Biological markers for anxiety disorders,OCD and PTSD – a consensus statement. Part I: Neuroimaging and genetics

Objectives: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive–compulsive disorder (OCD) and post-traumatic stress disorder (PTSD).

Methods: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network.

Results: The present article (Part I) summarises findings on potential biomarkers in neuroimaging studies, including structural brain morphology, functional magnetic resonance imaging and techniques for measuring metabolic changes, including positron emission tomography and others. Furthermore, this review reports on the clinical and molecular genetic findings of family, twin, linkage, association and genome-wide association studies. Part II of the review focuses on neurochemistry, neurophysiology and neurocognition.

Conclusions: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high-quality research has accumulated that will improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.     

Long-term effects of cardiac rehabilitation on end-exercise heart rate recovery after myocardial infarction.

BACKGROUND: Heart rate recovery (HRR) is a marker of vagal tone that is a powerful predictor of mortality in patients with coronary artery disease. DESIGN: This study aims at evaluating the effects of long-term exercise training on HRR after acute myocardial infarction (AMI), in order to clarify whether prolonged exercise training could maintain a long-term improvement of HRR. METHODS: Forty-four patients after AMI were enrolled in a 3-month hospital-based exercise training programme. At the end, patients were subdivided into two groups: group A (n=22), patients discharged with a specific home-based exercise training programme and instructions for improving leisure-time physical activity; group B (n=22), patients discharged with generic instructions to maintain physical activity. All patients underwent a cardiopulmonary exercise test before, at the end of 3 months exercise training and at 6 months follow-up. RESULTS: At the end of the hospital-based exercise training programme we observed an increase in peak oxygen consumption [VO2peak; from 13.9+/-3.6 to 18+/-2.7 ml/kg per min (A) and from 14.1+/-3.9 to 17.9+/-2.1 ml/kg per min (B), P<0.001] and in HRR [from 17.1+/-1.8 to 23.4+/-1.4 beats/min (A), and from 18.8+/-2.1 to 24.3+/-1.9 beats/min (B), P<0.001]. At 6 months' follow-up we observed a further improvement in VO2peak (from 18.0+/-2.7 to 20.3+/-2.7 ml/kg per min, P<0.001) and in HRR (from 23.4+/-1.4 to 27.8+/-2.1 beats/min, P<0.001) in group A, but a significant decrease in VO2peak and in HRR in group B (P<0.001). CONCLUSION: Long-term exercise training is useful for maintaining or improving the beneficial results of the standard 3-month exercise training programme on cardiovascular capacity and HRR. This observation may bear beneficial prognostic effects on patients after AMI.     

Current views on anthracycline cardiotoxicity

Anthracyclines are well established and effective anticancer agents used to treat a variety of adult and pediatric cancers. Unfortunately, these drugs are also among the commonest chemotherapeutic agents that have been recognized to cause cardiotoxicity. In the last years, several experimental and clinical investigations provided new information and perspectives on anthracycline-related cardiotoxicity. In particular, molecular mechanisms of cardiotoxicity have been better elucidated, early diagnosis has improved through the use of advanced noninvasive cardiac imaging techniques, and emerging data indicate a genetic predisposition to develop anthracycline-related cardiotoxicity. In this article, we review established and new knowledge about anthracycline cardiotoxicity, with special focus on recent advances in cardiotoxicity diagnosis and genetic profiling.     

Prevalence,severity and correlates of fatigue in newly diagnosed patients with myelodysplastic syndromes

The primary objective of this study was to investigate factors associated with fatigue severity in newly diagnosed patients with higher‐risk myelodysplastic syndromes (MDS). The secondary objectives were to assess symptom prevalence and to examine the relationships between fatigue, quality of life (QoL) and overall symptom burden in these patients. The analyses were conducted in 280 higher‐risk MDS patients. Pre‐treatment patient‐reported fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT)‐Fatigue scale and QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 (EORTC QLQ‐C30). Female gender (P = 0·018), poor performance status (i.e., ECOG of 2–4) (P < 0·001) and lower levels of haemoglobin (Hb) (P = 0·026) were independently associated with higher fatigue severity. The three most prevalent symptoms were as follows: fatigue (92%), dyspnoea (63%) and pain (55%). Patients with higher levels of fatigue also had greater overall symptom burdens. The mean global QoL scores of patients with the highest versus those with the lowest levels of fatigue were 29·2 [standard deviation (SD), 18·3] and 69·0 (SD, 18·8), respectively and this difference was four times the magnitude of a clinically meaningful difference. Patient‐reported fatigue severity revealed the effects of disease burden on overall QoL more accurately than did degree of anaemia. Special attention should be given to the female patients in the management of fatigue.     

Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide Using Non–First-Degree Related Donors

Outcomes of nonmyeloablative (NMA) haploidentical (haplo) blood or marrow transplant (BMT) with post-transplantation cyclophosphamide (PTCy) using non–first-degree relatives are unknown. We evaluated 33 consecutive adult patients (median age, 56 years) with hematologic malignancies who underwent NMA haplo T cell–replete BMT with PTCy at Johns Hopkins using second- or third-degree related donors. Donors consisted of 10 nieces (30%), 9 nephews (27%), 7 first cousins (21%), 5 grandchildren (15%), and 2 uncles (6%). Thirty-one patients (94%) reached full donor chimerism by day 60. The estimated cumulative incidence (CuI) of grades II to IV acute graft-versus-host disease (aGVHD) at day 180 was 24% (90% confidence interval [CI], 9% to 38%). Only 1 patient experienced grades III to IV aGVHD. At 1 year the CuI of chronic GVHD was 10% (90% CI, 0% to 21%). The CuI of nonrelapse mortality at 1 year was 5% (90% CI, 0% to 14%). At 1 year the probability of relapse was 31% (90% CI, 12% to 49%), progression-free survival 64% (90% CI, 48% to 86%), and overall survival 95% (90% CI, 87% to 100%). The 1-year probability of GVHD-free, relapse-free survival was 57% (90% CI, 41% to 79%). NMA haplo BMT with PTCy from non–first-degree relatives is an acceptably safe and effective alternative donor platform, with results similar to those seen with first-degree relatives.     

Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44

Sulfatase modifying factor 1 (SUMF1) encodes for the formylglicine generating enzyme, which activates sulfatases by modifying a key cysteine residue within their catalytic domains. SUMF1 is mutated in patients affected by multiple sulfatase deficiency, a rare recessive disorder in which all sulfatase activities are impaired. Despite the absence of canonical retention/retrieval signals, SUMF1 is largely retained in the endoplasmic reticulum (ER), where it exerts its enzymatic activity on nascent sulfatases. Part of SUMF1 is secreted and paracrinally taken up by distant cells. Here we show that SUMF1 interacts with protein disulfide isomerase (PDI) and ERp44, two thioredoxin family members residing in the early secretory pathway, and with ERGIC-53, a lectin that shuttles between the ER and the Golgi. Functional assays reveal that these interactions are crucial for controlling SUMF1 traffic and function. PDI couples SUMF1 retention and activation in the ER. ERGIC-53 and ERp44 act downstream, favoring SUMF1 export from and retrieval to the ER, respectively. Silencing ERGIC-53 causes proteasomal degradation of SUMF1, while down-regulating ERp44 promotes its secretion. When over-expressed, each of three interactors favors intracellular accumulation. Our results reveal a multistep control of SUMF1 trafficking, with sequential interactions dynamically determining ER localization, activity and secretion.     

Central effects of galcanezumab in migraine: a pilot study on Steady State Visual Evoked Potentials and occipital hemodynamic response in migraine patients

BackgroundThe discovery of the prominent action of Calcitonin Gene Related Peptide –CGRP- on trigeminal afferents and meningeal vessels, opened a new era in migraine treatment. However, how the block of nociceptive afferents could act on central mechanisms of migraine is still not clear. In this pilot study we aimed to test the effect of 3 months Galcanezumab (CGA) therapy on occipital visual reactivity in migraine patients, using the Steady State Visual Evoked Potentials-SSVEPs and Functional Near Infrared Spectroscopy –fNIRS.MethodThirteen migraine patients underwent clinical and neurophysiological examination in basal condition (T0), 1 h after GCA injection (T1) and after 3 months of GCA treatment (T2). Ten healthy volunteers were also evaluated.ResultsAt T2, there was a reduction of headache frequency and disability. At T2, the EEG power significantly diminished as compared to T0 and T1 at occipital sites, and the topographical analysis confirmed a restoration of SSVEPs within normal values. The Oxyhemoglobin levels in occipital cortex, which were basically increased during visual stimulation in migraine patients, reverted to normal values at T2.ConclusionsThe present pilot study indicates that Galcanezumab could act on cortical targets located beyond the pain network, restoring the abnormal occipital reactivity. This effect could indicate the possible disease modifying properties of CGRP related monoclonal antibodies.