Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease. In a prospective trial, we tested whether image-guided ...intensity-modulated radiation therapy (IMRT) can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5½ weeks.
Pelvic nodal and prostatic image-guided IMRT was delivered to 53 National Comprehensive Cancer Network (NCCN) high-risk patients to a nodal dose of 56 Gy in 2-Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy, and 50 of 53 patients received androgen deprivation for a median duration of 12 months.
The median follow-up time was 25.4 months (range, 4.2-57.2). No early Grade 3 Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events v.3.0 genitourinary (GU) or gastrointestinal (GI) toxicities were seen. The cumulative actuarial incidence of Grade 2 early GU toxicity (primarily alpha blocker initiation) was 38%. The rate was 32% for Grade 2 early GI toxicity. None of the dose-volume descriptors correlated with GU toxicity, and only the volume of bowel receiving ≥30 Gy correlated with early GI toxicity (p = 0.029). Maximum late Grades 1, 2, and 3 GU toxicities were seen in 30%, 25%, and 2% of patients, respectively. Maximum late Grades 1 and 2 GI toxicities were seen in 30% and 8% (rectal bleeding requiring cautery) of patients, respectively. The estimated 3-year biochemical control (nadir + 2) was 81.2 ± 6.6%. No patient manifested pelvic nodal failure, whereas 2 experienced paraaortic nodal failure outside the field. The six other clinical failures were distant only.
Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient, resource-efficient, and well-tolerated 28-fraction schedule. Pelvic nodal dose escalation may be an option in any future exploration of potential benefits of pelvic radiation therapy in high-risk prostate cancer patients.
1 Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
2 The Centre for Environment, Fisheries, and Aquaculture Science, Weymouth ...Laboratory, Barrack Road, The Nothe, Weymouth, Dorset DT4 8UB, UK
3 Division of Statistics, University of California, Davis, CA 95616, USA
4 Institute of Microbiology, Department of Clinical Microbiology, The Hebrew University-Hadassah Medical School, Ein Karen, Jerusalem, Israel
Correspondence Ronald Hedrick rphedrick{at}ucdavis.edu
Koi herpesvirus (KHV) has been associated with devastating losses of common carp ( Cyprinus carpio carpio ) and koi ( Cyprinus carpio koi ) in North America, Europe, Israel and Asia. A comparison of virion polypeptides and genomic restriction fragments of seven geographically diverse isolates of KHV indicated that with one exception they represented a homogeneous group. A principal environmental factor influencing the onset and severity of disease is water temperature. Optimal growth of KHV in a koi fin cell line occurred at temperatures from 1525 °C. There was no growth or minimal growth at 4, 10, 30 or 37 °C. Experimental infections of koi with KHV at a water temperature of 23 °C resulted in a cumulative mortality of 95·2 %. Disease progressed rapidly but with lower mortality (89·495·2 %) at 28 °C. Mortality (85·0 %) also occurred at 18 °C but not at 13 °C. Shifting virus-exposed fish from 1323 °C resulted in the rapid onset of mortality.
Rainbow trout (Oncorhynchus mykiss) and brown trout (Salmo trutta) represent two salmonid genera separated for 15--20 million years. cDNA sequences were determined for the classical MHC class I heavy ...chain gene UBA and the MHC class II beta-chain gene DAB from 15 rainbow and 10 brown trout. Both genes are highly polymorphic in both species and diploid in expression. The MHC class I alleles comprise several highly divergent lineages that are represented in both species and predate genera separation. The class II alleles are less divergent, highly species specific, and probably arose after genera separation. The striking difference in salmonid MHC class I and class II evolution contrasts with the situation in primates, where lineages of class II alleles have been sustained over longer periods of time relative to class I lineages. The difference may arise because salmonid MHC class I and II genes are not linked, whereas in mammals they are closely linked. A prevalent mechanism for evolving new MHC class I alleles in salmonids is recombination in intron II that shuffles alpha 1 and alpha 2 domains into different combinations.
Since 1998, episodes of mass mortality have occurred in populations of common carp Cyprinus carpio carpio in Israel and in populations of koi Cyprinus carpio koi in Israel and the USA. A herpesvirus ...isolated from infected fish has been shown in experimental studies to induce disease and mortality similar to those observed in outbreaks at infected farms. Initial characteristics of the virus show that it is clearly different from Herpesvirus cyprini (CHV), the most commonly known herpesvirus from cyprinid fish. The koi herpesvirus (KHV) has 31 virion polypeptides. Twelve of the virion polypeptides of KHV have similar molecular weights to those of CHV and 10 are similar to those of channel catfish virus (CCV). Both virion polypeptide and restriction fragment length polymorphism analyses of genomic DNA showed that the first KHV isolates from Israel and the USA were identical. In contrast, the genomic DNA restriction fragments clearly distinguish KHV from CHV and CCV. A polymerase chain reaction (PCR) assay to detect the virus in koi tissues was developed with sequences obtained from 1 restriction fragment of KHV DNA. The PCR assay effectively detected a 484 base pair sequence from KHV but did not amplify genomic DNA from either CHV or CCV. The PCR assay detected as little as 1 pg of KHV DNA mixed with 100 ng of host DNA. Viral sequences were amplified from koi obtained from field collections and from koi that were experimentally exposed to 10(2) TCID50 ml(-1) of KHV via the waterborne route. All KHV exposed fish dying of infection between 8 and 10 d post exposure or surviving to 14 d post exposure were found to be positive by PCR, while unexposed control koi were all negative. The assay also showed the presence of KHV DNA in tissues of koi obtained from farms in Israel. The PCR assay should assist virus isolation procedures and histologic and electron microscopic analyses now commonly used to detect KHV infection. Current studies are examining the possibility of using the PCR to detect KHV DNA in live fish and the relative sensitivity and specificity of the KHV PCR assay compared with other diagnostic tests.
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► UV irradiation at doses of 10–80mJ/cm2 inactivated waterborne infective stages of Myxobolus cerebralis. ► Attachment and penetration of infective stages of M. cerebralis to rainbow ...trout were unaffected by UV irradiation. ► UV-irradiated M. cerebralis initially replicated but then aborted development in rainbow trout. ► UV-irradiated M. cerebralis provided protection to subsequent exposures to fully infective parasites.
Myxobolus cerebralis is a microscopic metazoan parasite (Phylum Myxozoa: Myxosporea) associated with salmonid whirling disease. There are currently no vaccines to minimise the serious negative economical and ecological impacts of whirling disease among populations of salmonid fish worldwide. UV irradiation has been shown to effectively inactivate the waterborne infective stages or triactinomyxons of M. cerbralis in experimental and hatchery settings but the mechanisms by which the parasite is compromised are unknown. Treatments of triactinomyxons with UV irradiation at doses from 10 to 80mJ/cm2 either prevented (20–80mJ/cm2) or significantly inhibited (10mJ/cm2) completion of the parasite life cycle in experimentally exposed juvenile rainbow trout (Oncorhynchus mykiss). However, even the highest doses of UV irradiation examined (80mJ/cm2) did not prevent key steps in the initiation of parasite infection, including attachment and penetration of the epidermis of juvenile rainbow trout as demonstrated by scanning electron and light microscopy. Furthermore, replication of UV-treated parasites within the first 24h following invasion of the caudal fin was suggested by the detection of concentrations of parasite DNA by quantitative PCR comparable to that among fish exposed to an equal concentration of untreated triactinomyxons. Subsequent development of parasites treated with an 80mJ/cm2 dose of UV irradiation however, was impaired as demonstrated by the decline and then lack of detection of parasite DNA; a trend beginning at 10days and continuing thereafter until the end of the study at 46days post parasite exposure. Treatments of triactinomyxons with a lower dose of UV irradiation (20mJ/cm2) resulted in a more prolonged survival with parasite DNA detected, although at very low concentrations, in fish up to 49days post parasite exposure. The successful invasion but only short-term survival of parasites treated with UV in rainbow trout resulted in a protective response to challenges with fully infective triactinomyxons. Prior treatments of juvenile rainbow trout with UV-treated triactinomyxons (10 and 20mJ/cm2) resulted in a reduced prevalence of infection and significantly lower concentrations of cranial myxospores (two direct measures of the severity of whirling disease) compared with trout receiving no prior treatments when assessed 5months post parasite exposure to fully infective triactinomyxons.
The rosette agent is an obligate intracellular parasite that causes morbidity and mortality in salmonid fish. In laboratory cultures, the spore stage (2–6 μm diam.) replicates in a salmonid cell line ...by sequential asexual division, giving rise to daughter cells. If infected cell cultures are transferred to distilled water, the spore stage undergoes internal division to give rise to at least 5 cells each of which develops into a uniflagellated zoospore with a body of approximately 2 μm and a flagellum approximately 10 μm long. Zoosporulation does not occur in cell culture medium alone, artificial seawater, or phosphate-buffered saline. This parasite is currently classified as a member of the Class Mesomycetozoea (formerly Ichthyosporea) based on phylogenetic analyses of the small subunit ribosomal DNA of three different isolates from fish. Given these new morphological observations combined with the available molecular phylogenetic data on other mesomycetozoeans, we propose to classify the rosette agent as Sphaerothecum destruens, n. g., n. sp. This new genus has unique features including (1) intracellular development of spore stages in various organs eliciting a host granulomatous response; and (2) the differentiation of mature spores into multiple, flagellated zoospores. Taken together, these characteristics clearly distinguish it from the closely related genera Dermocystidium and Rhinosporidium.
The synthesis of a series of phenethanolamine aniline agonists that contain an aniline ring on the right-hand side of the molecule substituted at the meta position with a benzoic acid or a pyridyl ...carboxylate is described. Several of the analogues (e.g., 34, 36−38, 40, and 44) have high β3 adrenergic receptor (AR) potency and selectivity against β1 and β2 ARs in Chinese hamster ovary (CHO) cells expressing β ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives of at least 1.5 h. Among the compounds described herein, the 3,3‘-biarylaniline carboxylate derivatives 36, 38 and the phenylpyridyl derivative 44 demonstrated outstanding in vitro properties and reasonable dog pharmacokinetic profiles. These three analogues also showed dose dependent β3 AR mediated responses in mice. The ease of synthesis and superior dog pharmacokinetics of compound 38 relative to that of 44 in combination with its in vitro profile led us to choose this compound as a development candidate for the treatment of type 2 diabetes.
Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Diagnostic methods were used to identify and quantify Myxobolus cerebralis, a ...myxozoan parasite of salmonid fish. In this study, 7-week-old, pathogen-free rainbow trout (Oncorhynchus mykiss) were experimentally infected with M. cerebralis and at 7 months postinfection were evaluated with 5 diagnostic assays: 1) pepsin-trypsin digest (PTD) to detect and enumerate spores found in cranial cartilage, 2) 2 different histopathology grading scales that provide a numerical score for severity of microscopic lesions in the head, 3) a conventional single-round polymerase chain reaction (PCR), 4) a nested PCR assay, and 5) a newly developed quantitative real-time TaqMan PCR. There were no significant differences (P > 0.05) among the 5 diagnostic assays in distinguishing between experimentally infected and uninfected control fish. The 2 histopathology grading scales were highly correlated (P
Whirling disease: re-emergence among wild trout Hedrick, Ronald P.; Adkison, Mark A.; El-Matbouli, Mansour ...
Immunological reviews,
December 1998, Letnik:
166, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Whirling disease of rainbow trout is caused by Myxobolus cerebralis, a myxozoan parasite possessing a life cycle well adapted to the natural environments where salmonid fish are found. Whirling ...disease was first described in Europe in 1898 among farmed rainbow trout but recent occurrences have been devastating to wild trout in North America. The disease is considered a major threat to survival of wild rainbow trout in the intermountain west of the United States. Difficulties in containing the spread and potentially eliminating the pathogen are tied to features of a complex life cycle involving two hosts, the salmonid fish and an aquatic oligochaete. Details of the morphologic development of the parasite have been described in each host but only now are we beginning to appreciate the breadth of interactions between these developmental forms and the sequential responses of the host. Fundamental mechanisms of the recognition and attachment of the parasite to the hosts, how host immunity is evaded and the unknown influences of environmental factors all contribute to a rather poor understanding of the biology of the parasite. Although the biology and ecology of the salmonid host are better known than for the oligochaete host, our knowledge is inadequate to interpret their complex interactions with the parasite. This uncertainty precludes the development of effective management activities designed to enhance the viability and productivity of wild trout populations in M. cerebralis‐ positive river systems. Improving our understanding of the hosts, the parasite and the environmental factors determining their interaction should provide for more focused and effective control methods for containing the spread and devastating effects whirling disease is causing to our wild trout populations.
An enzyme linked immunosorbent assay(ELISA)detected the presence of anti-koi herpesvirus(KHV)antibodies in the serum of koi or colored carp(Cyprinus carpio)following either natural or experimental ...exposures to KHV.Concentrations of anti-KHV antibodies were detected at serum dilutions as great as 1:62, 500 in a population of koi kept in virus-free water for 1 year following a naturally occurring outbreak due to KHV.At serum dilutions less than 1:2, 500 cross reactions with a second herpes-like viral agent Cyprinid herpesvirus 1 (CyHV-1) was detected in serum from both experimentally and naturally KHV exposed koi. Passive immunization by administration of anti-KHV antibodies from koi recovered from previous virus infections to naive koi provided only partial and transient protection to waterborne challenges with KHV. Koi that maintained high levels of serum anti-KHV antibodies after 1 year in virus-free water are deemed as suspect carriers of the virus. The identification of suspect carriers by screening of koi and common carp populations, including potential broodstocks, with the KHV ELISA should improve the ability to control this important viral pathogen.
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