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.     

Human Rights and Review of the Involuntary Status of Patients with a Mental Illness: Kracke after Momcilovic

Arguably, Australia's most significant judicial pronouncement on the human rights of those with mental illnesses was made in 2009 by Justice Bell, the then President of the Victorian Civil and Administrative Tribunal (“VCAT”). The decision is an exhaustive analysis of the application of the Charter of Human Rights and Responsibilities Act 2006 (Vic) to the involuntary status of a person subject to a community treatment order in Victoria. It occurred in the context of delays in the conduct of reviews of the status of a mentally ill person by Victoria's Mental Health Review Board (“the Board”). The outcome of the hearing was a declaration that the Board had breached the person's human rights to a fair hearing, even though the person's involuntary status on a community treatment order was not disturbed by VCAT. Whilst some important aspects of Justice Bell's decision concerning the general methodology to be applied when analysing human rights were overturned in the subsequent Court of Appeal decision of R v Momcilovic [2010] VSCA 50, the latter decision did not concern mental health and so leaves Kracke as the most detailed articulation and analysis of human rights within this difficult sphere.     

Evaluation of corticospinal excitability in cervical myelopathy, before and after surgery, with transcranial magnetic stimulation: a pilot study

Purpose

A pilot study to examine the impact of cervical myelopathy on corticospinal excitability, using transcranial magnetic stimulation, and to investigate whether motor evoked potential (MEP) and silent period (SP) recruitment curve (RC) parameters can detect changes in corticospinal function pre- and post-surgery.

Methods

We studied six cervical myelopathy patients undergoing surgery and six healthy controls. Clinical and functional scores and neurophysiological parameters were examined prior to and 3 months following the surgery.

Results

MEP latencies for abductor pollicis brevis (APB) and tibialis anterior (TA) muscles and central motor conduction time were prolonged pre- and post-surgery; SP durations were differentially altered. There were significant differences in parameters of RCs for (1) MEP area in APB (max values, S50) and TA (slope) between controls and patients pre- and post-surgery and (2) SP duration in APB (max values) between patients pre-surgery and controls.

Conclusions

The findings of this pilot study suggest an uncoupling of excitatory and inhibitory pathways, which persists at 3 months following cord decompression. RCs for MEP and SP at 3 months provide more information on the functional status of the cord and prompts for a longer term follow-up.     

First in-Human Gallbladder Cryoablation in a Patient with Acute Calculous Cholecystitis Initially Treated with a Cholecystostomy Tube

A 71-year-old poor surgical candidate with acute calculous cholecystitis was initially managed with cholecystostomy tube drainage for 28 days. He subsequently underwent gallbladder cryoablation under moderate sedation with 3 cryoprobes and 2 separate 10-8-10 freeze-thaw cycles targeting the gallbladder neck/body and fundus followed by cholecystostomy tube removal. He was discharged 1 day after ablation. Magnetic resonance and hepatobiliary iminodiacetic acid scan 1 month postablation demonstrated a thick-walled, distended gallbladder and no filling of the cystic duct. Magnetic resonance 3 months postablation demonstrated retraction of the gallbladder wall with luminal collapse. The patient denied any pain after discharge and is asymptomatic 3 months after ablation.     

Temporal profile of subventricular zone progenitor cell migration following quinolinic acid-induced striatal cell loss

A number of studies have demonstrated directed migration of neural progenitor cells to sites of brain injury and disease, however a detailed examination of when a cell is "born" in relation to injury induction and the migratory response of that cell has not previously been determined. This study therefore examined the temporal correlation between progenitor cell proliferation ("birth") and neuroblast migratory response into the damaged striatum following quinolinic acid (QA) lesioning of the adult rat striatum. Retroviral labeling of subventricular zone (SVZ)-derived progenitor cells demonstrated that cell loss in the QA-lesioned striatum increased progenitor cell migration through the rostral migratory stream (RMS) for up to 30 days. In addition, a population of dividing cells originating from the SVZ generated doublecortin positive neuroblasts that migrated into the damaged striatum in response to cell loss invoked by the QA lesion. Quantification of bromodeoxyuridine (BrdU)-labeled cells co-expressing doublecortin revealed that the majority of cells present in the damaged striatum were generated from progenitor cells dividing within 2 days either prior to or following the QA lesion. In contrast, cells dividing 2 or more days following QA lesioning, migrated into the striatum and exhibited a glial phenotype. These results demonstrate that directed migration of SVZ-derived cells and neuroblast differentiation in response to QA lesioning of the striatum is acute and transient. We propose this is predominantly due to a reduced capacity over time for newly generated neuroblasts to respond to the lesioned environment due to a loss or inhibition of migratory cues.     

GABAergic processes in the mesencephalic tegmentum modulate the occurrence of active (rapid eye movement) sleep in guinea pigs

The ventrolateral subdivision of the periaqueductal gray (vlPAG) and the adjacent dorsal mesencephalic reticular formation (dMRF) are involved in the modulation of active (rapid eye movement) sleep (AS). In order to determine the effects on AS of the suppression of neuronal activity in these regions, muscimol, a GABA receptor A (GABA(A)) receptor agonist, and bicuculline, a GABA(A) receptor antagonist, were microinjected bilaterally in guinea pigs and the states of sleep and wakefulness were examined. The main effect of muscimol was an increase in AS; this increase occurred in conjunction with a reduction in the time spent in wakefulness. The powerful effect of muscimol was striking especially when considering the small amount of naturally-occurring AS that is present in this species. Additional observable effects that were induced by muscimol were: 1) long lasting episodes of hypotonia/atonia during wakefulness and quiet sleep that included a lack of extensor tone in the hind limbs, and 2) frequently occurring cortical spindles, similar to those observed during naturally-occurring quiet sleep (sleep spindles), that were present during wakefulness. Conversely, bilateral microinjections of bicuculline induced a prolonged state of wakefulness and blocked the effect of subsequent injections of muscimol. These data suggest that endogenous GABA acts on GABA(A) receptors within the vlPAG and dMRF to promote AS in the guinea pig.