Documentation of advance care planning forms in patients with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive weakness. Survival is typically only a few years from symptom onset. The often-predictable disease course creates opportunities to complete advance care planning (ACP) forms. The Physician Orders for Life-Sustaining Treatment (POLST) is a broadly used ACP paradigm to communicate end-of-life wishes but has not been well-studied in the ALS population. METHODS: In this retrospective chart review study, patients diagnosed with ALS seen between 2014 and 2018 at an academic ALS center were identified. Demographic information, clinical characteristics, and ACP data were collected. RESULTS: Of 513 patients identified, 30% had an ACP document. POLST forms were competed in 16.6% of patients with 73.8% of forms signed by a neurologist. Only 5.1% of patients saw a palliative care physician. Palliative care consultation was associated with having an POLST on file (P < .001). Patients with completed POLST forms were significantly more likely to have been seen in clinic more frequently (P < .001) and have a lower ALS Functional Rating Scale-Revised score on last visit (P = .005). DISCUSSION: Less than one third of patients with ALS completed an ACP document, and only a small percentage completed POLST forms. The data suggest a need for greater documentation of goals of care in the ALS population.

Central Venous Obstruction-Induced Intracranial Hypertension in Hemodialysis Patients: An Underrecognized Cause of Elevated Intracranial Pressure.

BACKGROUND: Central venous obstruction (stenosis or occlusion) is common in patients with renal failure on hemodialysis and may be associated with intracranial hypertension (IH). Causes include vein injury from an endoluminal device, lumen obstruction from a device or thrombus, external vein compression, and high venous flow leading to vein intimal hyperplasia. A combination of high venous flow and central venous obstruction can lead to intracranial venous hypertension, impaired cerebrospinal fluid (CSF) resorption, and subsequent IH. EVIDENCE ACQUISITION: We conducted a search of the English literature using the Ovid MEDLINE Database and PubMed, with a focus on reports involving IH and central venous obstruction in the setting of hemodialysis. We reviewed CSF flow dynamics, the risk factors and causes of central venous obstruction, and the evaluation, management, and outcomes of central venous obstruction-induced IH. RESULTS: Twenty-four cases of IH related to central venous obstruction in hemodialysis patients were identified. Twenty patients had headaches (83.3%) and 9 had visual symptoms (37.5%). The brachiocephalic vein was the most common site of stenosis or occlusion (20/24, 83.3%). Twenty-one patients (87.5%) had resolution of IH with treatment. Two patients died from complications of IH (8.3%). CONCLUSIONS: Central venous obstruction-induced IH is likely underrecognized by clinicians and mimics idiopathic IH. Hemodialysis patients with IH should be screened with computed tomography venography of the chest. Optimal treatment is with vascular intervention or a CSF diversion procedure and can help prevent vision loss from papilledema or nervous system damage. Medical management may be appropriate in mild cases or as a bridge to definitive interventional treatment. Increased awareness among clinicians has potential to facilitate the timely diagnosis of this treatable condition with potential for good neurologic and visual outcomes.

Novel endogenous N-acyl amides activate TRPV1-4 receptors, BV-2 microglia, and are regulated in brain in an acute model of inflammation.

A family of endogenous lipids, structurally analogous to the endogenous cannabinoid, N-arachidonoyl ethanolamine (Anandamide), and called N-acyl amides have emerged as a family of biologically active compounds at TRP receptors. N-acyl amides are constructed from an acyl group and an amine via an amide bond. This same structure can be modified by changing either the fatty acid or the amide to form potentially hundreds of lipids. More than 70 N-acyl amides have been identified in nature. We have ongoing studies aimed at isolating and characterizing additional members of the family of N-acyl amides in both central and peripheral tissues in mammalian systems. Here, using a unique in-house library of over 70 N-acyl amides we tested the following three hypotheses: (1) Additional N-acyl amides will have activity at TRPV1-4, (2) Acute peripheral injury will drive changes in CNS levels of N-acyl amides, and (3) N-acyl amides will regulate calcium in CNS-derived microglia. Through these studies, we have identified 20 novel N-acyl amides that collectively activate (stimulating or inhibiting) TRPV1-4. Using lipid extraction and HPLC coupled to tandem mass spectrometry we showed that levels of at least 10 of these N-acyl amides that activate TRPVs are regulated in brain after intraplantar carrageenan injection. We then screened the BV2 microglial cell line for activity with this N-acyl amide library and found overlap with TRPV receptor activity as well as additional activators of calcium mobilization from these lipids. Together these data provide new insight into the family of N-acyl amides and their roles as signaling molecules at ion channels, in microglia, and in the brain in the context of inflammation.

Targeted lipidomics in Drosophila melanogaster identifies novel 2-monoacylglycerols and N-acyl amides.

Lipid metabolism is critical to coordinate organ development and physiology in response to tissue-autonomous signals and environmental cues. Changes to the availability and signaling of lipid mediators can limit competitiveness, adaptation to environmental stressors, and augment pathological processes. Two classes of lipids, the N-acyl amides and the 2-acyl glycerols, have emerged as important signaling molecules in a wide range of species with important signaling properties, though most of what is known about their cellular functions is from mammalian models. Therefore, expanding available knowledge on the repertoire of these lipids in invertebrates will provide additional avenues of research aimed at elucidating biosynthetic, metabolic, and signaling properties of these molecules. Drosophila melanogaster is a commonly used organism to study intercellular communication, including the functions of bioactive lipids. However, limited information is available on the molecular identity of lipids with putative biological activities in Drosophila. Here, we used a targeted lipidomics approach to identify putative signaling lipids in third instar Drosophila larvae, possessing particularly large lipid mass in their fat body. We identified 2-linoleoyl glycerol, 2-oleoyl glycerol, and 45 N-acyl amides in larval tissues, and validated our findings by the comparative analysis of Oregon-RS, Canton-S and w1118 strains. Data here suggest that Drosophila represent another model system to use for the study of 2-acyl glycerol and N-acyl amide signaling.

Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment.

Cisplatin, a platinum-derived chemotherapeutic agent, produces mechanical and coldallodynia reminiscent of chemotherapy-induced neuropathy in humans. The endocannabinoid system represents a novel target for analgesic drug development. The endocannabinoid signaling system consists of endocannabinoids (e.g. anandamide (AEA) and 2-arachidonoylglycerol (2-AG)), cannabinoid receptors (e.g. CB(1) and CB(2)) and the enzymes controlling endocannabinoid synthesis and degradation. AEA is hydrolyzed by fatty-acid amide hydrolase (FAAH) whereas 2-AG is hydrolyzed primarily by monoacylglycerol lipase (MGL). We compared effects of brain permeant (URB597) and impermeant (URB937) inhibitors of FAAH with an irreversible inhibitor of MGL (JZL184) on cisplatin-evoked behavioral hypersensitivities. Endocannabinoid modulators were compared with agents used clinically to treat neuropathy (i.e. the opioid analgesic morphine, the anticonvulsant gabapentin and the tricyclic antidepressant amitriptyline). Cisplatin produced robust mechanical and cold allodynia but did not alter responsiveness to heat. After neuropathy was fully established, groups received acute intraperitoneal (i.p.) injections of vehicle, amitriptyline (30 mg/kg), gabapentin (100 mg/kg), morphine (6 mg/kg), URB597 (0.1 or 1 mg/kg), URB937 (0.1 or 1 mg/kg) or JZL184 (1, 3 or 8 mg/kg). Pharmacological specificity was assessed by coadministering each endocannabinoid modulator with either a CB(1) (AM251 3 mg/kg), CB(2) (AM630 3 mg/kg), TRPV1 (AMG9810 3 mg/kg) or TRPA1 (HC030031 8 mg/kg) antagonist. Effects of cisplatin on endocannabinoid levels and transcription of receptors (CB(1), CB(2), TRPV1, TRPA1) and enzymes (FAAH, MGL) linked to the endocannabinoid system were also assessed. URB597, URB937, JZL184 and morphine reversed cisplatin-evoked mechanical and cold allodynia to pre-cisplatin levels. By contrast, gabapentin only partially reversed the observed allodynia while amitriptyline, administered acutely, was ineffective. CB(1) or CB(2) antagonists completely blocked the anti-allodynic effects of both FAAH (URB597, URB937) and MGL (JZL184) inhibitors to mechanical and cold stimulation. By contrast, the TRPV1 antagonist AMG9810 blocked the anti-allodynic efficacy of both FAAH inhibitors, but not the MGL inhibitor. By contrast, the TRPA1 antagonist HC30031 did not attenuate anti-allodynic efficacy of any endocannabinoid modulator. When the levels of endocannabinoids were examined, cisplatin increased both anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels in the lumbar spinal cord and decreased 2-AG levels (but not AEA) in dorsal hind paw skin. RT-PCR showed that mRNA for FAAH, but not other markers, was upregulated by cisplatin treatment in lumbar spinal cord. The present studies demonstrate that cisplatin alters endocannabinoid tone and that inhibition of endocannabinoid hydrolysis alleviates chemotherapy-induced mechanical and cold allodynia. The anti-allodynic effects of FAAH and MGL inhibitors are mediated by CB(1) and CB(2) cannabinoid receptors, whereas TRPV1, but not TRPA1, -dependent mechanisms contribute to the anti-allodynic efficacy of FAAH (but not MGL) inhibitors. Strikingly, endocannabinoid modulators potently suppressed cisplatin-evoked allodynia with a rapid onset and showed efficacy that equaled or exceeded that of major classes of anti-neuropathic pain medications used clinically. Thus, inhibition of endocannabinoid hydrolysis, via FAAH or MGL inhibitors, represents an efficacious pharmacological approach for suppressing chemotherapy-induced neuropathic pain.