Análisis de las características clínicas y patológicas de pacientes HER2 positivo: estudio en dos poblaciones socioculturales diferentes / Analysis of clinical and pathological features of HER2-positive patients: study in two different socio-cultural populations

Introducción: La sobreexpresión del receptor de membrana HER2/neu se ha asociado a un pronóstico más desfavorable. La importancia clínica de medición, radica en que la sobreexpresión de la proteína sugiere peor pronóstico; por lo tanto, se ha convertido en mandatorio su estudio. Objetivo: Analizar las cualidades clínicas y patológicas de tumores que sobreexpresan HER2 en dos poblaciones con diferente nivel sociocultural y económico, subagrupadas acorde a su atención hospitalaria o a través de una cobertura médica. Resultados: Se observó que la proteína se encontraba sobreexpresada en un 13,42%,con una mediana de edad de 59,19 años. La mediana de tamaño tumoral fue de 22,58 mm, encontrándose una diferencia significativa entre el grupo hospitalario (27,76 mm) y el de atención privada (17,15 mm). Un 65,10% de estas pacientes presentaban un tamaño tumoral menor a 1 cm, pero un 55,82% de las pacientes presentaban compromiso ganglionar axilar y un 11,63% eran estadio IV. Al analizar el compromiso metastásico, se observó un mayor porcentaje en el subgrupo HER+ con respecto al RH+ HER–, pero menor al subgrupo TN (11,63% vs. 7,48% vs. 37,03%), teniendo valor estadísticamente significativo (p<0,0001). Conclusión: A pesar de no encontrar datos fidedignos que nos permitan aseverar la vinculaciónentre el "ambioma" a través de mecanismos epigenéticos, en la diferenciación tumoral, creemos probable que las diferencias socioculturales tengan injerencia directa o indirectamente en la promoción, supresión o diferenciación tumoral.

Nicotinic acetylcholine receptors as targets for antidepressants.

While the monoamine deficiency hypothesis of depression is still most commonly used to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that is not adequately explained by the hypothesis. This article draws attention to contributions from another apparently common pharmacological property of antidepressant medications--the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence is presented suggesting the hypercholinergic neurotransmission, which is associated with depressed mood states, may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. In support of this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder. If this hypothesis is supported by further preclinical and clinical research, nicotinic acetylcholine receptor antagonists may represent a novel class of therapeutic agents for treating mood disorders.

Mecamylamine effects on haloperidol-induced catalepsy and defecation.

Recent clinical experience with Tourette syndrome (TS) patients suggests that the nicotinic receptor antagonist, mecamylamine (Inversine), may be a useful adjunct to neuroleptic therapy for controlling tic symptom. This is consistent with previous preclinical findings demonstrating that mecamylamine can potentiate the cataleptic effects of neuroleptics in rats. However, these earlier preclinical studies employed high doses (1-2.5 mg/kg) of mecamylamine that may not be clinically relevant since human doses of mecamylamine used to treat TS have been much lower (0.03-0.1 mg/kg). In order to test the potential therapeutic properties of mecamylamine preclinically, we conducted catalepsy experiments in rats employing both a low and high dose of mecamylamine in combination with haloperidol. Sixty-four male Sprague Dawley rats were randomized into four treatment groups (n = 16/group). Each rat received an injection of either saline or mecamylamine (0.1 or 3.0 mg/kg s.c.) followed one hour later with a second injection of either saline or haloperidol (0.4 mg/kg s.c.). The bar test was used to measure duration of catalepsy at 3 hrs following the second injection. The results demonstrated that only the mecamylamine treated rats showed statistically significant haloperidol-induced catalepsy when measured at 3 hrs. In addition, haloperidol-induced defecation was not affected by the 0.1 mg/kg mecamylamine dose, but completely abolished by the 3.0 mg/kg dose. These findings suggest that a clinically relevant dose of mecamylamine (0.1 mg/kg) can affect the duration of haloperidol-induced catalepsy without having significant effects on gastrointestinal function.

Nicotine induced seizures blocked by mecamylamine and its stereoisomers.

Recent genetic research has shown that certain forms of epilepsy may arise from mutations in the genes encoding for the alpha7 and alpha4 neuronal nicotinic acetylcholine receptor (nAChR) ion channels. These receptors are also involved with the induction of nicotine-induced seizures. (+/-)-Mecamylamine (Inversine), a classic nAChR antagonist, potently inhibits nicotine-induced seizures. The purpose of the present study was to assess the inhibitory effects of (+/-)-mecamylamine and its stereoisomers on nicotine-induced seizures in male Sprague-Dawley rats. Rats received saline, (+/-)-mecamylamine, R-(-)-mecamylamine, or S-(+)-mecamylamine (s.c.) at doses of 0.1, 0.3, or 1.0 mg/kg 15 minutes prior to nicotine injection, 3.6 mg/kg (s.c.), an optimal dose for seizure induction. Rats were observed for 30 minutes with seizure latency, duration, and severity as primary measures and locomotor activity recorded as a secondary measure at 5-minute intervals. The results indicate that mecamylamine and each of its stereoisomers block nicotine-induced seizures in a dose-related manner and suggest that the S-(+/-)- mecamylamine isomer has inhibitory properties more similar to the racemic than to the R-(-)-mecamylamine isomer. The results of this study may be clinically important for the future design of novel anti-seizure medications.

Corticosterone-attenuating and anxiolytic properties of mecamylamine in the rat.

1. The available evidence suggests that stress induced release of acetylcholine (ACh) in the brain has a significant role in mediating neuroendocrine, emotional, and physiological responses to stress. Recent findings also suggest that stress indirectly (via acetylcholine) and nicotine directly stimulates the HPA axis through activation of nAChRs. 2. Our working hypothesis is that under stressful conditions, nicotinic receptor antagonists, such as mecamylamine, should act to attenuate the activation of the HPA axis and exhibit anxiolytic behavioral effects. The purpose of this study was to determine whether or not mecamylamine would: a) produce anxiolytic effects in rats on the elevated plus maze and b) blunt the plasma corticosterone response to predator stress in rats. 3. Results suggested that mecamylamine has anxiolytic properties under stressful conditions. In the EPM experiment, mecamylamine (0.3 mg/kg) produced increased time spent in the open arms. Similarly, in the predator stressor experiment, mecamylamine blunted the stress-induced plasma corticosterone response, with the lowest dose of mecamylamine (0.1 mg/kg). 4. These findings may have important therapeutic implications since clinical observations have shown that low doses of mecamylamine reduce tension and anxiety in patients with Tourette syndrome.

Effects of a Baking Soda Gum on extrinsic dental stain: results of a longitudinal 4-week assessment.

An evaluation of the effects of ARM & HAMMER DENTAL CARE The Baking Soda Gum (AHDC) on extrinsic dental stain was made in 48 subjects presenting with measurable extrinsic stain. The subjects were randomized to use either the baking soda gum or a non-baking soda placebo gum for 20 minutes twice daily after lunch and dinner while brushing once daily. The procedure of limited brushing was chosen to simulate the level of hygiene normally practiced by participants entering a clinical study. After 4 weeks, the reduction in measurable extrinsic stain in the baking soda gum group was statistically significant (P = .0044) relative to baseline. Statistical analysis of the placebo gum group revealed no significant change in extrinsic stain from baseline. The magnitude of the unadjusted longitudinal reduction in extrinsic stain in the baking soda gum group was 29.7% at 4 weeks.

A clinical investigation to evaluate reduction in dental stain provided by the once-daily use of a breath mint or chewing gum.

An evaluation of the effects of ARM & HAMMER DENTAL CARE The Baking Soda Gum on extrinsic dental stain was performed on 85 subjects presenting with measurable extrinsic stain. The subjects were randomized to use either the baking soda chewing gum or a breath mint placebo once daily after lunch while brushing once daily. The chewing gum was chewed for 20 minutes for each use and the breath mint was kept in the mouth until completely dissolved. The subjects were instructed to brush once daily to simulate the level of hygiene normally practiced by subjects, thereby avoiding the well-reported Hawthorne effect experienced in clinical trials instituting twice-daily brushing. Examinations postbaseline were performed after 2 and 4 weeks. The reduction in measurable extrinsic stain in the baking soda gum group vs the breath mint control was statistically significant at 2 weeks (P < .0002) and at 4 weeks (P < .0008). Statistical analysis of the data revealed a significant change in extrinsic stain from baseline for both groups. The magnitude of the unadjusted longitudinal reduction in extrinsic stain in the baking soda gum group was 51% at 4 weeks.

Locomotor behavioral effects of prenatal and postnatal nicotine exposure in rat offspring.

The purpose of this study was to determine if prenatal/postnatal nicotine exposure results in hyperactive offspring. Rat offspring were exposed to nicotine, through implantation of osmotic minipumps in dams, at levels of 0.75, 1.5 and 3.0 mg/kg/day, for 19 days prenatally and 16 days postnatally. Offspring were measured for gestation length, body weight, litter size, sex difference and locomotor activity. No significant effects were shown for gestation length, litter size or male to female pup ratio. However, higher percentage of pup deaths resulted from nicotine-exposed dams than from control dams. Significantly less litter body weight was shown in nicotine-exposed offspring on postnatal day 1 when compared to controls. However, these offspring surpassed the control groups in litter body weight on postnatal day 14 and 21. Hyperactivity was shown in offspring exposed to prenatal/postnatal nicotine at levels of 0.75 and 3.0 mg/kg/day on postnatal day 14, but not on postnatal day 21 or at the 1.5 mg/kg/day condition. Results are consistent with the hypothesis that rat offspring are susceptible to the neurochemical and neurobehavioral effects of prenatal/postnatal nicotine exposure.

The efficacy of a novel toothbrush design.

The single-blind study compared a novel toothbrush design (Aquafresh Flex soft, medium, and firm bristle versions) to a widely-available, standard brush with soft bristles. Subjects (n = 32-35/group, mean age = 46 yrs) were randomly assigned to the four groups and instructed to maintain their normal oral hygiene routine. Safety, as well as plaque (Turesky et al. index as modified by Soparkar) and gingivitis (Loe-Silness index as modified by Lobene) were evaluated for the Ramfjord teeth at baseline, two weeks, and six weeks. At termination, all brands were considered to be safe. After two weeks, the mean plaque scores for each of the four groups were reduced significantly, although a difference between the control group and the test groups could not be demonstrated. Between two and six weeks, the mean plaque scores for the test brushes leveled off while the corresponding score for the control brush increased significantly (p = 0.02). The gingivitis scores showed a similar pattern. This pattern suggests more favorable user acceptance for the test brushes, which is consistent with information provided by the subjects on a post-study questionnaire. Presumably, this phenomenon is associated with the unique design of the test brushes.

Long-term evaluation of a prebrushing dental rinse for the control of dental plaque and gingivitis.

One hundred and three adults completed a double-blind, 6-month controlled study to assess the effects of rinsing with Plax (Oral Care Division of Pfizer Inc., New York, NY) before brushing on plaque, gingivitis and calculus. All the parameters were evaluated at baseline and after three and six months of home use of either Plax or placebo rinse. Microbiological components of plaque were monitored. Following prolonged use as a prebrushing rinse, Plax was no more effective than placebo in reducing plaque, gingivitis and calculus.

Reduced formation of supragingival calculus with use of fluoride-zinc chloride dentifrice.

Results of this comparative, double-blind, clinical study show that fluoride dentifrice with 2.0% zinc chloride is effective in reducing calculus accumulation after a dental prophylaxis. The data also confirm earlier observations on calculus formation in that accumulation was not constant during the two 3-month study phases.