Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression. METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. CONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

1-n-Butyl-3-methylimidazolium-2-carboxylate: a versatile precatalyst for the ring-opening polymerization of ε-caprolactone and rac-lactide under solvent-free conditions.

The ring-opening polymerization of ε-caprolactone (ε-CL) and rac-lactide (rac-LA) under solvent-free conditions and using 1-n-butyl-3-methylimidazolium-2-carboxylate (BMIM-2-CO2) as precatalyst is described. Linear and star-branched polyesters were synthesized by successive use of benzyl alcohol, ethylene glycol, glycerol and pentaerythritol as initiator alcohols, and the products were fully characterized by (1)H and (13)C{(1)H} NMR spectroscopy, gel permeation chromatography (GPC), and differential scanning calorimetry (DSC). BMIM-2-CO2 acts as an N-heterocyclic carbene precursor, resulting from in situ decarboxylation, either by heating under vacuo (method A) or by addition of NaBPh4 (method B). Possible catalytic and deactivation mechanisms are proposed.

Medical interns' view of their undergraduate medical education in Uppsala: an alumnus study with clear attitude differences between women and men.

BACKGROUND: An alumni study of graduates from the medical school in Uppsala, was performed to give input into an ongoing reform process. AIMS: This study aimed to investigate how medical interns view their undergraduate medical education and the extent to which they felt that the curriculum prepared them for their current positions. METHODS: A web-based questionnaire was sent out via mail in 2005 to all past graduates who had qualified in Uppsala in 2003. RESULTS: Replies were obtained from 69 of 102 students (68%). The most apparent suggested change of the education was increased integration of preclinical and clinical teaching. Correlations were found between student satisfaction with the medical school and perceived teacher attitude, encouragement to reflect, and the graduates' perception of having sufficient practical abilities. Significant gender differences were found regarding perceived clinical ability and concerning feedback and encouragement from the teachers. CONCLUSIONS: Our results suggest more direct feedback from the teachers and more integration between basic sciences and clinical education. Female and male students may have different needs. A key question is therefore to encourage teachers to learn about gender since female and male students should equally experience respectful encounters with teachers and doctors acting as role models.

Effects of measurement of plasma activity input on normalization of glomerular filtration rate to plasma volume in dogs.

Glomerular filtration rate (GFR) normalized to body fluid volumes to adjust for differing body size and conformation is more physiologically correct than a relationship with body weight (BW). GFR can be normalized to plasma volume by a renographic method that uses the Rutland-Patlak plot with plasma activity and kidney activity inputs. A plasma time-activity curve is obtained from a region of interest (ROI) of the left ventricle (LV), the size of which is in theory not critical. The aims of the study were to evaluate the effect of different LV ROI sizes, the effect of extravascular activity in the thorax over the LV ROI, and different time intervals for the semilogarithmic LV plot. Seventy-two scintigrams were used, with three different-sized automatic and a manual LV ROI, all with and without subtracting extravascular activity, and with LV curve time intervals of 30-120 s and 60-240 s. GFR/plasma volume was not affected by LV ROI sizes but significantly affected by extravascular activity subtraction and different time intervals. Subtracting extravascular activity from the LV ROI did not improve precision, but increased variability caused by different LV ROI sizes and time intervals chosen for the LV plot. The ROI for measuring extravascular activity apparently contained a considerable and variable intravascular component, which when subtracted, created noisy and unreliable LV curves. Manual LV ROI, without extravascular subtraction, and a time interval for LV input between 1 and 4 min are recommended as they gave the least variability determined by statistical analysis. With these methods, normal individual GFR/plasma volume in normal beagle dogs was 29.2 +/- 6.5 ml/min/l.

SLC7A9 cDNA cloning and mutational analysis of SLC3A1 and SLC7A9 in canine cystinuria.

Cystinuria is a genetic disorder in the domestic dog that leads to recurrent urolith formation. The genetic basis of the disorder is best characterized in humans and is caused by mutations in one of the amino acid transporter genes SLC3A1 or SLC7A9, which results in hyperexcretion of cystine and the dibasic amino acids in the urine and subsequent precipitation of cystine due to its low solubility in urine. In this study we describe the cloning of the canine SLC7A9 cDNA and present a thorough mutation analysis of the coding SLC3A1 and SLC7A9 regions in cystinuric dogs of different breeds. Mutation analysis of the two cystinuria disease genes revealed one SLC7A9 mutation (A217T) and two SLC3A1 mutations (I192V and S698G) in French and English Bulldogs that affect nonconserved amino acid residues, arguing against functional impact on the proteins. The absence of deleterious mutations linked to cystinuria in the remainder of our panel of cystinuric dogs is surprising because SLC3A1 or SLC7A9 mutations explain approximately 70% of all human cystinuria cases studied. The present study, along with previous investigations of canine and human cystinuria, implies that regulatory parts of the SLC3A1 and SLC7A9 genes as well as other unknown genes may harbor mutations causing cystinuria.

Effects of meloxicam on renal function in dogs with hypotension during anaesthesia.

OBJECTIVE: To evaluate the effects of meloxicam on renal function in dogs anaesthetized and rendered hypotensive with acepromazine-thiopental-isoflurane. ANIMALS: Eight healthy beagles, four males and four females, 25.6 +/- 19.3 months old and weighing 12.8 +/- 2.0 kg. MATERIALS AND METHODS: Either meloxicam suspension at a dose of 0.133 mL kg(-1) (0.2 mg kg(-1)) or 0.133 mL kg(-1) saline solution (control), were given by mouth (PO) in a randomized, cross-over fashion. The treatment or control was given 3 hours before anaesthesia. Dogs were sedated with intramuscular acepromazine 0.1 mg kg(-1). Anaesthesia was induced with intravenous thiopental, followed by tracheal intubation and maintenance with isoflurane in oxygen and air, delivered using a semi-closed breathing system. Renal function was quantified using serum biochemistry, urinalysis and glomerular filtration rate measured by scintigraphy. Analysis of variance or Friedman anova were used for statistical analysis. RESULTS: Values (mean +/- SD) for mean arterial blood pressure did not differ significantly between treatments but was low (54 +/- 7 mmHg) during anaesthesia. Glomerular filtration rate did not differ significantly between treatments or over time, and results of urine and serum analysis were within reference ranges after meloxicam treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam caused no adverse effects on renal function when given to healthy dogs anaesthetized and rendered hypotensive with acepromazine, thiopental and isoflurane.