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To determine how the LURN-SI-10, a novel questionnaire developed by the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN), compares with the International Prostate Symptom Score (IPSS) in men with lower urinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia (BPH). Specifically, to assess convergent validity and determine how frequently the LURN-SI-10 identifies symptoms not captured by the IPSS.Men presenting with BPH/LUTS were prospectively administered LURN-SI-10 and IPSS questionnaires. Urinary incontinence (UI) including post-void dribbling (PVD), urgency urinary incontinence (UUI), stress urinary incontinence (SUI), as well as bladder pain were considered present if the patient reported "about half the time or more" on LURN-SI-10. Correlations between LURN-SI-10 and IPSS were assessed as continuous and categorical variables. Multivariable linear regression analysis was performed to determine associations with symptom scores.LURN-SI-10 and IPSS were highly correlated in men with BPH/LUTS (r = 0.82, n = 429), as were respective bother and quality of life scores (ρ = 0.74). The LURN-SI-10 identified additional symptoms including PVD (24%), UUI (13%), SUI (2%), and pain (8%). Men with any UUI, SUI, or PVD had on average a 7.6-point higher LURN-SI-10 score than those without UI (P.001) and 8.0-point higher IPSS score than those without UI (P.001).The LURN-SI-10 correlates strongly with the IPSS, but the LURN-SI-10 identifies additional important symptomatology in men with LUTS. This additional information may improve the evaluation and treatment of men with BPH/LUTS. Further prospective studies of the LURN-SI-10 is warranted.

Over-activation of the endocannabinoid/CB

Obesity is a global medical problem; its common form is known as diet-induced obesity (DIO); however, there are several rare genetic disorders, such as Prader–Willi syndrome (PWS), that are also associated with obesity (genetic-induced obesity, GIO). The currently available therapeutics for treating DIO and GIO are very limited, and they result in only a partial improvement. Cannabidiolic acid (CBDA), a constituent of Cannabis sativa, gradually decarboxylates to cannabidiol (CBD). Whereas the anti-obesity properties of CBD have been reasonably identified, our knowledge of the pharmacology of CBDA is more limited due to its instability. To stabilize CBDA, a new derivative, CBDA-O-methyl ester (HU-580, EPM301), was synthesized. The therapeutic potential of EPM301 in appetite reduction, weight loss, and metabolic improvements in DIO and GIO was tested in vivo. EPM301 (40 mg/kg/d, i.p.) successfully resulted in weight loss, increased ambulation, as well as improved glycemic and lipid profiles in DIO mice. Additionally, EPM301 ameliorated DIO-induced hepatic dysfunction and steatosis. Importantly, EPM301 (20 and 40 mg/kg/d, i.p.) effectively reduced body weight and hyperphagia in a high-fat diet-fed Magel2null mouse model for PWS. In addition, when given to standard-diet-fed Magel2null mice as a preventive treatment, EPM301 completely inhibited weight gain and adiposity. Lastly, EPM301 increased the oxidation of different nutrients in each strain. All together, EPM301 ameliorated obesity and its metabolic abnormalities in both DIO and GIO. These results support the idea to further promote this synthetic CBDA derivative toward clinical evaluation in humans.

Small molecules targeting peripheral CB1 receptors have therapeutic potential in a variety of disorders including obesity-related, hormonal, and metabolic abnormalities, while avoiding the psychoactive effects in the central nervous system. We applied our in-house algorithm, iterative stochastic elimination, to produce a ligand-based model that distinguishes between CB1R antagonists and random molecules by physicochemical properties only. We screened ∼2 million commercially available molecules and found that about 500 of them are potential candidates to antagonize the CB1R. We applied a few criteria for peripheral activity and narrowed that set down to 30 molecules, out of which 15 could be purchased. Ten out of those 15 showed good affinity to the CB1R and two of them with nanomolar affinities (Ki of ∼400 nM). The eight molecules with top affinities were tested for activity: two compounds were pure antagonists, and five others were inverse agonists. These molecules are now being examined in vivo for their peripheral versus central distribution and subsequently will be tested for their effects on obesity in small animals.

Organic Te(IV) compounds (organotelluranes) differing in their labile ligands exhibited anti-integrin activities in vitro and anti-metastatic properties in vivo. They underwent ligand substitution with l-cysteine, as a thiol model compound. Unlike inorganic Te(IV) compounds, the organotelluranes did not form a stable complex with cysteine, but rather immediately oxidized it. The organotelluranes inhibited integrin functions, such as adhesion, migration, and metalloproteinase secretion mediation in B16F10 murine melanoma cells. In comparison, a reduced derivative with no labile ligand inhibited adhesion of B16F10 cells to a significantly lower extent, thus pointing to the importance of the labile ligands of the Te(IV) atom. One of the organotelluranes inhibited circulating cancer cells in vivo, possibly by integrin inhibition. Our results extend the current knowledge on the reactivity and mechanism of organotelluranes with different labile ligands and highlight their clinical potential.

Among a multitude of hormonal and metabolic complications, individuals with Prader-Willi syndrome (PWS) exhibit significant bone abnormalities, including decreased BMD, osteoporosis, and subsequent increased fracture risk. Here we show in mice that loss of Magel2, a maternally imprinted gene in the PWS critical region, results in reduced bone mass, density, and strength, corresponding to that observed in humans with PWS, as well as in individuals suffering from Schaaf-Yang syndrome (SYS), a genetic disorder caused by a disruption of the MAGEL2 gene. The low bone mass phenotype in Magel2-/- mice was attributed to reduced bone formation rate, increased osteoclastogenesis and osteoclast activity, and enhanced trans-differentiation of osteoblasts to adipocytes. The absence of Magel2 in humans and mice resulted in reduction in the fatty acid amide bone homeostasis regulator, N-oleoyl serine (OS), whose levels were positively linked with BMD in humans and mice as well as osteoblast activity. Attenuating the skeletal abnormalities in Magel2-/- mice was achieved with chronic administration of a novel synthetic derivative of OS. Taken together, Magel2 plays a key role in modulating bone remodeling and mass in PWS by affecting OS levels and activity. The use of potent synthetic analogs of OS should be further tested clinically as bone therapeutics for treating bone loss. © 2018 American Society for Bone and Mineral Research.