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Norman J Marcus,1,2 Lexi Robbins,1 Aya Araki,1 Edward J Gracely,3,4 Theoharis C Theoharides5,6 1Norman Marcus Pain Institute, New York, NY, USA; 2Department of Anesthesiology and Neurological Surgery, Weill Cornell Medicine, New York, NY, USA; 3Family, Community & Preventative Medicine, Drexel University College of Medicine, Philadelphia, PA, USA; 4School of Public Health, Epidemiology and Biostatistics, Drexel University, Philadelphia, PA, USA; 5Department of Immunology, Tufts University School of Medicine, Boston, MA, USA; 6Institute for Neuro-Immune Medicine, Nova, Southeaster University, Clearwater, FL, USACorrespondence: Norman J Marcus, Private Practice, Norman Marcus Pain Institute, 30 E. 40th Street, Ste 1100, New York, NY, 10016, USA, Tel +01 (212) 532-7999, Email njm@nmpi.comPurpose: Despite the availability of a wide variety of analgesics, many patients with chronic pain often experience suboptimal pain relief in part related to the absence of any medication to address the nociplastic component of common pain syndromes. Low-dose naltrexone has been used for the treatment of chronic pain, typically at 4.5 mg per day, even though it is also noted that effective doses of naltrexone for chronic pain presentations range from 0.1 to 4.5 mg per day. We performed an observational analysis to determine the range of effective naltrexone daily dosing in 41 patients with chronic musculoskeletal pain.Methods: Charts of 385 patients, 115 males, 270 females, ages 18– 92, were reviewed. Two hundred and sixty patients with chronic diffuse, symmetrical pain were prescribed a titrating dose of naltrexone to determine a maximally effective dose established by self-report of 1) reduction of diffuse/generalized and/or severity level of pain and/or 2) positive effects on mood, energy, and mental clarity. Brief Pain Inventory and PROMIS scales were given pre- and post-determining a maximally effective naltrexone dose.Results: Forty-one patients met all criteria for inclusion, successfully attained a maximally effective dose, and completed a pre- and post-outcome questionnaire. Hormesis was demonstrated during the determination of the maximally effective dosing, which varied over a wide range, with statistically significant improvement in BPI.Conclusion: The maximally effective dose of low-dose naltrexone for the treatment of chronic pain is idiosyncratic, suggesting the need for 1) dosage titration to establish a maximally effective dose and 2) the possibility of re-introduction of low-dose naltrexone to patients who had failed initial trials on a fixed dose of naltrexone.Plain language summary: Low-dose naltrexone (LDN) has been used to treat chronic pain. There is, however, no agreed on effective dose, leaving clinicians without guidelines on initiating treatment with naltrexone. It appears that the dose of LDN for any patient is idiosyncratic, and in a small study, ranges from 0.1 to 6.0 mg/day. Understanding the various possible mechanisms of action of LDN may help the clinician to understand how and why it can effectively reduce chronic pain. A titration schedule to establish the maximally effective dose for chronic myofascial pain is presented.Keywords: myalgia, low-dose naltrexone, chronic pain, hypermobile Ehlers Danlos syndrome, nociplastic pain, musculoskeletal pain

Precambrian banded iron formations (BIFs) are iron- and silica-rich (bio)chemical sediments that are widely believed to have been precipitated by microbial oxidation of dissolved Fe(II). The by-product of these metabolisms - insoluble ferric iron - would have settled through the water column, often as aggregates with the cell biomass. While the mineralogy, composition and physical properties of cell-iron mineral aggregates formed by anaerobic Fe(II)-oxidising photoferrotrophic bacteria have been extensively studied, there are limited studies that characterise cyanobacteriairon mineral aggregates that formed during oxygenic photosynthesis. This gap in knowledge is important because it impacts sedimentation velocities and the Fe(III) to organic carbon (Corg) ratios in the marine sediment pile. Here, we used a recently introduced approach to precisely measure the sedimentation velocity of cyanobacteria-ferrihydrite aggregates and the Fe(III):Corg ratios of the cyanobacteria-ferrihydrite aggregates over a wide range of pH and initial Fe(II) concentrations under predicted Palaeoproterozoic atmospheric conditions. Our results indicate that it was highly unlikely BIFs formed at pH <7 via chemical oxidation due to the insufficient sedimentation velocity, even at the maximum predicted Fe(II) concentration of 1800 µM with excess oxygen. Instead, large Banded Iron Formation (BIF) deposits, such as those associated with the ca. 2.47 Ga Kuruman Formation in South Africa, would only had been deposited at minimum Fe(II) concentrations of 500 mM at pH 7 or 250 mM at pH 8. The Fe:Corg ratios in cyanobacteriaferrihydrite sediments formed during initially anoxic Fe(II) oxidation experiments represent the maximum values under each condition because we specifically extracted samples after all Fe(II) was oxidised. The Fe(III) to organic carbon ratio was consistently below 4, which is also the ratio required for dissimilatory Fe(III) reduction (DIR). This result indicates that biomass in this case was in excess, which contradicts the low organic carbon content seen in most BIFs. Thus, we suggest that biomass was either physically separated from ferrihydrite aggregates during sedimentation under the influence of ocean currents and waves, or it was degraded prior to DIR. The mineralogical and geochemical evidences of both oxide and carbonate facies from the Kuruman Iron Formation (IF) suggest that ferrihydrite was most likely the precursor along with a significant initial organic carbon input, supporting the proposed cyanobacterially-mediated BIF depositional model and experimental results. [ABSTRACT FROM AUTHOR]

Background and objectivesObesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis.Materials and methodsMale C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay.ResultsLentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects.ConclusionsCathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.