reported assessment data, we calculated facility-level mobility and self-care quality measure scores and examined reliability of these scores using split-half analysis and Pearson product-moment correlations, Spearman rank correlations, and intraclass correlation coefficients (ICC 2,1 ). We examined construct validity of these scores by comparing facility-level quality measure scores by facility stroke disease-specific certification status., Results: Reported as percentages meeting or exceeding expectations, IRF quality measure scores ranged from 8.3% to 90.1% for mobility and 9.0% to 90.3% for self-care. IRF scores, when split in half to examine reliability, showed strong, positive correlations for the mobility (Pearson = 0.898, Spearman = 0.898, ICC = 0.898) and self-care (Pearson = 0.886, Spearman = 0.874, ICC = 0.886) scores. When stratified by provider volume, ICCs remained strong. Construct validity analyses showed IRFs with stroke disease-specific certification had higher mean and median scores than IRFs without certification, and a greater proportion of IRFs that were certified had higher scores., Conclusion and Implications: Our results support the reliability and construct validity of the IRF quality measures Discharge mobility and Discharge self-care scores. Reported as percentages meeting or exceeding expectations, these quality measures are designed to be more consumer-friendly compared to change scores., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. All rights reserved.)

Background: Cediranib, an oral anti-angiogenic VEGFR 1-3 inhibitor, was studied at a daily dose of 20 mg in combination with platinum-based chemotherapy and as maintenance in a randomised trial in patients with first relapse of 'platinum-sensitive' ovarian cancer and has been shown to improve progression-free survival (PFS)., Patients and Methods: ICON6 (NCT00532194) was an international three-arm, double-blind, placebo-controlled randomised trial. Between December 2007 and December 2011, 456 women were randomised, using stratification, to receive either chemotherapy with placebo throughout (arm A, reference); chemotherapy with concurrent cediranib, followed by maintenance placebo (arm B, concurrent); or chemotherapy with concurrent cediranib, followed by maintenance cediranib (arm C, maintenance). Due to an enforced redesign of the trial in September 2011, the primary endpoint became PFS between arms A and C which we have previously published, and the overall survival (OS) was defined as a secondary endpoint, which is reported here., Results: After a median follow-up of 25.6 months, strong evidence of an effect of concurrent plus maintenance cediranib on PFS was observed [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.72, P < 0.0001]. In this final update of the survival analysis, 90% of patients have died. There was a 7.4-month difference in median survival and an HR of 0.86 (95% CI: 0.67-1.11, P = 0.24) in favour of arm C. There was strong evidence of a departure from the assumption of non-proportionality using the Grambsch-Therneau test (P = 0.0031), making the HR difficult to interpret. Consequently, the restricted mean survival time (RMST) was used and the estimated difference over 6 years by the RMST was 4.8 months (95% CI: -0.09 to 9.74 months)., Conclusions: Although a statistically significant difference in time to progression was seen, the enforced curtailment in recruitment meant that the secondary analysis of OS was underpowered. The relative reduction in the risk of death of 14% risk of death was not conventionally statistically significant, but this improvement and the increase in the mean survival time in this analysis suggest that cediranib may have worthwhile activity in the treatment of recurrent ovarian cancer and that further research should be undertaken., Competing Interests: Disclosure ACE-T, HH, MV, ED, BP, LF, and AMS declare no conflicts of interest. JAL has attended AstraZeneca, GSK, Clovis Oncology, MSD, Eisai, Pfizer advisory boards and spoken at symposia with remuneration and has institutional grants from AstraZeneca and MSD. TJP reports grants, personal fees, non-financial support from Roche; personal fees from Novartis; personal fees from AstraZeneca, other fees paid to the institution from multiple other pharmaceutical companies and research organisations in connection with the costs of running a broad research portfolio, outside the submitted work. GCJ attended AstraZeneca advisory board and has received research funding for investigator-led trials. Also research grant from Roche. GJSR has attended advisory boards for AstraZeneca, Amgen and OXiGENE, in addition to data management costs from the MRC. SBK has attended an AstraZeneca advisory board. AO is Principal Investigator for investigator-initiated trials with AstraZeneca and has institutional grants from AstraZeneca outside the submitted work, and non compensated membership of steering committees with AstraZeneca and Clovis and a noncompensated advisory role with AstraZeneca and GSK. MF has attended advisory board meetings for AstraZeneca, Takeda, Novartis, MSD and Lilly and received personal fees. Travel support from AstraZeneca, research funding to institution for investigator-initiated trials. AG-M reports personal fees for advisory boards to Amgen, AstraZeneca, Clovis, Genmab, GSK-TESARO, Novartis, MSD, Oncoinvent, PharmaMar, Pfizer-Merck, Roche, SOTIO. RSK reports grants from Cancer Research UK and AstraZeneca, as well as drug supply from AstraZeneca. MKBP reports an educational grant from AstraZeneca., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Exposure to many environmental chemicals, including metals, often does not occur in isolation, hence requires assessment of the associations between exposure to mixtures of chemicals and human health., Objectives: To investigate associations of a metal mixture of lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) in children with autism spectrum disorder (ASD), additively or interactively with each of three glutathione S-transferase (GST) genes ( GSTP1 , GSTT1 , and GSTM1 )., Method: Using data from 266 case-control pairs of Jamaican children (2-8 years old), we fitted negative and positive generalized weighted quantile sum (gWQS) regression models to assess the aforementioned associations., Results: Based on additive and interactive negative gWQS models adjusted for maternal age, parental education, child's parish, and seafood consumption, we found inverse associations of the overall mixture score with ASD [MOR (95% CI): 0.70 (0.49, 0.99); P < 0.05) and [MOR (95%CI): 0.46 (0.25, 0.84); P = 0.01], respectively. In an unadjusted negative gWQS model, we found a marginally significant interaction between GSTP1 and a mixture of three metals (Pb, Hg, and Mn) ( P = 0.07) while the association was no longer significant after adjustment for the same covariates ( P = 0.24)., Conclusions: Differences in diet between ASD and control groups may play a role in the inverse associations we found. The possible interactive association between Mn and GSTP1 in ASD based on gWQS is consistent with our previous reports. However, possible interaction of GSTP1 with Pb and Hg in ASD requires further investigation and replication., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

In this work, a bioresorbable Mg-ZKQX6000 (Mg-6Zn-0.6Zr-0.4Ag-0.2Ca (wt%)) alloy was severely plastically deformed via equal channel angular pressing (ECAP) according to three unique hybrid routes at low temperatures (200 °C to 125 °C). The roles of ECAP processing on microstructure, and ensuing mechanical properties and corrosion rates, are assessed. Microstructurally, ECAP induces a complex plethora of features, especially variations in grain sizes and precipitates' sizes, distributions, and morphologies for individual cases. Mechanically, ECAP generally refined grain size, resulting in ultra-high strength levels of about 400 MPa in ultimate tensile strength for several cases; however, deformation via ECAP of precipitates induced embrittlement and low elongation to failure levels. Corrosion testing, conducted in simulated bodily fluid at bodily pH levels to mimic conditions in the human body, revealed consistent corrosion rates across several techniques (mass loss, hydrogen evolution, and electrochemical impedance spectroscopy (EIS)), showing that severe plastic deformation deteriorates corrosion resistance for this material. In-situ corrosion monitoring explained that corrosion accelerated after ECAP due to the creation of heterogeneous, anodic shear zones, which exhibited dense regions of refined grains and fine precipitates. Suggestions for future design and thermomechanical processing of Mg alloys for bioresorbable orthopedic implants are provided., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides are suspected to play a role in autism spectrum disorder (ASD)., Objectives: To investigate associations of PCBs and OC pesticides with ASD in Jamaican children and explore possible interaction between PCBs or OC pesticides with glutathione S -transferase (GST) genes ( GSTT1 , GSTM1 , GSTP1 ) in relation to ASD., Methods: Participants included n=169 age- and sex-matched case-control pairs of Jamaican children 2-8 years old. Socioeconomic status and food frequency data were self-reported by the parents/guardians. Blood from each participant was analyzed for 100 PCB congeners and 17 OC pesticides and genotyped for three GST genes. PCBs and OC pesticides concentrations below the limit of detection (LoD) were replaced with (LoD/√2). We used conditional logistic regression (CLR) models to assess associations of PCBs and OC pesticides with ASD, individually or interactively with GST genes ( GSTT1 , GSTM1 , GSTP1 )., Results: We found inverse associations of PCB-153 [adjusted MOR (95% CI) = 0.44 (0.23-0.86)] and PCB-180 [adjusted MOR (95% CI) = 0.52 (0.28-0.95)] with ASD. When adjusted for covariates in a CLR the interaction between GSTM1 and PCB-153 became significant ( P < 0.01)., Discussion: Differences in diet between ASD and typically developing control groups may play a role in the observed findings of lower concentrations of PCB-153 and PCB-180 in individuals with ASD than in controls. Considering the limited sample size and high proportion of concentrations below the LoD, these results should be interpreted with caution but warrant further investigation into associations of PCBs and OC pesticides with ASD., Competing Interests: Conflict of interest The authors declare no conflict of interest.

Ten global harbours were assessed for sediment quality by quantifying the magnitude of anthropogenic change and ecological risk. Anthropogenic change (enrichment) was high for Derwent River and Sydney estuary, moderate for Santander Harbour, Rio de Janeiro and Dublin Port, slight for Hong Kong, minimal for Darwin. All 10 enrichment indices used showed similar results. Derwent River sediment was rated at high ecological risk, followed by Sydney and Santander estuaries with moderate risk. Auckland and Darwin sediments exhibited minimal ecological risk and sediment in the remaining harbours (Dublin, Hong Kong, Ravenna, Ria de Vigo and Rio de Janeiro) were assessed at slight ecological risk. The extraordinary variety of environments and types/quantities/qualities of data investigated resulted in as much a critique and development of methodology, as an assessment of human impact, including unique techniques for elemental normalisation and contaminant classification. Recommendations for an improved technical framework for sediment quality assessment are provided., Competing Interests: Declaration of competing interest The paper is an original manuscript that has not been published previously and is not currently being considered for publication elsewhere. The work is unfunded and there is no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: We previously reported a significant interactive association between polymorphisms of GSTP1 and blood manganese concentrations (BMC) with autism spectrum disorder (ASD) in Jamaican children. In this paper, we investigate the same interactive association with ASD while adjusting for the mixture of four metals (lead, mercury, cadmium, and arsenic)., Method: We used data from 163 case-control pairs of children 2-8 years of age from our autism project in Jamaica, in which we collected blood for heavy metals analysis at enrollment. To minimize potential multicollinearity between concentrations of the four metals, we generated a mixture index using generalized weighted quantile sum regression, which was used in conditional logistic regression models to control for the four metals while assessing the interactive association between GSTP1 and BMC with ASD., Results: Similar to the findings we reported previously, we found that in co-dominant and dominant models for GSTP1, among children with the Ile/Ile genotype, those with BMC > 12μg/L had 4.6 and 4.27 times higher odds of ASD compared to those with BMC < 12μg/L (adjusted Matched Odds Ratio (MOR) = 4.6, 95% CI: 1.21 - 17.42 and adjusted MOR = 4.27, 95% CI: 1.15 - 15.85, respectively). In the co-dominant model, for children with the Ile/Val and Val/Val genotypes, the adjusted MORs were 1.26 (95% CI: 0.32, 5.01) and 0.26 (95% CI: 0.05, 1.42), respectively., Conclusions: After adjusting for the mixture of four metals, the interactive association of BMC and GSTP1 with ASD remained significant with similar magnitude of associations. Results should be interpreted cautiously., Competing Interests: Conflict of interest The authors declare no conflict of interest.

Background: Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1-3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer., Methods: In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase. Participants were randomly allocated (2:3:3), with five stratification factors and in alternating blocks, to receive placebo alongside chemotherapy and then placebo only maintenance (arm A; reference), cediranib 20 mg once-daily alongside chemotherapy then placebo only maintenance (arm B; concurrent), or cediranib 20 mg once-daily alongside chemotherapy then cediranib 20 mg once-daily maintenance (arm C; maintenance). Patients continued treatment to progression or excessive toxic effects. The primary efficacy endpoint was progression-free survival between arms A and C. Efficacy analysis was by intention to treat. Safety was assessed in all patients who received the allocated study drug. This trial is registered with ClinicalTrials.gov, number NCT00532194; the ISRCTN registry, number ISRCTN68510403; and ANZ Clinical Trials Registry, number ACTRN1261000016003., Findings: We randomly assigned 486 [corrected] women between Nov 13, 2007, and Dec 23, 2011; results presented are for 456 patients randomly assigned subsequent to the 30mg safety phase. During a median of 19·5 months (IQR 14-26) follow-up, 113 (96%) of 118 women assigned to arm A and 141 (86%) of 164 assigned to arm C had disease progression. Median progression-free survival was 11·0 months (95% CI 10·4-11·7) in arm C and 8·7 months (7·7-9·4) in arm A (hazard ratio 0·56, 0·44-0·72, p<0·0001). 156 (90%) of 174 patients in arm B had disease progression, and median progression-free survival was 9·9 months (95% CI 9·4-10·5). Diarrhoea, neutropenia, hypertension, and voice changes were significantly more common, during chemotherapy with cediranib, and diarrhoea, hypothyroidism and voice changes were more common during maintenance. Poor compliance with cediranib was noted during maintenance treatment with toxic effects being the most common cause for discontinuation., Interpretation: Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful improvement [corrected] in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up., Funding: Medical Research Council, Cancer Research UK, Canadian Cancer Society Research Institute, Cancer Australia, National Gynecological Cancer Centre, and AstraZeneca., (Copyright © 2016 Ledermann et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

We used data from 100 age- and sex-matched case-control pairs (age 2-8 years) from Jamaica to investigate whether there is an interaction between glutathione-S-transferase (GST) genes and blood manganese concentrations (BMC) in relation to Autism Spectrum Disorder (ASD). Our findings, indicate that among children who had the Ile/Ile genotype for GST pi 1 ( GSTP1 ), those with BMC ≥ 12µg/L had about 4 times higher odds of ASD than those with BMC < 12µg/L, ( P =0.03) under a co-dominant genetic model. After adjusting for potential confounders, among the subgroup of children with genotype Ile/Ile, those with BMC ≥ 12µg/L had about six times higher odds of ASD than those with BMC < 12µg/L, ( P =0.04). The results were similar when a recessive genetic model was used. These findings suggest a possible synergic effect of BMC and GSTP1 in ASD. Since our analysis included a variety of genetic models and was not adjusted for multiple testing, replication in other populations is warranted.

Objectives: In this study, we examined the effects of birth weight (BWT) and early life socioeconomic circumstances (SEC) on systolic blood pressure (SBP) and diastolic blood pressure (DBP) among Jamaican young adults., Study Design and Setting: Longitudinal study of 364 men and 430 women from the Jamaica 1986 Birth Cohort Study. Information on BWT and maternal SEC at child's birth was linked to information collected at 18-20 years old. Sex-specific multilevel linear regression models were used to examine whether adult SBP/DBP was associated with BWT and maternal SEC., Results: In unadjusted models, SBP was inversely related to BWT z-score in both men (β, -0.82 mm Hg) and women (β, -1.18 mm Hg) but achieved statistical significance for women only. In the fully adjusted model, one standard deviation increase in BWT was associated with 1.16 mm Hg reduction in SBP among men [95% confidence interval (CI): 2.15, 0.17; P = 0.021] and 1.34 mm Hg reduction in SBP among women (95% CI: 2.21, 0.47; P = 0.003). Participants whose mothers had lower SEC had higher SBP compared with those with mothers of high SEC (β, 3.4-4.8 mm Hg for men, P < 0.05 for all SEC categories and 1.8-2.1 for women, P > 0.05)., Conclusion: SBP was inversely related to maternal SEC and BWT among Jamaican young adults., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We investigated the role of glutathione S-transferase ( GST ) genes in Autism Spectrum Disorder (ASD). We used data from 111 pairs of age- and sex-matched ASD cases and typically developing (TD) controls between 2-8 years of age from Jamaica to investigate the role of GST pi 1 ( GSTP1 ), GST theta 1 ( GSTT1 ), and GST mu 1 ( GSTM1 ) polymorphisms in susceptibility to ASD. In univariable conditional logistic regression models we did not observe significant associations between ASD status and GSTT1 , GSTM1 , or GSTP1 genotype (all P > 0.15). However, in multivariable conditional logistic regression models, we identified a significant interaction between GSTP1 and GSTT1 in relation to ASD. Specifically, in children heterozygous for the GSTP1 Ile105Val polymorphism, the odds of ASD was significantly higher in those with the null GSTT1 genotype than those with the other genotypes [Matched Odds Ratio (MOR) = 2.97, 95% CI (1.09, 8.01), P = 0.03]. Replication in other populations is warranted.

Human exposure to cadmium has adverse effects on the nervous system. Utilizing data from 110 age- and sex-matched case-control pairs (220 children) ages 2-8 years in Kingston, Jamaica, we compared the 75 th percentile of blood cadmium concentrations in children with and without Autism Spectrum Disorder (ASD). In both univariable and multivariable Quantile Regression Models that controlled for potential confounding factors, we did not find any significant differences between ASD cases and typically developing (TD) controls with respect to the 75 th percentile of blood cadmium concentrations, ( P > 0.22). However, we found a significantly higher 75 th percentile of blood cadmium concentrations in TD Jamaican children who consumed shellfish (lobsters, crabs) ( P < 0.05), fried plantain ( P <0.01), and boiled dumpling ( P <0.01). We also observed that children living in Jamaica have an arithmetic mean blood cadmium concentration of 0.16μg/L which is similar to that of the children in developed countries and much lower than that of children in developing countries. Although our results do not support an association between blood cadmium concentrations and ASD, to our knowledge, this study is the first to report levels of blood cadmium in TD children as well as those with ASD in Jamaica.

Arsenic is a toxic metal with harmful effects on human health, particularly on cognitive function. Autism Spectrum Disorders (ASDs) are lifelong neurodevelopmental and behavioral disorders manifesting in infancy or early childhood. We used data from 130 children between 2 and 8 years (65 pairs of ASD cases with age- and sex-matched control), to compare the mean total blood arsenic concentrations in children with and without ASDs in Kingston, Jamaica. Based on univariable analysis, we observed a significant difference between ASD cases and controls (4.03 μg/L for cases vs. 4.48 μg/L for controls, P<0.01). In the final multivariable General Linear Model (GLM), after controlling for car ownership, maternal age, parental education levels, source of drinking water, consumption of "yam, sweet potato, or dasheen", "carrot or pumpkin", "callaloo, broccoli, or pak choi", cabbage, avocado, and the frequency of seafood consumption per week, we did not find a significant association between blood arsenic concentrations and ASD status (4.36 μg/L for cases vs. 4.65 μg/L for controls, P=0.23). Likewise, in a separate final multivariable GLM, we found that source of drinking water, eating avocado, and eating "callaloo, broccoli, or pak choi" was significantly associated with higher blood arsenic concentrations (all three P<0.05). Based on our findings, we recommend assessment of arsenic levels in water, fruits, and vegetables, as well as increased awareness among the Jamaican population regarding potential risks for various exposures to arsenic., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The Centers for Disease Control and Prevention (CDC), Division of HIV/AIDS Prevention (DHAP) conducted outcome monitoring studies on evidence-based interventions (EBIs) provided by CDC-funded community-based organizations (CBOs). Critical to the success of outcome monitoring was the ability of CBOs to recruit and retain clients in evaluation studies. Two EBIs, Video Opportunities for Innovative Condom Education and Safer Sex (VOICES/VOCES) and Healthy Relationships, were evaluated using repeated measure studies, which require robust follow-up retention rates to increase the validity and usefulness of the findings. The retention rates were high for both VOICES/VOCES CBOs (95.8% at 30 days and 91.1% at 120 days), and Healthy Relationships CBOs (89.5% at 90 days and 83.5% at 180 days). This paper presents an overview of the retention of clients, challenges to follow-up, and strategies developed by CBOs to achieve high retention rates. These strategies and rates are discussed within the context of the CBOs' target populations and communities., (Published by Elsevier Ltd.)

The active form of vitamin D (1alpha, 25-dihydroxycholecalciferol; calcitriol) has potent anti-neoplastic activity in the management of a number of human malignancies. Despite promising data to suggest that calcitriol is an effective adjunct to current chemotherapy modalities, the role of calcitriol in animal neoplasia is poorly understood. Vitamin D inhibits growth of canine mast cell tumours (MCTs) in vitro, presumably due to ligand-mediated activation of the vitamin D receptor (VDR). The aim of the present study was to examine immunohistochemically the expression of the VDR by reactive and neoplastic canine cutaneous mast cells. Expression was graded according to frequency, intensity and score (frequency x intensity). VDR expression was found in all samples containing reactive mast cells (n=9), and in 67 of 69 (97%) MCTs selected from each of the three Patnaik grades. The frequency and score of VDR labelling was greater in MCTs compared with reactive mast cells (P=0.0005 and 0.001, respectively). There was no difference in VDR frequency between the MCT grades, but the frequency of labelling in grade 3 MCTs was higher than for reactive mast cells (P=0.001). There was no association between tumour mitotic index and any of the three VDR variables (all P>0.16). VDR is widely expressed by reactive and neoplastic canine mast cells in vivo. VDR expression is unlikely to represent an independent prognostic factor, but its presence within biopsy specimens might be used to identify patients that are suited to high-dose vitamin D therapeutic trials., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The LGI1 gene has been implicated in tumor cell invasion through regulation of the ERK pathway. To determine whether human prostate cancer cells (PC3, 22RV, Du145) are similarly affected by exposure to LGI1, we conducted scratch wound assays and demonstrated that the secreted LGI1 protein can reduce cell motility, an essential component of invasion and metastasis. These studies have now been extended to an in vivo mouse model of prostate cancer. Using a BAC transgenic mouse expressing a GFP reporter gene under the control of cis regulatory elements, we demonstrated that LGI1 is highly expressed in the normal prostate epithelium. To determine whether loss of LGI1 expression is associated with development and progression of murine prostate cancer, we bred the GFP reporter BAC transgenic mice with TRAMP mice which undergo early hyperplasia and progressive stages of prostate cancer. In the F1 animals, although the surrounding normal prostate epithelium expressed high levels of LGI1 in the double transgenic mice, the LGI1 gene had been inactivated even at the earliest stages of hyperplasia. This observation supports the suggestion that inactivation of LGI1 in certain cell types is related to tumor progression. Taken together these results suggest that LGI1 may be an important molecule for the arrest of prostate cancer cell invasion and possibly as a biomarker for early detection of prostate hyperplasia., (Copyright 2009 Elsevier Inc. All rights reserved.)

Background: Doxorubicin is an active compound in epithelial ovarian cancer (EOC), but adding it to carboplatin-paclitaxel causes toxicity. Toxicity can be reduced by weekly administration. We examined the tolerability of weekly paclitaxel in combination with carboplatin and doxorubicin., Patients and Methods: Chemotherapy naïve patients with EOC were treated with doxorubicin (50 mg/m(2) day 1), carboplatin (AUC 6 day 1) and paclitaxel (days 1, 8, 15, 21), 28-day cycle. Three patients were treated at each paclitaxel dose level, starting at 60, 75 and 90 mg/m(2)/week. If more than two patients in a cohort experienced dose-limiting toxicity (DLT) three more patients were treated at the dose level below., Results: Twelve patients with advanced EOC received a median of six cycles (range 2-6) of the three-drug combination. DLT occurred at dose level 3: prolonged grade 4 febrile neutropenia, 1 patient; grade 3 peripheral neuropathy, 1 patient. All six patients treated at dose level 2 experienced short-lived grade 4 neutropenia, which led to dose modifications resulting in an actual delivered dose of paclitaxel of 64 mg/m(2)/week. Eight out of 12 patients had measurable disease on CT scan: four obtained a partial remission; three had stable disease., Conclusions: The combination of carboplatin, doxorubicin and paclitaxel in patients with EOC is active and its main toxicity is myelosuppression. Dose intensity of paclitaxel can be maintained in a three-drug combination through weekly administration (65 mg/m(2)).

During hibernation, animals undergo metabolic changes that result in reduced utilization of glucose and oxygen. Fat is known to be the preferential source of energy for hibernating animals. Malonyldialdehyde (MDA) is an end product of fatty acid oxidation, and is generally used as an index of lipid peroxidation. We report here that peroxidation of lipids is increased in the plasma and in the membranes of red blood cells in black bears during hibernation. The plasma MDA content was about four fold higher during hibernation as compared to that during the active, non-hibernating state (P < 0.0001). Similarly, MDA content of erythrocyte membranes was significantly increased during hibernation (P < 0.025). The activity of Ca(2+)/Mg(2+)-ATPase in the erythrocyte membrane was significantly decreased in the hibernating state as compared to the active state. Na(+)/K(+)-ATPase activity was also decreased, though not significant, during hibernation. These results suggest that during hibernation, the bears are under increased oxidative stress, and have reduced activities of membrane-bound enzymes such as Ca(2+)/Mg(2+)-ATPase and Na(+)/K(+)-ATPase. These changes can be considered part of the adaptive for survival process of metabolic depression.

Background: Ineffective tumour antigen processing is recognised as an important cause of failure of immunotherapy in melanoma. GM-CSF may augment the cytotoxic lymphocyte response by activating antigen-presenting cells. This study evaluates a schedule combining GM-CSF with biochemotherapy., Patients and Methods: Nineteen patients with advanced malignant melanoma received cisplatin (25 mg/m2 days 1-3). dacarbazine (220 mg/m2 days 1-3), interleukin-2 (9 MIU/m2/24 h) and interferon-alpha2b (5 MIU/m2) both days 6-10 and days 17-21, and tamoxifen 40 mg/day continuously. Subcutaneous GM-CSF was given in escalating doses to three cohorts: 1) 450 microg/m2 days 4-5 and 15-16; 2) as 1) plus 225 microg/m2 days 6-10 and 17-21; 3) 450 microg/m2 days 4-10 and 15-21. Each cycle was 28 days., Results: Constitutional side effects were the major non-haematological toxicity and lymphopaenia the main haematological toxicity. Six patients responded (32%, 95% confidence interval: 13%-57%), two patients had complete remission. There was an apparent trend for increasing responses with increasing GM-CSF dose; zero of six responses in cohort 1, two of seven in cohort 2 and three of six in cohort 3 (P = 0.016). Median overall survival was 6.2 months. Increasing GM-CSF doses significantly increased serum concentrations of neopterin and TNF-alpha., Conclusions: The combination of GM-CSF with biochemotherapy is feasible and there appears to be a dose-response relationship with GM-CSF in terms of host immunological response, and possibly clinical efficacy.

Metastatic melanoma is an incurable condition with a median survival of about 6 months. Chemotherapy can result in objective tumour responses but only in a minority of cases and remissions are short-lived, 3-6 months. DTJC is the most active single agent with response rates of 15-20% and although combination chemotherapy can result in higher response rates there is no response duration or survival advantage. Phase II studies have suggested that combining chemotherapy with biological response modifiers may result in higher response rates, in the order of 50% and the results of two large randomized trials investigating this approach are awaited. Adjuvant trials currently focus on interferon and/or vaccine strategies. Further data are required before any adjuvant treatment can be regarded as standard., (Copyright 1999 Harcourt Publishers Ltd.)

Epidermal growth factor (EGF) is a multifunctional regulator of mammary epithelial cells (MEC) that transduces its signals through the EGF receptor (EGFR). To clarify the role of the EGFR in the mammary gland, EGFR expression, localization and function were examined during different developmental stages in rats. Immunoblot analysis demonstrated high levels of EGFR during puberty, pregnancy and involution as well as at sexual maturity, and low levels throughout lactation. An immunohistochemical assay was used to show that EGFR was distinctly expressed in a variety of cell types throughout mammary glands from virgin rats and rats during pregnancy and involution, and was down-regulated in all cell types throughout lactation. To examine the relationship between EGFR expression and function, primary MEC were cultured under conditions that induced physiologically relevant growth, morphogenesis and lactogenesis. Cultured MEC expressed an in vivo-like profile of EGFR. EGFR was high in immature MEC, down-regulated in functionally differentiated MEC, and then up-regulated in terminally differentiated and apoptotic MEC. An inhibitor of the tyrosine kinase domain of EGFR was used to demonstrate that EGFR signaling was required for growth and differentiation of immature MEC, and for survival of terminally differentiated MEC, but not for maintaining functional differentiation.

Mandelate racemase (EC 5.1.2.2) catalyzes the interconversion of the two stereoisomers of mandelic acid. A fixed-time assay for the quantification of mandelate racemase activity has been developed. The assay involves enzymatic conversion of R-mandelate to S-mandelate (or the reverse reaction) followed by separation and detection of the substrate and product using isocratic reversed-phase high-performance liquid chromatography on a Sumichiral OA-6100 column and absorbance detection. This method offers an economical and efficient alternative to the existing circular dichroism-based and coupled assays., (Copyright 1999 Academic Press.)

Background: Among an independent group of subjects selected for their history of violent, impulsive behaviors and nonviolent control subjects, we attempted to replicate the finding that plasma docosahexaenoic acid concentrations were negatively correlated with cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations., Methods: CSF 5-HIAA and homovanillic acid (HVA), fasting total cholesterol, and plasma fatty acid concentrations were examined in violent and nonviolent subjects matched for their severity of alcohol dependence., Results: Violent subjects had significantly higher lifetime violence and hostility ratings and lower concentrations of CSF 5-HIAA than nonviolent subjects. Plasma docosahexaenoic acid was negatively correlated with CSF 5-HIAA only among violent subjects., Conclusions: This observational study suggests that dietary essential fatty acids may change neurotransmitter concentrations. Prospective dietary intervention trials will be required to determine if increasing dietary intake of docosahexaenoic acid will increase or decrease either CSF 5-HIAA concentrations or impulsive and violent behaviors.

The expression of human MDR1 P-glycoprotein (Pgp) in the capillary endothelial cells of the central nervous system has been demonstrated. The brain capillary endothelial cells maintain the structure and function of the blood-brain barrier. Recently, the human MDR1 Pgp (and its mouse homologue MDR1a Pgp) has been shown to function as an important part of this barrier, pumping out xenobiotics from endothelial cells into the lumen of capillaries resulting in the protection of the brain parenchyma. To examine whether the endothelial cells of the newly formed capillaries during neoangiogenesis within malignant human brain tumors express MDR1 Pgp, 35 adult surgical brain tumor specimens (29 gliomas and 6 tumors metastatic to the brain) were obtained from previously untreated patients and studied by a new immunohistochemical sandwich method developed in our laboratory using the JSB-1 monoclonal antibody. JSB-1 is specific for the Pgp product of the human MDR1 (and not MDR3) gene. This sensitive method allows the detection of Pgp in capillary endothelial cells of normal brain in conventional paraffin sections after formalin fixation. The endothelial cells of the newly formed capillaries in 25 of 29 gliomas (86%) and 3 of 6 metastatic tumors, immunostained positive for MDR1 Pgp. The tumor cells in 7 of 35 cases were also positive for Pgp. In the 35 brain tumor cases investigated, the endothelial cells were Pgp positive in the tumor-brain border and in the brain further from the tumor. Capillary endothelial cells of neovasculature in 137 malignant tumors (non-brain) obtained from previously untreated patients showed no MDR1 Pgp expression. These results demonstrated that MDR1 Pgp is expressed not only in the capillaries of normal brain but also in the majority of the newly formed capillaries of brain tumors. Multidrug resistance of brain tumors may result not only from the expression of resistance markers in neoplastic cells but also from the MDR1 Pgp expression in endothelial cells of tumor capillaries. Pgp in this special localization can exclude chemotherapeutic agents from tumor cells that are located around the capillaries. The therapeutic benefit and selectivity of chemotherapeutic agents in combination with a Pgp-reversing agent should be evaluated.

Small-angle scattering and electron microscopy studies of fd gene 5 protein (g5p) and reconstituted g5p.nucleic acid complexes have been used to test models for the complexes and evaluate their uniqueness. In addition, we have obtained new information on the dependence of nucleotide type and protein/nucleotide (P/N) ratio on the structure of the complexes. Reconstituted complexes were made with single-stranded fd viral DNA (fd ssDNA), poly[d(A)] and poly[r(A)]. All complexes form similar left-handed, flexible superhelices having approximately the same diameter, but the pitch differs among these complexes. The g5p protein is a dimer in solution and the dimers associate to form a superhelical framework to which the polynucleotide is attached. The combined X-ray and neutron scattering data confirm the nucleic acid is inside the protein superhelix. A Monte Carlo integration modeling procedure applied to the scattering data was used to systematically test large numbers of possible models for each complex, and previously proposed models based on parameters obtained from electron microscopy were found to be essentially correct and unique. The data on the complexes with different P/N ratios showed that mass per unit length values decreased while the rise per dimer and pitch of the superhelix increased for g5p.fd-ssDNA complexes with decreasing P/N ratios.

We have developed a new immunoperoxidase "sandwich" staining method for amplified detection of P-glycoprotein (Pgp) that is suitable for use on formalin-fixed, paraffin-embedded (conventional) tissue sections. This was accomplished by substantially changing the procedure described by Chan (1988) so as to increase specific staining intensity and to decrease nonspecific background staining. To determine the most appropriate primary antibody for the assay, we compared the immunoreactivity of JSB-1, C494, and C219 monoclonal antibodies recognizing internal epitopes of Pgp, and MRK16 and 4E3 monoclonal antibodies recognizing external epitopes of Pgp. Paraffin sections of Pgp-positive normal human tissues (adrenal, liver, kidney, and brain), of renal tumors, and of cell pellets of sensitive and multidrug resistant human tumor cell lines (MCF-7, KB) were used for comparisons. Immunostaining was excellent with JSB-1, moderate with C494, and very weak with C219. MRK16 and 4E3 showed no reaction. Nonspecific background staining was reduced by 1) omitting immunoglobulin G from secondary antibodies; 2) decreasing the concentration of peroxidase-antiperoxidase complex; and 3) utilizing casein solution for blocking and washing. Pretreatment of sections before immunostaining was also simplified. Using JSB-1, the threshold for detection of elevated Pgp corresponded to less than two-fold relative resistance to doxorubicin. Applying this method, we found two of 26 non-small cell lung cancers were positive for Pgp, consistent with previous results of others using frozen sections. This new immunoperoxidase sandwich staining method using JSB-1 now allows reliable Pgp detection in sections of formalin-fixed, paraffin-embedded (archived) surgical specimens and small biopsy materials commonly used for diagnostic purposes.

It is well known that in different tissues, dihydropyridines bind at nanomolar concentrations to a receptor and block voltage-operated Ca2+ channels. In studies reported here, Harderian gland tissue homogenates from intact male hamsters exhibited significant dihydropyridine binding (Bmax = 1700 fmoles/mg protein) of high affinity (Kd = 1.1 nM). Tissue homogenates from female animals exhibited a similar Kd value (1.35 nM) but receptor density per mg protein was significantly reduced (Bmax = 270 fmoles). Dihydropyridine binding of Harderian gland tissue homogenates from castrated males was reduced greater than 80% (Bmax = 225 fmoles/mg protein). Treatment of castrated males with subcutaneous testosterone pellets resulted in significant restoration of dihydropyridine binding activity (approximately 80%, Bmax = 1630 fmoles/mg protein) with a comparable binding constant (Kd = 1.50 nM) as observed for noncastrated, control animals. Addition of testosterone (ex vivo) to homogenates from castrated hamsters did not restore dihydropyridine binding to control levels. These data indicate: (a) the Harderian gland from male hamsters exhibits significant dihydropyridine binding; (b) ligand binding is abolished following castration; and (c) significant restoration of dihydropyridine binding occurs following in vivo testosterone treatment. The dependence of dihydropyridine binding restoration upon in vivo steroid hormone administration suggests probable involvement of the steroid at the transcriptional level although non-genomic mechanisms such as the binding of testosterone to a receptor resident in the plasma membrane and subsequent activation of Ca2+ channels can not be ruled out.

The applicability of a multilayer immunoperoxidase "sandwich" method (IpS) developed by Chan14 for the amplified detection of P-glycoprotein (Pgp) was investigated. The authors examined 15 formalin-fixed cell lines, as well as formalin-fixed, paraffin-embedded sections from single biopsies of 46 sarcomas. The cell lines included sensitive and multidrug resistant sublines (KB, A2780, MCF-7, HeLa) with various relative degrees of resistance to doxorubicin (Dox). The sarcoma biopsy specimens were selected on the basis of the results obtained in Western blot (WB) detection of Pgp (22 positive and 24 negative by WB) using C219 and C494 monoclonal antibodies to Pgp. The IpS method employed C219. The least resistant cell line in which Pgp could be detected by IpS was fivefold resistant to doxorubicin, whereas Pgp was detected by WB in cells greater than twofold resistant. Cell lines having greater than fivefold resistance to Dox were positive by both IpS and WB analyses. The less resistant cell lines contained more nonreactive cells whereas the highly resistant cell lines showed more homogeneous strong membrane reactions. Among the six cell lines determined to be Pgp negative by WB analysis, no false positive immunostaining by IpS existed. One of 22 WB positive and 7 of 24 WB-negative sarcoma biopsy specimens were positive by IpS methods. Reaction varied and was always focal (a minimum of 3-5 cells, ranging up to 3-4 high power fields) indicating pronounced heterogeneous distribution of Pgp. Thus, WB can detect low average (overall) levels of Pgp in tumor samples but such low concentrations of PgP at the single cell are not detectable by IpS methods. However, IpS can discern among many Pgp-negative cells small subpopulations of immunoreactive cells, which are not detected by WB analysis due to Pgp dilution by the membrane protein of numerous Pgp negative cells. IpS and WB used together as complementary methods can provide more complete information about Pgp distribution and content, particularly in the case of heterogeneous human tumors. The IpS method is more suitable for less drastically treated (not embedded) cell line specimens than for paraffin-embedded (routine) sections. Some modification of the present IpS protocol seems necessary to increase its sensitivity and reduce the disparity with WB results.

This North Carolina case study addresses the migration of anesthesiologists into subspecialty, clinical areas of anesthesiology over a 4-year period (1984 to 1987). Three hundred fourteen members of the North Carolina Society of Anesthesiologists (NCSA) were surveyed using a one-page questionnaire. The response rate was 93.6%. The questionnaire elicited data to characterize the magnitude of change in anesthesiologist manpower, to assess emerging subspecialization, to describe the flux of anesthesiologists entering and leaving practice, and to detail evolving modes of practice. Results indicated a net increase in manpower averaging 8.8% per year in academic programs, whereas clinical community practitioners increased physician positions at a rate three times the former (27% increase per year). Of 184 anesthesiologists recruited to North Carolina over 4 years, 75 different residency programs were represented; 48% of new anesthesiologists were from southern educational programs and 44% entered practice with fellowships (i.e., postgraduate year 4 to 5). The principal fellowship was cardiac (33%). Subspecialty areas were represented in all 53 reporting clinical practices. The principal practice mode emerging was hospital-based, same day surgery (85%) followed by pediatric anesthesia (81%), perioperative pain management (68%), obstetric anesthesia (63%), and an anesthesia "clinic" (54%). Respondents expected additional practice options over the next 3 years with anesthesia for ambulatory diagnostic and therapeutic modalities projected to emerge at the fastest rate. In conclusion, anesthesiologists in North Carolina seem to be filling unmet needs in obstetric and cardiac anesthesia, critical care, ambulatory surgery, and pain therapy units. These observations may represent a vignette of the national scene.

NG108-15 cells contain both the inhibitory and stimulatory guanyl nucleotide-binding regulatory proteins of the cyclase system. Choleragen activates cyclase directly by ADP-ribosylating the stimulatory guanyl nucleotide-binding protein; prostaglandin E1 does not further increase activity of cells treated with maximally effective concentrations of choleragen. Including pertussis toxin during incubation with this concentration of choleragen, however, further augments both cyclase activity and cAMP accumulation by intact cells. These observations suggest that the inhibitory guanyl nucleotide-binding protein exerts basal inhibition on catalytic activity which cannot be overcome by maximally effective concentrations of choleragen, stimulatory hormones, or both.

The design of a thin quartz cell suitable for absorption and circular dichroism measurements in the vacuum ultraviolet is described. Important features of the cell are (1) that it can be disassembled for cleaning and reproducibly reassembled with path lengths up to 0.3 mm, and (2) that strain in the windows from the compressed sample can be relieved by a sample overflow port. The latter feature allows the cell to be used for circular dichroism as well as absorption measurements.

Subcellular localization of nonesterified cholesterol has been determined in normal human fibroblasts from cultures incubated with human low density lipoprotein (LDL). Nonesterified and esterified cholesterol content of fibroblasts, grown initially in the absence of cholesterol, increased significantly after a 1-hour incubation with LDL. Digitonin was used to localize nonesterified cholesterol that was accumulated within multivesicular and lamellar lysosomal inclusions. This was observed only in fibroblasts from cultures incubated with LDL. Accumulation of LDL-derived nonesterified cholesterol within lysosomes is consistent with the suggestion of other investigators that LDL is metabolized within lysosomes.

Effects of fatty acids, prostaglandins, and phospholipids on the activity of purified cGMP-stimulated cyclic nucleotide phosphodiesterase from calf liver were investigated. Prostaglandins A2, E1, E2, F1 alpha, and F2 alpha, thromboxane B2, and most phospholipids were without effect; lysophosphatidylcholine was a potent inhibitor. Several saturated fatty acids (carbon chain length 14-24), at concentrations up to 1 mM, had little or no effect on hydrolysis of 0.5 microM [3H]cGMP or 0.5 microM [3H]cAMP with or without 1 microM cGMP. In general, unsaturated fatty acids were inhibitory, except for myristoleic and palmitoleic acids which increased hydrolysis of 0.5 microM [3H]cAMP. The extent of inhibition by cis-isomers correlated with the number of double bonds. Increasing concentrations of palmitoleic acid from 10 to 100 microM increased hydrolysis of [3H]cAMP with maximal activation (60%) at 100 microM; higher concentrations were inhibitory. Palmitoleic acid inhibited cGMP hydrolysis and cGMP-stimulated cAMP hydrolysis with IC50 values of 110 and 75 microM, respectively. Inhibitory effects of palmitoleic acid were completely or partially prevented by equimolar alpha-tocopherol. Palmitelaidic acid, the trans isomer, had only slightly inhibitory effects. The effects of palmitoleic acid (100 microM) were dependent on substrate concentration. Activation was maximal with 1 microM [3H]cAMP and was reduced with increasing substrate; with greater than 10 microM cAMP, palmitoleic had no effect. Inhibition of cGMP hydrolysis was maximal at 2.5 microM cGMP and was reduced with increasing cGMP; at greater than 100 microM cGMP palmitoleic acid increased hydrolysis slightly. Palmitoleic acid did not affect apparent Km or Vmax for cAMP hydrolysis, but increased the apparent Km (from 17 to 60 microM) and Vmax for cGMP hydrolysis with little or no effect on the Hill coefficient for either substrate. These results suggest that certain hydrophobic domains play an important role in modifying the catalytic specificity of the cGMP-stimulated phosphodiesterase for cAMP and cGMP.

Adult male Syrian hamsters were exposed daily for 12 weeks to 11 h/day of cool white fluorescent light (350 +/- 50 microW/cm2) followed by an additional 3 h of near ultraviolet (339-317 nm), blue (435-500 nm), green (515-550 nm), yellow (558-636 nm) or red (653-668 nm) light at an irradiance of 0.2 microW/cm2 or to total darkness. Animals exposed to the wavelengths between 558-668 nm (yellow or red half peak bandwidths) or those receiving a total of 13 h of darkness/day had suppressed circulating levels of thyroxine (T4), a depressed free T4 index (FT4I) and a higher T3/T4 ratio compared to animals receiving a total of 14 h of white light (350 +/- 50 microW/cm2). These results suggest that specific wavelengths of light can affect the neuroendocrine-thyroid axis.

Using fluorescence microscopy, we have quantified low density lipoprotein (LDL) binding by indirect immunofluorescence and cellular cholesterol with the fluorescent sterol-binding polyene, filipin, in individual cultured human fibroblasts from normal subjects and from patients with heterozygous and homozygous familial hypercholesterolemia. LDL binding by fibroblasts from heterozygous patients was about 40% of that of the normal cells, and cholesterol accumulation upon incubation with LDL was decreased to a similar degree. Most fibroblasts from homozygous patients bound no detectable LDL and only rare cells demonstrated any accumulation of cholesterol after incubation with LDL.

Two hundred two autologous pulmonary valves were transplanted into the aortic position between 1967 and 1982 at the National Heart Hospital in London. The indication for operation was congenital or acquired aortic valve disease, and the patients were followed for periods from 1 to 4 years. The patients were not anti-coagulated, but the entire series has been completely free from thromboembolism or bleeding. The actuarial prediction of freedom from valve-related deaths was 82 +/- 6% at the end of the fourteenth year after operation; deaths were due to reoperations for technical failure and to infective endocarditis. Event-free survival of the autologous pulmonary valve in the aortic position was 73 +/- 6% after 14 years at risk. Valve failure resulted mainly from technical problems encountered during the early years of surgical experience. There was no macroscopic or histological evidence of calcification in any of the failed valves. The right ventricular outflow was reconstructed with an aortic homograft in the majority of patients; 81 +/- 5% of these homografts demonstrated event-free performance over a 12-year follow-up period. It is concluded that the long-term performance of a pulmonary autograft inserted for aortic valve disease is superior to that of any other valve substitute and that the operation offers an almost ideal means of aortic valve replacement in appropriate patients.