Reversal of visceral hypersensitivity in rat by Menthacarin® , a proprietary combination of essential oils from peppermint and caraway, coincides with mycobiome modulation.

BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder associated with altered gastrointestinal microflora and increased nociception to colonic distension. This visceral hypersensitivity can be reversed in our rat maternal separation model by fungicides. Menthacarin® is a proprietary combination of essential oils from Mentha x piperita L. and Carum carvi. Because these oils exhibit antifungal and antibacterial properties, we investigated whether Menthacarin® can reverse existing visceral hypersensitivity in maternally separated rats. METHODS: In non-handled and maternally separated rats, we used the visceromotor responses to colorectal distension as measure for visceral sensitivity. We evaluated this response before and 24 hours after water-avoidance stress and after 7 days treatment with Menthacarin® or control. The pre- and post-treatment mycobiome and microbiome were characterized by sequencing of fungal internal transcribed spacer 1 (ITS-1) and bacterial 16s rDNA regions. In vitro antifungal and antimicrobial properties of Menthacarin® were studied with radial diffusion assay. KEY RESULTS: Menthacarin® inhibited in vitro growth of yeast and bacteria. Water-avoidance caused visceral hypersensitivity in maternally separated rats, and this was reversed by treatment. Multivariate analyses of ITS-1 and 16S high throughput data showed that maternal separation, induced changes in the myco- and microbiome. Menthacarin® treatment of non-handled and maternally separated rats shifted the mycobiomes to more similar compositions. CONCLUSIONS & INFERENCES: The development of visceral hypersensitivity in maternally separated rats and the Menthacarin® -mediated reversal of hypersensitivity is associated with changes in the mycobiome. Therefore, Menthacarin® may be a safe and effective treatment option that should be tested for IBS.

Effects of unexpected changes in visual scenes on the human acoustic startle response and prepulse inhibition.

Prepulse inhibition (PPI) refers to the process wherein startle responses to salient stimuli (e.g., startling sound pulses) are attenuated by the presentation of another stimulus (e.g., a brief pre-pulse) immediately before the startling stimulus. Accordingly, deficits in PPI reflect atypical sensorimotor gating that is linked to neurobehavioral systems underlying responsivity to emotionally evocative cues. Little is known about the effects of changes in visual contextual information in PPI among humans. In this study, the effects of introducing unexpected changes in the visual scenes presented on a computer monitor on the human auditory startle response and PPI were assessed in young adults. Based on our animal data showing that unexpected transitions from a dark to a light environment reduce the startle response and PPI in rats after the illumination transition, it was hypothesized that novel changes in visual scenes would produce similar effects in humans. Results show that PPI decreased when elements were added to or removed from visual scenes, and that this effect declined after repeated presentations of the modified scene, supporting the interpretation that the PPI reduction was due to novel information being processed. These findings are the first to demonstrate that novel visual stimuli can impair sensorimotor gating of auditory stimuli in humans.

Attenuation of auditory startle and prepulse inhibition by unexpected changes in ambient illumination through dopaminergic mechanisms.

We investigated the role of dopaminergic mechanisms in the attenuation of the acoustic startle response and prepulse inhibition (PPI) in rats by the introduction of unexpected changes in environment illumination. Experiment 1 showed that Dark-to-Light transitions robustly reduce startle responses and PPI. Experiment 2 showed that this phenomenon habituates across repeated testing sessions and reappears after an interval without testing. Experiment 3 demonstrated that haloperidol blocks the startle and PPI-reducing effect of the Dark-to-Light transition. We show how a computational model of acoustic startle response and prepulse inhibition can be extended to incorporate the empirical effects demonstrated in this study. We conclude that sensory gating as measured by prepulse inhibition is markedly attenuated in situations where novel stimuli are introduced during a test session and that dopaminergic systems may be involved in the dynamic changes evoked by the onset of illumination.

Startle and prepulse inhibition as a function of background noise: a computational and experimental analysis.

Schmajuk and Larrauri [Schmajuk NA, Larrauri JA. Neural network model of prepulse inhibition. Behav Neurosci 2005;119:1546-62.] introduced a real-time model of acoustic startle, prepulse inhibition (PPI) and facilitation (PPF) in animals and humans. The model assumes that (1) positive values of changes in noise level activate an excitatory and a facilitatory pathway, and (2) absolute values of changes in noise level activate an inhibitory pathway. The model describes many known properties of the phenomena and the effect of brain lesions on startle, PPI, and PPF. The purpose of the present study is to (a) establish the magnitude of startle and PPI as a function of pulse, prepulse, and background intensity, and (b) test the model predictions regarding an inverted-U function that relates startle to the intensity of the background noise.

The nicotinic antagonist mecamylamine preferentially inhibits cocaine vs. food self-administration in rats.

Nicotinic acetylcholine systems play important roles in addiction, and nicotinic receptor stimulation stimulates dopamine release while the nicotinic antagonist mecamylamine reduces it. Reid et al. [Neuropsychopharmacology 20 (1999) 297.] recently found in human cocaine addicts that mecamylamine reduced cue-elicited cocaine craving. The current study assessed the impact of mecamylamine on cocaine self-administration in rats. Female Sprague-Dawley rats (N=7) were implanted with intravenous (iv) catheters and trained to lever press for cocaine (0.32 mg/kg/infusion FR-1 with a 60-s timeout) in 45-min sessions. After 2 weeks of training, the rats were injected with saline or mecamylamine (1, 2, or 4 mg/kg sc) 10 min before the session. They received the same dose for 1 week with 1 week of uninjected testing between doses. Mecamylamine, compared to saline, significantly (P<.05) reduced the number of cocaine infusions per session with each of these doses. This effect did not appear to be due to a generalized reduction in behavioral activity. Another set of female Sprague-Dawley rats (N=8) were trained to lever press for food reinforcement. In these rats, the 1 and 2-mg/kg mecamylamine doses had no effect on food self-administration. Significant reductions in food self-administration were not seen unless the high dose of 4-mg/kg mecamylamine was used. Nicotinic antagonist treatment reduces cocaine self-administration in rats at doses that do not cause generalized effects on food-reinforced responding. Nicotinic antagonistic treatment may be a useful new approach to treat cocaine addiction.

Prenatal nicotine effects on memory in rats: pharmacological and behavioral challenges.

Cigarette smoking during pregnancy has been shown in a variety of studies to be associated with cognitive deficits in the children. Nicotine administration to rats during gestation has been found to cause subtle cognitive effects in the offspring. Some individual differences in cognitive impairment may be related to prenatal nicotine effects on noradrenergic (NE) systems. In the current study, 10 Sprague-Dawley rat dams were infused with approximately 2 mg/kg/day of nicotine ditartrate via osmotic minipumps and 10 control dams were exposed to vehicle-containing minipumps from gestational day (GD) 4-20. Starting on postnatal day (PND) 50, the offspring were tested for T-maze rewarded spatial alternation with intertrial intervals of 0, 10, 20, or 40 s. There was a sex- and delay-dependent effect of prenatal nicotine exposure on T-maze alternation. Nicotine-exposed males showed a significant deficit at the 0 s delay. In radial-arm maze (RAM) acquisition training there were no significant nicotine effects. However, significant nicotine-related effects were seen with subsequent behavioral and pharmacological challenges in the RAM. Changing the RAM testing location to an identical maze in a different room elicited a significant choice accuracy deficit in the prenatal nicotine-exposed rats compared with controls. Acute nicotine challenge did not cause any differential effects in the prenatal nicotine and control groups. During the isoproterenol (beta-NE agonist) challenge phase there appeared a significant facilitation of choice accuracy and speeding of response in the prenatal nicotine exposure group which was not seen in the control group. The alpha-NE agonist phenylpropanolamine caused a significant deficit in control females but not in the females prenatally exposed to nicotine. No differential effects of the alpha-NE antagonist phenoxybenzamine were seen in the prenatal nicotine and control groups. Throughout RAM testing there was a significant sex effect with males having better choice accuracy than females. These results demonstrate that the persisting cognitive effects of prenatal exposure to 2 mg/kg/day cause subtle effects in cognitive performance which can be elicited with behavioral and pharmacological challenge. These results also support previous studies suggesting the involvement of NE systems in persisting effects of prenatal nicotine exposure.

Sertraline attenuates hyperphagia in rats following nicotine withdrawal.

Chronic nicotine administration can decrease food consumption and body weight. Abrupt withdrawal from nicotine can cause the reverse effect, hyperphagia and rapid weight gain. In the current study, the efficacy of sertraline, a serotonin reuptake inhibitor, on nicotine withdrawal-induced hyperphagia and rapid weight gain was assessed in rats. Sertraline was found to be effective in reversing the increase in feeding that occurred after withdrawal from chronic nicotine administration. Sertraline caused a dose-related decrease in food consumption in control rats not given nicotine. Doses of 5 and 10 mg/kg/day caused significant decreases while 2.5 mg/kg/day caused a slight though nonsignificant decrease in food consumption. Rats in which nicotine was abruptly withdrawn after 3 weeks of administration showed a significant increase in food consumption relative to controls. This increase was eliminated by the high dose of sertraline (10 mg/kg/day), but not by the lower two doses (2.5 and 5 mg/kg/day). Water consumption was affected in a similar fashion. Body weight gain was also affected by sertraline. During the first week after nicotine withdrawal, rats rapidly gained weight, but sertraline attenuated this. The 10-mg/kg dose of sertraline significantly attenuated the nicotine withdrawal-induced weight gain. These results suggest that sertraline can counteract the hyperphagia and rapid weight gain associated with nicotine withdrawal, and might therefore be a useful adjunct to smoking cessation.

Evolución de pacientes con mejor pronóstico en cáncer de mama / Evolution of patients with best prognosis in breast cancer

En una serie de 23 pacientes seguidas durante 4 y 5 años, se pudo constatar una alta correlación entre aquellas con tumores RE+ desplazables y la evolución favorables de su enfermedad (11 de 12 casos - 91 por ciento), así como una correlación entre los tumores RE+ poco desplazables y la evolución desfavorable de la enfermedad (3 de 4 casos - 75 por ciento). Este último grupo se homologa con los tumores RE - cuya evolución fue desfavorable. En esta serie, los tumores RE+ de las pacientes con evolución favorable, presentaron valores de RPg mayores de los RE (10 de 12 casos - 83 por ciento). En las pacientes con tumores RE+ la evolución desfavorable, los valores de RPg no fueron mayores que RE (3 de 4 casos - 75 por ciento). Los estudios anatomo-patológicos indicaron que los tumores RE+ desplazables presentaron mayor proporción de células más diferenciadas que el grupo de tumores RE. Los otros indicadores histológicos examinados: necrosis, desmoplasia, invasión linfocitaria, no mostraron correlación con grado de dependencia hormonal ni con la prueba de desplazamiento por Tam

Evolución de pacientes con mejor pronóstico en cáncer de mama / Evolution of patients with best prognosis in breast cancer

En una serie de 23 pacientes seguidas durante 4 y 5 años, se pudo constatar una alta correlación entre aquellas con tumores RE+ desplazables y la evolución favorables de su enfermedad (11 de 12 casos - 91 por ciento), así como una correlación entre los tumores RE+ poco desplazables y la evolución desfavorable de la enfermedad (3 de 4 casos - 75 por ciento). Este último grupo se homologa con los tumores RE - cuya evolución fue desfavorable. En esta serie, los tumores RE+ de las pacientes con evolución favorable, presentaron valores de RPg mayores de los RE (10 de 12 casos - 83 por ciento). En las pacientes con tumores RE+ la evolución desfavorable, los valores de RPg no fueron mayores que RE (3 de 4 casos - 75 por ciento). Los estudios anatomo-patológicos indicaron que los tumores RE+ desplazables presentaron mayor proporción de células más diferenciadas que el grupo de tumores RE. Los otros indicadores histológicos examinados: necrosis, desmoplasia, invasión linfocitaria, no mostraron correlación con grado de dependencia hormonal ni con la prueba de desplazamiento por Tam

Comparison of psyllium hydrophilic mucilloid and cellulose as adjuncts to a prudent diet in the treatment of mild to moderate hypercholesterolemia.

The effects of the administration of 5.1 g of psyllium or placebo (cellulose) twice daily for 16 weeks were compared as adjuncts to a prudent diet in the management of moderate hypercholesterolemia in a parallel, double-blind study. Psyllium decreased the total cholesterol level by 5.6% and the low-density lipoprotein cholesterol level by 8.6%, whereas the levels were unchanged in the placebo group. The high-density lipoprotein cholesterol level decreased during the diet stabilization period in both groups and returned to near-baseline values by week 16. Plasma triglyceride levels did not change substantially in either group. Subject compliance to treatment was greater than 95%. These data suggest that psyllium hydrophilic mucilloid in a twice-daily regimen may be a useful and safe adjunct to a prudent diet in the treatment of moderate hypercholesterolemia.

Effects of zinc deficiency on lead toxicity in rats.

The effect of zinc deficiency on the toxicity of dietary lead in rats, as measured by body weight changes, tissue lead retention, and choice behavior in a complex maze was studied. Weanling rats were fed a zinc-free semipurified diet which was supplemented via drinking solutions with either 2 or 20 ppm zinc and 0, 10, or 100 ppm lead. During exposure, choice behavior was quantified in a radial maze. After a 3-week period on diet, the animals' physical development was assessed, and the retention of lead and zinc in bone and brain were determined by atomic absorption spectroscopy. Zinc deficiency slowed rats' weight gain, did not affect relative organ weights, increased the retention of lead in both calvarium and in brain, and reduced the accuracy of performance in the maze. Lead exposure at 100 ppm reduced body weight and increased relative organ weights, and reduced maze accuracy at both 10 and 100 ppm. Neither treatment affected the rats' running speed through the maze. Lead exposure and zinc deficiency exerted additive effects on body weight. The two treatments did not interact in the behavioral assay.

The influence of pyridoxine in diabetic peripheral neuropathy.

To determine the role of pyridoxine in the treatment of diabetic peripheral neuropathy, 18 symptomatic diabetic patients were treated with vitamin B6 or placebo in a double-blind controlled study. Only one patient had a low plasma pyridoxal phosphate level at the start of the study. After 4 mo of treatment with pyridoxine hydrochloride (50 mg three times daily) 6 of 9 pyridoxine-treated and 4 of 9 placebo-treated patients noted significant relief from their neuropathic symptoms. There was no difference between the two groups with regard to fasting plasma glucose, motor nerve conduction velocity, or ophthalmologic examination at the beginning or at the conclusion of the study. Our results suggest that vitamin B6 deficiency is not a factor in the etiology of diabetic peripheral neuropathy. Furthermore, treating diabetic peripheral neuropathy with high dose vitamin B6 or placebo results in a similar frequency of symptomatic improvement.