RESUMEN
Salmonella enterica can survive in surface waters (SuWa), and the role of nonhost environments in its transmission has acquired increasing relevance. In this study, we conducted comparative genomic analyses of 172 S. enterica isolates collected from SuWa across 3 months in six states of central Mexico during 2019. S. enterica transmission dynamics were assessed using 87 experimental and 112 public isolates from Mexico collected during 2002 through 2019. We also studied genetic relatedness between SuWa isolates and human clinical strains collected in North America during 2005 through 2020. Among experimental isolates, we identified 41 S. enterica serovars and 56 multilocus sequence types (STs). Predominant serovars were Senftenberg (n = 13), Meleagridis, Agona, and Newport (n = 12 each), Give (n = 10), Anatum (n = 8), Adelaide (n = 7), and Infantis, Mbandaka, Ohio, and Typhimurium (n = 6 each). We observed a high genetic diversity in the sample under study, as well as clonal dissemination of strains across distant regions. Some of these strains are epidemiologically important (ST14, ST45, ST118, ST132, ST198, and ST213) and were genotypically close to those involved in clinical cases in North America. Transmission network analysis suggests that SuWa are a relevant source of S. enterica (0.7 source/hub ratio) and contribute to its dissemination as isolates from varied sources and clinical cases have SuWa isolates as common ancestors. Overall, the study shows that SuWa act as reservoirs of various S. enterica serovars of public health significance. Further research is needed to better understand the mechanisms involved in SuWa contamination by S. enterica, as well as to develop interventions to contain its dissemination in food production settings. IMPORTANCE Surface waters are heavily used in food production worldwide. Several human pathogens can survive in these waters for long periods and disseminate to food production environments, contaminating our food supply. One of these pathogens is Salmonella enterica, a leading cause of foodborne infections, hospitalizations, and deaths in many countries. This research demonstrates the role of surface waters as a vehicle for the transmission of Salmonella along food production chains. It also shows that some strains circulating in surface waters are very similar to those implicated in human infections and harbor genes that confer resistance to multiple antibiotics, posing a risk to public health. This study contributes to expand our current knowledge on the ecology and epidemiology of Salmonella in surface waters.
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Salmonella enterica , Agricultura , Acuicultura , Genómica , Humanos , México/epidemiología , Salmonella enterica/genéticaRESUMEN
Opioids are widely prescribed for pain management, and prescription opioid misuse in adolescents has become a major epidemic in the United States and worldwide. Emerging data indicate that adolescence represents a critical period of brain development, and exposure to opioids during adolescence may increase the risk of addiction in adulthood. There is growing evidence that disruptions in brain glial function may be implicated in numerous chronic neuropathologies. Evidence suggests that glial mechanisms have an important role in the development and maintenance of opioid abuse and the risk for addiction. This review will describe glial and neuroimmune mechanisms involved in opioid use disorders during adolescence, which may increase substance use disorder liability later in life. Moreover, this review will identify some important neuro-glial targets, involved in opioid abuse and addiction, to develop future preventions and treatment strategies.
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Neuroglía , Neuroinmunomodulación , Trastornos Relacionados con Opioides , Adolescente , Adulto , Humanos , Neuroglía/fisiología , Neuroinmunomodulación/fisiología , Trastornos Relacionados con Opioides/epidemiología , Trastornos Relacionados con Opioides/fisiopatología , Estados Unidos/epidemiologíaRESUMEN
Excessive alcohol (ethanol) consumption negatively impacts social, emotional, as well as cognitive function and well-being. Thus, identifying behavioral and/or biological predictors of excessive ethanol consumption is important for developing prevention and treatment strategies against alcohol use disorders (AUDs). Sex differences in alcohol consumption patterns are observed in humans, primates, and rodents. Selectively bred high alcohol-drinking rat lines, such as the "HAD-1" lines are recognized animal models of alcoholism. The present work examined sex differences in alcohol consumption, object recognition, and exploratory behavior in male and female HAD-1 rats. Naïve male and female HAD-1 rats were tested in an object recognition test (ORT) prior to a chronic 24 h intermittent ethanol access procedure for five weeks. Object recognition parameters measured included exploratory behavior, object investigation, and time spent near objects. During the initial training trial, rearing, active object investigation and amount of time spent in the object-containing section was significantly greater in female HAD-1 rats compared to their male counterparts. During the subsequent testing trial, time spent in the object-containing section was greater in female, compared to male, rats; but active object investigation and rearing did not statistically differ between females and males. In addition, female HAD-1 rats consumed significantly more ethanol than their male counterparts, replicating previous findings. Moreover, across all animals there was a significant positive correlation between exploratory behavior in ORT and ethanol consumption level. These results indicate there are significant sex differences in cognitive performance and alcohol consumption in HAD-1 rats, which suggests neurobiological differences as well.
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Consumo de Bebidas Alcohólicas/fisiopatología , Alcoholismo/fisiopatología , Cognición/fisiología , Conducta Exploratoria/fisiología , Caracteres Sexuales , Animales , Depresores del Sistema Nervioso Central/administración & dosificación , Etanol/administración & dosificación , Femenino , Masculino , Prueba de Campo Abierto/fisiología , Ratas , Reconocimiento en Psicología , AutoadministraciónRESUMEN
Ultrasonic vocalizations (USVs) have been established as an animal model of emotional status and are often utilized in drug abuse studies as motivational and emotional indices. Further USV functionality has been demonstrated in our recent work showing accurate identification of selectively-bred high versus low alcohol-consuming male rats ascertained exclusively from 22 to 28kHz and 50-55kHz FM USV acoustic parameters. With the hypothesis that alcohol-sensitive sex differences could be revealed through USV acoustic parameters, the present study examined USVs and alcohol consumption in male and female selectively bred high-alcohol drinking (HAD-1) rats. For the current study, we examined USV data collected during a 12-week experiment in male and female HAD-1 rats. Experimental phases included Baseline (2weeks), 4-h EtOH Access (4weeks), 24-h EtOH Access (4weeks) and Abstinence (2weeks). Findings showed that both male and female HAD-1 rats spontaneously emitted a large number of 22-28kHz and 50-55kHz FM USVs and that females drank significantly more alcohol compared to males over the entire course of the experiment. Analyses of USV acoustic characteristics (i.e. mean frequency, duration, bandwidth and power) revealed distinct sex-specific phenotypes in both 50-55kHz FM and 22-28kHz USV transmission that were modulated by ethanol exposure. Moreover, by using a linear combination of these acoustic characteristics, we were able to develop binomial logistic regression models able to discriminate between male and female HAD-1 rats with high accuracy. Together these results highlight unique emotional phenotypes in male and female HAD-1 rats that are differentially modulated by alcohol experience.
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Consumo de Bebidas Alcohólicas/genética , Etanol/administración & dosificación , Motivación/efectos de los fármacos , Caracteres Sexuales , Vocalización Animal/efectos de los fármacos , Animales , Femenino , Masculino , Ratas , UltrasonidoRESUMEN
The purpose of this review is to present up-to-date pharmacological, genetic, and behavioral findings from the alcohol-preferring P rat and summarize similar past work. Behaviorally, the focus will be on how the P rat meets criteria put forth for a valid animal model of alcoholism with a highlight on its use as an animal model of polysubstance abuse, including alcohol, nicotine, and psychostimulants. Pharmacologically and genetically, the focus will be on the neurotransmitter and neuropeptide systems that have received the most attention: cholinergic, dopaminergic, GABAergic, glutamatergic, serotonergic, noradrenergic, corticotrophin releasing hormone, opioid, and neuropeptide Y. Herein, we sought to place the P rat's behavioral and neurochemical phenotypes, and to some extent its genotype, in the context of the clinical literature. After reviewing the findings thus far, this chapter discusses future directions for expanding the use of this genetic animal model of alcoholism to identify molecular targets for treating drug addiction in general.
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Alcoholismo/tratamiento farmacológico , Alcoholismo/genética , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Farmacogenética , Animales , HumanosRESUMEN
Chronic ethanol consumption is known to downregulate expression of the major glutamate transporter 1 (GLT-1), which increases extracellular glutamate concentrations in subregions of the mesocorticolimbic reward pathway. While ß-lactam antibiotics were initially identified as potent upregulators of GLT-1 expression, only ceftriaxone has been extensively studied in various drug addiction models. Therefore, in this study, adult male alcohol-preferring (P) rats exposed chronically to ethanol were treated with other ß-lactam antibiotics, ampicillin, cefazolin or cefoperazone (100mg/kg) once daily for five consecutive days to assess their effects on ethanol consumption. The results demonstrated that each compound significantly reduced ethanol intake compared to the saline-treated control group. Importantly, each compound significantly upregulated both GLT-1 and pAKT expressions in the nucleus accumbens and prefrontal cortex compared to saline-treated control group. In addition, only cefoperazone significantly inhibited hepatic aldehyde dehydrogenase-2 enzyme activity. Moreover, these ß-lactams exerted only a transient effect on sucrose drinking, suggesting specificity for chronically inhibiting ethanol reward in adult male P rats. Cerebrospinal fluid concentrations of ampicillin, cefazolin or cefoperazone have been confirmed using high-performance liquid chromatography. These findings demonstrate that multiple ß-lactam antibiotics demonstrate efficacy in reducing alcohol consumption and appear to be potential therapeutic compounds for treating alcohol abuse and/or dependence. In addition, these results suggest that pAKT may be an important player in this effect, possibly through increased transcription of GLT-1.
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Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Antibacterianos/uso terapéutico , Depresores del Sistema Nervioso Central/efectos adversos , Etanol/efectos adversos , Transportador 2 de Aminoácidos Excitadores/metabolismo , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Aldehído Deshidrogenasa/metabolismo , Aldehído Deshidrogenasa Mitocondrial , Ampicilina/líquido cefalorraquídeo , Ampicilina/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Cefazolina/líquido cefalorraquídeo , Cefazolina/uso terapéutico , Cefoperazona/líquido cefalorraquídeo , Cefoperazona/uso terapéutico , Condicionamiento Operante/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Preferencias Alimentarias/efectos de los fármacos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Proteínas Mitocondriales/metabolismo , Núcleo Accumbens/metabolismo , Proteína Oncogénica v-akt/metabolismo , Corteza Prefrontal/metabolismo , Ratas , Sacarosa/administración & dosificación , Edulcorantes/administración & dosificación , Factores de TiempoRESUMEN
The human inflammatory response can result in the alteration of drug clearance through effects on metabolizing enzymes or transporters. In this article we briefly review the theory of how cancer can lead to indirect changes in drug metabolism, review acute phase proteins and cytokines as markers of changes in cytochrome P450 (CYP) activity in cancer patients, and provide clinical case examples of how the inflammation in advanced cancer patients can lead to altered CYP-mediated drug clearance.
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Neoplasias/metabolismo , Proteínas de Fase Aguda/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Citocinas/metabolismo , Interacciones Farmacológicas , Humanos , Imidazoles/farmacología , Indoles/farmacocinética , Inflamación/metabolismo , Metaanálisis como Asunto , Midazolam/farmacocinética , Neoplasias/inmunología , Proteína Quinasa C beta/antagonistas & inhibidores , Piridinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
PURPOSE: Laparoscopic incisional hernioplasty (LIH) bridges the fascial gap between the rectus muscles with a posteriorly placed mesh, and is a low recurrence alternative to other reconstructions. It is unclear if this repair optimizes the function of the abdominal wall. We hypothesize that significant medialization of the fascial edges occurs in patients who undergo LIH. METHODS: Two hundred fifty-eight patients underwent LIH by a single surgeon between 2004 and 2012. 44 of these had pre- and postoperative CT scans that illustrated the gap between the rectus muscles. All 44 patients underwent LIH with polyester composite mesh, with suture and tack fixation. The distance between the fascial edges on the pre- and postoperative CT scans was compared. Percent medialization was calculated for each defect. RESULTS: Average fascial separation reduction was 0.8 cm (6.56-5.76 cm, 12.2 % medialization, p < 0.0001). 36 of 44 patients demonstrated a reduction in hernia defect width (81.8 %): these defects reduced 1.09 cm (6.47-5.38 cm, 16.9 % medialization, p < 0.0001). In defects wider than 5 cm, the width reduced by 0.94 cm (8.48-7.54 cm, n = 26, 10.6 % medialization, p = 0.004). The use of meshes ≥500 cm(2) reduced the defect by 0.95 cm (8.42-7.47 cm, 11.23 % medialization, n = 22, p = 0.005). CONCLUSIONS: Significant medialization of the rectus muscles is evident in most patients undergoing LIH. Although the rectus muscles are not ideally approximated, this may help improve the function of the anterior abdominal wall. Further technical refinements and material improvements may improve the reconstructive results of the LIH.
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Pared Abdominal , Fasciotomía , Hernia Ventral/cirugía , Herniorrafia , Laparoscopía , Complicaciones Posoperatorias , Pared Abdominal/fisiopatología , Pared Abdominal/cirugía , Femenino , Hernia Ventral/fisiopatología , Herniorrafia/efectos adversos , Herniorrafia/instrumentación , Herniorrafia/métodos , Humanos , Laparoscopía/efectos adversos , Laparoscopía/instrumentación , Laparoscopía/métodos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/fisiopatología , Complicaciones Posoperatorias/cirugía , Recuperación de la Función , Recto del Abdomen/fisiopatología , Recto del Abdomen/cirugía , Recurrencia , Estudios Retrospectivos , Mallas Quirúrgicas , Resultado del TratamientoRESUMEN
Increased glutamatergic neurotransmission appears to mediate the reinforcing properties of drugs of abuse, including ethanol (EtOH). We recently reported that the administration of ceftriaxone (CEF), a ß-lactam antibiotic known to upregulate glutamate transporter 1 (GLT1) levels/activity, decreased the maintenance of EtOH intake in adult male alcohol-preferring (P) rats. In the present study, we tested whether CEF administration would reduce the acquisition and maintenance of EtOH drinking in adolescent and adult female P rats. The rats were treated with saline or 200mg/kg ceftriaxone for 7 days (starting at 35 or 75 days old, respectively) followed by the EtOH acquisition test. Five weeks later the effects of CEF were examined regarding the maintenance of EtOH intake. For the maintenance test, half of the animals that received CEF during acquisition received CEF for 7 days and the other half received saline for 7 days. Saline-treated acquisition animals were treated similarly. The results indicated that pretreatment with ceftriaxone reduced the maintenance of EtOH intake in both animals that started as adolescents and those that started as adults. However, the beneficial effect of CEF was more pronounced in rats pretreated with CEF as adults compared with rats pretreated as adolescents. Reductions in EtOH intake by ceftriaxone were paralleled by an upregulation of GLT1 protein levels in both the nucleus accumbens (â¼25% in rats starting at both ages) and prefrontal cortex (â¼50% in rats starting as peri-adolescents and â¼65% in those starting as adults). These findings provide further support for GLT1-associated mechanisms in high alcohol-consuming behavior, and hold promise for the development of effective treatments targeting alcohol abuse and dependence.
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Alcoholismo/metabolismo , Antibacterianos/farmacología , Encéfalo/efectos de los fármacos , Ceftriaxona/farmacología , Transportador de Glucosa de Tipo 1/metabolismo , Consumo de Bebidas Alcohólicas/metabolismo , Consumo de Bebidas Alcohólicas/prevención & control , Animales , Western Blotting , Encéfalo/metabolismo , Femenino , RatasRESUMEN
Methionine aminopeptidase-2 (MetAP2) processes N-terminal methionine from nascent cellular proteins. Inhibition of MetAP2 has been shown to block angiogenesis and suppress tumor growth in preclinical tumor models. However, the biological role of MetAP2 in cancer is not well understood. We examined the effect of three distinct chemical classes of MetAP2 inhibitors on the growth of a panel of human cancer cells in vitro. All MetAP2 inhibitors caused inhibition of tumor cell growth in both anchorage-dependent and, particularly, in anchorage-independent manner. These data prompted us to examine the possible roles of MetAP2 in cancers. Ectopic expression of MetAP2 in NIH-3T3 cells caused transformation, evidenced by the formation of foci in monolayer culture and growth of large colonies in soft agar. Overexpression of MetAP2 in an immortalized bronchial epithelial cell line NL20 accelerated growth. These phenotypes induced by the overexpression of MetAP2 were reversed by the treatment with MetAP2 inhibitors, indicating that the catalytic function of MetAP2 was essential. Accordingly, overexpression of a catalytically inactive MetAP2 resulted in growth retardation of HT1080 tumor cells, suggesting a dominant-negative role of the inactive MetAP2 mutant. Finally, we analysed the expression of MetAP2 in patient cancer samples by immunohistochemistry. Moderate-to-high staining was identified in the majority of breast, colon, lung, ovarian and prostate carcinomas examined. These data suggest that MetAP2 plays an important role in tumor cell growth and may contribute to tumorigenesis.
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Aminopeptidasas/biosíntesis , Transformación Celular Neoplásica , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Metaloendopeptidasas/biosíntesis , Animales , Catálisis , Línea Celular Tumoral , Proliferación Celular , Genes Dominantes , Humanos , Inmunohistoquímica , Ratones , Células 3T3 NIH , Fenotipo , Estructura Terciaria de ProteínaRESUMEN
Alcohol and drug abuse continue to be a major public health problem in the United States and other industrialized nations. Extensive preclinical research indicates the mesolimbic dopamine (DA) pathway and associated regions mediate the rewarding and reinforcing effects of drugs of abuse and natural rewards, such as food and sex. The serotonergic (5-HT) system, in concert with others neurotransmitter systems, plays a key role in modulating neuronal systems within the mesolimbic pathway. A substantial portion of this modulation is mediated by activity at the 5-HT3 receptor. The 5-HT3 receptor is unique among the 5-HT receptors in that it directly gates an ion channel inducing rapid depolarization that, in turn, causes the release of neurotransmitters and/or peptides. Preclinical findings indicate that antagonism of the 5-HT3 receptor in the ventral tegmental area, nucleus accumbens or amygdala reduces alcohol self-administration and/or alcohol-associated effects. Less is known about the effects of 5-HT3 receptor activity on the self-administration of other drugs of abuse or their associated effects. Clinical findings parallel the preclinical findings such that antagonism of the 5-HT3 receptor reduces alcohol consumption and some of its subjective effects. This review provides an overview of the structure, function, and pharmacology of 5-HT3 receptors, the role of these receptors in regulating DA neurotransmission in mesolimbic brain areas, and discusses data from animal and human studies implicating 5-HT3 receptors as targets for the development of new pharmacological agents to treat addictions.
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Encéfalo/metabolismo , Receptores de Serotonina 5-HT3/fisiología , Antagonistas del Receptor de Serotonina 5-HT3 , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Trastornos Relacionados con Sustancias/etiología , Trastornos del Sistema Nervioso Inducidos por Alcohol/tratamiento farmacológico , Trastornos del Sistema Nervioso Inducidos por Alcohol/metabolismo , Trastornos del Sistema Nervioso Inducidos por Alcohol/fisiopatología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Química Encefálica/efectos de los fármacos , Dopamina/metabolismo , Humanos , Activación del Canal Iónico/efectos de los fármacos , Activación del Canal Iónico/fisiología , Sistema Límbico/efectos de los fármacos , Sistema Límbico/metabolismo , Sistema Límbico/fisiopatología , Serotonina/metabolismo , Trastornos Relacionados con Sustancias/metabolismoRESUMEN
Chronic ethanol (EtOH) drinking produces neuronal alterations within the limbic system. To investigate changes in protein expression levels associated with EtOH drinking, inbred alcohol-preferring (iP) rats were given one of three EtOH access conditions in their home-cages: continuous ethanol (CE: 24h/day, 7days/week access to EtOH), multiple scheduled access (MSA: four 1-h sessions during the dark cycle/day, 5 days/week) to EtOH, or remained EtOH-naïve. Both MSA and CE groups consumed between 6 and 6.5g of EtOH/kg/day after the 3rd week of access. On the first day of EtOH access for the seventh week, access was terminated at the end of the fourth MSA session for MSA rats and the corresponding time point (2300h) for CE rats. Ten h later, the rats were decapitated, brains extracted, the nucleus accumbens (NAcc) and amygdala (AMYG) microdissected, and protein isolated for 2-dimensional gel electrophoretic analyses. In the NAcc, MSA altered expression levels for 12 of the 14 identified proteins, compared with controls, with six of these proteins altered by CE access, as well. In the AMYG, CE access changed expression levels for 22 of the 27 identified proteins, compared with controls, with 8 of these proteins altered by MSA, as well. The proteins could be grouped into functional categories of chaperones, cytoskeleton, intracellular communication, membrane transport, metabolism, energy production, or neurotransmission. Overall, it appears that EtOH drinking and the conditions under which EtOH is consumed, differentially affect protein expression levels between the NAcc and AMYG. This may reflect differences in neuroanatomical and/or functional characteristics associated with EtOH self-administration and possibly withdrawal, between these two brain structures.
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Consumo de Bebidas Alcohólicas/metabolismo , Amígdala del Cerebelo/metabolismo , Depresores del Sistema Nervioso Central/administración & dosificación , Etanol/administración & dosificación , Núcleo Accumbens/metabolismo , Proteínas/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Proteínas del Citoesqueleto/metabolismo , Esquema de Medicación , Electroforesis en Gel Bidimensional , Enzimas/metabolismo , Etanol/farmacología , Femenino , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Núcleo Accumbens/efectos de los fármacos , Mapeo Peptídico , Proteómica/métodos , Ratas , Ratas Endogámicas , Autoadministración , Factores de TiempoRESUMEN
BACKGROUND: The low-dose stimulatory effect of ethanol (EtOH) in rats has been hypothesized to reflect its hedonic effects and to be associated with a genetic predisposition toward high alcohol preference. To test the hypothesis that phenotypes associated with high alcohol preference in adulthood are also present in adolescent rats at the time of onset of alcohol drinking, the current study examined the effects of EtOH on locomotor activity (LMA) during adolescence in lines of rats selectively bred for divergent alcohol intakes. METHODS: Subjects were adolescent (31-40 days of age) rats from the alcohol-preferring (P) and -nonpreferring (NP) lines and from the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) replicate lines. On day 1, all subjects (n = 8-10/line/gender/dose) received intraperitoneal saline injections and were placed in the activity monitor for 30 min. On day 2, subjects received intraperitoneal saline or 0.25, 0.50, 0.75, 1.0, or 1.5 g EtOH/kg. RESULTS: The LMA of male and female P rats was increased with low doses (0.25-0.75 g/kg) and decreased at the highest dose (1.5 g/kg) of EtOH. Similar effects were observed with low doses of EtOH on the LMA of HAD-1 and HAD-2 rats. None of the EtOH doses stimulated LMA in the NP, LAD-1, or LAD-2 rats, although all of the low-alcohol-intake lines of rats showed decreased LMA at the highest dose of EtOH. Only the P rats among the high-alcohol-consuming lines of rats showed decreased LMA at the highest dose of EtOH. CONCLUSION: Selective breeding for high alcohol consumption seems to be associated with increased sensitivity to the low-dose stimulating effects of EtOH and reduced sensitivity to the high-dose motor-impairing effects of ethanol. The expression of these phenotypes emerges during adolescence by the age of onset of alcohol-drinking behavior.
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Consumo de Bebidas Alcohólicas/fisiopatología , Etanol/administración & dosificación , Actividad Motora/efectos de los fármacos , Factores de Edad , Consumo de Bebidas Alcohólicas/genética , Animales , Cruzamiento/métodos , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Actividad Motora/genética , Ratas , Ratas Wistar , Especificidad de la EspecieRESUMEN
Matrix metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2) are expressed in both sporadic and familial adenomatous colonic polyps and tumours and have been independently shown to play causal roles in intestinal tumour formation in mouse models of colon cancer. The apparent roles of these enzymes in intestinal tumorigenesis led us to examine, in the Min mouse model of colon cancer, if selective COX-2 and MMP inhibitors provide additive or synergistic therapeutic benefits in intestinal tumour prevention. The broad-spectrum MMP inhibitor (A-177430; MMPI) and the selective COX-2 inhibitor (A-285969; COX-2I) both showed dose-dependent inhibition of the number of adenomas in Min mice. Using suboptimal doses, the MMPI reduced tumour multiplicity by 32%, the COX-2I by 48% and, both agents in combination resulted in a 67% decrease compared to control demonstrating a cooperative effect on intestinal tumorigenesis. Apoptosis, proliferation, and angiogenesis were assayed in tumors from each treatment group. These agents in combination allowed for a lowered dosage to be administered to achieve significant biological effects. Clinically, this could potentially reduce side effects associated with currently used MMP and COX-2 inhibitors. Together, these compounds could represent an easily tolerated chemopreventive approach.
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Adenoma/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias Intestinales/tratamiento farmacológico , Isoenzimas/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz , Péptidos Cíclicos/uso terapéutico , Prostaglandina-Endoperóxido Sintasas/metabolismo , Adenoma/patología , Animales , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Neoplasias Intestinales/patología , Ratones , Ratones Endogámicos C57BLRESUMEN
Selective breeding has been used to develop the alcohol-preferring (P) and -nonpreferring (NP) rats, with the P rat having lower CNS levels of dopamine (DA) and reduced DA innervation in the nucleus accumbens compared with the NP rat. The acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR are experimental behaviors altered by DA agonists. We examined whether functional differences in amphetamine (AMPH)-modified ASR and PPI exist between P and NP rats. AMPH [0.0 (saline), 1.0, 2.0, or 4.0 mg/kg] was injected 15 min prior to placement into a startle apparatus. After a 5-min habituation period, rats were given approximately twelve 95-, 105-, or 115-dB white-noise burst (ASR) and PPI trials. As adults, P rats were sensitive to AMPH potentiation of the ASR to a greater extent than NP rats. During adolescence, P and NP rats had similar levels of AMPH-potentiated ASR. As adults, NP rats displayed potentiated, rather than disrupted, PPI at the 1.0-mg/kg dose, whereas P rats displayed the expected disrupted PPI at the 4.0-mg/kg dose. As adolescents, NP rats did not display significant differences in PPI after AMPH, whereas P rats displayed dose-dependent disruption of PPI, which was significant at the 4.0-mg/kg dose. The limited effect of AMPH on increasing the ASR and the presence of AMPH-potentiated PPI at the lowest dose in the adult NP rat suggests reduced functioning of the interactions between DA circuits and the neurocircuitry mediating the ASR and PPI, compared with P rats. However, the neurocircuitry mediating PPI does not appear to be fully developed in the adolescent NP rat. The present findings also indicate that lower levels of DA content and immunoreactive fibers in the P rat may not reflect reduced DA neuronal activity, because the P rat displayed AMPH-potentiated ASR, and, at the highest dose, AMPH disruption of PPI during both adulthood and adolescence.
Asunto(s)
Envejecimiento/psicología , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/psicología , Anfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Inhibidores de Captación de Dopamina/farmacología , Reflejo de Sobresalto/efectos de los fármacos , Estimulación Acústica , Animales , Dopamina/fisiología , Relación Dosis-Respuesta a Droga , Femenino , RatasRESUMEN
The biology and behavior of pear psylla, Cacopsylla pyricola Foerster, on a transgenic clone of 'Bartlett' pear, Pyrus communis L., containing a synthetic antimicrobial gene, D5C1, was compared with that of a nontransgenic parental clone to determine whether there were any nontarget effects. The gene construct also contained the marker gene nptII (aminoglycoside 3'-phosphotransferase II) that encodes for antibiotic resistance to identify transformed plants. The purpose of the original transformation was to enhance pear resistance to the bacterial disease fireblight caused by Erwinia amylovora (Burr.) Winslow et al. The biology and behavior of pear psylla on a transgenic clone were compared with a nontransgenic parental pear clone in short- (< or = 7-d) and long-term (32-d) studies. Short-term studies indicated pear psylla adults preferred to settle and oviposit, and nymphs fed more and developed slightly faster, on transgenic pear compared with nontransgenic pear. In contrast, a long-term study on psylla colony development showed considerably fewer eggs, nymphs, and adults were produced on transgenic pear. Although adults reared on transgenic pear did not have weight affected, females produced fewer eggs and nymphal hatch was significantly reduced on the transgenic pear clone. Our results suggest that pear psylla biology and behavior are initially enhanced on this transgenic pear clone. However, chronic exposure of psylla populations to transformed pear plants that express the nptII marker and lytic peptide genes had detrimental effects on pear psylla reproductive biology. Field studies would be required to determine the specific effects of each gene on pear psylla biology and behavior and whether these effects would be expressed under natural conditions. The four-fold reduction in psylla population levels that resulted on this disease resistant transgenic pear line would be an added benefit to a pear integrated pest management (IPM) program. Overall, this study demonstrates that genetically altering plants to control one particular organism can have unintentional yet beneficial effects against other nontarget pest organisms in agricultural crops.
Asunto(s)
Erwinia/genética , Helechos/crecimiento & desarrollo , Genes Bacterianos/fisiología , Hemípteros/fisiología , Animales , Proteínas Bacterianas/genética , Bioensayo , Conducta Alimentaria , Femenino , Ninfa/crecimiento & desarrollo , Oviposición , Enfermedades de las Plantas , Plantas Modificadas Genéticamente , Factores de Tiempo , Transformación GenéticaRESUMEN
BACKGROUND: The complexity and risks of the surgical treatment of ulcerative colitis are greater in patients with fulminant disease. Subtotal colectomy is frequently offered to such patients to control acute disease and restore immunological and nutritional status prior to a restorative procedure. The role of laparoscopy in this setting is poorly defined. METHODS: The records of 18 patients with poorly controlled fulminant colitis on aggressive immunosuppressive therapy who underwent laparoscopic subtotal colectomy were reviewed. RESULTS: Postoperative complications occurred in six patients (33%). Postoperative length of stay was 5.0 +/- 0.3 days vs 8.8 +/- 1.8 days (p<0.05) for a group of six patients who had undergone open subtotal colectomy for the same indications. Systemic steroids were withdrawn in all patients, and 17 patients subsequently underwent proctectomy and pelvic pouch construction. CONCLUSIONS: The relatively high morbidity rate in these patients is likely related to their compromised status at the time of surgery. Laparoscopic subtotal colectomy in patients with fulminant ulcerative colitis allows for earlier hospital discharge, facilitates subsequent pelvic pouch, construction, and provides an excellent alternative to conventional two- and three-stage surgical treatment.
Asunto(s)
Colitis Ulcerosa/cirugía , Laparoscopía/métodos , Enfermedad Aguda , Adolescente , Adulto , Colectomía/efectos adversos , Colectomía/métodos , Reservorios Cólicos , Femenino , Humanos , Laparoscopía/efectos adversos , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Factores de TiempoRESUMEN
In June 2000, vancomycin-intermediate Staphylococcus aureus (VISA) was isolated from a 27-year-old home health-care patient following a complicated cholecystectomy. Two VISA strains were identified with identical MICs to all antimicrobials tested except oxacillin and with closely related pulsed-field gel electrophoresis types. The patient was treated successfully with antimicrobial therapy, biliary drainage, and reconstruction. Standard precautions in the home health setting appear successful in preventing transmission.
Asunto(s)
Antibacterianos/farmacología , Servicios de Atención de Salud a Domicilio , Infecciones Estafilocócicas/microbiología , Resistencia a la Vancomicina , Vancomicina/farmacología , Adulto , ADN Bacteriano/análisis , Femenino , Humanos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional , Pruebas de Sensibilidad Microbiana , Enfermeras y Enfermeros , Factores de Riesgo , Infecciones Estafilocócicas/transmisión , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/crecimiento & desarrollo , Resistencia a la Vancomicina/genéticaRESUMEN
BACKGROUND: The alcohol deprivation effect (ADE) is a temporary increase in the voluntary intake of ethanol solutions following a period of alcohol deprivation. Multiple deprivations can prolong the expression of an ADE. This study examined the effects of initial deprivation length, concurrent exposure to multiple ethanol concentrations, and number of deprivation exposures on the magnitude and duration of the ADE in alcohol-preferring (P) rats. METHODS: Adult female P rats received 24-hr free-choice access to 10, 20, and 30% ethanol and water for 6 weeks. Rats were then randomly assigned to three groups; one group served as a nondeprived control, whereas the other two groups were initially deprived of ethanol for 2 or 8 weeks. The ethanol solutions were restored to both deprived groups for 2 weeks before the groups were deprived of ethanol for another 2 weeks. This cycle was repeated three times for a total of four deprivations. RESULTS: After the initial ethanol deprivation period, both deprived groups displayed a similar 2-fold increased ethanol intake (g/Kg/day) during the initial 24-hr period when ethanol was restored. Both deprived groups showed greater than 2-fold increases in intake of the 20 and 30% ethanol solutions after re-exposure. Ethanol consumption returned to baseline levels within 2 weeks, before the subsequent deprivation period. Multiple deprivations increased the magnitude of the ADE over that observed in the first deprivation during the initial 24-hr period of re-exposure and prolonged the duration of the ADE. In addition, repeated deprivations increased ethanol intake in the first 2-hr period of re-exposure and produced blood ethanol levels in excess of 150 mg/100 ml. CONCLUSIONS: Alterations in the reinforcing and/or aversive effects of alcohol occurred after a single prolonged deprivation and were enhanced with repeated deprivations.