Cannabis laws: an analysis of costs

There is evidence that the use of cannabis is increasing in Australia, with stable black-market prices, despite the 9-year National Campaign Against Drug Abuse, increasing expenditure to enforce the laws against cannabis use, and the seizure of large plantations of cannabis plants. Recent government data are used to estimate the conservative cost of drug-law enforcement against cannabis use as being $329m in 1991-92. Alternatives to the existing regime are examined, including expiation, decriminalization, and legalization.     

The human toxicity of marijuana: a critique of a review by Nahas and Latour

A review entitled “The human toxicity of marijuana” was published in 1992 in the Medical Journal of Australia. The authors claimed that the adverse effects of cannabis use have been trivialized and that the effects are much more serious than earlier reported. We have made a careful study of this review and examined the claims made. We compared the claims of the authors with the information contained in the documents they cited and found that at least 28 of the 35 citations in this article were cited inaccurately. Five of these publications were misquoted, or the findings of the study were not fully reported. Twenty-three citations contained other errors, leaving only six to eight (two citations could not be retrieved because of their obscurity) accurate citations among 35. All of these inaccuracies operate in the direction of finding an adverse effect of marijuana.     

AMPA receptors shape Ca2+ responses in cortical oligodendrocyte progenitors and CG-4 cells

Intracellular calcium signals triggered by glutamate receptor activation were studied in primary cortical oligodendrocyte lineage cells and in the oligodendrocyte cell line CG-4. Glutamate, kainate, and AMPA (30-300 μM) increased [Ca ²⁺]_i in both types of cells at the stage of oligodendrocyte progenitors (O-2A; GD3⁺) or pro-oligodendroblasts (04⁺). The peak amplitude of Ca²⁺ responses to glutamate receptor agonists was significantly larger in cortical cells. In CG-4 and in cortical cells, the majority (more than 90%) of bipolar GD3⁺ or multipolar 04⁺ cells responded to kamate. In all the cells analyzed, kainate was more efficacious than AMPA and glutamate. The percentage of bipolar or multipolar cells responding to glutamate was significantly lower in the CG-4 cell line than in primary cultures. Cellular responses typical of metabotropic glutamate receptor activation were observed in 20% of the cortical O-2A progenitors, but in none of the CG-4 cells. The AMPA-selective antagonist GYKI 52466 blocked kainate-induced Ca²⁺ responses in cortical O-2A cells. The selective AMPA receptor modulator cyclothiazide (30 μM) greatly potentiated the effects of AMPA (30-100 μM) on [Ca ²⁺]_i in cortical and CG-4 cells. Our findings indicate that Ca²⁺ responses in cells of the oligodendrocyte lineage are primarily shaped by functional AMPA receptors. © 1995 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Ischaemia induced alternans of action potential duration in the intact-heart: dependence on coronary flow, preload and cycle length

Clinical and experimental evidence relate action potential duration(APD) alternans to ischaemic heart disease and ventricular arrhythmias.The present investigation was performed to study the quantitativerelationship between APD alternans and the degree ofischaemia,loading conditions and cycle length (CL) in an intact heart. Monophasic action potentials (MAP) were simultaneously recordedby contact electrodes from two left (LV) undone right ventricular(RV) sites in 20 Langendorff-perfused rabbit hearts. The preparationswere subjected to global ischaemia at flow rates ranging from40% of normal flow to complete cessation of flow. Pacing wasperformed at either constant or regularly changing CL. The magnitudeof APD alternans was expressed as beat-to-beat differences inaction potential duration of two consecutive MAPs. During normalper fusion, neither very fast pacing at a CL of 200 ms nor periodicalrate switches resulted in persistent APD alternans. Pacing ata constant CL of 800 ms did not induce A PD alternans at completecessation of flow for 6 min. However, alternans developed progressivelyat a constant CL of 400 ms after 2.8±0.3 min of completeischaemia at the pre-loaded LV, andafter 4.6±0.4 minat the unloaded RV (P<0.01). The reduction of preload atthe LV from 15 to 5 mmftg end-diastolic pressure delayed developmentof APD alternans from 2.8±0.3 min to 4.3±0.4 min(P < 0.05) at 400 ms CL. Following graded under per fusionof 40%, 20% and 10% of initial flow, persistent APD alternansdeveloped in relation to the degree of flow reduction and increasedprogressively with duration ofischaemia. APD alternans at theLV always preceded the onset of APD alternans at the RV. Inexperiments with identical flow rates the shortest CL of 200ms resulted in the greatest and earliest initiation of APD alternanscompared to the longer CL (P<0.01, P<0.001). An increasein CL from 400 to 800 ms immediately abolished APD alternans,generated by the shorter CL, at any time during the 6 min periodof complete ischaemia. Similarly, increasing the cycle lengthfrom 200 or 400 to 600 ms eliminated APD alternans up to 6 minof ischaemia and significantly reduced its magnitude between7 and 10 min within a few beats. We conclude that persistent APD alternans is a characteristicfinding in the rabbit heart during global ischaemia. It is asensitive parameter of the severity of ischaemia and dependson the degree and duration of ischaemia as well as on the preload.The CL appears to have an independent effect on the generationof APD alternans, which is functionally separate from the effectof CL on the ischaemic burden. An eventual impact of these observationscould be the application of APD alternans as a diagnostic toolin electrophysiological examinations of myocardial ischaemiain experimental and clinical settings.     

Effects of adenosine on electrical activity of isolated guinea pig hearts

Summary Negative chronotropic and dromotropic effects of adenosine seem to be responsible for its antiarrhythmic action on supraventricular tachyarrhythmias. To further characterize the effects of adenosine on supraventricular arrhythmias heart rate, conduction, refractoriness, the time to steady-state of AV-nodal conduction slowing and of sinus rate reduction were evaluated.Changes of heart rate, conduction intervals and effective refractory periods were determined by the use of a high-resolution ECG recording technique in isolated guinea pig hearts perfused by the method of Langendorff.Adenosine in concentrations of 3 and 10 M reduced sinus rate and prolonged AV-nodal conduction significantly, while intraventricular and His bundle conduction were not altered. The maximal effect of adenosine on the sinus node and AV nodal conduction occurred after 636±109 and 111±35 (mean±SE) beats, respectively.During programmed stimulation at a cycle length of 250 ms, adenosine reduced atrial ERP in a dose-dependent manner. At cycle lengths of 170 and 200 ms, adenosine increased the atrial ERP at 3 M, and then progressively shortened the ERP at higher doses. At all adenosine concentrations used, the usual rate-dependent adaption in ERP was suppressed.These observations explain the efficacy of adenosine against supraventricular tachyarrhythmias where the AV-node forms a part of a reentrant circuit. Adenosine shortened the atrial ERP, but at high pacing rates also led to a relative prolongation of the atrial ERP as the rate-dependent adaption was suppressed. These opposite effects of adenosine may explain earlier contradictory findings of its action on atrial arrhythmias.     

Time course of the anti-oedematous effect of O-(β-hydroxyethyl)-rutosides in healthy volunteers

Summary O-(-hydroxyethyl)-rutosides (HR) is used for the treatment of disorders of the venous and microcirculatory systems. In order to evaluate the time course of its activity, the effect of HR on a provocation model of orthostatic oedema in healthy volunteers was used. After a 2 week placebo run-in period, 16 healthy volunteers were randomized to HR (2 tablets of 500 mg/day) of placebo for a further 3 weeks, in a double-blind parallel design. Oedema was provoked by standing motionless for 1 h, with measurement of leg volume before and afterwards. The procedure was undertaken at entry to the study and then weekly during the entire 5 week period.There were no significant differences in the extent of oedema produced by the orthostatic challenge during the 2 week run-in period or in the subjects who continued on placebo (90 arbitrary units i.e. 48 ml). During the 3 week treatment with HR, however, there was a progressive reduction (–1.1, –5.9, and –7.6 arbitrary units after 1, 2, and 3 weeks, respectively) in the volume of induced oedema, which was significant after 2 and 3 weeks of treatment compared to the placebo group.     

GABA-mediated synaptic transmission in neuroendocrine cells: a patch-clamp study in a pituitary slice preparation

Patch-clamp recording techniques were applied to thin slices of the rat pituitary gland in order to study synaptic transmission between hypothalamic nerve terminals and neuroendocrine cells of the intermediate lobe. Inhibitory postsynaptic currents (IPSCs) could be evoked by electrical stimulation of afferent neuronal fibres in the surrounding tissue of the slice. The IPSCs could be evoked in an all-or-nothing mode depending on the stimulus intensity, suggesting that single afferent fibres were stimulated. They had a chloride-dependent reversal potential and were blocked by bicuculline (K _d=0.1 M), indicating that they were mediated by -aminobutyric acid A (GABA_A) receptors. In symmetrical chloride solutions the current/voltage relation of the IPSC peak amplitudes was linear. The IPSCs were characterized by a fast (1–2 ms) rise time and a biexponential decay, with time constants of 21±4 ms and 58±14 ms at a holding potential of –60 mV (n=6 cells). Both decay time constants increased with depolarization in an exponential manner. Spontaneously occurring IPSCs had a time course that was similar to that of evoked IPSCs. These miniature IPSCs, recorded in 1 M tetrodotoxin, displayed an amplitude distribution that was well fitted by single Gaussian functions, with a mean value of its maxima of 18.1±2.3 pA (n=4 cells). Amplitude histograms of evoked IPSCs were characterized by multiple peaks with a modal amplitude of about 18 pA (n=6 cells). These findings indicate the quantal nature of GABAergic synaptic transmission in this system, with a quantal conductance step of about 280 pS. Single-channel currents underlying the IPSCs were studied by bath application of GABA to outside-out patches excised from intermediate lobe cells. Such GABA-induced currents revealed two conductance levels of 14 pS and 26 pS. In conclusion, GABAergic synaptic transmission in neuroendocrine cells of the pituitary has properties that are quite similar to those observed in neurones of the central nervous system.     

Cytologic diagnosis of cavernous hemangioma of the liver with fine-needle biopsy.

We present the cytopathologic findings in seven cases of cavernous hemangiomas of the liver diagnosed by direct "squash" smears made on tissue obtained through image-guided fine-needle biopsy. The diagnosis in each case was confirmed histologically. Utilizing this simple cytologic technique, the morphologic findings in these common hepatic lesions are as accurate and diagnostic as histologic examination.     

Effects of prostacyclin analogue,OP-2507, on function and metabolism in the ischemic working rat heart

We examined the effects of a new stable prostacyclin analogue, OP-2507, on myocardial function and metabolism in the ischemic working rat heart preparation. The hearts were perfused with Krebs-Henseleit bicarbonate (KHB) buffer, and whole heart ischemia was induced by one-way aortic valve for 15min follows by reperfusion for 30min. In the treated hearts, OP-2507, 20ng·ml^–1, was administered to KHB buffer from the beginning to the end of experiment. During ischemia, coronary flow in the OP-2507 group increased significantly more than that in the control group. The mechanical performance of both groups was impaired after ischemia. However, the recovery of coronary flow, cardiac output, peak systolic pressure and LV dP/dT_max was significantly higher in the treated group than in the control group. The incidence of ventricular fibrillation during reperfusion was 100% and 25% in the control and the OP-2507 groups, respectively. Myocardial ATP content was significantly higher in the treated hearts than that in the control hearts. These results indicate that this stable prostacyclin analogue is beneficial in myocardial ischemia, even without its well known action of preventing platelet aggregation.(Oguchi T, Kashimoto S, Nakamura T, et al.: Effects of prostacyclin analogue, OP-2507, on function and metabolism in the ischemic working rat heart. J Anesth 6: 446–454, 1992)     

Monosynaptic Interjoint Reflexes and their Central Modulation During Fictive Locomotion in Crayfish

An in vitro preparation of the crayfish nervous system has been utilized to study an interjoint reflex pathway and its variability during rhythmic locomotor activity. The coxo-basal chordotonal organ (CBCO) is a joint stretch receptor spanning the second joint of walking legs in crayfish, where it encodes joint movements and position. Mechanical stimulation (stretch and release) of the CBCO and electrical stimulation of the CBCO nerve elicits reflex responses in promotor and remotor motor neurons innervating muscles moving the basal thoraco-coxal (TC) leg joint. Promotor and remotor motor neurons receive monosynaptic excitatory inputs from at least four CBCO afferents, including both stretch- and release-sensitive CBCO afferents. In a tonic preparation, in which there is no tendency to produce alternating bursts of activity in antagonistic motor neurons, the reflex responses were evoked during each cycle of imposed movement. However, when the preparation became rhythmic and produced bouts of fictive locomotion, the reflex responses were unstable and their gain was phasically modulated. Paired recordings indicate that such a modulation of the monosynaptic interjoint reflex could be due to both a phasic change in the excitability of the motor neurons and presynaptic inhibition that reduces the excitatory input from CBCO primary afferents.