Robert A. Swarm

Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo.

Certain disease states are characterized by disturbances in production, accumulation or clearance of protein. In Alzheimer disease, accumulation of amyloid-β (Aβ) in the brain and disease-causing mutations in amyloid precursor protein or in enzymes that produce Aβ indicate dysregulation of production or clearance of Aβ. Whether dysregulation of Aβ synthesis or clearance causes the most common form of Alzheimer disease (sporadic, >99% of cases), however, is not known. Here, we describe a method to determine the production and clearance rates of proteins within the human central nervous system (CNS). We report the first measurements of the fractional production and clearance rates of Aβ in vivo in the human CNS to be 7.6% per hour and 8.3% per hour, respectively. This method may be used to search for novel biomarkers of disease, to assess underlying differences in protein metabolism that contribute to disease and to evaluate treatments in terms of their pharmacodynamic effects on proposed disease-causing pathways.

An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice

The antidepressant drug citalopram decreased CSF amyloid-β in healthy humans, and in an aged transgenic mouse model of Alzheimer’s disease, it decreased ISF amyloid-β in a dose-dependent manner. Reducing Amyloid-β with SSRIs Higher rates of cognitive decline have been shown in cognitively normal individuals with increased brain amyloid burden, suggesting that increased amyloid burden represents a preclinical phase of Alzheimer’s disease (AD). Increased amyloid burden can occur decades before the onset of cognitive symptoms. Working in an AD mouse model and in healthy young humans, Sheline et al. tested whether an antidepressant drug could help to lower brain amyloid burden. The drug used in this study, citalopram, belongs to the selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs. The authors selected this drug because serotonin signaling is known to suppress generation of amyloid-β (Aβ) in animal models of AD. They show that in an aged transgenic AD mouse model, citalopram decreased brain Aβ concentrations in a dose-dependent manner. Further, citalopram halted the growth of preexisting brain amyloid plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram’s effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo, and there was a 38% decrease in total CSF Aβ concentrations. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer’s disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor, decreased Aβ in brain interstitial fluid in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of preexisting plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram’s effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable isotope labeling kinetics, with CSF sampling during acute dosing of citalopram. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials.

CURRENT TRENDS IN PERIOPERATIVE PAIN MANAGEMENT

Wider use of optimized multimodal accelerated postoperative recovery programs require that anesthesiologists step out of traditional operating room anesthesia roles and even beyond current pain management consultant roles. Development of optimal postoperative recovery services requires close collaboration between anesthesiologists, surgeons, nurses, physical therapists, administrators, and others involved in the management of patients after surgery. Optimization of perioperative care is an ongoing process enhanced by clinical investigation; however, making significant improvements to clinical practice does not have to wait for additional research data, but should proceed now, with broader application of techniques known to enhance rehabilitation and recovery. Based on existing data, the challenges of developing perioperative recovery services seem likely to be rewarded with improved patient outcomes and reduced cost.

NCCN Frameworks for Resource Stratification of NCCN Guidelines: Adult Cancer Pain and Palliative Care

The NCCN Framework aims to provide adapted guidelines for low- and middle-resource countries to improve the experience of patients with cancer. In particular, the NCCN Frameworks for Adult Cancer Pain and Palliative Care and were designed to help expand access to pain management and palliative care for patients in low-resource countries. The NCCN Framework is one of several tools that can improve cancer care in the developing world. The NCCN Harmonized Guidelines for Sub-Saharan Africa, a collaborative effort between NCCN, American Cancer Society, Clinton Health Access Initiative, and African Cancer Coalition, was developed to harmonize NCCN recommendations with local guidelines across Africa and to make best use of available services and resources.

Epidurals in Pancreatic Resection Outcomes (E-PRO) study: protocol for a randomised controlled trial

Introduction Epidural analgesia provides an important synergistic method of pain control. In addition to reducing perioperative opioid consumption, the deliverance of analgesia into the epidural space, effectively creating a sympathetic blockade, has a multitude of additional potential benefits, from decreasing the incidence of postoperative delirium to reducing the development of persistent postsurgical pain (PPSP). Prior studies have also identified a correlation between the use of epidural analgesia and improved oncological outcomes and survival. The aim of this study is to evaluate the effect of epidural analgesia in pancreatic operations on immediate postoperative outcomes, the development of PPSP and oncological outcomes in a prospective, single-blind, randomised controlled trial. Methods The Epidurals in Pancreatic Resection Outcomes (E-PRO) study is a prospective, single-centre, randomised controlled trial. 150 patients undergoing either pancreaticoduodenectomy or distal pancreatectomy will be randomised to receive an epidural bupivacaine infusion following anaesthetic induction followed by continued epidural bupivacaine infusion postoperatively in addition to the institutional standardised pain regimen of hydromorphone patient-controlled analgesia (PCA), acetaminophen and ketorolac (intervention group) or no epidural infusion and only the standardised postoperative pain regimen (control group). The primary outcome was the postoperative opioid consumption, measured in morphine or morphine-equivalents. Secondary outcomes include patient-reported postoperative pain numerical rating scores, trend and relative ratios of serum inflammatory markers (interleukin (IL)-1β, IL-6, tumour necrosis factor-α, IL-10), occurrence of postoperative delirium, development of PPSP as determined by quantitative sensory testing, and disease-free and overall survival. Ethics and dissemination The E-PRO trial has been approved by the institutional review board. Recruitment began in May 2016 and will continue until the end of May 2018. Dissemination plans include presentations at scientific conferences and scientific publications. Trial registration number NCT02681796.

Citalopram decreases acute CSF beta-amyloid concentration in young, healthy study participants

MCI Abeta+ ADAS-cog 1.290 [0.869-1.807] 3 0.944 [0.597-1.384] 5 0.720 [0.275-1.374] 5 1.487 [1.177-1.830] 3 logPALZ 1.276 [0.897-1.794] 4 1.193 [0.778-1.802] 4 1.106 [0.681-1.734] 4 1.379 [0.902-2.043] 4 HCI 1.468 [1.106-1.910] 2 1.638 [1.148-2.346] 2 2.839 [1.475-4.949] 2 1.634 [1.148-2.262] 2 MetaROI 1.268 [0.808-1.964] 5 1.337 [0.772-2.292] 3 1.373 [0.733-2.470] 3 1.052 [0.671-1.640] 5 Hipp. volume 2.022 [1.466-2.779] 1 1.610 [1.151-2.255] 1 3.716 [1.908-6.448] 1 2.501 [1.725-3.654] 1 Tau — — — 0.792 [0.583-1.016] 6 Abeta — — 0.068 [-0.163-0.315] 7 MCI Hippo+ ADAS-cog 0.797 [0.548-1.063] 5 0.723 [0.480-0.985] 5 0.384 [0.169-0.612] 5 1.075 [0.780-1.399] 5 logPALZ 1.662 [1.006-2.564] 2 0.739 [0.418-1.156] 4 0.847 [0.496-1.337] 4 1.171 [0.785-1.677] 4 HCI 1.377 [0.977-1.859] 4 1.374 [0.890-2.050] 2 1.378 [0.659-2.508] 2 1.666 [1.087-2.485] 2 MetaROI 1.531 [0.784-2.849] 3 0.861 [0.419-1.648] 3 1.044 [0.435-1.999] 3 1.049 [0.611-1.703] 6 Hipp. volume 2.035 [1.472-2.751] 1 1.614 [1.154-2.202] 1 3.013 [1.598-5.388] 1 2.661 [1.756-4.208] 1 Tau — — — 1.385 [0.031-3.509] 3 Abeta — — — -0.085 [-0.336-0.160] 7 Table 1 Clinical features and diagnostic biological markers at different time points inMCI patients positive to either Abeta 1-42 (MCI Abeta+, n1⁄474, age1⁄47567 years, 36% females) or hippocampal volume (MCI Hippo+, n1⁄451, age 1⁄47567, 37% females) AD biomarkers.

364 PERIOPERATIVE ANALGESIA DECREASES PHANTOM LIMB PAIN FREQUENCY AND INTENSITY AFTER AMPUTATION. A PROSPECTIVE, RANDOMIZED, DOUBLE‐BLIND CLINICAL TRIAL

D. 4.84 cm consequently. When the last needle position was assessed, we found that the trace of the accessory obturator nerve was different than the obturator nerve. Conclusions:We found that the incidence of the accessory obturator nerve was 12.5%. In the literature this range was reported between 10% and 30%. The incidence of the accessory obturator nerve might decrease the clinical efficacy and success of the incidence of the obturator nerve block. Therefore, blockade of accessory obturator nerve and the obturator nerve should be planned concomitantly.