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1.
Ann Oncol ; 29(1): 215-222, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29045551

ABSTRACT

Background: Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however, >30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Patients and methods: A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS). Results: Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR = 3.21 (1.35-7.67); P = 0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR = 2.71 (1.11-6.63); P = 0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR = 3.23 (1.22-8.59); P = 0.019] whilst CAPRA itself was not significant [HR = 1.88, (0.52-6.77); P = 0.332]. A high concordance [100% (61.5-100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance. Conclusions: The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.


Subject(s)
Biopsy/methods , Prostatic Neoplasms/pathology , Prostatic Neoplasms/radiotherapy , Aged , Cohort Studies , Disease-Free Survival , Gene Expression Profiling , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Proportional Hazards Models , Prostatic Neoplasms/genetics , Reproducibility of Results , Retrospective Studies , Risk Assessment/methods , Risk Factors
2.
Neuroimage ; 149: 233-243, 2017 04 01.
Article in English | MEDLINE | ID: mdl-28159689

ABSTRACT

Computational anatomy studies typically use T1-weighted magnetic resonance imaging contrast to look at local differences in cortical thickness or grey matter volume across time or subjects. This type of analysis is a powerful and non-invasive tool to probe anatomical changes associated with neurodevelopment, aging, disease or experience-induced plasticity. However, these comparisons could suffer from biases arising from vascular and metabolic subject- or time-dependent differences. Differences in blood flow and volume could be caused by vasodilation or differences in vascular density, and result in a larger signal contribution of the blood compartment within grey matter voxels. Metabolic changes could lead to differences in dissolved oxygen in brain tissue, leading to T1 shortening. Here, we analyze T1 maps and T1-weighted images acquired during different breathing conditions (ambient air, hypercapnia (increased CO2) and hyperoxia (increased O2)) to evaluate the effect size that can be expected from changes in blood flow, volume and dissolved O2 concentration in computational anatomy studies. Results show that increased blood volume from vasodilation during hypercapnia is associated with an overestimation of cortical thickness (1.85%) and grey matter volume (3.32%), and that both changes in O2 concentration and blood volume lead to changes in the T1 value of tissue. These results should be taken into consideration when interpreting existing morphometry studies and in future study design. Furthermore, this study highlights the overlap in structural and physiological MRI, which are conventionally interpreted as two independent modalities.


Subject(s)
Brain Mapping/methods , Brain/diagnostic imaging , Adult , Brain/blood supply , Brain/metabolism , Cerebrovascular Circulation/physiology , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Young Adult
3.
Cereb Cortex ; 27(9): 4537-4548, 2017 09 01.
Article in English | MEDLINE | ID: mdl-27600851

ABSTRACT

The reciprocal cortico-cerebellar loops that underlie cerebellar contributions to motor and cognitive behavior form one of the largest systems in the primate brain. Work with non-human primates has shown that the dentate nucleus, the major output nucleus of the cerebellum, contains topographically distinct connections to both motor and non-motor regions, yet there is no evidence for how the cerebellar cortex connects to the dentate nuclei in humans. Here we used in-vivo sub-millimeter diffusion imaging to characterize this fundamental component of the cortico-cerebellar loop, and identified a pattern of superior motor and infero-lateral non-motor connectivity strikingly similar to that proposed by animal work. Crucially, we also present first evidence that the dominance for motor connectivity observed in non-human primates may be significantly reduced in man - a finding that is in accordance with the proposed increase in cerebellar contributions to higher cognitive behavior over the course of primate evolution.


Subject(s)
Cerebellar Nuclei/physiology , Magnetic Resonance Imaging , Nerve Net/physiology , Neural Pathways/physiology , Animals , Brain Mapping , Cerebellum/physiology , Humans , Magnetic Resonance Imaging/methods , Primates
4.
Cerebellum ; 13(3): 338-45, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24281851

ABSTRACT

A growing literature points to a specific role of the cerebellum in affect processing. However, understanding of affect processing disturbances following discrete cerebellar lesions is limited. We administered the Tübingen Affect Battery to assess recognition of emotional facial expression and emotional prosody in 15 patients with a cerebellar infarction and 10 age-matched controls. On emotional facial expression tasks, patients compared to controls showed impaired selection and matching of facial affect. On prosody tasks, patients showed marked impairments in naming affect and discriminating incongruencies. These deficits were more pronounced for negative affects. Our results confirm a significant role of the cerebellum in processing emotional recognition, a component of social cognition.


Subject(s)
Brain Ischemia/physiopathology , Emotions/physiology , Facial Expression , Pattern Recognition, Visual/physiology , Recognition, Psychology/physiology , Adult , Aged , Female , Humans , Image Processing, Computer-Assisted , Male , Middle Aged , Neuropsychological Tests
5.
Mol Psychiatry ; 18(2): 195-205, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22182935

ABSTRACT

Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750,000 high-quality genetic markers on a combined sample of ∼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63,000 case-control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.


Subject(s)
Bipolar Disorder/ethnology , Bipolar Disorder/genetics , Genetic Predisposition to Disease , Meta-Analysis as Topic , Polymorphism, Single Nucleotide , Ankyrins/genetics , Ankyrins/metabolism , Antidepressive Agents/pharmacology , Asian People/genetics , Cell Line, Transformed , Cytokines/genetics , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Gene Frequency , Genome-Wide Association Study , Humans , Lectins/genetics , Lectins/metabolism , Lithium Chloride/pharmacology , Male , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , RNA, Messenger/metabolism , Receptors, Prostaglandin/genetics , Receptors, Prostaglandin/metabolism , Time Factors , Valproic Acid/pharmacology , White People/genetics
6.
Nat Genet ; 42(2): 128-31, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20081856

ABSTRACT

The major mood disorders, which include bipolar disorder and major depressive disorder (MDD), are considered heritable traits, although previous genetic association studies have had limited success in robustly identifying risk loci. We performed a meta-analysis of five case-control cohorts for major mood disorder, including over 13,600 individuals genotyped on high-density SNP arrays. We identified SNPs at 3p21.1 associated with major mood disorders (rs2251219, P = 3.63 x 10(-8); odds ratio = 0.87; 95% confidence interval, 0.83-0.92), with supportive evidence for association observed in two out of three independent replication cohorts. These results provide an example of a shared genetic susceptibility locus for bipolar disorder and MDD.


Subject(s)
Chromosomes, Human, Pair 3/genetics , Genetic Loci/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Mood Disorders/genetics , Humans , Polymorphism, Single Nucleotide/genetics
7.
Psychiatr Genet ; 17(5): 274-86, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17728666

ABSTRACT

BACKGROUND: Linkage of bipolar disorder to a broad region on chromosome 13q has been supported in several studies including a meta-analysis on genome scans. Subsequent reports have shown that variations in the DAOA (G72) locus on 13q33 display association with bipolar disorder but these may not account for all of the linkage evidence in the region. OBJECTIVE: To identify additional susceptibility loci on 13q32-q33 by linkage disequilibrium mapping and explore the impact of phenotypic heterogeneity on association. METHODS: In the initial phase, 98 single nucleotide polymorphism (SNPs) located on 13q32-q33 were genotyped on 285 probands with bipolar disorder and their parents were drawn from families in the NIMH Genetics Initiative consortium for bipolar disorder (NIMH1-4) and two other series. Fine scale mapping using one family series (NIMH1-2) as the test sample was targeted on a gene that displayed the highest evidence of association. A secondary analysis of familial component phenotypes of bipolar disorder was conducted. RESULTS: Three of seven SNPs in DOCK9, a gene that encodes an activator of the Rho-GTPase Cdc42, showed significant excess allelic transmission (P=0.0477-0.00067). Fine scale mapping on DOCK9 yielded evidence of association at nine SNPs in the gene (P=0.02-0.006). Follow-up tests detected excess transmission of the same allele of rs1340 in two out of three other sets of families. The association signals were largely attributable to maternally transmitted alleles (rs1927568: P=0.000083; odds ratio=3.778). A secondary analysis of familial component phenotypes of bipolar disorder detected significant association across multiple DOCK9 markers for racing thoughts, psychosis, delusion during mania and course of illness indicators. CONCLUSION: These results suggest that DOCK9 contributes to both risk and increased illness severity in bipolar disorder. We found evidence for the effect of phenotypic heterogeneity on association. To our knowledge this is the first report to implicate DOCK9 or the Rho-GTPase pathway in the etiology of bipolar disorder.


Subject(s)
Bipolar Disorder/genetics , Genetic Predisposition to Disease , Genetic Variation , Guanine Nucleotide Exchange Factors/genetics , Polymorphism, Single Nucleotide , Bipolar Disorder/physiopathology , Family , Female , Humans , Linkage Disequilibrium , Male , Phenotype , Severity of Illness Index
8.
Biol Psychiatry ; 56(1): 18-23, 2004 Jul 01.
Article in English | MEDLINE | ID: mdl-15219468

ABSTRACT

BACKGROUND: We have reported genetic linkage between bipolar disorder and markers on chromosome 6q16.3-22.1 in the National Institute of Mental Health Genetics Initiative wave 3 pedigrees. Here we test for: 1) robustness of the linkage to differing analysis methods, genotyping error, and gender-specific maps; 2) parent-of-origin effects; and 3) interaction with markers within the schizophrenia linkage region on chromosome 6p. METHODS: Members of 245 families ascertained through a sibling pair affected with bipolar I or schizoaffective-bipolar disorder were genotyped with 18 markers spanning chromosome 6. Nonparametric linkage analysis was performed. RESULTS: Linkage to 6q is robust to analysis method, gender-specific map differences, and genotyping error. The locus confers a 1.4-fold increased risk. Affected siblings share the maternal more often than the paternal chromosome (p =.006), which could reflect a maternal parent-of-origin effect. There is a positive correlation between family-specific linkage scores on 6q and those on 6p22.2 (r =.26; p <.0001). Linkage analysis for each locus conditioned on evidence of linkage to the other increases the evidence for linkage at both loci (p <.0005). Logarithm of the odds (LOD) scores increased from 2.26 to 5.42 on 6q and from.35 to 2.26 on 6p22.2. CONCLUSIONS: These results support linkage of bipolar disorder to 6q, uncover a maternal parent-of-origin effect, and demonstrate an interaction of this locus with one on chromosome 6p22.2, previously linked only to schizophrenia.


Subject(s)
Bipolar Disorder/genetics , Chromosomes, Human, Pair 6 , Genetic Linkage , Genetic Predisposition to Disease , Bipolar Disorder/epidemiology , Epistasis, Genetic , Female , Humans , Lod Score , Male , National Institute of Mental Health (U.S.) , Pedigree , Psychotic Disorders/genetics , Schizophrenia/genetics , United States/epidemiology
9.
Vet Surg ; 25(1): 88-97, 1996.
Article in English | MEDLINE | ID: mdl-8719091

ABSTRACT

Selected metabolites, hormones and cardiovascular variables were measured in halothane anesthetized horses during 1 hour of dopamine infusion at a rate of 5 micrograms/kg/min (low) and 10 micrograms/kg/min (high), and for 1 hour after infusion. Plasma cortisol increased twofold in the low-infusion group but did not change significantly in the high-infusion group. Plasma nonesterified fatty acids, blood glucose, blood lactate, and plasma insulin increased in the high-infusion group. There was little difference in heart rate, systolic, diastolic, and mean arterial blood pressure between the two groups. The high infusion was associated with arrhythmias in several horses, and one horse showed ventricular fibrillation and died. If metabolic and hormonal changes are used as markers of a "stress response" in anesthetized horses the results must be carefully interpreted if a sympathomimetic agent such as dopamine is administered to maintain cardiovascular stability.


Subject(s)
Anesthesia, Inhalation/veterinary , Anesthetics, Inhalation , Dopamine , Halothane , Horses/metabolism , Animals , Blood Glucose/drug effects , Fatty Acids, Nonesterified/blood , Female , Hemodynamics/drug effects , Hemodynamics/physiology , Horses/surgery , Hydrocortisone/blood , Infusions, Intravenous/veterinary , Insulin/blood , Male
10.
Healthc Syst Strategy Rep ; 12(20): 8-10, 1995 Sep 29.
Article in English | MEDLINE | ID: mdl-10184451

ABSTRACT

After suffering two costly legal losses, a provider-owned rural Wisconsin integrated delivery system under attack by one of the state's most powerful payers has won a potentially sweeping legal victory. A federal appeals court has rejected charges by Blue Cross & Blue Shield of Wisconsin and the Blues' HMO, CompCare, that the Marshfield Clinic monopolized a 10-county market in north-central Wisconsin. The Wisconsin Blues took Marshfield to court early last year, charging the clinic with controlling such a large section of the north-central Wisconsin market that CompCare couldn't gain a foothold. A federal jury in January agreed, slapping the rural IDS with a $48.5 million damage award for 19 counts of anticompetitive conduct. A federal district court judge later shrank the damages--but did little to the verdict. Charles J. Steele, an antitrust attorney with Washington, D.C.'s Foley & Lardner, explains what happened next.


Subject(s)
Antitrust Laws , Delivery of Health Care, Integrated/legislation & jurisprudence , Rural Health Services/legislation & jurisprudence , Economic Competition/legislation & jurisprudence , Wisconsin
13.
Proc Natl Acad Sci U S A ; 91(6): 2255-9, 1994 Mar 15.
Article in English | MEDLINE | ID: mdl-8134383

ABSTRACT

DNA processing occurs in ciliates at autogamy and conjugation when new macronuclei are formed from micronuclei and old macronuclei degrade. Processing of micronuclear DNA consists of removal of certain internal sequences, chromosomal fragmentation, addition of new telomeres, and amplification. Aside from a recent brief report, internal eliminated sequences have not been described in Paramecium. In this paper we characterize nine internal eliminated sequences found within and near the gene that codes for surface protein A in Paramecium tetraurelia. Of these nine, seven are located within the translated portion of the gene, and all include short, inverted terminal repeats. The characteristic sequence, TA, appears at the boundaries of all of the internal eliminated sequences.


Subject(s)
Micronucleus, Germline/metabolism , Paramecium/genetics , Sequence Deletion , Animals , Base Sequence , DNA Transposable Elements , DNA, Protozoan/metabolism , Molecular Sequence Data , Paramecium/growth & development , Protein Biosynthesis
14.
Equine Vet J ; 22(5): 313-6, 1990 Sep.
Article in English | MEDLINE | ID: mdl-2121473

ABSTRACT

The effect of general anaesthesia and arthroscopic surgery on blood glucose and lactate, plasma non-esterified fatty acids, insulin, beta-endorphin and cortisol was investigated in seven horses. Animals were premedicated with xylazine and anaesthesia was induced with guaifenesin and sodium thiamylal and maintained with halothane vaporised in oxygen. Blood samples were collected in the pre-, intra- and post operative period. Induction of anaesthesia was associated with a transient hyperglycaemia and a significant rise in plasma insulin levels. Plasma insulin values fell during surgery but showed a significant increase post operatively. Surgery stimulated a small but significant rise in plasma beta-endorphin and cortisol values but these had returned to baseline values in the early post operative period. No changes in blood lactate were recorded.


Subject(s)
Anesthesia, General/veterinary , Arthroscopy/veterinary , Horses/surgery , Joints/surgery , Anesthesia, General/adverse effects , Animals , Blood Glucose/analysis , Blood Pressure , Blood Proteins/analysis , Carbon Dioxide/blood , Fatty Acids, Nonesterified/blood , Female , Hematocrit/veterinary , Horses/blood , Hydrogen-Ion Concentration , Insulin/blood , Intraoperative Period , Lactates/blood , Male , Oxygen/blood , beta-Endorphin/blood
19.
Clin Chim Acta ; 94(1): 41-9, 1979 May 16.
Article in English | MEDLINE | ID: mdl-88284

ABSTRACT

A rapid enzyme linked immunoassay for pregnancy specific beta 1-glycoprotein is described. The method is sensitive and precise (within batch C.V. = 6.5-7.4%) and should be suitable for the biochemical monitoring of pregnancy and the investigation of patients suffering from various malignancies.


Subject(s)
Beta-Globulins/analysis , Pregnancy , Female , Humans , Immune Sera , Immunoenzyme Techniques , Time Factors
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