From NEW SCIENTIST
Human Molecular Genetics
hmg.oxfordjournals.org
September 9, 2011
Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder
Emma L. Dempster1,†, Ruth Pidsley1,†, Leonard C. Schalkwyk1, Sheena Owens2, Anna Georgiades2, Fergus Kane2, Sridevi Kalidindi2, Marco Picchioni2,3, Eugenia Kravariti2, Timothea Toulopoulou2, Robin M. Murray2 and Jonathan Mill1,*
+ Author Affiliations
1MRC Social, Genetic and Developmental Psychiatry Centre and
2Department of Psychosis Studies, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK and
3St Andrew's Academic Centre, Northampton NN1 5BG, UK
↵*To whom correspondence should be addressed at: SGDP Centre, Institute of Psychiatry, King's College London, Denmark Hill, London SE5 8AF, UK. Tel: +44 2078480859; Fax: +44 2078480866; Email: jonathan.mill@kcl.ac.uk
↵† These authors contributed equally to this work.
Received July 12, 2011.
Accepted September 7, 2011.
Abstract
Studies of the major psychoses, schizophrenia (SZ) and bipolar disorder (BD), have traditionally focused on genetic and environmental risk factors, although more recent work has highlighted an additional role for epigenetic processes in mediating susceptibility. Since monozygotic (MZ) twins share a common DNA sequence, their study represents an ideal design for investigating the contribution of epigenetic factors to disease etiology. We performed a genome-wide analysis of DNA methylation on peripheral blood DNA samples obtained from a unique sample of MZ twin pairs discordant for major psychosis. Numerous loci demonstrated disease-associated DNA methylation differences between twins discordant for SZ and BD individually, and together as a combined major psychosis group. Pathway analysis of our top loci highlighted a significant enrichment of epigenetic changes in biological networks and pathways directly relevant to psychiatric disorder and neurodevelopment. The top psychosis-associated, differentially methylated region, significantly hypomethylated in affected twins, was located in the promoter of ST6GALNAC1 overlapping a previously reported rare genomic duplication observed in SZ. The mean DNA methylation difference at this locus was 6%, but there was considerable heterogeneity between families, with some twin pairs showing a 20% difference in methylation. We subsequently assessed this region in an independent sample of postmortem brain tissue from affected individuals and controls, finding marked hypomethylation (>25%) in a subset of psychosis patients. Overall, our data provide further evidence to support a role for DNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD.
© The Author 2011. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
02 October 2011
01 October 2011
U.British Columbia Emeritus Prof Psychology Robert D.HARE CM PhD on PSYCHOPATHS
Original idea of post from READER'S DIGEST article
readersdigest.ca/september
http://www.hare.org/
HARE Psychopathy Checklist revised (PCL-R)
Prof Hare estimates a 1% psychopathy prevalence` rate: a problem for Clinicians.
readersdigest.ca/september
http://www.hare.org/
HARE Psychopathy Checklist revised (PCL-R)
Prof Hare estimates a 1% psychopathy prevalence` rate: a problem for Clinicians.
30 September 2011
ISID NEWS
The SEPTEMBER 2011 of the ISID NEWS (the official newsletter of the International Society for Infectious Diseases) is now available online.
15th International Congress on Infectious Diseases (ICID)
The 15th ICID will be held in Bangkok, Thailand on June 13-16, 2012
For more information, go to http://www.isid.org/icid/ or Join the 15th ICID Mailing List
ISID Neglected Tropical Diseases Meeting
Slide presentations of many of the symposia and plenary talks are now posted as pdf files online at http://ntd.isid.org/
Any individual interested in infectious diseases may become a member of the Society for FREE.
Subscription to the online International Journal of Infectious Diseases is free from June 2011 through May 2012.
15th International Congress on Infectious Diseases (ICID)
The 15th ICID will be held in Bangkok, Thailand on June 13-16, 2012
For more information, go to http://www.isid.org/icid/ or Join the 15th ICID Mailing List
ISID Neglected Tropical Diseases Meeting
Slide presentations of many of the symposia and plenary talks are now posted as pdf files online at http://ntd.isid.org/
Any individual interested in infectious diseases may become a member of the Society for FREE.
Subscription to the online International Journal of Infectious Diseases is free from June 2011 through May 2012.
29 September 2011
UK :SUN Paracetamol liver failure from self-medication
from UK: SUN
A young mum battling what she thought was a lingering cold died after continually guzzling paracetamol pills and LEMPSIP (paracetamol+phenylephrine).
Fitness instructor Donna Bishop, 25, kept up her daily cocktail of over-the-counter remedies despite her GP diagnosing a chest infection.
The mum of one — who had caught a cold two weeks earlier — would wash the tablets down with the hot drink, an inquest heard yesterday.
LEMPSIP also contains paracetamol (650 mg)— and her health slowly deteriorated as she unwittingly overdosed on the painkiller.
A pal told how even when Donna, of Warndon Villages, Worcester, kept being sick she was convinced the remedies would help her — and took more. Days after her doctor put her on antibiotics Donna went to hospital complaining of mouth ulcers and difficulty swallowing.
She was prescribed co-codamol — which also contains paracetamol. Next day her sister found her woozy and jaundiced.
Donna went to hospital where a senior registrar advised tests, including one for paracetamol poisoning. She went home BEFORE having the tests, only to be re-admitted hallucinating hours later. Donna died of liver failure the same day.
A nurse told the inquest in Stourport-on-Severn how up until the end the mum denied taking paracetamol.
Donna's mum Nicky, 46, said after a coroner's narrative verdict that the paracetamol killed her: "It's horrible. I don't want other families to go through this."
A young mum battling what she thought was a lingering cold died after continually guzzling paracetamol pills and LEMPSIP (paracetamol+phenylephrine).
Fitness instructor Donna Bishop, 25, kept up her daily cocktail of over-the-counter remedies despite her GP diagnosing a chest infection.
The mum of one — who had caught a cold two weeks earlier — would wash the tablets down with the hot drink, an inquest heard yesterday.
LEMPSIP also contains paracetamol (650 mg)— and her health slowly deteriorated as she unwittingly overdosed on the painkiller.
A pal told how even when Donna, of Warndon Villages, Worcester, kept being sick she was convinced the remedies would help her — and took more. Days after her doctor put her on antibiotics Donna went to hospital complaining of mouth ulcers and difficulty swallowing.
She was prescribed co-codamol — which also contains paracetamol. Next day her sister found her woozy and jaundiced.
Donna went to hospital where a senior registrar advised tests, including one for paracetamol poisoning. She went home BEFORE having the tests, only to be re-admitted hallucinating hours later. Donna died of liver failure the same day.
A nurse told the inquest in Stourport-on-Severn how up until the end the mum denied taking paracetamol.
Donna's mum Nicky, 46, said after a coroner's narrative verdict that the paracetamol killed her: "It's horrible. I don't want other families to go through this."
27 September 2011
UK: DAILY STAR Possible poisoning of three Hospital patients
By Daily Star Reporter
POLICE probing the deaths of three hospital patients by poisoning have called in a top pathologist who investigated the 1997 death of Princess Diana.
Prof Robert Forrest has joined officers who suspect two saboteurs may have hit Stepping Hill Hospital in Stockport, Gtr Manchester.
Tracey Arden, 44, Arnold Lancaster, 71, and Derek Weaver, 83, all died after being given saline drips contaminated with insulin.
Prof.Forrest told Diana’s inquest tests on the blood of her driver Henri Paul suggested “cock-up or conspiracy”.
POLICE probing the deaths of three hospital patients by poisoning have called in a top pathologist who investigated the 1997 death of Princess Diana.
Prof Robert Forrest has joined officers who suspect two saboteurs may have hit Stepping Hill Hospital in Stockport, Gtr Manchester.
Tracey Arden, 44, Arnold Lancaster, 71, and Derek Weaver, 83, all died after being given saline drips contaminated with insulin.
Prof.Forrest told Diana’s inquest tests on the blood of her driver Henri Paul suggested “cock-up or conspiracy”.
26 September 2011
LANCET: Ovarian teratoma and autoimmune encephalitis
Lancet Neurol. Author manuscript; available in PMC 2009 December 1.
Published in final edited form as:
Lancet Neurol. 2008 December; 7(12): 1091–1098.
Published online 2008 October 11. doi: 10.1016/S1474-4422(08)70224-2 PMCID: PMC2607118
NIHMSID: NIHMS74544
Copyright notice and Disclaimer
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies
Josep Dalmau, Amy J Gleichman,* Ethan G Hughes,* Jeffrey E Rossi, Xiaoyu Peng, Meizan Lai, Scott K Dessain, Myrna R Rosenfeld, Rita Balice-Gordon, and David R Lynch
Department of Neurology (J Dalmau MD, J E Rossi BA, M Lai MD, M R Rosenfeld MD, D R Lynch MD) and Department of Neuroscience (A J Gleichman BS, E G Hughes BS, X Peng BS, R Balice-Gordon PhD), University of Pennsylvania, Philadelphia, PA, USA; Lankenau Institute for Medical Research, Wynnewood, PA, USA (S K Dessain MD); Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA (D R Lynch)
Correspondence to: Josep Dalmau, Division of Neuro-Oncology, Department of Neurology, 3 W Gates, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA, Email: josep.dalmau@uphs.upenn.edu
*These authors contributed equally to this paper
The publisher's final edited version of this article is available at Lancet Neurol
A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures.
Methods
We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters.
Findings
Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0.004) and fewer neurological relapses (p=0.009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients’ antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal.
Interpretation
A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies.
NMDA receptors are ligand-gated cation channels with crucial roles in synaptic transmission and plasticity. The receptors are heteromers of NR1 subunits that bind glycine and NR2 (A, B, C, or D) subunits that bind glutamate.1 NR1 and NR2 combine to form receptor subtypes with distinct pharmacological properties, localisation, and ability to interact with intracellular messengers. Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke, whereas low activity produces symptoms of schizophrenia.2–4We recently identified a disorder, designated anti-NMDA-receptor encephalitis, that associates with antibodies against NR1–NR2 heteromers and results in a characteristic neuropsychiatric syndrome.5 The first patients identified were young women with ovarian teratoma who presented with psychosis or memory problems, rapidly progressing to multiple neurological deficits requiring prolonged intensive care support. Despite the severity of the disorder, patients often recovered after tumour removal and immunotherapy, suggesting an immune-mediated pathogenesis. Preliminary studies suggested the target epitopes were located in extracellular regions of NR1–NR2B NMDA receptors.5 However, selective disruption of receptors containing NR2B, which are predominantly expressed in the forebrain and hippocampus, would not explain the extensive deficits of patients. We postulated that the crucial epitopes were present in the more widely expressed NR1 subunit. If the antibodies were pathogenic we reasoned that their effects on NMDA receptors would be reversible because most patients recover.We report the clinical features of 100 patients, analysing the frequency and type of tumour association, antibody titres, and response to treatment. We also investigate the epitopic region of the NMDA receptor and how antibodies affect NMDA receptors in primary cultures of hippocampal neurons.
Published in final edited form as:
Lancet Neurol. 2008 December; 7(12): 1091–1098.
Published online 2008 October 11. doi: 10.1016/S1474-4422(08)70224-2 PMCID: PMC2607118
NIHMSID: NIHMS74544
Copyright notice and Disclaimer
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies
Josep Dalmau, Amy J Gleichman,* Ethan G Hughes,* Jeffrey E Rossi, Xiaoyu Peng, Meizan Lai, Scott K Dessain, Myrna R Rosenfeld, Rita Balice-Gordon, and David R Lynch
Department of Neurology (J Dalmau MD, J E Rossi BA, M Lai MD, M R Rosenfeld MD, D R Lynch MD) and Department of Neuroscience (A J Gleichman BS, E G Hughes BS, X Peng BS, R Balice-Gordon PhD), University of Pennsylvania, Philadelphia, PA, USA; Lankenau Institute for Medical Research, Wynnewood, PA, USA (S K Dessain MD); Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA (D R Lynch)
Correspondence to: Josep Dalmau, Division of Neuro-Oncology, Department of Neurology, 3 W Gates, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA, Email: josep.dalmau@uphs.upenn.edu
*These authors contributed equally to this paper
The publisher's final edited version of this article is available at Lancet Neurol
A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures.
Methods
We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters.
Findings
Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0.004) and fewer neurological relapses (p=0.009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients’ antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal.
Interpretation
A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies.
NMDA receptors are ligand-gated cation channels with crucial roles in synaptic transmission and plasticity. The receptors are heteromers of NR1 subunits that bind glycine and NR2 (A, B, C, or D) subunits that bind glutamate.1 NR1 and NR2 combine to form receptor subtypes with distinct pharmacological properties, localisation, and ability to interact with intracellular messengers. Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke, whereas low activity produces symptoms of schizophrenia.2–4We recently identified a disorder, designated anti-NMDA-receptor encephalitis, that associates with antibodies against NR1–NR2 heteromers and results in a characteristic neuropsychiatric syndrome.5 The first patients identified were young women with ovarian teratoma who presented with psychosis or memory problems, rapidly progressing to multiple neurological deficits requiring prolonged intensive care support. Despite the severity of the disorder, patients often recovered after tumour removal and immunotherapy, suggesting an immune-mediated pathogenesis. Preliminary studies suggested the target epitopes were located in extracellular regions of NR1–NR2B NMDA receptors.5 However, selective disruption of receptors containing NR2B, which are predominantly expressed in the forebrain and hippocampus, would not explain the extensive deficits of patients. We postulated that the crucial epitopes were present in the more widely expressed NR1 subunit. If the antibodies were pathogenic we reasoned that their effects on NMDA receptors would be reversible because most patients recover.We report the clinical features of 100 patients, analysing the frequency and type of tumour association, antibody titres, and response to treatment. We also investigate the epitopic region of the NMDA receptor and how antibodies affect NMDA receptors in primary cultures of hippocampal neurons.
ISMH: TESTOSTERONE & CARDIOVASCULAR DISEASE
Testosterone Deficiency as a Risk Factor for Cardiovascular Disease
September 26, 2011
Male gender, diabetes mellitus, and obesity, are known risk factors for the development of cardiovascular disease. Increasing attention has been given in recent years to the link between testosterone deficiency and increased risk of cardiometabolic disease. Recent meta-analyses have demonstrated a correlation between metabolic syndrome (e.g., commonly defined as obesity, diabetes/insulin resistance, hypertension, dyslipoproteinemia and gout) and lower serum testosterone levels.
Hypogonadotropic hypogonadism occurs in up to 33% of men with type 2 diabetes. The Massachusetts Male Aging Study found that low levels of testosterone and sex hormone binding globulin (SHBG) are independent risk factors for the development of type 2 diabetes. In addition, this study demonstrated that low serum testosterone predicts the development of metabolic syndrome.
Declining serum testosterone levels throughout a man’s life are associated with an increase in all-cause mortality and an increase in atherosclerosis, visceral obesity, insulin resistance, dyslipidemia, and hypertension, the key components of the metabolic syndrome. Prospective clinical trials in men with prostate cancer who have undergone androgen deprivation therapy have found increased cardiovascular risk by increasing body weight, reducing insulin sensitivity, and/or resulting in dyslipidemia.
Reference: Ullah MI, Washington T, Kazi M, et al. Testosterone deficiency as a risk factor for cardiovascular disease. Horm Met Res 2001;43:153-164.
September 26, 2011
Male gender, diabetes mellitus, and obesity, are known risk factors for the development of cardiovascular disease. Increasing attention has been given in recent years to the link between testosterone deficiency and increased risk of cardiometabolic disease. Recent meta-analyses have demonstrated a correlation between metabolic syndrome (e.g., commonly defined as obesity, diabetes/insulin resistance, hypertension, dyslipoproteinemia and gout) and lower serum testosterone levels.
Hypogonadotropic hypogonadism occurs in up to 33% of men with type 2 diabetes. The Massachusetts Male Aging Study found that low levels of testosterone and sex hormone binding globulin (SHBG) are independent risk factors for the development of type 2 diabetes. In addition, this study demonstrated that low serum testosterone predicts the development of metabolic syndrome.
Declining serum testosterone levels throughout a man’s life are associated with an increase in all-cause mortality and an increase in atherosclerosis, visceral obesity, insulin resistance, dyslipidemia, and hypertension, the key components of the metabolic syndrome. Prospective clinical trials in men with prostate cancer who have undergone androgen deprivation therapy have found increased cardiovascular risk by increasing body weight, reducing insulin sensitivity, and/or resulting in dyslipidemia.
Reference: Ullah MI, Washington T, Kazi M, et al. Testosterone deficiency as a risk factor for cardiovascular disease. Horm Met Res 2001;43:153-164.
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