Certain disease states are characterized by disturbances in protein production, accumulation, or clearance. In the central nervous system (CNS), alterations in metabolism of proteins such as amyloid-beta (Aβ), alpha-synuclein, or tau may cause degenerative diseases such as Alzheimer's disease (AD), Parkinson's disease or fronto-temporal dementias respectively. In AD, dysregulation of Aβ metabolism is indicated by a massive buildup of this protein in the brains of those with AD. In rare, autosomal dominant forms of AD, mutations in the amyloid precursor protein or in components of the enzymes which produce Aβ (presenilin-1 and presenilin-2) appear to result in Aβ overproduction. However, whether dysregulation of Aβ metabolism (increased synthesis or clearance) causes the most common form of AD (sporadic >99%) is not known. Furthermore, there has not been a method available which could determine the synthesis or clearance rate of Aβ or any other protein produced in the CNS. This report describes a method to determine the production rate and clearance rate of proteins produced by the CNS in vivo in humans. We report the first measurements of the fractional production and clearance rates of Aβ in vivo in the human CNS to be 7.6%/hr and 8.2%/hr respectively. This method may be used to search for novel biomarkers of disease, assess underlying differences in protein metabolism that contribute to disease, and to evaluate treatments in terms of their pharmacodynamic properties on proposed disease causing pathways.

In recent years, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain have undergone substantial revisions focusing on the appropriate and safe prescription of opioid analgesics, optimization of nonopioid analgesics and adjuvant medications, and integration of nonpharmacologic methods of cancer pain management. This selection highlights some of these changes, covering topics on management of adult cancer pain including pharmacologic interventions, nonpharmacologic interventions, and treatment of specific cancer pain syndromes. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional aspects of this topic, including pathophysiologic classification of cancer pain syndromes, comprehensive pain assessment, management of pain crisis, ongoing care for cancer pain, pain in cancer survivors, and specialty consultations.

No abstract

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 (SSRI), decreased Aβ in brain interstitial fluid (ISF) 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 pre-existing 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 (SILK), 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.

Optimized epidural analgesia or intravenous PCA, starting 48 h preoperatively and continuing for 48 h postoperatively, decreases PLP at 6 months.

Pain is a common symptom associated with cancer and its treatment. Pain management is an important aspect of oncologic care, and unrelieved pain significantly comprises overall quality of life. These NCCN Guidelines list the principles of management and acknowledge the range of complex decisions faced in the management oncologic pain. In addition to pain assessment techniques, these guidelines provide principles of use, dosing, management of adverse effects, and safe handling procedures of pharmacologic therapies and discuss a multidisciplinary approach for the management of cancer pain.

No abstract

Opioids are a critical component of pain relief strategies for the management of patients with cancer and sickle cell disease. The escalation of opioid addiction and overdose in the United States has led to increased scrutiny of opioid prescribing practices. Multiple reports have revealed that regulatory and coverage policies, intended to curb inappropriate opioid use, have created significant barriers for many patients. The Centers for Disease Control and Prevention, National Comprehensive Cancer Network, and American Society of Clinical Oncology each publish clinical practice guidelines for the management of chronic pain. A recent JAMA Oncology article highlighted perceived variability in recommendations among these guidelines. In response, leadership from guideline organizations, government representatives, and authors of the original article met to discuss challenges and solutions. The meeting featured remarks by the Commissioner of Food and Drugs, presentations on each clinical practice guideline, an overview of the pain management needs of patients with sickle cell disease, an overview of perceived differences among guidelines, and a discussion of differences and commonalities among the guidelines. The meeting revealed that although each guideline varies in the intended patient population, target audience, and methodology, there is no disagreement among recommendations when applied to the appropriate patient and clinical situation. It was determined that clarification and education are needed regarding the intent, patient population, and scope of each clinical practice guideline, rather than harmonization of guideline recommendations. Clinical practice guidelines can serve as a resource for policymakers and payers to inform policy and coverage determinations.