Presynaptic alpha 2-autoinhibition in a vascular neuroeffector junction where ATP and noradrenaline act as co-transmitters.

1. alpha 2-Autoinhibition of transmitter release was investigated in the largest rami caecales of the rabbit ileocolic artery. Vasoconstriction, elicited by electrical field stimulation or by exogenous agonists, was measured as an increase in perfusion pressure. 2. Short periods of electrical stimulation elicited monophasic vasoconstriction, whereas longer periods (greater than 10 s) produced biphasic vasoconstriction. Prazosin had no significant effect on the first component of the biphasic vasoconstriction elicited by electrical stimulation, but did reduce the second component at higher frequencies. alpha, beta-Methylene ATP significantly attenuated the first component whilst the second component was relatively resistant. 3. The alpha 2-adrenoceptor antagonist yohimbine did not change responses evoked by very short pulse trains (less than 2 s) but enhanced responses to longer pulse trains. When vasoconstriction was biphasic, both phases were potentiated by yohimbine. 4. The results indicate that the vasoconstriction elicited by brief trains of sympathetic nerve impulses is mainly or exclusively mediated by ATP, whereas at longer pulse trains a noradrenergic component comes into play. The potentiation produced by yohimbine is due to interruption of presynaptic alpha 2-adrenoceptor-mediated autoinhibition of transmitter release. The autoinhibition affects both purinergic and adrenergic components of sympathetic neurotransmission.     

Antidepressant Use in Canada Has Stopped Increasing

Objective:

Large increases in the use of antidepressants (ADs) were reported in the past 2 decades in many countries, including Canada. Our objective was to determine whether this pattern of increasing use has continued, using data from a 2012 national mental health survey.

Method:

During the past 2 decades, a series of Canadian national health surveys have evaluated AD use in the household population. Some of these surveys have assessed past 2-day use whereas others have assessed self-reported past-month use. We applied meta-regression methods as a methodological strategy to address this heterogeneity and to examine long-term trends, incorporating 2012 data.

Results:

In keeping with prior reports, AD use rapidly increased in the 1990s and early 2000s. However, the 2012 data suggest that these increases have slowed or perhaps even stopped in recent years. A post hoc examination of longitudinal data from the National Population Health Survey reinforced the impression of a levelling off in the use of these medications.

Conclusion:

The frequency of AD use may now be stabilizing in the Canadian population. This emerging steady state may reflect a contemporary balance between the perceived need, perceived effectiveness, and acceptability of these medications in the general population.     

Depression and painful conditions: patterns of association with health status and health utility ratings in the general population

Purpose

Preference-weighted HRQoL (utility) ratings are increasingly used to guide clinical and resource allocation decisions, but their performance has not always been adequately explored. We sought to examine patterns of health utility ratings in community populations with depressive disorders and painful conditions.

Methods

We used two Canadian cross-sectional health surveys that obtained Comprehensive Health Status Measurement System/Health Utilities Index Mark 3 (HUI3) ratings and identified people with painful conditions and major depression. We estimated the frequency of item endorsements and mean utility ratings in these groups.

Results

Interesting differences between health state ratings and diagnostic categories were noted. For example, 71 % of those professionally diagnosed with migraine reported that they usually have “no pain.” Despite this, utility ratings were lower in those respondents with depressive episodes and in those with painful conditions. Greater than additive reductions in HUI3 scores were noted in most instances where both depressive disorders and painful conditions were present.

Conclusions

Health utility ratings confirm the clinical impression that painful conditions and depressive disorders magnify each other’s impact. Despite weak alignment between the health state definitions incorporated into utility ratings and the diagnostic concepts examined, the HUI3 appeared to capture HRQoL decrements and negative synergies associated with the co-occurrence of depressive episodes and painful conditions.     

Cimetidine as a first-line therapy for pedal verruca: eight-year retrospective analysis

Can cimetidine therapy effectively stimulate the body's immune response against warts? Several clinicians have anecdotally reported success using cimetidine against warts. Previous double-blind studies comparing cimetidine with placebo therapy have failed to statistically and scientifically corroborate those results. Between 1995 and 2002, 216 patients underwent an isolated course of oral cimetidine therapy for verruca plantaris. Our treatment outcomes closely parallel those obtained by other researchers. Cimetidine may be used as a safe, effective, lone treatment modality for verruca in all age groups.     

An overview of the effect of linoleic and conjugated-linoleic acids on the growth of several human tumor cell lines

Both n-6 and n-3 polyunsaturated fatty acids are dietary fats important for cell function, being involved in several physiologic and pathologic processes, such as tumorigenesis. Linoleic acid and conjugated linoleic acid, its geometrical and positional stereoisomer, were tested on several human tumor cell lines originating from different tissues and with different degrees of malignancy. This was to provide the widest possible view of the impact of dietary lipids on tumor development. While linoleic acid exerted different effects, ranging from inhibitory to neutral, even promoting growth, conjugated linoleic acid inhibited growth in all lines tested and was particularly effective against the more malignant cells, with the exception of mammary tumor cells, in which behavior was the opposite, the more malignant cell line being less affected. The inhibitory effect of conjugated linoleic acid on growth may be accompanied by different contributions from apoptosis and necrosis. The effects of conjugated linoleic acid on growth or death involved positive or negative variations in PPARs. The important observation is that a big increase of PPARalpha protein occurred in cells undergoing strong induction of apoptosis, whereas PPARbeta/delta protein decreased. Although PPARalpha and PPARbeta/delta seem to be correlated to execution of the apoptotic program, the modulation of PPARgamma appears to depend on the type of tumor cell, increasing as protein content, when inhibition of cell proliferation occurred. In conclusion, CLA may be regarded as a component of the diet that exerts antineoplastic activity and its effect may be antiproliferative or pro-apoptotic.     

Randomized,double-blind,placebo-controlled comparison of the analgesic efficacy of oxycodone 10 mg/acetaminophen 325 mg versus controlled-release oxycodone 20 mg in postsurgical pain

This randomized, controlled trial compared the analgesic efficacy and safety of the new oxycodone 10-mg/acetaminophen 325-mg formulation (Percocet) for the treatment of acute pain following oral surgery with double the dose of oxycodone alone (controlled-release [CR] oxycodone 20 mg [OxyContin]). A total of 150 male and female patients with > or = 2 full or partial bone-impacted mandibular molars, at least moderate persistent pain, and moderate trauma received a single dose of combination agent, CR oxycodone, or placebo following oral surgery and rated pain intensity and pain relief over the next 6 hours. The intent-to-treat population comprised 141 patients (55 on combination agent, 56 on oxycodone, and 30 on placebo). Combination agent and CR oxycodone were significantly superior to placebo for all efficacy measures. Combination agent was statistically superior to CR oxycodone in four of five outcome measures of pain intensity and pain relief (PPID, PPAR, SPID, and SPRID). It also provided a faster onset and 24% reduction in the number of patients reporting treatment-related adverse events compared with twice the dose of opioid alone. This new formulation offers the combination of two analgesic drugs with complementary mechanisms of action, which results in enhanced analgesia, an "opioid-sparing" effect, and an improved side effect and safety profile.     

Dye and electrotonic coupling between cultured hippocampal neurons

Electrotonic coupling was examined between hippocampal neurons in dissociated cell cultures. Injections of Lucifer yellow indicated that approximately 20% of the neurons were dye-coupled. Propionate, which causes cytoplasmic acidification, significantly decreased dye coupling. Simultaneous intracellular recordings from pairs of cultured neurons directly demonstrated electrotonic coupling. Therefore dissociated cell cultures can be used as a model system for the analysis of hippocampal electrotonic coupling.