Identification of Tobacco streak virus in Cranberry and the Association of TSV with Berry Scarring.

Cranberry plants bearing disfigured, scarred fruit were reported by growers in the major cranberry-growing region of central Wisconsin in July 2012. Plants bearing scarred fruit have since been observed in Massachusetts and New Jersey. Three complementary methods provided evidence of Tobacco streak virus (TSV) in symptomatic plants: (i) leaves and scarred berries tested positive for TSV by double-antibody sandwich enzyme-linked immunosorbent assay; (ii) quasi-isometric particles approximately 33 nm in diameter were extracted from leaves of symptomatic plants and visualized using transmission electron microscopy; and (iii) coat protein gene sequence analysis revealed 94 to 99% nucleotide similarity with reference TSV sequences. In newer cultivars, 99% of uprights with scarred berries tested positive for TSV. In older cultivars, 31% of uprights with scarred berries tested positive for TSV and the remaining 69% of uprights with scarred berries tested positive for Blueberry shock virus. TSV overwintered in cranberry plants, and leaves, pollen, and fruit tested positive for TSV the year following symptom occurrence. Attempts to inoculate cranberry using infected pollen or sap as inoculum failed, but several herbaceous hosts tested TSV positive following mechanical inoculation. Phylogenetic analysis of the coat protein gene of 26 TSV isolates from various cultivars of cranberry in Wisconsin, New Jersey, and Massachusetts revealed diversity. This work provides information that will be useful in understanding the epidemiology of TSV in cranberry and in the development of management strategies.

Effects of Simulated Hail Events and Subsequent Fungicide Applications on Cranberry Fruit Rot Incidence and Yield.

Storms containing hail are a common occurrence in Wisconsin, with a few or many cranberry (Vaccinium macrocarpon) growers being affected every year. Growers usually apply fungicides immediately following hail events to prevent fruit rot, despite a lack of research to support this practice. We conducted field trials in 2010 and 2011 to address the question of whether applying fungicides to injured fruit reduces fruit rot incidence (% rotten fruit). Hail damage was simulated by forcibly projecting pea gravel into cranberry beds using a mist-blower sprayer modified for this purpose, and the fungicides azoxystrobin or copper hydroxide were applied to fruit immediately after applying gravel. Fruit rot incidence and yield were evaluated within 2 weeks prior to commercial harvest in late September and early October. Fruit rot incidence was greater (P ≤ 0.05) and yield was lower (P < 0.05) in plots treated with gravel than in the nontreated control plots in six of seven trials. Fungicides did not reduce fruit rot incidence (P ≥ 0.05) in gravel-treated plots compared to the nontreated control in six of seven trials. However, in a trial conducted on relatively immature berries, fruit rot incidence in gravel-treated plots treated with azoxystrobin was less (P = 0.0103) than fruit rot incidence in gravel-treated plots receiving no fungicide treatment. In that same trial, fruit rot incidence was not reduced (P = 0.1243) in gravel-treated plots treated with copper hydroxide compared to gravel-treated plots that were not treated with fungicide. Results suggest that under most circumstances, if cranberries are damaged by hail, it is unlikely that an application of fungicide will reduce the amount of fruit rot at the time of harvest.

Effects of cherry leaf spot on photosynthesis in tart cherry 'Montmorency' foliage.

Results described here span a total of three field seasons and quantitatively depict the effects of an economically important fungal pathogen (Blumeriella jaapii) on tart cherry (Prunus cerasus 'Montmorency') leaf physiology. For the first time, leaf photosynthesis, stomatal conductance (g(s)), maximum ribulose-1,5-bisphosphate carboxylation rate (V(cmax)), and maximum electron transport (J(max)) were measured as functions of visible cherry leaf spot disease (CLS) severity. Defined as the proportion of chlorotic and necrotic tissue per leaf, CLS severity was estimated from leaves of mature 'Montmorency' trees in 2007, 2008, and 2009. Briefly, as visible disease severity increased, all of the leaf-level physiological parameters decreased significantly (P < 0.01) and disproportionately. Thus, the effects of visible symptoms on leaf photosynthetic metabolic function encroached upon asymptomatic tissue as well. Impairment of photosynthetic metabolism in 'Montmorency' tart cherry leaves due to CLS appears to be mediated through disproportionately large perturbations in g(s), V(cmax), and J(max). These findings offer a new perspective on the amount of damage that this serious disease can inflict.

Culture-dependent and culture-independent assessment of bacteria in the apple phyllosphere.

AIMS: Bacterial communities in the apple phyllosphere were examined quantitatively and qualitatively by applying culture-dependent and culture-independent methods. METHODS AND RESULTS: Populations estimated by viewing cells stained with 4',6-diamidino-2-phenylindole generally were at least 100-1000 times greater than populations estimated by culturing on tryptic soy agar (TSA). Of the 44 operational taxonomic units (OTUs; cut-off threshold of 97%) detected in total, five bacterial orders containing 23 OTUs were identified by culturing on TSA, whereas nine orders containing 33 OTUs were identified by 16S rRNA gene cloning of DNA extracted from apple leaf surfaces. Twelve of the 44 OTUs were shared between cultured isolates and 16S rRNA gene clones and included the orders Burkholderiales, Pseudomonadales, Rhizobiales and Sphingomonadales. Three OTUs within the genus Sphingomonas accounted for 40% of isolates and 68% of clones. The Actinomycetales were found only among isolates, whereas the Bacteroidales, Enterobacteriales, Myxococales and Sphingobacteriales were represented in the 16S rRNA gene clone libraries but were absent among isolates. CONCLUSIONS: Culture-independent methods revealed greater numbers and greater richness of bacteria on apple leaves than found by culturing. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to directly compare culture-dependent and independent approaches for assessing bacterial communities in the phyllosphere. The biases introduced by different methods will have a significant impact on studies related to phyllosphere ecology, biological control of plant diseases, reservoirs of antibiotic resistance genes and food safety.

Prognostic markers for myeloid neoplasms: a comparative review of the literature and goals for future investigation.

Myeloid neoplasms include cancers associated with both rapid (acute myeloid leukemias) and gradual (myelodysplastic syndromes and myeloproliferative neoplasms) disease progression. Percentage of blast cells in marrow is used to separate acute (rapid) from chronic (gradual) and is the most consistently applied prognostic marker in veterinary medicine. However, since there is marked variation in tumor progression within groups, there is a need for more complex schemes to stratify animals into specific risk groups. In people with acute myeloid leukemia (AML), pretreatment karyotyping and molecular genetic analysis have greater utility as prognostic markers than morphologic and immunologic phenotypes. Karyotyping is not available as a prognostic marker for AML in dogs and cats, but progress in molecular genetics has created optimism about the eventual ability of veterinarians to discern conditions potentially responsive to medical intervention. In people with myelodysplastic syndromes (MDS), detailed prognostic scoring systems have been devised that use various combinations of blast cell percentage, hematocrit, platelet counts, unilineal versus multilineal cytopenias and dysplasia, karyotype, gender, age, immunophenotype, transfusion dependence, and colony-forming assays. Predictors of outcome for animals with MDS have been limited to blast cell percentage, anemia versus multilineal cytopenias, and morphologic phenotype. Prognostic markers for myeloproliferative neoplasms (eg, polycythemia vera, essential thrombocythemia) include clinical and hematological factors and in people also include cytogenetics and molecular genetics. Validation of prognostic markers for myeloid neoplasms in animals has been thwarted by the lack of a large case series that requires cooperation across institutions and veterinary specialties. Future progress requires overcoming these barriers.

Recommended guidelines for the conduct and evaluation of prognostic studies in veterinary oncology.

There is an increasing need for more accurate prognostic and predictive markers in veterinary oncology because of an increasing number of treatment options, the increased financial costs associated with treatment, and the emotional stress experienced by owners in association with the disease and its treatment. Numerous studies have evaluated potential prognostic and predictive markers for veterinary neoplastic diseases, but there are no established guidelines or standards for the conduct and reporting of prognostic studies in veterinary medicine. This lack of standardization has made the evaluation and comparison of studies difficult. Most important, translating these results to clinical applications is problematic. To address this issue, the American College of Veterinary Pathologists' Oncology Committee organized an initiative to establish guidelines for the conduct and reporting of prognostic studies in veterinary oncology. The goal of this initiative is to increase the quality and standardization of veterinary prognostic studies to facilitate independent evaluation, validation, comparison, and implementation of study results. This article represents a consensus statement on the conduct and reporting of prognostic studies in veterinary oncology from veterinary pathologists and oncologists from around the world. These guidelines should be considered a recommendation based on the current state of knowledge in the field, and they will need to be continually reevaluated and revised as the field of veterinary oncology continues to progress. As mentioned, these guidelines were developed through an initiative of the American College of Veterinary Pathologists' Oncology Committee, and they have been reviewed and endorsed by the World Small Animal Veterinary Association.

Effects of Copper-Based Fungicides on Foliar Gas Exchange in Tart Cherry.

In the Great Lakes region of the United States, cherry growers are poised to re-adopt copper-based fungicides to manage cherry leaf spot disease (CLS), caused by Blumeriella jaapii. However, application of copper is often associated with leaf bronzing. In growth chamber experiments, bronzing was observed on foliage of tart cherry (Prunus cerasus 'Montmorency') seedlings 1 week following application of a copper-based fungicide, only when leaves were also exposed to nightly dew. In potted, 1-year-old trees outdoors, light-saturated rates of net CO2 assimilation (A) and stomatal conductance (gs) were not affected by treatment with copper sulfate, chlorothalonil, tebuconazole, or trifloxystrobin compared to a nonsprayed control. In 2005 and 2006, A and gs were measured during late summer on leaves of mature trees in an orchard subjected to the following fungicide programs: synthetic fungicides only; synthetic fungicides integrated with copper-based fungicides; or not sprayed. Bronzing symptoms were observed on trees sprayed with copper. Regression analysis revealed that neither A nor gs decreased as leaf surface area affected by bronzing increased (R2 = 0.004, P = 0.80 and R2 = 0.006, P = 0.74, respectively). Leaf bronzing associated with application of copper-based fungicides may therefore be inconsequential to foliar gas exchange in tart cherry during late summer.

Adaptation of an Apple Sooty Blotch and Flyspeck Warning System for the Upper Midwest United States.

A warning system for sooty blotch and flyspeck (SBFS) of apple, developed in the southeastern United States, uses cumulative hours of leaf wetness duration (LWD) to predict the timing of the first appearance of signs. In the Upper Midwest United States, however, this warning system has resulted in sporadic disease control failures. The purpose of the present study was to determine whether the warning system's algorithm could be modified to provide more reliable assessment of SBFS risk. Hourly LWD, rainfall, relative humidity (RH), and temperature data were collected from orchards in Iowa, North Carolina, and Wisconsin in 2005 and 2006. Timing of the first appearance of SBFS signs was determined by weekly scouting. Preliminary analysis using scatterplots and boxplots suggested that cumulative hours of RH ≥ 97% could be a useful predictor of SBFS appearance. Receiver operating characteristic curve analysis was used to compare the predictive performance of cumulative LWD and cumulative hours of RH ≥ 97%. Cumulative hours of RH ≥ 97% was a more conservative and accurate predictor than cumulative LWD for 15 site years in the Upper Midwest, but not for four site years in North Carolina. Performance of the SBFS warning system in the Upper Midwest and climatically similar regions may be improved if cumulative hours of RH ≥ 97% were substituted for cumulative LWD to predict the first appearance of SBFS.

Thoroughbred fatality and associated jockey falls and injuries in races in New South Wales and the Australian Capital Territory, Australia: 2009-2014.

Monitoring racehorse fatality and associated jockey falls provides benchmarks for intervention strategies. The aims of this study were to describe the incidence of and reasons for fatalities in Thoroughbred horses during flat races in the Australian Capital Territory and New South Wales (NSW), Australia, and to describe reported jockey falls and injuries associated with racehorse fatalities. A cohort study identified all racehorse fatalities reported through Racing NSW for the 2009-2010 to 2013-2014 racing seasons. Risks of racehorse fatality, fatal musculoskeletal injury, spontaneous death (as distinct from euthanasia) and racehorse fatality associated jockey falls and injuries were calculated using Poisson regression. A total of 167 horse fatalities were reported, with an overall incidence of 0.59 deaths/1000 starts. Forty-nine reasons for horse fatality were reported, although post-mortem examinations were conducted on only 52/165 (31.5%) horses. Musculoskeletal injury accounted for 144/167 (86.2%) fatalities, with an incidence of 0.52/1000 starts. Fractures comprised 96/167 (57.5%) fatalities, with the fetlock or proximal sesamoid bones being the most common fracture location, comprising 36/96 (37.5%) fractures. Only 22/166 (13.3%) racehorse fatalities were due to spontaneous death, representing an incidence of 0.08/1000 starts. A total of 50 racehorse fatality associated jockey falls were reported (incidence of 0.18/1000 starts), with 32 reported jockey injuries (incidence of 0.12/1000 starts). Most racehorse fatality associated jockey injuries occurred to the limbs (17/32, 53.1%), particularly the upper limb. The estimates for both horse fatality and associated jockey injury were comparable with previous estimates from other jurisdictions internationally.

Benzo(a)pyrene phenol production by perfused rat liver and its inhibition by ethanol.

A rapid and inexpensive method has been developed to estimate rates of benzo(a)pyrene phenol production by perfused rat liver. This method is based on the measurement of benzo(a)pyrene phenols utilizing a simple fluorometric procedure. Within 2 to 3 min after infusion of benzo(a)pyrene bound to serum albumin, phenols are excreted into the perfusate, primarily as glucuronide and sulfate conjugates. Maximal rates of phenol release were 8 to 10 nmol/g/hr in livers from control rats and 40 to 42 nmol/g/hr in livers from 3-methylcholanthrene-treated rats. Fasting of 3-methylcholanthrene-treated rats for 24 hr prior to perfusion experiments did not affect either the rate of phenol production or the extent of their conjugation. Ethanol (20 mM) inhibited rates of phenol formation by 50% in livers from fasted, 3-methylcholanthrene-treated rats but had no effect on benzo(a)pyrene hydroxylase activity in isolated hepatic microsomes. These data indicate that ethanol inhibits phenol formation from benzo(a)pyrene in intact liver, probably by diminishing the supply of the cofactor reduced nicotinamide adenine dinucleotide phosphate.

Base of skull and cervical spine chordomas in children treated by high-dose irradiation.

PURPOSE: To evaluate the outcome of children with base of skull or cervical spine chordomas treated by high dose irradiation. METHODS AND MATERIALS: Eighteen children, 4 to 18 years of age, with base of skull or cervical spine chordomas, received fractionated high-dose postoperative radiation using mixed photon and 160 MeV proton beams. The median tumor dose was 69 Cobalt Gray-equivalent (CGE) with a 1.8 CGE daily fraction. RESULTS: The median follow-up was 72 months. The 5-year actuarial survival was 68% and the 5-year disease-free survival (DFS) was 63%. The only significant prognostic factor was the location: patients with cervical spine chordomas had a worse survival than those with base of skull lesions (p = 0.008). The incidence of treatment-related morbidity was acceptable: two patients developed a growth hormone deficit corrected by hormone replacement, one temporal lobe necrosis, and one fibrosis of the temporalis muscle, improved by surgery. CONCLUSION: Chordomas in children behave similarly to those in adults: children can receive the same high-dose irradiation as adults with acceptable morbidity.

Neuropsychological function in adults after high dose fractionated radiation therapy of skull base tumors.

PURPOSE: To evaluate the long term effects of high dose fractionated radiation therapy on brain functioning prospectively in adults without primary brain tumors. METHODS AND MATERIALS: Seventeen patients with histologically confirmed chordomas and low grade chondrosarcomas of the skull base were evaluated with neuropsychological measures of intelligence, language, memory, attention, motor function and mood following surgical resection/biopsy of the tumor prior to irradiation, and then at about 6 months, 2 years and 4 years following completion of treatment. None received chemotherapy. RESULTS: In the patients without tumor recurrence or radiation necrosis, there were no indications of adverse effects on cognitive functioning in the post-acute through the late stages after brain irradiation. Even in patients who received doses of radiation up to 66 Cobalt Gy equivalent through nondiseased (temporal lobe) brain tissue, memory and cognitive functioning remained stable for up to 5 years after treatment. A mild decline in psychomotor speed was seen in more than half of the patients, and motor slowing was related to higher radiation doses in midline and temporal lobe brain structures. CONCLUSION: Results suggest that in adults, tolerance for focused radiation is relatively high in cortical brain structures.

Late rectal bleeding following combined X-ray and proton high dose irradiation for patients with stages T3-T4 prostate carcinoma.

PURPOSE: Dose escalation for prostate cancer by external beam irradiation is feasible by a 160 MeV perineal proton beam that reduces the volume of rectum irradiated. We correlated the total doses received to portions of the anterior rectum to study the possible relationship of the volume irradiated to the incidence of late rectal toxicity. METHODS: We have randomized 191 patients with stages T3 and T4 prostatic carcinoma to one of two treatment dose arms. These were: 1) 75.6 Cobalt-Gy-equivalent (CGE), 50.4 Gy delivered by 107-25 MV photons followed by 25.2 CGE delivered perineally by protons (Arm 1) or 2) 67.2 CGE delivered by 10-25 MV photons (Arm 2). RESULTS: With a median follow-up of 3.7 years, post-irradiation rectal bleeding (grades 1 and 2 only, none requiring surgery or hospitalization) from telangiectatic rectal mucosal vessels has occurred in 34% of 99 Arm-1 patients and 16% of 92 Arm-2 patients (p = 0.013). Dose-volume histograms (DVHs) for the anterior rectal wall, the posterior rectal wall and the total rectum in 41 patients treated on Arm 1 were calculated from the three dimensional dose distributions. Rectal bleeding has occurred in 14 or 34% of the 41 DVH-analyzed subset of Arm-1 patients. Both the fractional volume of the anterior rectum and the total dose received by fractional volumes of the anterior rectum significantly correlate with the actuarial probability of bleeding. CONCLUSIONS: Clinicians planning dose escalation to men with localized prostate cancer should approve with caution treatment plans raising more than 40% of the anterior rectum to more than 75 CGE without additional effort to protect the rectal mucosa because this late sequela data indicate that more than half of these men will otherwise have rectal bleeding.

Conservative treatment of uveal melanoma: local recurrence after proton beam therapy.

Twenty-three of 1006 (2.3%) uveal melanoma patients treated with proton beam therapy at the Harvard Cyclotron Laboratory between July 1975 and December 31, 1986 received additional treatment for documented (15 patients) or suspected (eight patients) tumor growth in the irradiated eye. Growth within the initially irradiated volume was documented at Massachusetts Eye and Ear Infirmary in 12 patients. Documented growth occurred in nine of 665 (1.4%) patients with small and intermediate size tumors, at times after treatment ranging from 6 to 48 months (median 16 months), and in three of 341 (.9%) patients with large tumors at 7, 11, and 12 months after treatment. Melanoma growing totally outside the treated volume was also documented in three additional patients at 7, 9, and 45 months; two of these were thought to be "ring melanomas". Eight patients had the treated eye removed elsewhere for suspected tumor growth. The additional treatment in these 23 patients was conservative in nine patients (repeat proton irradiation in five and laser photocoagulation in four). Thirteen underwent immediate enucleation and one had orbital exenteration. Ultimately, 17 of the 23 eyes (74%) were removed. Estimated probability of local control of the melanoma within the irradiated eye at 60 months was 96.3 +/- 1.5%. Dose distributions to the 12 patients with documented local failure within the irradiated volume were analyzed. Ten tumors recurred marginally in an area receiving less than the prescribed dose of 70 CGE (CGE = Cobalt Gray Equivalents = proton Gy X RBE 1.1), whereas only two recurred in the volume receiving full dose. Based on these data, it appears that a dose of 70 CGE in five fractions is associated with very high rates of local control in human uveal melanoma. It is reasonable to consider initiating studies using a lower total dose or a more protracted course, to determine if some of the observed complications are dose-related.

Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone.

PURPOSE: Following a thorough Phase I/II study, we evaluated by a Phase III trial high versus conventional dose external beam irradiation as mono-therapy for patients with Stage T3-T4 prostate cancer. Patient outcome following standard dose radiotherapy or following a 12.5% increase in total dose to 75.6 Cobalt Gray Equivalent (CGE) using a conformal perineal proton boost was compared for local tumor control, disease-free survival, and overall survival. METHODS AND MATERIALS: Stage T3-T4, Nx, N0-2, M0 patients received 50.4 Gy by four-field photons and were randomized to receive either an additional 25.2 CGE by conformal protons (arm 1--the high dose arm, 103 patients, total dose 75.6 CGE) or an additional 16.8 Gy by photons (arm 2--the conventional dose arm, 99 patients, total dose 67.2 Gy). Actuarial overall survival (OS), disease-specific survival (DSS), total recurrence-free survival (TRFS), (clinically free, prostate specific antigen (PSA) less than 4ng/ml and a negative prostate rebiopsy, done in 38 patients without evidence of disease) and local control (digital rectal exam and rebiopsy negative) were evaluated. RESULTS: The protocol completion rate was 90% for arm 1 and 97% for arm 2. With a median follow-up of 61 months (range 3 to 139 months) 135 patients are alive and 67 have died, 20 from causes other than prostate cancer. We found no significant differences in OS, DSS, TRFS or local control between the two arms. Among those completing randomized treatment (93 in arm 1 and 96 in arm 2), the local control at 5 and 8 years for arm 1 is 92% and 77%, respectively and is 80% and 60%, respectively for arm 2 (p = .089) and there are no significant differences in OS, DSS, and TRFS. The local control for the 57 patients with poorly differentiated (Gleason 4 or 5 of 5) tumors at 5 and 8 years for arm 1 is 94% and 84% and is 64% and 19% on arm 2 (p = 0.0014). In patients whose digital rectal exam had normalized following treatment and underwent prostate rebiopsy there was a lower positive rebiopsy rate for arm 1 versus arm 2 patients (28 vs. 45%) and also for those with well and moderately differentiated tumors versus poorly differentiated tumors (32 and 50%). These differences were not statistically significant. Grade 1 and 2 rectal bleeding is higher (32 vs. 12%, p = 0.002) as may be urethral stricture (19 vs. 8%, p = 0.07) in the arm 1 versus arm 2. CONCLUSIONS: An increase in prostate tumor dose by external beam of 12.5% to 75.6 CGE by a conformal proton boost compared to a conventional dose of 67.2 Gy by a photon boost significantly improved local control only in patients with poorly differentiated tumors. It has increased late radiation sequelae, and as yet, has not increased overall survival, disease-specific survival, or total recurrence-free survival in any subgroup. These results have led us to test by a subsequent Phase III trial the potential beneficial effect on local control and disease-specific survival of a 12.5% increase in total dose relative to conventional dose in patients with T1, T2a, and T2b tumors.

Clinicopathologic features of excised mitomycin filtering blebs.

Using light and electron microscopy, we examined two conjunctival filtering blebs that had been treated with mitomycin just prior to trabeculectomy and were later excised due to ocular hypotony. Light microscopy showed attenuated epithelium, loosely arranged subepithelial connective tissue, and scattered acute and chronic inflammatory cells. Electron microscopy also showed these findings and demonstrated the presence of presumably viable activated fibrocytes in the subepithelial connective tissue. The presence of inflammatory cells in the blebs was attributed to concurrent infections and suggests that mitomycin does not completely suppress, but may attenuate, the inflammatory response. The mechanism of hypotony and bleb failure in the two eyes was most likely a combination of over-filtration and a persistent wound leak due to a lack of postoperative subconjunctival fibrosis secondary to treatment with mitomycin.

Can the fatal toxicity of antidepressant drugs be predicted with pharmacological and toxicological data?

Antidepressant drugs are among the most common drugs involved in fatal poisoning and large variations between antidepressant drugs have been noted. Despite the fact that a large number of studies have calculated a fatal toxicity index (FTI) for antidepressants, no serious attempts have been made to compare the differences in fatal toxicity against known pharmacological and toxicological differences in receptor affinity. It is potentially from such data that screening of drugs during their pre-clinical development can be facilitated. We examined correlations between the FTI and noradrenaline (norepinephrine)/serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibition selectivity, the dose that is lethal to 50% of animals (LD50), lipid solubility, and antagonist activity at cholinergic, histaminergic, alpha-adrenergic and gamma-aminobutyric acid (GABA)A receptors or sodium and potassium channel blocking effects. We obtained data on the number of fatal poisonings between 1983 and 1992 in England and Wales caused by a single antidepressant drug from the Department of Health in the UK. This number was divided by the number of prescriptions in England for these drugs over this time to derive a FTI of deaths per million prescriptions. The highest FTIs were for amoxapine, viloxazine, desipramine and dothiepin. Lofepramine, paroxetine and fluoxetine had very low FTIs. Using Poisson regression, there was a significant positive relationship between the FTI of antidepressant drugs and their lethal toxicity in animals, and measures of their cardiac effects. The relative noradrenaline/serotonin reuptake inhibition, lipid solubility and their potency at histamine H1, muscarinic and alpha 1-adrenergic receptors had no substantial association with the FTI. Limited data suggest that some cardiac effects and potency as a GABAA antagonist may be important predictors of significant toxicity. Further data using standardised bio-assays are needed to compare the direct cardiac effects of antidepressants. Thus, the best current pre-clinical indicator of fatal toxicity in humans is the LD50 in animal studies. Clearly, there are humane and practical reasons for developing a better pre-clinical indicator of toxicity in overdose for this rapidly expanding group of drugs.

Time to second prostate-specific antigen failure is a surrogate endpoint for prostate cancer death in a prospective trial of therapy for localized disease.

OBJECTIVES: The most relevant endpoint in comparing the efficacy of curative therapies for prostate cancer is cancer-specific death. Prospective trials need to mature for a least a decade to yield meaningful cancer death data due to the long natural history of the disease amd the use of salvage androgen suppression. This delay may be long enough that the tested treatments are outdated by the time of reporting; thus, there is a need for reliable early surrogate endpoints for cancer survival. METHODS: This report evaluates 202 patients entered into a single institution prospective randomized study for T3-4 prostate cancer. Patients were accrued between 1982 and 1992 and received radical irradiation to either a standard dose of 67.2 Gy or a higher dose of 75.6 Gy. Median follow-up was 5.4 years. A total 76 men have received androgen suppression or orchiectomy for salvage following relapse. Of this group, 35 experienced a second relapse heralded by a rise in the serum prostate-specific antigen (PSA). RESULTS: The median survival from the time of second biochemical relapse (defined as a progression with a rise in serum PSA more than 10% above the nadir after androgen suppression) was 27 months. Kaplan-Meier analysis projected a 0% survival for this group at 4 years. All those dying after second biochemical failure died of the prostate cancer. CONCLUSIONS: Second PSA failure (or PSA progression on hormonal therapy) has potential as a surrogate for impending cancer death and its use as an endpoint in prospective studies could allow earlier reporting by 2 to 4 years.

A cost-effectiveness approach to drug subsidy and pricing in Australia.

The Australian government offers its citizens subsidies on a select list of pharmaceuticals. For a drug to qualify for inclusion on this list, its manufacturer must demonstrate that the drug is both clinically effective and cost-effective. In part, this measure, along with others, was introduced to improve clinical and economic outcomes. Although this evidence-based system has provided transparency and consistency in decision making about which drugs will be covered, it may not have contained the rate of increase in drug costs.