Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 82
Filter
1.
Support Care Cancer ; 28(7): 3165-3170, 2020 Jul.
Article in English | MEDLINE | ID: mdl-31707501

ABSTRACT

BACKGROUND: It is important to assess the prevalence of hypogonadism and to identify the correlation between hypogonadism and cancer treatment with quality of life (QoL) in germ cell tumor (GCT) survivors. METHODS: This is a single-center, non-randomized, prospective observational study in GCT survivors 18-50 years of age previously treated with surgery and chemotherapy (S+C) or surgery alone (S). Patients completed a validated QoL questionnaire at baseline, 3, and 6 months. Patients received supplemental testosterone as clinically indicated. Mean QoL scores were compared between two treatment groups (S+C vs. S) and within each group between survivors with hypogonadism (serum testosterone level < 300 ng/dL) versus without. A two-sided independent-groups t test was used to compare means. RESULTS: We evaluated 199 GCT survivors. At baseline, the prevalence of biochemical hypogonadism was 48% overall, 51% in S+C group, and 45% in S group (p = .4). Overall, there was no statistically significant difference in QoL scores between S+C and C groups, except the S+C group exhibited greater modified Aging Male Symptoms (AMS) at baseline and 6 months. Patients with hypogonadism reported more fatigue, poor sleep quality, and worse general health at baseline. There were no statistical differences in mean QOL scores between patients with testosterone < 300 ng/dL who received testosterone supplementation and who did not. CONCLUSION: A significant proportion of GCT survivors have low testosterone levels after platinum-based chemotherapy and surgery as well as with just surgery alone. GCT survivors treated with platinum-based chemotherapy exhibited more symptoms related to male aging compared with survivors treated with surgery alone.


Subject(s)
Hypogonadism/epidemiology , Neoplasms, Germ Cell and Embryonal/epidemiology , Testicular Neoplasms/epidemiology , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cancer Survivors/statistics & numerical data , Humans , Hypogonadism/blood , Male , Middle Aged , Neoplasms, Germ Cell and Embryonal/blood , Neoplasms, Germ Cell and Embryonal/drug therapy , Neoplasms, Germ Cell and Embryonal/surgery , Organoplatinum Compounds/administration & dosage , Prevalence , Prospective Studies , Quality of Life , Surveys and Questionnaires , Testicular Neoplasms/blood , Testicular Neoplasms/drug therapy , Testicular Neoplasms/surgery , Testosterone/administration & dosage , Testosterone/blood , Young Adult
2.
J Community Health ; 43(3): 534-542, 2018 06.
Article in English | MEDLINE | ID: mdl-29188464

ABSTRACT

Sleep-related infant deaths are a leading cause of infant mortality in Georgia, and these deaths are largely associated with unsafe sleep practices among caregivers. In early 2016, the Georgia Department of Public Health launched the Georgia Safe to Sleep Hospital Initiative, providing hospitals with safe infant sleep information and educational materials to be distributed to families and newborns. This study examined the knowledge and behaviors of a sample of Georgia parents after the implementation of the Hospital Initiative and identified the family characteristics and intervention components most closely associated with the knowledge and practice of safe infant sleep. The primary caretakers of all infants born in Georgia from August to October 2016 were invited to complete a web-based survey 1 month after hospital discharge. The final sample size included 420 parents of newborns, and the primary outcomes assessed included two measures of knowledge and four measures of infant sleep behaviors regarding infant sleep position and location. Most respondents demonstrated knowledge of the correct recommended sleep position (90%) and location (85%). Logistic regression revealed that receipt of information in the hospital was significantly correlated with safe sleep behaviors, and infant sleep habits tended to influence safe sleep practices. Additionally, Medicaid parents receiving bassinets from the hospital were 74% less likely to bed share (OR 0.26; 95% CI 0.007). Implementation of a statewide hospital initiative was associated with high levels of parental knowledge and behavior and may have been successful in reducing the practice of bed sharing among Medicaid parents.


Subject(s)
Beds , Health Knowledge, Attitudes, Practice , Health Promotion/methods , Infant Health , Parents , Georgia , Humans , Infant , Infant Equipment , Infant, Newborn , Safety , Sleep , Surveys and Questionnaires
3.
Pathology ; 49(7): 721-730, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29102042

ABSTRACT

Cancer stem-like cells are highly tumourigenic cells that can repopulate entire tumours after apparent successful treatment. Recent evidence suggests they interact with other cells in the tumour microenvironment, including immune cell subsets, to enhance their survival. The aim of this study was to determine whether the expression of immune cell markers in primary colon cancer impacts the prognostic significance of cancer stem-like cell marker expression. Immunohistochemistry was used to assess the expression of putative stem cell markers (ALDH1, CD44v6, CD133, Lgr5, SOX2) and immune cell related markers (CD3, CD8, FoxP3, PD-L1) in 104 patients with stage III colon cancer. Associations of marker expression with overall and cancer-specific survival were determined using Kaplan-Meier analysis. High SOX2 expression in the central tumour area was found to be an independent factor for poor cancer-specific survival [hazard ratio (HR) 6.19; 95% confidence interval (CI) 2.24-17.14; p=0.001]. When immune-related factors were taken into account, patients categorised as SOX2low/FoxP3high had good outcome (HR 0.164; 95%CI 0.066-0.406; p<0.0001) whereas patients categorised as SOX2high/PD-L1low had poor outcome (HR 8.992; 95%CI 3.397-23.803; p<0.0001). The prognostic value of the SOX2 cancer stem-like cell marker in colon cancer is modified by expression of immune-cell related factors FoxP3 and PD-L1.


Subject(s)
AC133 Antigen/metabolism , B7-H1 Antigen/metabolism , Biomarkers, Tumor/metabolism , Colonic Neoplasms/diagnosis , Forkhead Transcription Factors/metabolism , Neoplastic Stem Cells/pathology , SOXB1 Transcription Factors/metabolism , Aged , Aged, 80 and over , CD3 Complex/metabolism , Cohort Studies , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Middle Aged , Neoplastic Stem Cells/metabolism , Prognosis , Proportional Hazards Models , Retrospective Studies , Tissue Array Analysis , Tumor Microenvironment
4.
Pathology ; 49(1): 24-29, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27913042

ABSTRACT

Analysis of immunohistochemical expression is often a subjective and semiquantitative process that can lead to the inconsistent reporting of results. To assess the effect that region selection and quantification method have on results, five different cancer stem cell markers were used in this study to compare tissue scoring with digital analysis methods that used three different tissue annotation methods. Samples of tumour and normal mucosa were used from 10 consecutive stage II colon cancer patients and stained for the putative cancer stem cell markers ALDH1, CD44v6, CD133, Lgr5 and SOX2. Tissue scoring was found to have considerably different results to digital analysis with the three different digital methods harbouring concordant results overall. However, SOX2 on normal tissue and CD133 on tumour and normal tissue produced discordant results which could be attributed to the different regions of tissue that were analysed. It is important that quantification method and selection of analysis areas are considered as part of study design to ensure that reproducible and consistent results are reported in the literature.


Subject(s)
Biomarkers, Tumor/metabolism , Colonic Neoplasms/metabolism , Immunohistochemistry , Neoplastic Stem Cells/cytology , Aldehyde Dehydrogenase 1 Family , Antigens, CD/metabolism , Glycoproteins/metabolism , Humans , Immunohistochemistry/methods , Isoenzymes/metabolism , Retinal Dehydrogenase/metabolism
5.
Radiat Prot Dosimetry ; 170(1-4): 218-20, 2016 Sep.
Article in English | MEDLINE | ID: mdl-26362139

ABSTRACT

A simple in vitro dissolution test was used to provide a semi-quantitative comparison of the relative dissolution rates of samples of radioactive materials used at Atomic Weapons Establishment in a lung fluid surrogate (Ringer's solution). A wide range of dissolution rates were observed for aged legacy actinides, freshly produced actinide alloys and actinides from waste management operations.


Subject(s)
Actinoid Series Elements/analysis , Air Pollutants, Radioactive/analysis , Alloys/analysis , Isotonic Solutions/chemistry , Lung/radiation effects , Radiation Monitoring/methods , Radioactive Waste/analysis , Americium/analysis , Gamma Rays , Humans , Hydrogen-Ion Concentration , Models, Biological , Nuclear Warfare , Plutonium/analysis , Radiation Monitoring/instrumentation , Ringer's Solution , Solubility , Spectrum Analysis/methods , Temperature , United Kingdom , Uranium/analysis
6.
Br J Cancer ; 113(12): 1677-86, 2015 Dec 22.
Article in English | MEDLINE | ID: mdl-26645238

ABSTRACT

BACKGROUND: Foxp3+ regulatory T cells (Tregs) play a vital role in preventing autoimmunity, but also suppress antitumour immune responses. Tumour infiltration by Tregs has strong prognostic significance in colorectal cancer, and accumulating evidence suggests that chemotherapy and radiotherapy efficacy has an immune-mediated component. Whether Tregs play an inhibitory role in chemoradiotherapy (CRT) response in rectal cancer remains unknown. METHODS: Foxp3+, CD3+, CD4+, CD8+ and IL-17+ cell density in post-CRT surgical samples from 128 patients with rectal cancer was assessed by immunohistochemistry. The relationship between T-cell subset densities and clinical outcome (tumour regression and survival) was evaluated. RESULTS: Stromal Foxp3+ cell density was strongly associated with tumour regression grade (P=0.0006). A low stromal Foxp3+ cell density was observed in 84% of patients who had a pathologic complete response (pCR) compared with 41% of patients who did not (OR: 7.56, P=0.0005; OR: 5.27, P=0.006 after adjustment for presurgery clinical factors). Low stromal Foxp3+ cell density was also associated with improved recurrence-free survival (HR: 0.46, P=0.03), although not independent of tumour regression grade. CONCLUSIONS: Regulatory T cells in the tumour microenvironment may inhibit response to neoadjuvant CRT and may represent a therapeutic target in rectal cancer.


Subject(s)
Forkhead Transcription Factors/immunology , Rectal Neoplasms/drug therapy , Rectal Neoplasms/radiotherapy , T-Lymphocytes, Regulatory/immunology , Aged , Chemotherapy, Adjuvant , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Radiotherapy, Adjuvant , Treatment Outcome
7.
J Fish Biol ; 86(6): 1811-29, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25943427

ABSTRACT

The objectives of this work were to quantify the spatial and temporal distribution of the occurrence of anadromous fishes (alewife Alosa pseudoharengus, blueback herring Alosa aestivalis and American shad Alosa sapidissima) in the stomachs of demersal fishes in coastal waters of the north-west Atlantic Ocean. Results show that anadromous fishes were detectable and quantifiable in the diets of common marine piscivores for every season sampled. Even though anadromous fishes were not the most abundant prey, they accounted for c. 5-10% of the diet by mass for several marine piscivores. Statistical comparisons of these data with fish diet data from a broad-scale survey of the north-west Atlantic Ocean indicate that the frequency of this trophic interaction was significantly higher within spatially and temporally focused sampling areas of this study than in the broad-scale survey. Odds ratios of anadromous predation were as much as 460 times higher in the targeted sampling as compared with the broad-scale sampling. Analyses indicate that anadromous prey consumption was more concentrated in the near-coastal waters compared with consumption of a similar, but more widely distributed species, the Atlantic herring Clupea harengus. In the context of ecosystem-based fisheries management, the results suggest that even low-frequency feeding events may be locally important, and should be incorporated into ecosystem models.


Subject(s)
Diet/veterinary , Fishes , Food Chain , Animals , Atlantic Ocean , Conservation of Natural Resources , Fisheries , Gastrointestinal Contents , Maine , Predatory Behavior , Seasons
8.
Hernia ; 17(2): 259-61, 2013 Apr.
Article in English | MEDLINE | ID: mdl-21786146

ABSTRACT

An exhaustive search of the literature using the Pub Med database revealed no reports of round ligament lipomas mimicking acute appendicitis in pregnant patients. There are relatively few articles on round ligament lipomas and even less on round ligament lipomas during pregnancy. This case report is on a 27-year-old 24-week pregnant female who presented with signs and symptoms similar to acute appendicitis who in fact had a large right pelvic round ligament lipoma that was causing her pain.


Subject(s)
Adnexal Diseases/diagnosis , Appendicitis/diagnosis , Genital Neoplasms, Female/diagnosis , Lipoma/diagnosis , Pregnancy Complications, Neoplastic/diagnosis , Round Ligament of Uterus , Abdominal Pain/etiology , Adnexal Diseases/complications , Adnexal Diseases/surgery , Adult , Diagnosis, Differential , Female , Genital Neoplasms, Female/complications , Genital Neoplasms, Female/surgery , Gynecologic Surgical Procedures/methods , Hernia, Inguinal/complications , Hernia, Inguinal/surgery , Humans , Laparoscopy , Lipoma/surgery , Pregnancy , Pregnancy Complications, Neoplastic/surgery , Pregnancy Trimester, Second , Round Ligament of Uterus/surgery
9.
J Appl Toxicol ; 32(5): 350-7, 2012 May.
Article in English | MEDLINE | ID: mdl-22447616

ABSTRACT

Nanoparticles can be formed following degradation of medical devices such as orthopedic implants. To evaluate the safety of titanium alloy orthopedic materials, data are needed on the long-term distribution and tissue effects of injected titanium nanoparticles in experimental animals. In this study, we evaluated the tissue distribution and histopathological effects of titanium dioxide (TiO(2)) nanoparticles (approximately 120 nm diameter) in mice after intravenous (i.v.; 56 or 560 mg kg(-1) per mouse) or subcutaneous (s.c.; 560 or 5600 mg kg(-1) per mouse) injection on two consecutive days. Animals were examined 1 and 3 days, and 2, 4, 12 and 26 weeks after the final injection. When examined by light microscopy, particle agglomerates identified as TiO(2) were observed mainly in the major filtration organs - liver, lung and spleen - following i.v. injection. Particles were still observed 26 weeks after injection, indicating that tissue clearance is limited. In addition, redistribution within the histological micro-compartments of organs, especially in the spleen, was noted. Following s.c. injection, the largest particle agglomerates were found mainly in the draining inguinal lymph node, and to a lesser extent, the liver, spleen and lung. With the exception of a foreign body response at the site of s.c. injection and the appearance of an increased number of macrophages in the lung and liver, there was no histopathological evidence of tissue damage observed in any tissue at any time point.


Subject(s)
Liver/metabolism , Lung/metabolism , Lymph Nodes/metabolism , Nanoparticles , Titanium , Animals , Female , Injections, Intravenous , Injections, Subcutaneous , Liver/pathology , Lung/pathology , Lymph Nodes/pathology , Mice , Mice, Inbred BALB C , Nanoparticles/administration & dosage , Nanoparticles/toxicity , Spleen/metabolism , Spleen/pathology , Time Factors , Tissue Distribution , Titanium/administration & dosage , Titanium/metabolism , Titanium/toxicity
10.
J Fish Biol ; 80(1): 110-30, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22220893

ABSTRACT

The entire mitochondrial genome of the striped bass Morone saxatilis was sequenced together with the mitochondrial (mt) control regions of the white bass Morone chrysops, white perch Morone americana, yellow bass Morone mississippiensis, spotted seabass Dicentrarchus punctatus, European seabass Dicentrarchus labrax and the Japanese seabass Lateolabrax japonicus. The resultant 17 580 base pair circular genome of M. saxatilis contains 38 genes (13 proteins, 23 transfer RNAs and two ribosomal RNAs) and a control region bordered by the proline and phenylalanine mitochondrial tRNAs. Gene arrangement was similar to other vertebrates, except that the mt-nd6 gene was found within the control region rather than the canonical position between the mt-nd5 and mt-cyb genes. This translocation was found in all the Morone and Dicentrarchus species studied without functional copies or pseudogenes in the ancestral position. In L. japonicus, the mt-nd6 gene was found in the canonical position without evidence of an mt-nd6 gene in the control region. A Bayesian analysis of these and published mt-nd6 sequences from 45 other Perciformes grouped the Morone and Dicentrarchus species monophyletically with a probability of 1·00 with respect to L. japonicus and all other perciforms, and placed the Dicentrarchus species in the basal position. These data reinforce current placement of L. japonicus outside the Moronidae and provide a clear evolutionary character to define this family. The phylogeny of the Moronidae presented here also supports the hypothesis of an anadromous common ancestor to this family that gave rise to the North American estuarine and freshwater species. A series of tandem repeats previously reported in M. saxatilis was found in the control region of all Morone species between the mt-nd6 and mt-rnr1 genes, but not in either Dicentrarchus species, which reinforces the continued use of these two separate genera.


Subject(s)
Bass/classification , Bass/genetics , Genes, Mitochondrial/genetics , NADH Dehydrogenase/genetics , Phylogeny , Translocation, Genetic , Animals , Gene Order , Genome, Mitochondrial , Molecular Sequence Data
11.
J Radiol Prot ; 31(4): 445-52, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22090041

ABSTRACT

The Atomic Weapons Establishment (AWE) has routinely used high purity germanium crystals for in vivo monitoring, detection and measurement of radionuclides in the chest, wounds and whole body of personnel over the past 30 years. However, recent organisational changes have resulted in the relocation and modification of this capability. Hence, this paper reviews and compares the performance of the original twin six crystal detector arrays (contained within environmental radiation shielding), that were first used at AWE in 1980, with the latest unshielded systems that employ smaller numbers of larger crystals. It has been concluded that the required sensitivity of 20 mSv for actinides in the chest was achieved using the recently procured twin dual crystal detector arrays outside of the conventional heavy duty environmental radiation shield used with the original system. Sensitivities of around 1 µSv, for fission and activation products in the whole body and around 1 mSv, for actinides in wounds, were achieved using single large collimated, but otherwise unshielded, detectors.


Subject(s)
Actinoid Series Elements/analysis , Radioisotopes/analysis , Warfare , Whole-Body Counting/instrumentation , Equipment Design , Equipment Failure Analysis , Humans , Reproducibility of Results , Sensitivity and Specificity , United Kingdom
12.
Gene Ther ; 18(9): 867-73, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21472007

ABSTRACT

We previously demonstrated that transient stromal cell-derived factor-1 alpha (SDF-1) improved cardiac function when delivered via cell therapy in ischemic cardiomyopathy at a time remote from acute myocardial infarction (MI) rats. We hypothesized that non-viral gene transfer of naked plasmid DNA-expressing hSDF-1 could similarly improve cardiac function. To optimize plasmid delivery, we tested SDF-1 and luciferase plasmids driven by the cytomegalovirus (CMV) promoter with (pCMVe) or without (pCMV) translational enhancers or α myosin heavy chain (pMHC) promoter in a rodent model of heart failure. In vivo expression of pCMVe was 10-fold greater than pCMV and pMHC expression and continued over 30 days. We directly injected rat hearts with SDF-1 plasmid 1 month after MI and assessed heart function. At 4 weeks after plasmid injection, we observed a 35.97 and 32.65% decline in fractional shortening (FS) in control (saline) animals and pMHC-hSDF1 animals, respectively, which was sustained to 8 weeks. In contrast, we observed a significant 24.97% increase in animals injected with the pCMVe-hSDF1 vector. Immunohistochemistry of cardiac tissue revealed a significant increase in vessel density in the hSDF-1-treated animals compared with control animals. Increasing SDF-1 expression promoted angiogenesis and improved cardiac function in rats with ischemic heart failure along with evidence of scar remodeling with a trend toward decreased myocardial fibrosis. These data demonstrate that stand-alone non-viral hSDF-1 gene transfer is a strategy for improving cardiac function in ischemic cardiomyopathy.


Subject(s)
Chemokine CXCL12/genetics , Gene Transfer Techniques , Genetic Therapy/methods , Heart Failure/therapy , Plasmids , Animals , Chronic Disease , Genetic Vectors/metabolism , Heart Failure/genetics , Heart Failure/physiopathology , Myocardial Infarction/therapy , Myocardial Ischemia/therapy , Myocardium , Neovascularization, Physiologic , Promoter Regions, Genetic , Rats , Rats, Inbred Lew , Stromal Cells/metabolism , Time Factors
13.
J Radiol Prot ; 30(4): 789-96, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21149939

ABSTRACT

AWE has participated in two rounds of radionuclide measurement proficiency testing using 200 l waste drum standards prepared by the National Physical Laboratory (NPL). The results achieved, using the SNAP (spectral non-destructive assay platform) system, were generally within a few per cent of the true activities and gave confidence in the ability to allocate wastes to the correct categories in accordance with national legislation. This is important for reasons of public safety and also for minimisation of the amount of RSA (Radioactive Substances Act) Exempt material categorised as LLW (low level waste) as the UK's LLW storage capacity diminishes.


Subject(s)
Radioactive Waste/analysis , Radioisotopes/analysis , Software
14.
J Radiol Prot ; 29(3): 385-92, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19690359

ABSTRACT

Previous studies have shown that automated radioactive waste assay techniques, such as segmented gamma scanner (SGS) and automated qualitative and quantitative (AQ2), have severely underestimated fissile material due to either the malfunction or absence of appropriate lump correction routines. This paper examines the application of manual techniques, such as Monte Carlo N particle (MCNP) and spectral non-destructive assay platform (SNAP) software, to lump corrections in plutonium (Pu), enriched uranium (EU) and depleted uranium (DU) waste streams. Excellent results have been obtained when comparing MCNP with SNAP and applying the SNAP lump correction routine to a range of simulated and typical wastes containing various Pu and EU lump sizes. It has been concluded that the need for lump corrections was relatively rare and usually apparent from abnormal gamma ray peak area ratios, since most AWE waste streams are only lightly shielded.


Subject(s)
Algorithms , Artifacts , Radiation Protection/methods , Radioactive Waste/analysis , Radioisotopes/analysis , Radiometry/methods , Radiation Dosage , Sensitivity and Specificity
15.
J Radiol Prot ; 29(2): 201-10, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19454791

ABSTRACT

In 2002 a paper was presented at the 43rd Annual Meeting of the Institute of Nuclear Materials Management (INMM) on the assay of low level plutonium (Pu) in soft drummed waste (Miller 2002 INMM Ann. Meeting (Orlando, FL, 23-27 July 2002)). The technique described enabled the Atomic Weapons Establishment (AWE), at Aldermaston in the UK, to meet the stringent Low Level Waste Repository at Drigg (LLWRD) conditions for acceptance for the first time. However, it was initially applied to only low density waste streams because it relied on measuring the relatively low energy (60 keV) photon yield from Am-241 during growth. This paper reviews the results achieved when using the technique to assay over 10,000 waste packages and presents the case for extending the range of application to denser waste streams.


Subject(s)
Algorithms , Nuclear Warfare , Plutonium/analysis , Radiation Monitoring/methods , Radiation Protection/methods , Radioactive Waste/analysis , Radioactive Waste/prevention & control , Radiation Monitoring/standards , Radiation Protection/standards , United Kingdom
16.
Am J Physiol Heart Circ Physiol ; 295(1): H266-72, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18487435

ABSTRACT

Cold increases cutaneous vasoconstriction by unmasking the contractile activity of alpha(2C)-adrenoceptors (alpha(2C)-ARs) in vascular smooth muscle cells (VSMCs), which is mediated by the cold-induced mobilization of alpha(2C)-ARs from the transGolgi to the cell surface. The expression of alpha(2C)-ARs in human cutaneous VSMCs is under dual regulation by cyclic AMP: gene transcription is inhibited by cyclic AMP acting through protein kinase A but is increased by cyclic AMP acting through the exchange protein directly activated by cyclic AMP (EPAC) and the GTP-binding protein Rap1. Experiments were performed to further characterize the Rap1 signaling pathway. Forskolin (10 muM), the selective EPAC activator, 8-pCPT-2'-O-Me-cyclic AMP (CMC; 100 microM), or a constitutively active mutant of Rap1 (Rap1CA) increased the activity of c-Jun NH(2)-terminal kinase (JNK) in human cutaneous VSMCs. This was associated with the increased phosphorylation of c-Jun and activation of an activator protein (AP)-1 reporter construct, which were inhibited by the JNK inhibitor SP600125 (3 microM). Rap1CA increased the activity of an alpha(2C)-AR promoter-reporter construct, which was inhibited by SP600125 (3 microM) or by the mutation of an AP-1 binding site in the alpha(2C)-AR promoter. Furthermore, forskolin (10 microM) or CMC (100 microM) increased the expression of the alpha(2C)-AR protein, and these effects were inhibited by SP600125 (3 microM). Therefore, cyclic AMP increases the expression of alpha(2C)-ARs in cutaneous VSMCs by activating a novel Rap1 signaling pathway, mediated by the activation of JNK, AP-1, and the subsequent transcriptional activation of the alpha(2C)-AR gene. By increasing the expression of cold-responsive alpha(2C)-ARs, this pathway may contribute to enhanced cold-induced vasoconstriction in the cutaneous circulation, including Raynaud's phenomenon.


Subject(s)
Cyclic AMP/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Muscle, Smooth, Vascular/metabolism , Receptors, Adrenergic, alpha-2/metabolism , Signal Transduction , Skin/blood supply , Telomere-Binding Proteins/metabolism , Anthracenes/pharmacology , Cells, Cultured , Cold Temperature , Colforsin/pharmacology , Cyclic AMP/analogs & derivatives , Extracellular Signal-Regulated MAP Kinases/metabolism , Guanine Nucleotide Exchange Factors/metabolism , Humans , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/enzymology , Mutation , Phosphorylation , Promoter Regions, Genetic , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-jun/metabolism , Receptors, Adrenergic, alpha-2/drug effects , Receptors, Adrenergic, alpha-2/genetics , Shelterin Complex , Signal Transduction/drug effects , Telomere-Binding Proteins/genetics , Transcription Factor AP-1/metabolism , Transcriptional Activation , Up-Regulation , Vasoconstriction
17.
Ecol Appl ; 18(1): 234-45, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18372569

ABSTRACT

Regime shifts are a feature of many ecosystems. During the last 40 years, intensive commercial exploitation and environmental changes have driven substantial shifts in ecosystem structure and function in the northwest Atlantic. In the Georges Bank-southern New England region, commercially important species have declined, and the ecosystem shifted to one dominated by economically undesirable species such as skates and dogfish. Aggregated abundance indices indicate a large increase of small and medium-sized elasmobranchs in the early 1980s following the decline of many commercial species. It has been hypothesized that ecological interactions such as competition and predation within the Georges Bank region were responsible for and are maintaining the "elasmobranch outburst" at the heart of the observed ecosystem shift. We offer an alternative hypothesis invoking population connectivity among winter skate populations such that the observed abundance increase is a result of migratory dynamics, perhaps with the Scotian Shelf (i.e., it is an open population). Here we critically evaluate the survey data for winter skate, the species principally responsible for the increase in total skate abundance during the 1980s on Georges Bank, to assess support for both hypotheses. We show that time series from different surveys within the Georges Bank region exhibit low coherence, indicating that a widespread population increase was not consistently shown by all surveys. Further, we argue that observed length-frequency data for Georges Bank indicate biologically unrealistic population fluctuations if the population is closed. Neither finding supports the elasmobranch outburst hypothesis. In contrast, survey time series for Georges Bank and the Scotian Shelf are negatively correlated, in support of the population connectivity hypothesis. Further, we argue that understanding the mechanisms of ecosystem state changes and population connectivity are needed to make inferences about both the causes and appropriate management responses to large-scale system change.


Subject(s)
Ecosystem , Elasmobranchii/growth & development , Animals , Population Growth
18.
J Appl Toxicol ; 28(7): 815-28, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18418843

ABSTRACT

Limitations of existing biomarkers to detect liver injury in experimental animals highlight the need for additional tools to predict human toxicity. The utility of cytochrome c (cyt c) as a biomarker in serum and urine was evaluated in two rodent liver injury models. Adult Sprague-Dawley rats treated with acetaminophen or D-galactosamine (GalN) showed dose- and time-dependent histomorphological changes and TUNEL staining in liver consistent with hepatocellular necrosis, apoptosis and inflammation up to 72 h. Matching changes in serum alanine transaminase (ALT), aspartate transaminase (AST) and cyt c peaked at 24 h for either drug at the highest dose, cyt c falling rapidly at 48 hours with ALT and AST remained high. Intracellular transit of cyt c from mitochondria to the cytoplasm in damaged hepatocytes, and then to peripheral circulation, was observed by immunohistochemistry. Correlation coefficients between cyt c and serum diagnostic tests indicate the liver to be the primary source of cyt c. Urinary analysis for cyt c revealed time-dependent increase at 6 h, peaking at 24 h in GalN-treated rats in contrast with irregular patterns of urinary ALT and AST activity. Histological changes detected at 6 h preceded altered ALT, AST and cyt c at 12 and 18 h, respectively, in GalN-treated rats. These studies demonstrate cyt c to be a useful indicator of hepatic injury in rodents and support its utility as a non-invasive predictor of drug-induced hepatotoxicity, when utilized as a potential urinary biomarker.


Subject(s)
Biomarkers/metabolism , Chemical and Drug Induced Liver Injury/enzymology , Cytochromes c/metabolism , Acetaminophen/toxicity , Acute Disease , Animals , Apoptosis/drug effects , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Galactosamine/toxicity , Hepatocytes/drug effects , Hepatocytes/enzymology , Hepatocytes/pathology , Male , Mitochondria/drug effects , Mitochondria/enzymology , Necrosis/chemically induced , Rats , Rats, Sprague-Dawley
19.
Regul Toxicol Pharmacol ; 50(1): 87-97, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18069108

ABSTRACT

The use of transgenic rodents may overcome many limitations of traditional cancer studies. Regulatory perspectives continue to evolve as new models are developed and validated. The transgenic mouse, K6/ODC, develops epidermal tumors when exposed to genotoxic carcinogens. In this study, K6/ODC mice were evaluated for model fitness and health robustness in a 36-week study to determine oncogenic risk of residual DNA in vaccines from neoplastic cell substrates. K6/ODC and C57BL/6 mice were treated with T24-H-ras expression plasmid, carrier vector DNA, or saline topically or by subcutaneous injection. One group of K6/ODC mice received 7,12-dimethylbenz-[a]anthracene [DMBA] dermally. Only DMBA-treated mice developed papillomas by six weeks, increasing in incidence to 25 weeks. By week 11, many K6/ODC mice showed severe dehydration and dermal eczema. By week 32, (6/8) surviving K6/ODC mice showed loss of mobility and balance. Microscopic evaluation of tissues revealed dermal/sebaceous gland hyperplasia, follicular dystrophy, splenic atrophy, and amyloid deposition/neutrophilic infiltration within liver, heart, and spleen, in all K6/ODC mice. Pathology was not detected in C57BL/6 mice. Progressive adverse health, decreased survival, and failure to develop papillomas to the H-ras plasmid suggest that K6/ODC mice may be an inappropriate alternative model for detection of oncogenic DNA and pharmaceutical carcinogenicity testing.


Subject(s)
Disease Models, Animal , Drug Evaluation, Preclinical/methods , Keratin-6/genetics , Ornithine Decarboxylase/genetics , Skin Neoplasms/chemically induced , 9,10-Dimethyl-1,2-benzanthracene/administration & dosage , Animals , Carcinogenicity Tests/methods , Carcinogens/administration & dosage , Drug-Related Side Effects and Adverse Reactions , Kidney/drug effects , Kidney/pathology , Liver/drug effects , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Sarcoma Viruses, Murine/genetics , Skin Neoplasms/pathology , Spleen/drug effects , Spleen/pathology , Transfection
20.
Schizophr Res ; 68(2-3): 339-47, 2004 Jun 01.
Article in English | MEDLINE | ID: mdl-15099615

ABSTRACT

Data from the Scale of Prodromal Symptoms (SOPS) [Early Intervention in Psychotic Disorders, pp. 135-150] on 94 hitherto never-psychotic individuals were entered into a principal components analysis, revealing six components with an eigenvalue greater than 1.0. Based upon scree-plot analysis, further extractions were limited to three, then two, factors. Varimax rotation of the three-component extraction revealed factors with reasonable congruence with a priori content areas. All symptoms labeled as negative in the SOPS loaded on one factor, and four of five symptoms labeled as positive loaded on another. The remaining positive symptom, conceptual disorganization, has been found not to load with other positive-labeled symptoms in studies of schizophrenia using applicable instruments. All symptoms labeled as "general" in the SOPS loaded on a third factor, which appears to reflect the nonspecific psychological distress that might be expected in psychosis-naïve individuals experiencing the preliminary stages of a serious psychiatric disorder. The independence of this component from the positive and negative symptom factors suggests that the structure obtained suggests a clinical continuity between the at-risk presentations seen in this sample and established schizophrenia.


Subject(s)
Psychiatric Status Rating Scales/statistics & numerical data , Schizophrenia/diagnosis , Schizophrenic Psychology , Adolescent , Adult , Depressive Disorder/diagnosis , Depressive Disorder/psychology , Factor Analysis, Statistical , Female , Humans , Male , Principal Component Analysis , Psychometrics , Psychotic Disorders/diagnosis , Psychotic Disorders/psychology , Reproducibility of Results
SELECTION OF CITATIONS
SEARCH DETAIL
...