Publications by authors named "Mark Horowitz"

140 Publications

Methodology for altering omega-3 EPA+DHA and omega-6 linoleic acid as controlled variables in a dietary trial.

Clin Nutr 2021 Jun 12;40(6):3859-3867. Epub 2021 May 12.

Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background & Aims: Increasing dietary intake of n-3 EPA+DHA and lowering dietary n-6 LA is under investigation as a therapeutic diet for improving chronic pain syndromes as well as other health outcomes. Herein we describe the diet methodology used to modulate intake of n-3 and n-6 PUFA in a free living migraine headache population and report on nutrient intake, BMI and diet acceptability achieved at week 16 of the intensive diet intervention and week 22 follow-up time-point.

Methods: A total of 178 participants were randomized and began one of three diet interventions: 1) a high n-3 PUFA, average n-6 PUFA (H3) diet targeting 1500 mg EPA+DHA/day and 7% of energy (en%) from n-6 linoleic acid (LA), 2) a high-n-3 PUFA, low-n-6 PUFA (H3L6) targeting 1500 mg EPA+DHA/day and <1.8 en% n-6 LA or 3) a Control diet with typical American intakes of both EPA+DHA (<150 mg/day) and 7 en% from n-6 LA. Methods used to achieve diet change to week 16 include diet education, diet counseling, supply of specially prepared foods, self-monitoring and access to online diet materials. Only study oils and website materials were provided for the follow-up week 16 to week 22 periods. Diet adherence was assessed by multiple 24 h recalls administered throughout the trial. Diet acceptability was assessed in a subset of participants at 4 time points by questionnaire.

Results: At week 16 H3 and H3L6 diet groups significantly increased median n-3 EPA+DHA intake from 48 mg/2000 kcals at baseline to 1484 mg/2000 kcals (p < 0.0001) and from 44 mg/2000 kcals to 1341 mg/2000 kcals (p < 0.0001), respectively. In the Control group, EPA+DHA intake remained below the typical American intake with baseline median at 60 mg/2000 kcals and 80 mg/2000 kcals (p = 0.6) at week 16. As desired, LA intake was maintained in the H3 and Control group with baseline median of 6.5 en% to 7.1 en% (p = 0.4) at week 16 and from 6.5 en% to 6.8 en% (p = 1.0) at week 16, respectively. In the H3L6 group, n-6 LA decreased from 6.3 en% at baseline to 3.2 en% (p < 0.0001) at week 16. There were no significant changes in BMI or diet acceptability throughout the trial or between diet groups.

Conclusions: We find this diet method to be acceptable to research participants and successful in altering dietary n-3 EPA+DHA with and without concurrent decreases in n-6 LA. If n-6 LA of less than 3 en% is desired, additional techniques to limit LA may need to be employed.
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http://dx.doi.org/10.1016/j.clnu.2021.04.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293619PMC
June 2021

Systems genetics in diversity outbred mice inform BMD GWAS and identify determinants of bone strength.

Nat Commun 2021 06 7;12(1):3408. Epub 2021 Jun 7.

Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, VA, USA.

Genome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; however, their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD). Here, we use Diversity Outbred (DO) mice to directly address these limitations by performing a systems genetics analysis of 55 complex skeletal phenotypes. We apply a network approach to cortical bone RNA-seq data to discover 66 genes likely to be causal for human BMD GWAS associations, including the genes SERTAD4 and GLT8D2. We also perform GWAS in the DO for a wide-range of bone traits and identify Qsox1 as a gene influencing cortical bone accrual and bone strength. In this work, we advance our understanding of the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics.
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http://dx.doi.org/10.1038/s41467-021-23649-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184749PMC
June 2021

Risks and Benefits of Benzodiazepines.

JAMA 2021 06;325(21):2208-2209

Institute of Pharmaceutical Sciences, King's College London, London, England.

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http://dx.doi.org/10.1001/jama.2021.4513DOI Listing
June 2021

The dynamics of human bone marrow adipose tissue in response to feeding and fasting.

JCI Insight 2021 Jun 22;6(12). Epub 2021 Jun 22.

Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

BACKGROUNDAdipocytes were long considered inert components of the bone marrow niche, but mouse and human models suggest bone marrow adipose tissue (BMAT) is dynamic and responsive to hormonal and nutrient cues.METHODSIn this study of healthy volunteers, we investigated how BMAT responds to acute nutrient changes, including analyses of endocrine determinants and paracrine factors from marrow aspirates. Study participants underwent a 10-day high-calorie protocol, followed by a 10-day fast.RESULTSWe demonstrate (a) vertebral BMAT increased significantly during high-calorie feeding and fasting, suggesting BMAT may have different functions in states of caloric excess compared with caloric deprivation; (b) ghrelin, which decreased in response to high-calorie feeding and fasting, was inversely associated with changes in BMAT; and (c) in response to high-calorie feeding, resistin levels in the marrow sera, but not the circulation, rose significantly. In addition, TNF-α expression in marrow adipocytes increased with high-calorie feeding and decreased upon fasting.CONCLUSIONHigh-calorie feeding, but not fasting, induces an immune response in bone marrow similar to what has been reported in peripheral adipose tissue. Understanding the immunomodulatory regulators in the marrow may provide further insight into the homeostatic function of this unique adipose tissue depot.FUNDINGNIH grant R24 DK084970, Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH, award UL 1TR002541), and NIH grants P30 DK040561 and U19 AG060917S1.
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http://dx.doi.org/10.1172/jci.insight.138636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262500PMC
June 2021

Should gabapentinoids be prescribed long-term for anxiety and other mental health conditions?

Addict Behav 2021 08 2;119:106943. Epub 2021 Apr 2.

South London and Maudsley NHS Foundation Trust, Denmark Hill, Camberwell, London SE5 8AZ, United Kingdom. Electronic address:

Prescription rates for gabapentinoids are rising in England. Pregabalin is currently recommended by NICE for the treatment of anxiety. Gabapentinoids have some overlap with the action of benzodiazepines, and have similar issues with tolerance, dependence, addiction and withdrawal. They were scheduled as class C controlled drugs in 2019 because of these risks. There were 244 deaths due to poisoning recorded by the ONS in 2019 involving pregabalin. Poisonings due to pregabalin usually involve concomitant use of opioids or other drugs. The rate of deaths involving pregabalin has been rising steeply for the last 10 years, and now exceeds those attributed to diazepam, fentanyl, the tricyclics as a group or SSRIs as a group. Evidence for the use of pregabalin in anxiety is derived from short-term trials, with marginal differences from placebo, which do not take into account the longer term effects of tolerance, dependence and withdrawal. We call on NICE to re-evaluate their support for use of pregabalin in anxiety in light of its known harms. The use of gabapentinoids off-label for other psychiatric conditions should also be re-considered. In general, psychotropic medications require longer term efficacy and safety studies before allowing widespread use.
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http://dx.doi.org/10.1016/j.addbeh.2021.106943DOI Listing
August 2021

Approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults.

Cochrane Database Syst Rev 2021 04 15;4:CD013495. Epub 2021 Apr 15.

Clinical Pharmacology Unit, Department of Basic and Applied Medical Sciences, Ghent University, Ghent, Belgium.

Background: Depression and anxiety are the most frequent indication for which antidepressants are prescribed. Long-term antidepressant use is driving much of the internationally observed rise in antidepressant consumption. Surveys of antidepressant users suggest that 30% to 50% of long-term antidepressant prescriptions had no evidence-based indication. Unnecessary use of antidepressants puts people at risk of adverse events. However, high-certainty evidence is lacking regarding the effectiveness and safety of approaches to discontinuing long-term antidepressants.

Objectives: To assess the effectiveness and safety of approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults.

Search Methods: We searched all databases for randomised controlled trials (RCTs) until January 2020.

Selection Criteria: We included RCTs comparing approaches to discontinuation with continuation of antidepressants (or usual care) for people with depression or anxiety who are prescribed antidepressants for at least six months. Interventions included discontinuation alone (abrupt or taper), discontinuation with psychological therapy support, and discontinuation with minimal intervention. Primary outcomes were successful discontinuation rate, relapse (as defined by authors of the original study), withdrawal symptoms, and adverse events. Secondary outcomes were depressive symptoms, anxiety symptoms, quality of life, social and occupational functioning, and severity of illness.

Data Collection And Analysis: We used standard methodological procedures as expected by Cochrane.

Main Results: We included 33 studies involving 4995 participants. Nearly all studies were conducted in a specialist mental healthcare service and included participants with recurrent depression (i.e. two or more episodes of depression prior to discontinuation). All included trials were at high risk of bias. The main limitation of the review is bias due to confounding withdrawal symptoms with symptoms of relapse of depression. Withdrawal symptoms (such as low mood, dizziness) may have an effect on almost every outcome including adverse events, quality of life, social functioning, and severity of illness. Abrupt discontinuation Thirteen studies reported abrupt discontinuation of antidepressant. Very low-certainty evidence suggests that abrupt discontinuation without psychological support may increase risk of relapse (hazard ratio (HR) 2.09, 95% confidence interval (CI) 1.59 to 2.74; 1373 participants, 10 studies) and there is insufficient evidence of its effect on adverse events (odds ratio (OR) 1.11, 95% CI 0.62 to 1.99; 1012 participants, 7 studies; I² = 37%) compared to continuation of antidepressants, without specific assessment of withdrawal symptoms. Evidence about the effects of abrupt discontinuation on withdrawal symptoms (1 study) is very uncertain. None of these studies included successful discontinuation rate as a primary endpoint. Discontinuation by "taper" Eighteen studies examined discontinuation by "tapering" (one week or longer). Most tapering regimens lasted four weeks or less. Very low-certainty evidence suggests that "tapered" discontinuation may lead to higher risk of relapse (HR 2.97, 95% CI 2.24 to 3.93; 1546 participants, 13 studies) with no or little difference in adverse events (OR 1.06, 95% CI 0.82 to 1.38; 1479 participants, 7 studies; I² = 0%) compared to continuation of antidepressants, without specific assessment of withdrawal symptoms. Evidence about the effects of discontinuation on withdrawal symptoms (1 study) is very uncertain. Discontinuation with psychological support Four studies reported discontinuation with psychological support. Very low-certainty evidence suggests that initiation of preventive cognitive therapy (PCT), or MBCT, combined with "tapering" may result in successful discontinuation rates of 40% to 75% in the discontinuation group (690 participants, 3 studies). Data from control groups in these studies were requested but are not yet available. Low-certainty evidence suggests that discontinuation combined with psychological intervention may result in no or little effect on relapse (HR 0.89, 95% CI 0.66 to 1.19; 690 participants, 3 studies) compared to continuation of antidepressants. Withdrawal symptoms were not measured. Pooling data on adverse events was not possible due to insufficient information (3 studies). Discontinuation with minimal intervention Low-certainty evidence from one study suggests that a letter to the general practitioner (GP) to review antidepressant treatment may result in no or little effect on successful discontinuation rate compared to usual care (6% versus 8%; 146 participants, 1 study) or on relapse (relapse rate 26% vs 13%; 146 participants, 1 study). No data on withdrawal symptoms nor adverse events were provided. None of the studies used low-intensity psychological interventions such as online support or a changed pharmaceutical formulation that allows tapering with low doses over several months. Insufficient data were available for the majority of people taking antidepressants in the community (i.e. those with only one or no prior episode of depression), for people aged 65 years and older, and for people taking antidepressants for anxiety.

Authors' Conclusions: Currently, relatively few studies have focused on approaches to discontinuation of long-term antidepressants. We cannot make any firm conclusions about effects and safety of the approaches studied to date. The true effect and safety are likely to be substantially different from the data presented due to assessment of relapse of depression that is confounded by withdrawal symptoms. All other outcomes are confounded with withdrawal symptoms. Most tapering regimens were limited to four weeks or less. In the studies with rapid tapering schemes the risk of withdrawal symptoms may be similar to studies using abrupt discontinuation which may influence the effectiveness of the interventions. Nearly all data come from people with recurrent depression.   There is an urgent need for trials that adequately address withdrawal confounding bias, and carefully distinguish relapse from withdrawal symptoms. Future studies should report key outcomes such as successful discontinuation rate and should include populations with one or no prior depression episodes in primary care, older people, and people taking antidepressants for anxiety and use tapering schemes longer than 4 weeks.
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http://dx.doi.org/10.1002/14651858.CD013495.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092632PMC
April 2021

A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse.

Schizophr Bull 2021 Jul;47(4):1116-1129

Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, Camberwell, London SE5 8AF, UK.

The process of stopping antipsychotics may be causally related to relapse, potentially linked to neuroadaptations that persist after cessation, including dopaminergic hypersensitivity. Therefore, the risk of relapse on cessation of antipsychotics may be minimized by more gradual tapering. There is converging evidence that suggests that adaptations to antipsychotic exposure can persist for months or years after stopping the medication-from animal studies, observation of tardive dyskinesia in patients, and the clustering of relapses in this time period after the cessation of antipsychotics. Furthermore, PET imaging demonstrates a hyperbolic relationship between doses of antipsychotic and D2 receptor blockade. We, therefore, suggest that when antipsychotics are reduced, it should be done gradually (over months or years) and in a hyperbolic manner (to reduce D2 blockade "evenly"): ie, reducing by one quarter (or one half) of the most recent dose of antipsychotic, equivalent approximately to a reduction of 5 (or 10) percentage points of its D2 blockade, sequentially (so that reductions become smaller and smaller in size as total dose decreases), at intervals of 3-6 months, titrated to individual tolerance. Some patients may prefer to taper at 10% or less of their most recent dose each month. This process might allow underlying adaptations time to resolve, possibly reducing the risk of relapse on discontinuation. Final doses before complete cessation may need to be as small as 1/40th a therapeutic dose to prevent a large decrease in D2 blockade when stopped. This proposal should be tested in randomized controlled trials.
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http://dx.doi.org/10.1093/schbul/sbab017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266572PMC
July 2021

Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice.

J Bone Miner Res 2021 May 18;36(5):942-955. Epub 2021 Feb 18.

Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1 mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1 mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1 mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1 mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4254DOI Listing
May 2021

Antipsychotics and mortality - more clarity needed.

Psychol Med 2020 12 2;50(16):2814-2815. Epub 2020 Dec 2.

University College, London, UK.

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http://dx.doi.org/10.1017/S0033291720004535DOI Listing
December 2020

The 'patient voice': patients who experience antidepressant withdrawal symptoms are often dismissed, or misdiagnosed with relapse, or a new medical condition.

Ther Adv Psychopharmacol 2020 9;10:2045125320967183. Epub 2020 Nov 9.

University College London, London, UK.

Background: Stopping antidepressants commonly causes withdrawal symptoms, which can be severe and long-lasting. National Institute for Health and Care Excellence (NICE) guidance has been recently updated to reflect this; however, for many years withdrawal (discontinuation) symptoms were characterised as 'usually mild and self-limiting over a week'. Consequently, withdrawal symptoms might have been misdiagnosed as relapse of an underlying condition, or new onset of another medical illness, but this has never been studied.

Method: This paper outlines the themes emerging from 158 respondents to an open invitation to describe the experience of prescribed psychotropic medication withdrawal for petitions sent to British parliaments. The accounts include polypharmacy (mostly antidepressants and benzodiazepines) but we focus on antidepressants because of the relative lack of awareness about their withdrawal effects compared with benzodiazepines. Mixed method analysis was used, including a 'lean thinking' approach to evaluate common failure points.

Results: The themes identified include: a lack of information given to patients about the risk of antidepressant withdrawal; doctors failing to recognise the symptoms of withdrawal; doctors being poorly informed about the best method of tapering prescribed medications; patients being diagnosed with relapse of the underlying condition or medical illnesses other than withdrawal; patients seeking advice outside of mainstream healthcare, including from online forums; and significant effects on functioning for those experiencing withdrawal.

Discussion: Several points for improvement emerge: the need for updating of guidelines to help prescribers recognise antidepressant withdrawal symptoms and to improve informed consent processes; greater availability of non-pharmacological options for managing distress; greater availability of best practice for tapering medications such as antidepressants; and the vital importance of patient feedback. Although the patients captured in this analysis might represent medication withdrawal experiences that are more severe than average, they highlight the current inadequacy of health care systems to recognise and manage prescribed drug withdrawal, and patient feedback in general.
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http://dx.doi.org/10.1177/2045125320967183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659022PMC
November 2020

Molecular Pathways Linking Oxylipins to Nociception in Rats.

J Pain 2021 03 6;22(3):275-299. Epub 2020 Oct 6.

Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.

Oxylipins are lipid peroxidation products that participate in nociceptive, inflammatory, and vascular responses to injury. Effects of oxylipins depend on tissue-specific differences in accumulation of precursor polyunsaturated fatty acids and the expression of specific enzymes to transform the precursors. The study of oxylipins in nociception has presented technical challenges leading to critical knowledge gaps in the way these molecules operate in nociception. We applied a systems-based approach to characterize oxylipin precursor fatty acids, and expression of genes coding for proteins involved in biosynthesis, transport, signaling and inactivation of pro- and antinociceptive oxylipins in pain circuit tissues. We further linked these pathways to nociception by demonstrating intraplantar carrageenan injection induced gene expression changes in oxylipin biosynthetic pathways. We determined functional-biochemical relevance of the proposed pathways in rat hind paw and dorsal spinal cord by measuring basal and stimulated levels of oxylipins throughout the time-course of carrageenan-induced inflammation. Finally, when oxylipins were administered by intradermal injection we observed modulation of nociceptive thermal hypersensitivity, providing a functional-behavioral link between oxylipins, their molecular biosynthetic pathways, and involvement in pain and nociception. Together, these findings advance our understanding of molecular lipidomic systems linking oxylipins and their precursors to nociceptive and inflammatory signaling pathways in rats. PERSPECTIVE: We applied a systems approach to characterize molecular pathways linking precursor lipids and oxylipins to nociceptive signaling. This systematic, quantitative evaluation of the molecular pathways linking oxylipins to nociception provides a framework for future basic and clinical research investigating the role of oxylipins in pain.
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http://dx.doi.org/10.1016/j.jpain.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954900PMC
March 2021

Tapering Antipsychotic Treatment.

JAMA Psychiatry 2021 Feb;78(2):125-126

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

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http://dx.doi.org/10.1001/jamapsychiatry.2020.2166DOI Listing
February 2021

Identifying oxidized lipid mediators as prognostic biomarkers of chronic posttraumatic headache.

Pain 2020 12;161(12):2775-2785

Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD, United States.

Chronic posttraumatic headache (PTH) is among the most common and disabling sequelae of traumatic brain injury (TBI). Current PTH treatments are often only partially effective and have problematic side effects. We previously showed in a small randomized trial of patients with chronic nontraumatic headaches that manipulation of dietary fatty acids decreased headache frequency, severity, and pain medication use. Pain reduction was associated with alterations in oxylipins derived from n-3 and n-6 fatty acids, suggesting that oxylipins could potentially mediate clinical pain reduction. The objective of this study was to investigate whether circulating oxylipins measured in the acute setting after TBI could serve as prognostic biomarkers for developing chronic PTH. Participants enrolled in the Traumatic Head Injury Neuroimaging Classification Protocol provided serum within 3 days of TBI and were followed up at 90 days postinjury with a neurobehavioral symptom inventory (NSI) and satisfaction with life survey. Liquid chromatography-tandem mass spectrometry methods profiled 39 oxylipins derived from n-3 docosahexaenoic acid (DHA), and n-6 arachidonic acid and linoleic acid. Statistical analyses assessed the association of oxylipins with headache severity (primary outcome, measured by headache question on NSI) as well as associations between oxylipins and total NSI or satisfaction with life survey scores. Among oxylipins, 4-hydroxy-DHA and 19,20-epoxy-docosapentaenoate (DHA derivatives) were inversely associated with headache severity, and 11-hydroxy-9-epoxy-octadecenoate (a linoleic acid derivative) was positively associated with headache severity. These findings support a potential for DHA-derived oxylipins as prognostic biomarkers for development of chronic PTH.
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http://dx.doi.org/10.1097/j.pain.0000000000001983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669546PMC
December 2020

Barriers to stopping neuroleptic (antipsychotic) treatment in people with schizophrenia, psychosis or bipolar disorder.

Ther Adv Psychopharmacol 2020 6;10:2045125320937910. Epub 2020 Jul 6.

Division of Psychiatry, University College London, London, UK.

Most guidelines recommend long-term, indefinite neuroleptic (or antipsychotic) treatment for people with schizophrenia, recurrent psychosis or bipolar disorder, on the basis that these medications reduce the chance of relapse. However, neuroleptics have significant adverse effects, including sexual dysfunction, emotional blunting, metabolic disturbance and brain shrinkage, and patients often request to stop them. Evidence for the benefits of long-term treatment is also not as robust as generally thought. Short-term randomised trials show higher rates of relapse among those whose neuroleptic treatment is discontinued compared with those on maintenance treatment, but they are confounded by adverse effects associated with the withdrawal of established medication. Some longer-term studies show possible advantages of medication reduction and discontinuation in terms of improved social functioning and recovery. Therefore, there is a good rationale for supporting patients who wish to stop their medication, especially given the patient choice agenda favoured by The National Institute for Clinical Excellence (NICE). The major barrier to stopping antipsychotics is an understandable fear of relapse among patients, their families and clinicians. Institutional structures also prioritise short-term stability over possible long-term improvements. The risk of relapse may be mitigated by more gradual reduction of medication, but further research is needed on this. Psychosocial support for patients during the process of reducing medication may also be useful, particularly to enhance coping skills. Guidelines to summarise evidence on ways to reduce medication would be useful. Many patients want to try and stop neuroleptic medication for good reasons, and psychiatrists can help to make this a realistic option by supporting people to do it as safely as possible, with the best chance of a positive outcome.
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http://dx.doi.org/10.1177/2045125320937910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338640PMC
July 2020

Barriers to stopping neuroleptic (antipsychotic) treatment in people with schizophrenia, psychosis or bipolar disorder.

Ther Adv Psychopharmacol 2020 6;10:2045125320937910. Epub 2020 Jul 6.

Division of Psychiatry, University College London, London, UK.

Most guidelines recommend long-term, indefinite neuroleptic (or antipsychotic) treatment for people with schizophrenia, recurrent psychosis or bipolar disorder, on the basis that these medications reduce the chance of relapse. However, neuroleptics have significant adverse effects, including sexual dysfunction, emotional blunting, metabolic disturbance and brain shrinkage, and patients often request to stop them. Evidence for the benefits of long-term treatment is also not as robust as generally thought. Short-term randomised trials show higher rates of relapse among those whose neuroleptic treatment is discontinued compared with those on maintenance treatment, but they are confounded by adverse effects associated with the withdrawal of established medication. Some longer-term studies show possible advantages of medication reduction and discontinuation in terms of improved social functioning and recovery. Therefore, there is a good rationale for supporting patients who wish to stop their medication, especially given the patient choice agenda favoured by The National Institute for Clinical Excellence (NICE). The major barrier to stopping antipsychotics is an understandable fear of relapse among patients, their families and clinicians. Institutional structures also prioritise short-term stability over possible long-term improvements. The risk of relapse may be mitigated by more gradual reduction of medication, but further research is needed on this. Psychosocial support for patients during the process of reducing medication may also be useful, particularly to enhance coping skills. Guidelines to summarise evidence on ways to reduce medication would be useful. Many patients want to try and stop neuroleptic medication for good reasons, and psychiatrists can help to make this a realistic option by supporting people to do it as safely as possible, with the best chance of a positive outcome.
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http://dx.doi.org/10.1177/2045125320937910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338640PMC
July 2020

Posterior Tibial Tendinopathy and Osteopenia as Primary Symptoms of Celiac Disease: A Case Report.

J Foot Ankle Surg 2020 May - Jun;59(3):553-559. Epub 2020 Apr 3.

Director, Department of Orthopaedic Surgery, MedStar Union Memorial Hospital, Baltimore, MD.

This case report describes posterior tibial tendon (PTT) tendinopathy, valgus deformity with tenosynovitis, and osteopenia at the medial malleolus as the primary symptoms of a young patient with celiac disease (CD) without gastrointestinal symptoms. CD is an autoimmune condition that is a chronic inflammatory disorder of the small intestine triggered by ingestion of gluten in individuals with a particular genetic background. Without typical gastrointestinal symptoms, CD patients are often misdiagnosed or undiagnosed. The patient was diagnosed with CD by duodenal biopsy. He underwent a surgical procedure, including medial displacement calcaneal osteotomy, tenosynovectomy of the PTT and flexor digitorum longus (FDL), FDL transfer to the navicular for a pes planovalgus deformity, and drilling of the medial malleolus for a stress reaction. The mechanism of the PTT tear and associated heel valgus deformity was assumed to be related to the fact that his heel alignment on the affected side changed gradually from normal to valgus and pes planus owing to CD and mechanical stress, because his normal-side heel alignment was neutral before surgery and at final follow-up. His operated ankle was pain-free, with full range of motion, 1.5 years after surgery. The patient was able to restart running and exercise gradually. Foot and ankle specialists should consider the possibility of CD in patients presenting with a PTT tear without injury or trauma and osteopenia with no obvious reason.
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http://dx.doi.org/10.1053/j.jfas.2019.09.009DOI Listing
April 2021

Glucocorticoids prime the inflammatory response of human hippocampal cells through up-regulation of inflammatory pathways.

Brain Behav Immun 2020 07 16;87:777-794. Epub 2020 Mar 16.

Stress, Psychiatry and Immunology (SPI) Lab, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Increased pro-inflammatory cytokines and an overactive hypothalamic-pituitary-adrenal (HPA) axis have both been implicated in the pathogenesis of depression. However, these explanations appear contradictory because glucocorticoids are well recognised for their anti-inflammatory effects. Two hypotheses exist to resolve this paradox: the mediating presence of glucocorticoid receptor resistance, or the possibility that glucocorticoids can potentiate inflammatory processes in some circumstances. We sought to investigate these hypotheses in a cell model with significant relevance to depression: human hippocampal progenitor cells. We demonstrated that dexamethasone in vitro given for 24 hours and followed by a 24 hours rest interval before an immune challenge potentiates inflammatory effects in these neural cells, that is, increases the IL-6 protein secretion induced by stimulation with IL-1β (10 ng/mL for 24 hours) by + 49% (P < 0.05) at a concentration of 100 nM and by + 70% (P < 0.01) for 1 μM. These effects are time- and dose-dependent and require activation of the glucocorticoid receptor. Gene expression microarray assays using Human Gene 2.1st Array Strips demonstrated that glucocorticoid treatment up-regulated several innate immune genes, including chemokines and Nod-like receptor, NLRP6; using transcription factor binding motifs we found limited evidence that glucocorticoid resistance was induced in the cells. Our data suggests a mechanism by which stress may prime the immune system for increased inflammation and suggests that stress and inflammation may be synergistic in the pathogenesis of depression.
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http://dx.doi.org/10.1016/j.bbi.2020.03.012DOI Listing
July 2020

Reporting Guidelines, Review of Methodological Standards, and Challenges Toward Harmonization in Bone Marrow Adiposity Research. Report of the Methodologies Working Group of the International Bone Marrow Adiposity Society.

Front Endocrinol (Lausanne) 2020 28;11:65. Epub 2020 Feb 28.

Laboratory of Regenerative Hematopoiesis, Institute of Bioengineering and Swiss Institute for Experimental Cancer Research, Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

The interest in bone marrow adiposity (BMA) has increased over the last decade due to its association with, and potential role, in a range of diseases (osteoporosis, diabetes, anorexia, cancer) as well as treatments (corticosteroid, radiation, chemotherapy, thiazolidinediones). However, to advance the field of BMA research, standardization of methods is desirable to increase comparability of study outcomes and foster collaboration. Therefore, at the 2017 annual BMA meeting, the International Bone Marrow Adiposity Society (BMAS) founded a working group to evaluate methodologies in BMA research. All BMAS members could volunteer to participate. The working group members, who are all active preclinical or clinical BMA researchers, searched the literature for articles investigating BMA and discussed the results during personal and telephone conferences. According to the consensus opinion, both based on the review of the literature and on expert opinion, we describe existing methodologies and discuss the challenges and future directions for (1) histomorphometry of bone marrow adipocytes, (2) BMA imaging, (3) BMA imaging, (4) cell isolation, culture, differentiation and modulation of primary bone marrow adipocytes and bone marrow stromal cell precursors, (5) lineage tracing and BMA modulation, and (6) BMA biobanking. We identify as accepted standards in BMA research: manual histomorphometry and osmium tetroxide 3D contrast-enhanced μCT for quantification, specific MRI sequences (WFI and H-MRS) for studies, and RT-qPCR with a minimal four gene panel or lipid-based assays for quantification of bone marrow adipogenesis. Emerging techniques are described which may soon come to complement or substitute these gold standards. Known confounding factors and minimal reporting standards are presented, and their use is encouraged to facilitate comparison across studies. In conclusion, specific BMA methodologies have been developed. However, important challenges remain. In particular, we advocate for the harmonization of methodologies, the precise reporting of known confounding factors, and the identification of methods to modulate BMA independently from other tissues. Wider use of existing animal models with impaired BMA production (e.g., , Kit) and development of specific BMA deletion models would be highly desirable for this purpose.
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http://dx.doi.org/10.3389/fendo.2020.00065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059536PMC
February 2021

Transpubic variant of congenital prepubic sinus on magnetic resonance imaging.

Pediatr Radiol 2020 06 24;50(7):1010-1012. Epub 2020 Jan 24.

Department of Radiology, Staten Island University Hospital Northwell Health, 475 Seaview Ave., Staten Island, NY, 10305, USA.

Congenital prepubic sinus is a very rare urogenital anomaly that manifests as a tubular structure of varying histological findings that drains to the skin overlying the pubic symphysis. This tract has been observed to course above, below or, in only a handful of cases, directly through the pubis. We report a case of congenital prepubic sinus with this unusual transpubic course in an 18-year-old man. The patient was initially taken to the operating room for excision of a presumed inclusion cyst. At the time of surgery, the collection was found to track proximally and was excised down to the level of the pubic symphysis. Subsequent magnetic resonance (MR) imaging established the diagnosis of congenital prepubic sinus. We describe the different anatomical courses of congenital prepubic sinus, hypotheses of its pathogenesis, and the use of MR imaging in both diagnosis and surgical planning.
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http://dx.doi.org/10.1007/s00247-020-04619-yDOI Listing
June 2020

Plasma oxylipins and unesterified precursor fatty acids are altered by DHA supplementation in pregnancy: Can they help predict risk of preterm birth?

Prostaglandins Leukot Essent Fatty Acids 2020 02 13;153:102041. Epub 2019 Dec 13.

School of Agriculture, Food and Wine, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.

Oxidized lipids derived from omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids, collectively known as oxylipins, are bioactive signaling molecules that play diverse roles in human health and disease. Supplementation with n-3 docosahexaenoic acid (DHA) during pregnancy has been reported to decrease the risk of preterm birth in singleton pregnancies, which may be due to effects of DHA supplementation on oxylipins or their precursor n-6 and n-3 fatty acids. There is only limited understanding of the levels and trajectory of changes in plasma oxylipins during pregnancy, effects of DHA supplementation on oxylipins and unesterified fatty acids, and whether and how oxylipins and their unesterified precursor fatty acids influence preterm birth. In the present study we used liquid chromatography-tandem mass spectrometry to profile oxylipins and their precursor fatty acids in the unesterified pool using plasma samples collected from a subset of pregnant Australian women who participated in the ORIP (Omega-3 fats to Reduce the Incidence of Prematurity) study. ORIP is a large randomized controlled trial testing whether daily supplementation with n-3 DHA can reduce the incidence of early preterm birth compared to control. Plasma was collected at study entry (≈pregnancy week 14) and again at ≈week 24, in a subgroup of 48 ORIP participants-12 cases with spontaneous preterm (<37 weeks) birth and 36 matched controls with spontaneous term (≥40 weeks) birth. In the combined preterm and term pregnancies, we observed that in the control group without DHA supplementation unesterified AA and AA-derived oxylipins 12-HETE, 15-HETE and TXB2 declined between weeks 14-24 of pregnancy. Compared to control, DHA supplementation increased unesterified DHA, EPA, and AA, DHA-derived 4-HDHA, 10-HDHA and 19,20-EpDPA, and AA-derived 12-HETE at 24 weeks. In exploratory analysis independent of DHA supplementation, participants with concentrations above the median for 5-lipoxygenase derivatives of AA (5-HETE, Odds Ratio (OR) 8.2; p = 0.014) or DHA (4-HDHA, OR 8.0; p = 0.015) at 14 weeks, or unesterified AA (OR 5.1; p = 0.038) at 24 weeks had higher risk of spontaneous preterm birth. The hypothesis that 5-lipoxygenase-derived oxylipins and unesterified AA could serve as mechanism-based biomarkers predicting spontaneous preterm birth should be evaluated in larger, adequately powered studies.
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http://dx.doi.org/10.1016/j.plefa.2019.102041DOI Listing
February 2020

Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency.

J Bone Miner Res 2020 03 5;35(3):528-539. Epub 2019 Dec 5.

Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Biallelic ENPP1 deficiency in humans induces generalized arterial calcification of infancy (GACI) and/or autosomal recessive hypophosphatemic rickets type 2 (ARHR2). The latter is characterized by markedly increased circulating FGF23 levels and renal phosphate wasting, but aberrant skeletal manifestations associated with heterozygous ENPP1 deficiency are unknown. Here, we report three adult men with early onset osteoporosis who presented with fractures in the thoracic spine and/or left radius, mildly elevated circulating FGF23, and hypophosphatemia. Total hip bone mineral density scans demonstrated osteoporosis (Z-score < -2.5) and HRpQCT demonstrated microarchitectural defects in trabecular and cortical bone. Next-generation sequencing revealed heterozygous loss-of-function mutations in ENPP1 previously observed as biallelic mutations in infants with GACI. In addition, we present bone mass and structure data as well as plasma pyrophosphate (PPi) data of two siblings suffering from ARHR2 in comparison to their heterozygous and wild-type family members indicative of an ENPP1 gene dose effect. The skeletal phenotype in murine Enpp1 deficiency yielded nearly identical findings. Ten-week-old male Enpp1 mice exhibited mild elevations in plasma FGF23 and hypophosphatemia, and micro-CT analysis revealed microarchitectural defects in trabecular and cortical bone of similar magnitude to HRpQCT defects observed in humans. Histomorphometry revealed mild osteomalacia and osteopenia at both 10 and 23 weeks. The biomechanical relevance of these findings was demonstrated by increased bone fragility and ductility in Enpp1 mice. In summary, ENPP1 exerts a gene dose effect such that humans with heterozygous ENPP1 deficiency exhibit intermediate levels of plasma analytes associated with bone mineralization disturbance resulting in early onset osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184798PMC
March 2020

Impaired ATM activation in B cells is associated with bone resorption in rheumatoid arthritis.

Sci Transl Med 2019 11;11(519)

Section of Rheumatology, Allergy, and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06511, USA.

Patients with rheumatoid arthritis (RA) may display atypical CD21 B cells in their blood, but the implication of this observation remains unclear. We report here that the group of patients with RA and elevated frequencies of CD21 B cells shows decreased ataxia telangiectasia-mutated (ATM) expression and activation in B cells compared with other patients with RA and healthy donor controls. In agreement with ATM involvement in the regulation of V(D)J recombination, patients with RA who show defective ATM function displayed a skewed B cell receptor (BCR) Igκ repertoire, which resembled that of patients with ataxia telangiectasia (AT). This repertoire was characterized by increased Jκ1 and decreased upstream Vκ gene segment usage, suggesting improper secondary recombination processes and selection. In addition, altered ATM function in B cells was associated with decreased osteoprotegerin and increased receptor activator of nuclear factor κB ligand (RANKL) production. These changes favor bone loss and correlated with a higher prevalence of erosive disease in patients with RA who show impaired ATM function. Using a humanized mouse model, we also show that ATM inhibition in vivo induces an altered Igκ repertoire and RANKL production by immature B cells in the bone marrow, leading to decreased bone density. We conclude that dysregulated ATM function in B cells promotes bone erosion and the emergence of circulating CD21 B cells, thereby contributing to RA pathophysiology.
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http://dx.doi.org/10.1126/scitranslmed.aaw4626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167286PMC
November 2019

How do we determine whether antidepressants are useful or not?

Lancet Psychiatry 2019 11;6(11):888

Institute of Pharmaceutical Science, King's College London, London, UK.

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http://dx.doi.org/10.1016/S2215-0366(19)30344-XDOI Listing
November 2019

Temperature and time-dependent effects of delayed blood processing on oxylipin concentrations in human plasma.

Prostaglandins Leukot Essent Fatty Acids 2019 11 5;150:31-37. Epub 2019 Sep 5.

University of Adelaide, Adelaide, SA, Australia.

Background: Oxidized derivatives of polyunsaturated fatty acids, collectively known as oxylipins, are labile bioactive mediators with diverse roles in human physiology and pathology. Oxylipins are increasingly being measured in plasma collected in clinical studies to investigate biological mechanisms and as pharmacodynamic biomarkers for nutrient-based and drug-based interventions. Whole blood is generally stored either on ice or at room temperature prior to processing. However, the potential impacts of delays in processing, and of temperature prior to processing, on oxylipin concentrations are incompletely understood.

Objective: To evaluate the effects of delayed processing of blood samples in a timeframe that is typical of a clinical laboratory setting, using typical storage temperatures, on concentrations of representative unesterified oxylipins measured by liquid chromatography-tandem mass spectrometry.

Design: Whole blood (drawn on three separate occasions from a single person) was collected into 5 mL purple-top potassium-EDTA tubes and stored for 0, 10, 20, 30, 60 or 120 min at room temperature or on wet ice, followed by centrifugation at 4 °C for 10 min with plasma collection. Each sample was run in duplicate, therefore there were six tubes and up to six data points at each time point for each oxylipin at each condition (ice/room temperature). Representative oxylipins derived from arachidonic acid, docosahexaenoic acid, and linoleic acid were quantified by liquid chromatography tandem mass spectrometry. Longitudinal models were used to estimate differences between temperature groups 2 h after blood draw.

Results: We found that most oxylipins measured in human plasma in traditional potassium-EDTA tubes are reasonably stable when stored on ice for up to 2 h prior to processing, with little evidence of auto-oxidation in either condition. By contrast, in whole blood stored at room temperature, substantial time-dependent increases in the 12-lipoxygenase-derived (12-HETE, 14-HDHA) and platelet-derived (thromboxane B2) oxylipins were observed.

Conclusion: These findings suggest that certain plasma oxylipins can be measured with reasonable accuracy despite delayed processing for up to 2 h when blood is stored on ice prior to centrifugation. 12-Lipoxygenase- and platelet-derived oxylipins may be particularly sensitive to post-collection artifact with delayed processing at room temperature. Future studies are needed to determine impacts of duration and temperature of centrifugation on oxylipin concentrations.
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http://dx.doi.org/10.1016/j.plefa.2019.09.001DOI Listing
November 2019

Glucocorticoid Resistance: Is It a Requisite for Increased Cytokine Production in Depression? A Systematic Review and Meta-Analysis.

Front Psychiatry 2019 28;10:423. Epub 2019 Jun 28.

Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.

Glucocorticoid resistance-reduced function of the glucocorticoid receptor (GR)-is seen in many depressed patients. It is argued that this resistance to glucocorticoids leads to failure of normal feedback regulation on the immune system. High levels of pro-inflammatory cytokines result. We sought to identify evidence supporting or refuting a link between glucocorticoid resistance and immune dysregulation in depression and to summarize retrieved evidence in aggregate form. We systematically reviewed and meta-analyzed studies that examined cytokine levels in depressed patients compared with controls and that also reported a measure of glucocorticoid resistance. These measures included plasma cortisol, the dexamethasone suppression test (DST), expression levels, and the results of assays of GR function. We conducted four separate meta-analyses to test for moderating effects of glucocorticoid resistance on cytokine production in depression. After sub-grouping 32 studies by the ratio of cortisol levels in patients compared with controls, we observed a trend for increasing glucocorticoid resistance (i.e., the most hypercortisolemic patients) to be associated with increased production of interleukin (IL)-6 [ = 0.94; 95% CI (0.29, 1.59)] and tumour necrosis factor (TNF)-α [ = 0.46; 95% CI (0.12, 0.79)]. We stratified nine studies that reported DST results by relative glucocorticoid resistance between patients and controls, identifying a trend for higher glucocorticoid resistance in patients, compared with controls, to be associated with higher cytokine production in patients (170 patients and 187 controls). This was particularly evident when studies were sub-grouped by source of cytokine-plasma ( = 1.04; 95% CI, 0.57-1.50) versus ( = 0.24; 95% CI, -0.20 to 0.67). Stratifying the four studies (147 patients and 118 controls) that used assays of GR function or expression to quantify glucocorticoid resistance revealed variable contributions to cytokine production in patients compared with controls (overall effect size: = 1.35; 95% CI 0.53-2.18). Combining our analyses of studies that reported DST results with those that used assays of GR function or expression to quantify glucocorticoid resistance (302 patients and 277 controls), we noted that although depressed patients produced more cytokines than controls ( = 1.02; 95% CI, 0.55-1.49), there was no evident positive correlation between glucocorticoid resistance and inflammation. Our work provides some support for a model conceptualizing glucocorticoid resistance as a requisite for increased inflammation in depression. The limited number of studies identified highlights the need for purpose-designed investigations that directly examine the relationship between glucocorticoid resistance and cytokine production in depression.
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http://dx.doi.org/10.3389/fpsyt.2019.00423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609575PMC
June 2019

Tapering of SSRI treatment to mitigate withdrawal symptoms - Authors' reply.

Lancet Psychiatry 2019 07;6(7):562-563

Institute of Pharmaceutical Science, King's College London, London, UK.

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http://dx.doi.org/10.1016/S2215-0366(19)30219-6DOI Listing
July 2019

Bone Marrow Adiposity: Basic and Clinical Implications.

Endocr Rev 2019 10;40(5):1187-1206

Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut.

The presence of adipocytes in mammalian bone marrow (BM) has been recognized histologically for decades, yet, until recently, these cells have received little attention from the research community. Advancements in mouse transgenics and imaging methods, particularly in the last 10 years, have permitted more detailed examinations of marrow adipocytes than ever before and yielded data that show these cells are critical regulators of the BM microenvironment and whole-body metabolism. Indeed, marrow adipocytes are anatomically and functionally separate from brown, beige, and classic white adipocytes. Thus, areas of BM space populated by adipocytes can be considered distinct fat depots and are collectively referred to as marrow adipose tissue (MAT) in this review. In the proceeding text, we focus on the developmental origin and physiologic functions of MAT. We also discuss the signals that cause the accumulation and loss of marrow adipocytes and the ability of these cells to regulate other cell lineages in the BM. Last, we consider roles for MAT in human physiology and disease.
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http://dx.doi.org/10.1210/er.2018-00138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686755PMC
October 2019

Tapering of SSRI treatment to mitigate withdrawal symptoms.

Lancet Psychiatry 2019 Jun 5;6(6):538-546. Epub 2019 Mar 5.

Institute of Pharmaceutical Science, King's College London, London, UK.

All classes of drug that are prescribed to treat depression are associated with withdrawal syndromes. SSRI withdrawal syndrome occurs often and can be severe, and might compel patients to recommence their medication. Although the withdrawal syndrome can be differentiated from recurrence of the underlying disorder, it might also be mistaken for recurrence, leading to long-term unnecessary medication. Guidelines recommend short tapers, of between 2 weeks and 4 weeks, down to therapeutic minimum doses, or half-minimum doses, before complete cessation. Studies have shown that these tapers show minimal benefits over abrupt discontinuation, and are often not tolerated by patients. Tapers over a period of months and down to doses much lower than minimum therapeutic doses have shown greater success in reducing withdrawal symptoms. Other types of medication associated with withdrawal, such as benzodiazepenes, are tapered to reduce their biological effect at receptors by fixed amounts to minimise withdrawal symptoms. These dose reductions are done with exponential tapering programmes that reach very small doses. This method could have relevance for tapering of SSRIs. We examined the PET imaging data of serotonin transporter occupancy by SSRIs and found that hyperbolically reducing doses of SSRIs reduces their effect on serotonin transporter inhibition in a linear manner. We therefore suggest that SSRIs should be tapered hyperbolically and slowly to doses much lower than those of therapeutic minimums, in line with tapering regimens for other medications associated with withdrawal symptoms. Withdrawal symptoms will then be minimised.
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http://dx.doi.org/10.1016/S2215-0366(19)30032-XDOI Listing
June 2019

Mapping Histological Slice Sequences to the Allen Mouse Brain Atlas Without 3D Reconstruction.

Front Neuroinform 2018 11;12:93. Epub 2018 Dec 11.

Department of Electrical Engineering, Stanford University, Stanford, CA, United States.

Histological brain slices are widely used in neuroscience to study the anatomical organization of neural circuits. Systematic and accurate comparisons of anatomical data from multiple brains, especially from different studies, can benefit tremendously from registering histological slices onto a common reference atlas. Most existing methods rely on an initial reconstruction of the volume before registering it to a reference atlas. Because these slices are prone to distortions during the sectioning process and often sectioned with non-standard angles, reconstruction is challenging and often inaccurate. Here we describe a framework that maps each slice to its corresponding plane in the Allen Mouse Brain Atlas (2015) to build a plane-wise mapping and then perform 2D nonrigid registration to build a pixel-wise mapping. We use the L2 norm of the histogram of oriented gradients difference of two patches as the similarity metric for both steps and a Markov random field formulation that incorporates tissue coherency to compute the nonrigid registration. To fix significantly distorted regions that are misshaped or much smaller than the control grids, we train a context-aggregation network to segment and warp them to their corresponding regions with thin plate spline. We have shown that our method generates results comparable to an expert neuroscientist and is significantly better than reconstruction-first approaches. Code and sample dataset are available at sites.google.com/view/brain-mapping.
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http://dx.doi.org/10.3389/fninf.2018.00093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297281PMC
December 2018
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