The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F‐PY‐PICA, 5F‐PY‐PINACA,and their analogs

5F‐PY‐PICA and 5F‐PY‐PINACA are pyrrolidinyl 1‐(5‐fluoropentyl)ind (az)ole‐3‐carboxamides identified in 2015 as putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS). 5F‐PY‐PICA, 5F‐PY‐PINACA, and analogs featuring variation of the 1‐alkyl substituent or contraction, expansion, or scission of the pyrrolidine ring were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography–quadrupole time‐of‐flight–mass spectrometry (LC–QTOF–MS). In competitive binding experiments against HEK293 cells expressing human cannabinoid receptor type 1 (hCB₁) or type 2 (hCB₂), all analogs showed minimal affinity for CB₁ (pK_i < 5), although several demonstrated moderate CB₂ binding (pK_i 5.45–6.99). In fluorescence‐based membrane potential assays using AtT20‐hCB₁ or ‐hCB₂ cells, none of the compounds (at 10 μM) produced an effect >50% of the classical cannabinoid agonist CP55,940 (at 1 μM) at hCB₁, although several showed slightly higher relative efficacy at hCB₂. Expansion of the pyrrolidine ring of 5F‐PY‐PICA to an azepane ( 8 ) conferred the greatest hCB₂ affinity (pK_i 6.99) and activity (pEC₅₀ 7.54, E_max 72%) within the series. Unlike other SCRA NPS evaluated in vivo using radio biotelemetry, 5F‐PY‐PICA and 5F‐PY‐PINACA did not produce cannabimimetic effects (hypothermia, bradycardia) in mice at doses up to 10 mg/kg.     

Digit ratio (2D:4D) and hand preference for writing in the BBC Internet Study

The ratio of the length of the second to the fourth digit (2D:4D) may be negatively correlated with prenatal testosterone. Hand preference has been linked with prenatal testosterone and 2D:4D. Here we show that 2D:4D is associated with hand preference for writing in a large internet sample (n>170,000) in which participants self-reported their finger lengths. We replicated a significant association between right 2D:4D and writing hand preference (low right 2D:4D associated with left hand preference) as well as a significant correlation between writing hand preference and the difference between left and right 2D:4D or Dr-l (low Dr-l associated with left hand preference). A new significant correlation between left 2D:4D and writing hand preference was also shown (high left 2D:4D associated with left hand preference). There was a clear interaction between writing hand preference and 2D:4D: The left 2D:4D was significantly larger than the right 2D:4D in male and female left-handed writers, and the right hand 2D:4D was significantly larger than the left hand 2D:4D in male and female right-handed writers.     

There's more to flow-mediated dilation than nitric oxide

Flow-mediated dilation (FMD) is the standard tool used to assess endothelial function. The premise behind the standard FMD test is that it serves as an endothelial-dependant nitric oxide bioassay; however, the endothelium may release additional dilatory molecules which contribute to FMD, most notably prostacyclin and endothelial-derived hyperpolarizing factor. The relative importance of these molecules to the dilatory response may vary substantially among individuals, particularly in response to a number of diseased states. This review discusses how each of these molecules may contribute to vasodilation, and considers the circumstances in which they may vary.     

Differences in outcomes between cholecalciferol and ergocalciferol supplementation in veterans with inflammatory bowel disease

Aim: Vitamin D deficiency is a global health issue associated with increased health‐care costs, and could play a role in the pathogenesis and management of inflammatory bowel disease. Prior studies show a high prevalence of vitamin D deficiency in veterans with inflammatory bowel disease. We aimed to examine the outcome differences in patients with inflammatory bowel disease, comparing treatment with ergocalciferol to cholecalciferol. Methods: A retrospective review of electronic medical records of patients with inflammatory bowel disease at a Veterans Affairs Medical Facility in the Southeastern United States was carried out. Those with at least one serum 25(OH) vitamin D level were included. Initial and follow‐up vitamin D values were recorded. The type of vitamin D supplementation, whether cholecalciferol or ergocalciferol, was documented. Costs in the year after measurement of vitamin D were divided into separate inpatient and outpatient categories. Results: Veterans (n = 108) with ulcerative colitis or Crohn's disease and an available 25(OH) vitamin D level were studied. There were differences in follow‐up vitamin D levels; those who received weekly ergocalciferol had higher subsequent levels than those who received cholecalciferol, especially at a second follow up, although differences did not achieve statistical significance. However, those who received vitamin D3 were less likely to use laboratory, pharmacy, radiology and fee‐based services, and had lower laboratory and pharmacy costs. Conclusions: Our data suggest that cholecalciferol replacement might improve outcomes to a greater extent than ergocalciferol, and might be better in limiting health‐care costs and expenses in patients with inflammatory bowel disease. Geriatr Gerontol Int 2012; 12: 475–480.     

Impairment‐ and activity/participation‐directed interventions in progressive language impairment: Clinical and theoretical issues

Abstract

The most salient and discussed features of agrammatism are the omission and substitution of grammatical morphemes, whether bound or free, in speech production. Cross-linguistic studies have shown that language-specific features determine the pattern of omissions and substitutions found; morphological markers are almost never omitted if the resulting form is a non-word; substitutions are mis-selections from existing paradigms. In the present paper we investigate the ways in which agrammatism is manifested in Algerian Arabic, a Semitic language where simple (Ø-prefixed and Ø-suffixed) words are described as consisting of three morphemes: the discontinuous consonantal root, the discontinuous vocalic base and a CV template or skeleton (McCarthy 1975). Our findings are comparable to those previously reported, in that the three agrammatic subjects who participated in this study do omit and substitute free-standing and bound grammatical markers, and never produce non-words. More specifically, their performance is characterized by omissions of linear bound morphemes in prefixed and suffixed words, as well as substitutions of morphologically complex forms by simpler and more frequent ones. An interpretation of the subjects' performance in the light of current linguistic and psycholinguistic theories on the lexicon is proposed.     

Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine

BACKGROUND: Coenzyme Q10 (CoQ10) has been suggested to be effective in the prevention of migraine, and levels can be quantified with standardized reference ranges. OBJECTIVE: This study documents the prevalence of CoQ10 deficiency in migraine headache and examines the potential effectiveness of supplementation. METHODS: We assessed patients attending a tertiary care center with frequent headaches for CoQ10 deficiency. We recommended patients with low CoQ10 levels begin supplementation with CoQ10 as part of their multidisciplinary treatment plan. We assessed response to treatment including correction of CoQ10 deficiency, overall headache improvement, and headache disability. RESULTS: CoQ10 was measured in 1550 patients (mean age 13.3 +/- 3.5, range 3 to 22 years). The mean total CoQ10 level was 0.60 +/- 0.20 microg/mL (range 0.21 to 1.77 microg/mL). Of these patients, 32.9% were below the reference range. Patients with low CoQ10 were recommended to start 1 to 3 mg/kg per day of CoQ10 in liquid gel capsule formulation. In a subset of patients who returned for timely follow-up (mean, 97 days), the total CoQ10 level improved to 1.20 +/- 0.59 microg/mL (P < .0001), while the headache frequency improved from 19.2 +/- 10.0 to 12.5 +/- 10.8 (P < .001) and headache disability assessed with PedMIDAS improved from 47.4 +/- 50.6 to 22.8 +/- 30.6 (P < .001). CONCLUSIONS: Deficiency of CoQ10 may be common in pediatric and adolescent migraine. Determination of deficiency and consequent supplementation may result in clinical improvement. Further analysis involving more scientifically rigorous methodology will be required to confirm this observation.