Search

Elevated plasma bilirubin levels are a frequent clinical finding. It can be secondary to alterations in any stage of its metabolism: (a) excess bilirubin production (i.e., pathologic hemolysis); (b) impaired liver uptake, with elevation of indirect bilirubin; (c) impaired conjugation, prompted by a defect in the UDP-glucuronosyltransferase; and (d) bile clearance defect, with elevation of direct bilirubin secondary to defects in clearance proteins, or inability of the bile to reach the small bowel through bile ducts. A liver lesion of any cause reduces hepatocyte cell number and may impair the uptake of indirect bilirubin from plasma and diminish direct bilirubin transport and clearance through the bile ducts. Various analytical methods are currently available for measuring bilirubin and its metabolites in serum, urine and feces. Serum bilirubin is determined by (1) diazo transfer reaction, currently, the gold-standard; (2) high-performance liquid chromatography (HPLC); (3) oxidative, enzymatic, and chemical methods; (4) direct spectrophotometry; and (5) transcutaneous methods. Although bilirubin is a well-established marker of liver function, it does not always identify a lesion in this organ. Therefore, for accurate diagnosis, alterations in bilirubin concentrations should be assessed in relation to patient anamnesis, the degree of the alteration, and the pattern of concurrent biochemical alterations.

Un aumento en los niveles plasmáticos de bilirrubina es una alteración frecuente. Puede deberse a cualquier causa que altere alguna de las fases de su metabolismo: a) producción excesiva de bilirrubina (ej. hemólisis patológica); b) defecto en la captación hepática, con aumento de bilirrubina indirecta); c) defecto de conjugación, por alteración del enzima encargada (UDP-glucuronosiltransferasa); y d) defecto de excreción biliar, con aumento de bilirrubina directa, por defectos en las proteínas encargadas de la excreción, o bien por la imposibilidad del paso de la bilis a través de los conductos biliares hasta el intestino. Una lesión hepática de cualquier causa, al disminuir el número de hepatocitos, puede producir una disminución de la captación de bilirrubina indirecta desde el plasma y una disminución del transporte y excreción de la bilirrubina directa hacia los conductillos biliares. Se pueden usar diferentes técnicas analíticas para medir la bilirrubina y sus metabolitos en el suero, la orina y las heces. La bilirrubina sérica se mide mediante (1) la "reacción diazo", actualmente el método de referencia; (2) cromatografía líquida de alta resolución (HPLC); (3) métodos oxidativos, enzimáticos y químicos; (4) espectrofotometría directa; y (5) métodos transcutáneos. Aunque la bilirrubina es un marcador clásico de disfunción hepática, no siempre indica una lesión de este órgano. Por tanto, para obtener un diagnóstico preciso, el significado de las alteraciones de este parámetro biológico ha de valorarse en conjunción con la anamnesis del paciente, la magnitud de la alteración, y el patrón de las alteraciones bioquímicas. acompañantes.

Metabolic-associated fatty liver disease (MAFLD) is defined as fat accumulation in the liver in the presence of metabolic alterations. This disorder is generally asymptomatic and may progress to severe liver disease, which are linked to inflammation and/or fibrosis. MAFLD has a high prevalence (26%) and therefore a considerable number of patients are at high risk of having advanced liver disease. This document provides an overview of the most relevant serological markers in the characterization and diagnosis of MAFLD. An example is provided of a routine diagnostic algorithm that incorporates serological testing. A range of useful serological scores are currently available for the management of MAFLD patients, especially for the stratification of patients at risk of fibrosis. A large proportion of the population is at risk of developing severe liver disease. The integration of non-invasive serological markers in the stratification of patients at risk for liver fibrosis may contribute to improve the control and management of MAFLD patients.

La enfermedad hepática grasa asociada a la disfunción metabólica (MAFLD) se define por el acúmulo de grasa en el hígado en presencia de alteraciones metabólicas. Suele cursar de forma asintomática y puede progresar a formas graves de enfermedad hepática, ligadas a la aparición de inflamación y/o fibrosis. Su prevalencia es muy elevada (26%), resultando en un alto número de pacientes con riesgo de presentar una enfermedad hepática avanzada. El presente documento describe los marcadores serológicos más relevantes en la caracterización y diagnóstico de la MAFLD, y se propone un ejemplo de su integración en un algoritmo diagnóstico en práctica clínica habitual. En la actualidad se dispone de índices serológicos útiles en el manejo de los pacientes con MAFLD, especialmente en la estratificación del riesgo de la presencia fibrosis. Una gran parte de la población está en riesgo de desarrollar enfermedad hepática grave. La integración de los marcadores serológicos no invasivos en la estratificación del riesgo de fibrosis hepática puede contribuir a un mejor control y manejo de los pacientes con MAFLD.

Several attempts have been made to compatibilize immiscible blends by introducing suitably-chosen polymer additives. This work studies the EPDM elastomer, chemically modified with maleic anhydride (MA), through reaction in solution of EPDM and MA, using dibenzoyl peroxide as an initiator. The best conditions for obtaining the maximum grafting were studied at different times and percentage weights of maleic anhydride. The evaluation of MA grafting onto EPDM was determined with multiple internal reflectance infrared spectroscopy as discussed in detail.

This study tackles the growing global concern about municipal waste management, particularly in cities like the Grand Guayaquil Metropolitan Area (GGA). Through realistic field studies on in situ household waste generation and geographic information system (GIS) tools, this work offers a framework to predict the quantities and types of recyclable household waste for any metropolitan area in Latin America. Over 4 weeks, students collected, sorted and weighed recyclable waste types, including plastic, paper, metal, glass and fabric, from 776 sampled household of the GGA. ArcGIS survey tool identified household locations and allowed to survey different socio-demographic features. With the help of ArcGIS interpolation method, the total household waste generation for GGA was predicted, and the classification of the different types of recyclable waste was also spatially distributed for the study area. The report identified notable trends in plastic waste, specifically polyethylene terephthalate waste's steady prevalence and 42% growth rate, emphasizing the importance of enhanced recycling techniques. Spatial density maps showed a heterogeneous waste distribution across the GGA, emphasizing locations with higher waste output. This study demonstrates that improving recyclable waste collection can be accomplished with a moderately cheap expenditure by collaborating with academia to overcome knowledge gaps. This strategy provides opportunities to mitigate the environmental impacts of poor waste management., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The cause of death can be attributed to malnutrition in 10-20% of cancer patients. Patients with sarcopenia present more chemotherapy toxicity, less progression-free time, less functional capacity and more surgical complications. Antineoplastic treatments have a high prevalence of adverse effects that compromise nutritional status. The new chemotherapy agents present direct toxicity on the digestive tract (nausea, vomiting, diarrhoea and/or mucositis). We present the frequency of adverse effects with nutritional impact of the most frequent chemotherapy agents used in the treatment of solid tumours, as well as strategies for early diagnosis and nutritional treatment., Material and Methods: Review of commonly used cancer treatments (cytotoxic agents, immunotherapy, targeted therapies) in colorectal, liver, pancreatic; lung, melanoma, bladder, ovary, prostate and kidney cancer. The frequency (%) of gastrointestinal effects, and those of grade ≥3 are recorded. A systematic bibliographic search was carried out in PubMed, Embase, UpToDate, international guides and technical data sheets., Results: They are shown in the form of tables in which the drugs appear together with the probability that they present any digestive adverse effect and the percentage of serious adverse effects (Grade ≥ 3)., Discussion: Antineoplastic drugs are associated with a high frequency of digestive complications with nutritional repercussions, which can reduce QoL and cause death as a result of malnutrition or due to the limiting effect of suboptimal treatments, closing the malnutrition-toxicity loop. It is necessary to inform the patient about the risks and establish local protocols regarding the use of antidiarrheal drugs, antiemetics and adjuvants in the management of mucositis. We propose action algorithms and dietary advice that can be used directly in clinical practice, to prevent the negative consequences of malnutrition., (Copyright © 2023. Published by Elsevier España, S.L.U.)

We present the case of an 18-yr-old female with 4 mo of progressive vision loss in the left eye. She underwent a computed tomography (CT) and magnetic resonance imaging (MRI), which revealed a large mass in the sphenoid sinus, sella, and anterior cranial fossa. This mass was T1 isointense, with heterogenous enhancement noted on T1 with gadolinium sequences. The mass was found to have calcifications and cystic portions on T2-weighted MRI scans and CT-based imaging. She underwent an endonasal endoscopic approach for resection of the mass. The tumor was found to be bloody, with islands of bone nests within the dura mater of the anterior cranial fossa. The patient improved postoperatively. The pathological diagnosis was found to be the psammomatoid variant of juvenile active ossifying fibroma (JAOF). We present the neuroimaging, anatomic nuances,1 and operative techniques used in this case. We also review the disease background of this rare lesion of the anterior skull base.2-4 The patient gave informed consent for the procedure and verbal consent for the publication of this article., (© Congress of Neurological Surgeons 2021.)

Objectives: To develop a predictive model of toxicity to chemotherapy in elderly patients with cancer, using the variables associated with sarcopenia, and to identify which of these parameters, sarcopenia or frailty, is the best predictor of toxicity to chemotherapy in the elderly., Material and Methods: A prospective observational study with patients ≥70 years treated with chemotherapy in the Cancer Unit for the Elderly, in the Medical Oncology Section of the Hospital Virgen de la Luz de Cuenca. The following tests will be performed by each patient before chemotherapy: muscle strength (handgrip, cylindrical handgrip, pinch gauge, hip flexion, knee extension), muscle mass (skeletal muscle mass index), and physical function (gait speed and 5STS test). The occurrence of severe toxicity will be recorded over a period of 4 months of chemotherapy treatment. It will be evaluated, using logistic regression analysis, whether sarcopenia (defined by the European Working Group on Sarcopenia in Older People) or frailty (defined by the phenotype of frailty) is the best predictor of chemotherapy toxicity. Using a multinomial logistic regression analysis, we will try to create the first model to predict toxicity to chemotherapy in elderly patients with diagnosis of cancer, based on the definition of sarcopenia., Conclusions: It is expected that the final analysis of this project will be useful to detect predictive factors of toxicity to chemotherapy in elderly patients with cancer., (Copyright © 2016 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: To quantify changes in visual function parameters and in the retinal nerve fiber layer and macular thickness over a 5-year period in patients with Parkinson's disease (PD)., Methods: Thirty patients with PD and 30 healthy subjects underwent a complete ophthalmic evaluation, including assessment of visual acuity, contrast sensitivity vision, color vision, and retinal evaluation with spectral-domain optical coherence tomography (SD-OCT). All subjects were reevaluated after 5 years to quantify changes in visual function parameters, the retinal nerve fiber layer, and macular thickness. Association between progressive ophthalmologic changes and disease progression was analyzed., Results: Changes were detected in visual function parameters and retinal nerve fiber layer thickness in patients compared with controls. Greater changes were found during the follow-up in the PD group than healthy subjects in visual acuity, contrast sensitivity, Lanthony color test (P < 0.016), in superotemporal and temporal retinal nerve fiber layer sectors (P < 0.001), and in macular thickness (all sectors except inner superior and inner inferior sectors, P < 0.001). Progressive changes in the retinal nerve fiber layer were associated with disease progression (r = 0.389, P = 0.028)., Conclusions: Progressive visual dysfunction, macular thinning, and axonal loss can be detected in PD. Analysis of the macular thickness and the retinal nerve fiber layer by SD-OCT can be useful for evaluating Parkinson's disease progression.

This study explores the technical viability of autologous fat grafting for immediate partial breast reconstruction following the primary conservative surgery for breast cancer; restoring volume, shape, and symmetry to the treated breast. We analyze the impact in relation to mammographic follow-up and the subjective degree of satisfaction with esthetic results and although we didn't have any local failure during the observation period; we understand that is too early for any kind of conclusion. From June of 2010 to July of 2011, 20 patients were selected for breast-conserving surgery (BCS) with partial breast reconstruction with autologous fat grafting performed during the same operation by the same medical team. The fat graft was injected in the subcutaneous and intraglandular breast tissue around the resected area. We performed an overcorrection, predicting a resorbing of about 30-50% of the volume grafted. All patients received the literature-based recommendations for breast cancer treatment with complementary radiotherapy. The follow-up period after the completion of radiotherapy ranged from 13 to 29 months. The average volume grafted was 121 cc and it was 2.1 times larger than the resected volume. The esthetic scores were considered very good or good in the majority of cases. Mammograms were taken every 6 months after radiotherapy and only one patient had a mammogram classified as BI-RADS 3, suggesting fat necrosis. The remaining patients were classified as BI-RADS 2. Immediate autologous fat grafting is a promising technique for partial breast reconstruction after BCS. It is associated with high patient and physician satisfaction. It is an alternative for reconstruction of small- and medium-sized breasts. This technique has the advantage that enables the reconstruction of defects in areas difficult to repair, particularly in the upper inner quadrants. It also may reduce the need for major glandular or myocutaneous flaps mobilization., (© 2015 Wiley Periodicals, Inc.)

Background: To assess management patterns and outcome in patients with glioblastoma multiforme (GBM) treated during 2008-2010 in Spain., Methods: Retrospective analysis of clinical, therapeutic, and survival data collected through filled questionnaires from patients with histologically confirmed GBM diagnosed in 19 Spanish hospitals., Results: We identified 834 patients (23% aged >70 years). Surgical resection was achieved in 66% of patients, although the extent of surgery was confirmed by postoperative MRI in only 41%. There were major postoperative complications in 14% of patients, and age was the only independent predictor (Odds ratio [OR], 1.03; 95% confidence interval [CI],1.01-1.05; P = .006). After surgery, 57% received radiotherapy (RT) with concomitant and adjuvant temozolomide, 21% received other regimens, and 22% were not further treated. In patients treated with surgical resection, RT, and chemotherapy (n = 396), initiation of RT ≤42 days was associated with longer progression-free survival (hazard ratio [HR], 0.8; 95% CI, 0.64-0.99; P = .042) but not with overall survival (HR, 0.79; 95% CI, 0.62-1.00; P = .055). Only 32% of patients older than 70 years received RT with concomitant and adjuvant temozolomide. The median survival in this group was 10.8 months (95% CI, 6.8-14.9 months), compared with 17.0 months (95% CI, 15.5-18.4 months; P = .034) among younger patients with GBM treated with the same regimen., Conclusions: In a community setting, 57% of all patients with GBM and only 32% of older patients received RT with concomitant and adjuvant temozolomide. In patients with surgical resection who were eligible for chemoradiation, initiation of RT ≤42 days was associated with better progression-free survival.

This paper has two aims: (i) to introduce a novel method for measuring which part of overall citation inequality can be attributed to differences in citation practices across scientific fields, and (ii) to implement an empirical strategy for making meaningful comparisons between the number of citations received by articles in 22 broad fields. The number of citations received by any article is seen as a function of the article's scientific influence, and the field to which it belongs. A key assumption is that articles in the same quantile of any field citation distribution have the same degree of citation impact in their respective field. Using a dataset of 4.4 million articles published in 1998-2003 with a five-year citation window, we estimate that differences in citation practices between the 22 fields account for 14% of overall citation inequality. Our empirical strategy is based on the strong similarities found in the behavior of citation distributions. We obtain three main results. Firstly, we estimate a set of average-based indicators, called exchange rates, to express the citations received by any article in a large interval in terms of the citations received in a reference situation. Secondly, using our exchange rates as normalization factors of the raw citation data reduces the effect of differences in citation practices to, approximately, 2% of overall citation inequality in the normalized citation distributions. Thirdly, we provide an empirical explanation of why the usual normalization procedure based on the fields' mean citation rates is found to be equally successful.

Background: This cross-sectional, nested cohort study assessed Female Sexual Function Index (FSFI) scores in postmenopausal women with breast cancer receiving primary chemotherapy., Methods: The FSFI questionnaire was administered to 24 postmenopausal women one month after diagnosis of breast cancer (post-diagnosis group) and one month after completion of the first cycle of primary anthracyclin-based chemotherapy (post-chemotherapy group). Scores were compared to those of 24 healthy postmenopausal women seeking routine gynecological care (control group). All patients were sexually active at the time of enrollment. Mean age was 57.29 ± 11.82 years in the breast cancer group and 52.58 ± 7.19 years in the control group., Results: Scores in all domains of the FSFI instrument were significantly lower in the post-diagnosis group than in controls (-41.3%, p < 0.001). A further major reduction in FSFI scores was evident on completion of one cycle of primary chemotherapy (down 46.7% from post-diagnosis scores, p < 0.003), again in all domains. Six patients (25%) ceased all sexual relations, in a significant change from baseline (p < 0.001). After one chemotherapy cycle, a further five patients ceased sexual activity, for a total of 11 (45.8%) participants--a borderline significant difference (p = 0.063)., Conclusion: The present study shows that female sexual function as assessed by the FSFI declines significantly at two distinct points in time: upon diagnosis of breast cancer and after administration of systemic chemotherapy.

One of the greatest challenges in the treatment of substance dependence is to reverse the control that drug-associated stimuli have gained over the addict's behavior, as these drug-associated memories increase the risk of relapse even after long periods of abstinence. We report here that inhibition of the atypical protein kinase C isoform PKCzeta and its constitutively active isoform PKMzeta with the pseudosubstrate inhibitor ZIP administered locally into the nucleus accumbens core reversibly inhibited the retrieval of drug-associated memory and drug (remifentanil) seeking, whereas a scrambled ZIP peptide or staurosporine, an effective inhibitor of c/nPKC-, CaMKII-, and PKA kinases that does not affect PKCzeta/PKMzeta activity, was without effect on these memory processes. Acquisition or extinction of drug-associated memory remained unaffected by PKCzeta- and PKMzeta inhibition.

We propose a new method to assess the merit of any set of scientific papers in a given field based on the citations they receive. Given a field and a citation impact indicator, such as the mean citation or the [Formula: see text]-index, the merit of a given set of [Formula: see text] articles is identified with the probability that a randomly drawn set of [Formula: see text] articles from a given pool of articles in that field has a lower citation impact according to the indicator in question. The method allows for comparisons between sets of articles of different sizes and fields. Using a dataset acquired from Thomson Scientific that contains the articles published in the periodical literature in the period 1998-2007, we show that the novel approach yields rankings of research units different from those obtained by a direct application of the mean citation or the [Formula: see text]-index.

Acquisition of drug-reinforced behavior is accompanied by a systematic increase of release of the neurotransmitter acetylcholine (ACh) rather than dopamine, the expected prime reward neurotransmitter candidate, in the nucleus accumbens core (AcbC), with activation of both muscarinic and nicotinic ACh receptors in the AcbC by ACh volume transmission being necessary for the drug conditioning. The present findings suggest that the AcbC ACh system is preferentially activated by drug reinforcers, because (1) acquisition of food-reinforced behavior was not paralleled by activation of ACh release in the AcbC whereas acquisition of morphine-reinforced behavior, like that of cocaine or remifentanil (tested previously), was, and because (2) local intra-AcbC administration of muscarinic or nicotinic ACh receptor antagonists (atropine or mecamylamine, respectively) did not block the acquisition of food-reinforced behavior whereas acquisition of drug-reinforced behavior had been blocked. Interestingly, the speed with which a drug of abuse distributed into the AcbC and was eliminated from the AcbC determined the size of the AcbC ACh signal, with the temporally more sharply delineated drug stimulus producing a more pronounced AcbC ACh signal. The present findings suggest that muscarinic and nicotinic ACh receptors in the AcbC are preferentially involved during reward conditioning for drugs of abuse vs sweetened condensed milk as a food reinforcer.

Although dopamine and glutamate transmission has been implicated in cocaine dependence, the effects of the extinction of cocaine self-administration on protein transporters in both of these neurotransmitter systems remain unknown. We have used a yoked-box procedure to simultaneously test rats in triads, one rat that actively self-administered cocaine (CONT), while the other two received yoked injections of either cocaine (NON-CONT) or saline (SALINE). The brains in each triad were removed and processed for quantitative autoradiography immediately after the last session of cocaine self-administration (Day 0), or after 1, 5, or 10 days of extinction, and excitatory amino acid transporters (EAATs) and dopamine transporter (DAT) binding was examined. When compared to NON-CONT and SALINE animals, binding of radioligand to EAATs was significantly lower in the hippocampal CA1 field and the cerebellar cortex of CONT rats on Day 0, although it was significantly higher after 1 day of extinction in the infralimbic cortex. No differences in EAAT binding were observed after 5 or 10 days of extinction in any of the brain regions analyzed. In contrast and at all the time points of extinction, binding to DAT was significantly enhanced in CONT animals when compared to SALINE and NON-CONT rats in different forebrain and mesencephalic regions, including the nucleus accumbens, ventral tegmental area or caudate putamen. These results suggest that changes in protein transporter binding after cocaine self-administration and extinction are transient for EAAT while they are more enduring for DAT, and that they depend on the type of access to cocaine.

Escalation of drug use, a hallmark of drug dependence, has traditionally been interpreted as reflecting the development of tolerance to the drug's effects. However, on the basis of animal behavioral data, several groups have recently proposed alternative explanations, i.e. that such an escalation of drug use might not be based on (1) tolerance, but rather be indicative of (2) sensitization to the drug's reinforcing effect, (3) reward allostasis, (4) an increase in the incentive salience of drug-associated stimuli, (5) an increase in the reinforcing strength of the drug reinforcer relative to alternative reinforcers, or (6) habit formation. From the pharmacological perspective, models 1-3 allow predictions about the change in the shape of drug dose-effect curves that are based on mathematically defined models governing receptor-ligand interaction and signal transduction. These predictions are tested in the present review, which also describes the other currently championed models for drug use escalation and other components of apparent 'reinforcement' (in its original meaning, like 'tolerance' or 'sensitization', a purely descriptive term). It evaluates the animal experimental approaches employed to support or prove the existence of each of the models and reinforcement components, and recapitulates the clinical evidence, which strongly suggests that escalation of drug use is predominantly based on an increase in the frequency of intoxication events rather than an increase in the dose taken at each intoxication event. Two apparent discrepancies in animal experiments are that (a) sensitization to overall reinforcement has been found more often for psychostimulants than for opioids, and that (b) tolerance to the reinforcing and other effects has been observed more often for opioids than for cocaine. These discrepancies are resolved by the finding that cocaine levels seem to be more tightly regulated at submaximum reinforcing levels than opioid levels are. Consequently, animals self-administering opioids are more likely to expose themselves to higher above-threshold doses than animals self-administering psychostimulants, rendering the development of tolerance to opioids more likely than tolerance to psychostimulants. The review concludes by making suggestions on how to improve the current behavioral experimental approaches., (Copyright (c) 2007 S. Karger AG, Basel.)

An individual's drug abuse pattern is determined by a multitude of factors. Among these, simple pharmacological determinants of within-binge drug consumption are sorely underinvestigated. We therefore determined if within-session operant responsing to the ultra-short-acting mu opioid agonist remifentanil (RMF) was determined by blood or brain RMF levels or changes thereof. Our peri-response analysis did not detect any "threshold" RMF level, either in blood or in the nucleus accumbens (NAc) core as a deep brain region that might determine a rat's "decision" to re-emit a response during a multiple-injection drug self-administration session. The peri-response analysis also failed to find any peak RMF level, either in blood or in the NAc core, which could serve as a "ceiling" level. Thus, our findings strongly suggest that titration of blood or brain RMF levels does not determine a rat's intra-session operant response.

Neurotransmitter release in the nucleus accumbens core (NACore) during the acquisition of remifentanil or cocaine reinforcement was determined in an operant runway procedure by simultaneous tandem mass spectrometric analysis of dopamine, acetylcholine, and remifentanil or cocaine itself. Run times for remifentanil or cocaine continually decreased over the five consecutive runs of the experiment. Intra-NACore dopamine, acetylcholine, and drug peaked with each intravenous remifentanil or cocaine self-administration and decreased to pre-run baseline with half-lives of approximately 10 min. As expected, remifentanil or cocaine peaks did not vary between the five runs. Surprisingly, however, drug-contingent dopamine peaks also did not change over the five runs, whereas acetylcholine peaks did. Thus, the acquisition of drug reinforcement was paralleled by a continuous increase in acetylcholine overflow in the NACore, whereas the overflow of dopamine, the expected prime neurotransmitter candidate for conditioning in drug reinforcement, did not increase. Local intra-accumbens administration by reverse microdialysis of either atropine or mecamylamine completely and reversibly blocked the acquisition of remifentanil reinforcement. Our findings suggest that activation of muscarinic and nicotinic acetylcholine receptors in the NACore by acetylcholine volume transmission is necessary during the acquisition phase of drug reinforcement conditioning.

Escalation of drug use by addicts has traditionally been interpreted as tolerance to the drug's effects. On the basis of animal behavioral data, several groups have recently proposed alternative explanations, i.e., that such an escalation of drug dose might not be based on tolerance but rather be indicative of (i) sensitization to the reinforcing effect or the incentive salience of the drug of abuse or (ii) shifts in baseline mood, i.e., allostasis. In the present study, the emergence of opioid tolerance or sensitization during the progression of opioid dependence was assessed by comparing the methadone doses that were initially required to alleviate the opioid withdrawal symptoms of intravenous opioid users who presented for detoxification upon 3-7 consecutive admissions over the course of up to 84 months. Upon the second admission, the 48 surveyed male patients needed 115 +/- 6% (p = 0.012) and the 32 female patients needed 121 +/- 12% (p = 0.01) of the methadone dose required upon the first admission. Upon the third admission, the respective values were 121 +/- 8% (males; p = 0.013) and 111 +/- 12% (females; n.s.), and upon the fourth admission, 125 +/- 14% (males; p = 0.026) and 131 +/- 14 (females; p = 0.01). Inter-admission intervals averaged 14 +/- 1 months (n = 135) for males and 13 +/- 1 months (n = 91) for females and were not significantly different across consecutive admissions, suggesting that tolerance did not develop faster upon repetition of abuse-withdrawal cycles. In conclusion, the intravenous opioid users surveyed in the present study developed only very moderate tolerance during the repeated abuse-detoxification cycles that were typical for their disease progression. The present data do not support the notion that sensitization to the opioids' reinforcing effects occurred in this naturalistic clinical sample., (Copyright 2006 S. Karger AG, Basel.)

Rationale: The ultra-short-acting mu opioid agonist analgesic/anesthetic remifentanil (RMF) is extremely rapidly eliminated from blood (half-life in rats, 0.3-0.7 min). This extremely fast elimination is thought to be the main reason why RMF maintains such high rates of responding in animal operant-conditioning models of drug addiction., Objective: The present study investigated if such a fast elimination of RMF also occurs in the extracellular space of the brain, i.e., in the pharmacokinetic compartment that is thought to be ultimately mediating the reinforcing effect, and hence, the abuse liability of drugs., Methods: Nucleus accumbens (NAC) RMF and dopamine (DA) were simultaneously quantified by in vivo microdialysis followed by tandem mass spectrometry both in rats that traversed an alley to receive intravenous injections of 0.032 mg kg(-1) RMF in an operant runway procedure (contingent RMF) and in rats that passively received RMF in the runway (noncontingent RMF)., Results: Regardless of the mode of administration (i.e., contingent or noncontingent), intra-accumbens RMF peaked in the first 10-min sample and decreased exponentially with a t(1/2) of 10.0+/-1.2 min (N=31). RMF-stimulated DA peaked in the 10-min sample immediately after the RMF peak and decreased with a time course very similar to that of RMF. Crosscorrelation of the NAC RMF and NAC DA curves showed them to be tightly synchronized. Noncontingent single-dose RMF was eliminated from the whole brain with a half-life of 1.1+/-0.2 min and from blood with a half-life of 0.3 min or less. The comparison of blood-vs-brain RMF pharmacokinetics with rat RMF self-administration behavior, either in operant runway (present study) or in lever-press-based operant-conditioning procedures, suggests that titration of blood RMF, whole-brain RMF, intra-accumbens RMF, or accumbal DA levels (assessed with the limited temporal resolution of in vivo microdialysis) does not determine a rat's decision to reemit a response during a multiple-injection drug self-administration session.

Introduction: The presence of eating disorders in bipolar population is not rare, with rates over 10 %, according to the few available epidemiologic studies, however the literature on this issue is still scarce. An even higher percentage of bipolar individuals suffer from serious problems related to eating behavior without fulfilling criteria for DSM-IV eating disorder., Methods: The Bipolar Eating Disorders Scale (BEDS) was designed on the basis of the existing eating scales, adjusted to the characteristics of bipolar disorders from the complaints of our sample of patients (n=350). Subsequently, a group of experts made the selection of the most representative and independent items in order to obtain a short, 10-item scale, aimed at assessing the intensity and frequency of eating dysfunctions in the bipolar population and not at diagnosis. We administered the scale to a healthy control group (n=55) to evaluate feasibility and to determine the cut-off score., Results: The BEDS is a 10-item simple, self-administered scale. Average time of completing this scale is about 1.13 min (1 min, 21 seconds) +/-26 seconds. Median score was 6 and the mean score was 6.6 with a standard deviation of 3.7, this being the reason why the cut-off point was found to be around 13 points. Patients receiving scores over 13 may require an individualized intervention to evaluate which were the main difficulties and to propose treatment., Conclusions: The BEDS allows for a rapid and effective evaluation of both the intensity and the frequency of eating dysfunctions in bipolar patients in order to perform an adequate intervention for the specific needs of each one of the patients.

The long-term effect of cocaine self-administration on corticotropin releasing factor (CRF) mRNA content in the hypothalamic CRF-containing neurons has not yet been established. The purpose of this study was to examine the time course effects of the extinction of cocaine self-administration behavior on CRF gene expression in the paraventricular nucleus of the hypothalamus (PVN) using in situ hybridization histochemistry (IHHS). Seventy-two littermate male Lewis rats were randomly assigned in triads to one of three conditions: (a) contingent intravenous self-administration of 1 mg/kg/injection of cocaine (CONT), (b) non-contingent injections of either 1 mg/kg/injection of cocaine (NONCONT) or (c) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to self-administer cocaine under a fixed ratio 5 (FR5) schedule of reinforcement for a minimum of 3 weeks. After stable baseline levels of drug intake had been reached, saline was substituted for drug. Following this first extinction period, cocaine self-administration was reinstated for an additional period of 2 weeks. Immediately after cessation of the last session of cocaine self-administration (Day 0) and 1, 5 and 10 days after the second extinction period, animal brains in each triad were removed to be processed for IHHS. CRF mRNA levels in the PVN were significantly lower in the NONCONT cocaine group at Day 0 compared to CONT or SALINE groups. On Day 1, hypothalamic CRF gene expression significantly decreased in the CONT cocaine group with respect to the SALINE group, but there were no differences between the cocaine groups or among the NONCONT cocaine and SALINE groups. After 5 and 10 days of extinction, no differences were found in CRF mRNA content in the PVN between the three conditions of this study. These results suggest that, after the extinction of cocaine self-administration, changes in hypothalamic CRF gene expression are differentially affected depending upon the type of cocaine administration, and that the stages of cocaine withdrawal might not be associated with enduring changes in hypothalamic CRF mRNA levels.

Previously, we have shown that Lewis (LEW) rats acquire faster than Fischer 344 (F344) rats operant food- and morphine-reinforced tasks under fixed-ratio schedules of reinforcement. The first purpose of the present work has been to study if differences in operant responding behavior may participate in the reported differences in morphine self-administration behavior between both inbred rat strains. To this end, we have analyzed the microstructure of responding obtained under a variable-interval (VI) of food reinforcement by calculating the inter-response time (IRT) for each rat strain. LEW rats exhibited shorter IRTs than F344 rats, suggesting that LEW rats may have an inherent high or compulsive operant responding activity. When subjects of both inbred rat strains were submitted to a schedule of morphine reinforcement of high responding requirements such as progressive ratio schedules, LEW rats also reached significantly higher breaking points and final response ratio than F344 rats for i.v. morphine self-administration. Given that there are neurochemical differences between both rat strains and that glutamatergic N-methyl-D-aspartate (NMDA) and dopaminergic D(1) receptors have been involved in operant responding behavior, a second purpose of this work has been to measure basal NMDA and D(1) receptor levels in these rat strains by quantitative receptor autoradiography. Compared to F344 rats, LEW rats showed higher basal NMDA receptor levels in frontal and cingulate cortex, caudate putamen, central amygdaloid nuclei, and intermediate white layer of superior colliculus, and higher basal D(1) receptor levels in several areas of hippocampus and thalamus, and substantia nigra pars reticulata. Taken together, these results suggest that an inherent high operant responding activity of LEW rats may have a role in the previous reported faster acquisition of opiate-reinforced behavior in operant self-administration paradigms under fixed-ratio schedules of reinforcement. In addition, a basal higher NMDA and D(1) receptor levels of LEW rats compared to F344 rats may participate in the neurochemical background that mediates the behavioral differences between both inbred rat strains.

The aim of the present work was to study the time course effects in levels of mRNA encoding N-methyl-d-aspartate receptor subunit 1 (NMDAR1) after long-term cocaine self-administration (1 mg/kg/ injection) and its extinction using a yoked-box procedure. NMDAR1 content was measured by quantitative in situ hybridization histochemistry in prefrontal cortex, caudate-putamen, nucleus accumbens, olfactory tubercle, and piriform cortex immediately after cessation of the last session of cocaine self-administration (Day 0) and 1, 5, and 10 days after the extinction period. The results show that long-term cocaine self-administration and its extinction alter NMDAR1 gene expression in these forebrain regions, and that the changes depend upon the brain region examined and the type of cocaine administration (contingent, noncontingent, and saline). Compared to saline and noncontingent cocaine administration, contingent cocaine produced an up-regulation in NMDAR1 gene expression on Day 0 in all the brain regions analyzed. NMDAR1 levels of contingent animals decreased progressively in the absence of cocaine, and the decrement persisted 10 days after the extinction of cocaine self-administration behavior in all the forebrain areas, with the exception of olfactory tubercle. In contrast, noncontingent cocaine administration did not produce any change in NMDAR1 gene expression on Day 0, and extinction resulted in an increase of NMDAR1 mRNA content on Days 1 and 5 and returned to control (saline) values on Day 10. These results suggest that an interaction between environmental stimuli and the pharmacological action of cocaine during drug self-administration and its extinction may represent an important factor in the regulation of cocaine effects on NMDAR1 gene expression.

The purpose of this study was to examine the time course effects of extinction of cocaine self-administration behavior on proenkephalin (PENK) gene expression in caudate-putamen nucleus (ST), nucleus accumbens (Acc), olfactory tubercle (Tu), piriform cortex (Pir), ventromedial hypothalamic nucleus (VMN), and central amygdala (Ce) as measured by in situ hybridization histochemistry. Seventy-two littermate male Lewis rats were randomly assigned in triads to one of three conditions: (1) contingent intravenous self-administration of 1 mg/kg/injection of cocaine (CONT); (2) noncontingent injections of either 1 mg/kg/injection of cocaine (NONCONT); or (3) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to self-administer cocaine under a FR5 schedule of reinforcement for a minimum of 3 weeks. After stable baseline levels of drug intake had been reached, saline was substituted for drug. Following this first extinction period, cocaine self-administration was reinstated for an additional period of 2 weeks. Immediately after cessation of the last session of cocaine self-administration (day 0) and 1-, 5-, and 10-day after the second extinction period, animal brains in each triad were removed to be processed for in situ hybridization. PENK mRNA levels were significantly higher in the cocaine groups when compared with SALINE group in the ST, Acc, Pir, and Tu regions on days 0, 1, 5, and 10 of the extinction and lower in the Ce region of CONT group when compared to NONCONT and SALINE groups on days 1, 5, and 10 of the extinction period. In the VMN nucleus, PENK mRNA content in CONT group versus NONCONT and SALINE groups was also lower, but there were statistically significant differences only on day 5. These results suggest that changes in PENK gene expression after contingent cocaine administration might be involved in cocaine withdrawal states.

We have previously shown that the acquisition rate of intravenous morphine self-administration under a fixed ratio one (FR1) schedule of reinforcement was greater in Lewis (LEW) than Fischer 344 (F344) rats. The purpose of the present experiment was to examine the relative motivational properties of morphine (1 mg/kg) or food under progressive ratio (PR) schedules of reinforcement in LEW and F344 rats. In addition, by using in situ hybridization histochemistry we have measured in both strains of rats the basal level of proenkephalin (PENK) gene expression in dorsal striatum and nucleus accumbens (NAcc). The results show that LEW rats responded to significantly higher breaking points (BPs) than F344 rats for intravenous morphine self-administration. In contrast, no differences were found in BPs for food pellets. Basal PENK mRNA levels were significantly higher in the dorsal striatum and nucleus accumbens of F344 than in LEW rats. Taken together, these results reveal a strain difference in the reinforcing efficacy of morphine and in the basal PENK gene expression in brain regions involved in the reinforcing actions of opiates. These data also suggest that the strain differences in opiate self-administration behavior found in this and other studies may be related, at least in part, to differences in basal opioid activity between LEW and F344 rats., (Copyright 1999 Elsevier Science B.V.)

Cannabis is the most widely used illicit drug in many western countries. Its psychoactive ingredient, delta9-tetrahydrocannabinol (THC), produces a variety of effects in animals and humans that are probably mediated by specific cannabinoid receptors in the brain and interactions with several neurotransmitter and neuromodulator systems. For instance, recent research has revealed an important mutual functional relationship between cannabinoids and endogenous opioid systems in mediating the pharmacological and behavioral actions produced by these agents, including their reinforcing effects. Perinatal exposure to and interactions between cannabinoids and opioids might also have long-term behavioral consequences lasting into adulthood. In this work, we present preliminary evidence examining the potential effects of maternal exposure to THC on the motivational properties of morphine in male and female adult rats, as measured by an intravenous opiate self-administration paradigm.

Opiates and cannabinoids are among the most widely consumed habit-forming drugs in humans. Several studies have demonstrated the existence of interactions between both kind of drugs in a variety of effects and experimental models. The present study has been focused to determine whether perinatal delta9-tetrahydrocannabinol (Delta9-THC) exposure affects the susceptibility to reinforcing effects of morphine in adulthood and whether these potential changes were accompanied by variations in mu opioid receptor binding in brain regions related to drug reinforcement. Adult female rats born from mothers that were daily treated with delta9-THC during gestation and lactation periods, exhibited a statistically significant increase in the rate of acquisition of intravenous morphine self-administration behavior when compared with females born from vehicle-exposed mothers, an effect that did not exist in delta9-THC-exposed male offspring. This increase was significantly greater on the last day of acquisition period. There were not significant differences when the subjects were lever pressing for food. In parallel, we have also examined the density of mu opioid receptors in the brain of adult male and female offspring that were exposed to Delta9-THC during the perinatal period. Collectively, perinatal exposure to delta9-THC produced changes in mu opioid receptor binding that differed regionally and that were mostly different as a function of sex. Thus, delta9-THC-exposed males exhibited a lower density for these receptors than their respective oil-exposed controls in the caudate-putamen area as well as in the amygdala (posteromedial cortical nucleus). On the contrary, delta9-THC-exposed females exhibited higher density of these receptors than their respective oil-exposed controls in the prefrontal cortex, the hippocampus (CA3 area), the amygdala (posteromedial cortical nucleus), the ventral tegmental area and the periaqueductal grey matter, whereas the binding was lower than control females only in the lateral amygdala. These results support the notion that perinatal delta9-THC exposure alters the susceptibility to morphine reinforcing effects in adult female offspring, in parallel with changes in mu opioid receptor binding in several brain regions., (Copyright 1998 Elsevier Science B.V.)

This study demonstrated the presence of viral particles suggestive of arthritis-encephalitis virus through the clinic, serologic, pathologic, immunohistochemic and ultrastructural studies in dairy goats. In the postmortem studies the tissues used were: synovial membrane, lungs and mammary gland from goats with clinical signs characteristic of the disease and positive for serum antibodies to the virus.

We have determined the blood lead levels of 1,242 children, from newborn to 14 years old, and 79 young mothers in a period of 10 months in Asturias (Spain). All of them were selected at random among those who consulted one of the three main hospitals in Asturias, but none were diagnosed as lead poisoning. We have found a mean blood lead level of 22.11 micrograms/dl; 23.55% had high levels (= 25 micrograms/dl). Sex was not significantly associated with blood lead levels either in the whole sample or in different age groups. Blood lead level increases rapidly from birth (19.3 micrograms/dl) to the age of one year (23.3 gamma/dl), fluctuating around this level until the age of 7. Then it declines with age until adolescence (19.6 micrograms/dl). From October (25.5 micrograms/dl) to July (20.9 micrograms/dl) the decrease in lead blood level was statistically significant. No difference has been found between urban and rural population. The decree of urbanization has not been found significant. The mean blood lead level in the mothers was 20.5 micrograms/dl.

A 19-years-old male was admitted for left bilobar pneumonia. All microbiologic studies in blood and in several samples obtained by bronchoscopy were negative. The patient worsened progressively despite antibiotherapy of a wide spectrum. A fine needle transparietal puncture was performed. The cultures of the sample were positive for Nocardia asteroides, a positive catalase germ. Immunologic studies initiated after this time showed negative tetrazolium nitroblue test, the results of which led to the diagnosis of chronic granulomatous disease. This disease is very infrequent and the polymorphonuclear leukocytes are genetically incapable of producing peroxides whose absence impedes lysis of the positive phagocytic catalase germs with which a histologic reaction is produced in the form of granulomas from which the name of the disease is derived.