Sensitization to apomorphine in pigeons is due to conditioning, subject to generalization but resistant to extinction

Apomorphine (Apo) administration induces a persistent bout of pecking in pigeons and other birds. Repeated injections of Apo in pigeons lead to sensitization, i.e. the pecking response to a particular dose increases up to a dose-dependent asymptotic level. It is also known that Apo-induced pecking can be classically conditioned to the cage environment where the animals experience the effect of the drug. Here we address the question of whether, and to what extent, the sensitization effect arises as a consequence of a conditioning or of a pharmacological process. An extinction experiment demonstrated that an extinction procedure supposed to be effective in inhibiting the conditioned pecking response was not effective in suppressing the sensitization to Apo, thus casting provisional doubt on the conditioning hypothesis. However, a conditioning experiment demonstrated that the sensitization effect undoubtedly involved an important component of conditioning to an experimental cage environment, but also suggested that there was an additional component possibly not due to learning. A generalization experiment, however, showed that this second component was very probably due to a stimulus generalization effect deriving from conditioning to the home cage, suggesting that learning can account for most, if not all, of the increase in Apo-induced pecking and that an exclusively pharmacological sensitization process plays, at best, a minor role. The apparent contrast between the results of the first experiment, indicating that the sensitization is not affected by inhibitory conditioning, and the results of the last two experiments, suggesting that the sensitization is due to excitatory conditioning, can be resolved by assuming that Apo induces a drug-state-dependent conditioning. These results are related to findings and arguments concerning the sensitization to psychostimulant drugs in mammals.     

Ways to increase adherence to allergen immunotherapy

Adherence to allergen immunotherapy (AIT) is crucial for its efficacy. Subcutaneous AIT requires monthly visits (or more extended in the case of venom immunotherapy), while sublingual AIT is performed with a daily intake of allergen drops. Non-adherence to an AIT schedule and premature discontinuation are common problems. Various studies have shown controversial results on the rate of AIT adherence. The aim of this review is to describe the problem of non-adherence and to offer some evidence-based advice to allergologists on how to increase it. Better patient education at the beginning of treatment, sharing with patients the decision on which type of immunotherapy to select and showing sincere interest in their treatment concerns are some tips that can help to increase adherence. A well organized allergologist time schedule not only increases safety but also offers the possibility of close follow-up and an increase in patient loyalty.     

Using genotyping to predict responses to anti-hypertensive treatment

Hypertension is prevalent and affects approximately 1 in every 4 adults in the Western world. Although many drugs are effective in treating hypertension, an individual's response to treatment is unpredictable. Pharmacogenetics holds the promise of becoming a tool to predict this response but obstacles and shortcomings need to be overcome. Significant developments in molecular biology, including the sequencing of the genome, the cataloguing of genetic variation and the development of microarray techniques, enable analysis of many genotypes simultaneously. However, despite these technical advances there are, as yet, no clinical applications of pharmacogenetics in anti-hypertensive treatment. It is therefore necessary to design prospective pharmacogenetic studies that aim to identify a genetic profile that will predict the response to anti-hypertensive treatment.     

优化教学方法激发学生学习主动性

针对药理学药物名称繁多、机制复杂，学生对其既怕学又不得不学的情况，尝试从优化教学内容？突皆苎举重点；教学紧密结合临床，使学生学以致用；应用多媒体技术手段，提高学生学习兴趣三方面着手，激发学生对药理学学习的主动性。     

Dyspepsia: how to manage and how to treat?

Recent guidelines for dyspepsia, defined as pain or discomfort centred in the upper abdomen, emphasize that in younger patients with no alarm features and not taking nonsteroidal anti-inflammatory drugs, testing for Helicobacter pylori and treatment of the infection if present is a standard of care. If H. pylori is not present, empirical management (e.g. acid suppression) is often prescribed. It is further recommended that if patients relapse or fail to respond to treatment then upper endoscopy be undertaken. However, these guidelines have become controversial for a number of reasons. Firstly, the prevalence of H. pylori infection is falling as is the incidence of peptic ulcer disease due to the infection. Idiopathic peptic ulcer disease is also being increasingly recognized. Furthermore, the cost-effectiveness of endoscoping treatment failures has been questioned, as the yield is low and patient management is usually not altered. Finally, it remains controversial whether the treatment of H. pylori infection in functional dyspepsia is of value, and two recent high quality meta-analyses have reached diametrically opposite conclusions. Alternative strategies, such as initially treating with acid suppression and then considering H. pylori infection in those who fail have been suggested, as has in low H. pylori prevalent regions the abandonment of a test-and-treat strategy. However, appropriate management trials of these alternative strategies in primary care are lacking. The management of patients with functional dyspepsia who fail initial antisecretory therapy is now difficult; prokinetics have fallen into some disrepute. Tricyclic antidepressants (at a low dose) may be useful in a subset, but adequate trials are lacking.     

To die or to sleep,perhaps to dream

Establishing social contacts is the raison d'être of neurons throughout their entire life span. To form and retain functional connections, neuronal differentiation and death are ruthlessly regulated in development and kept strictly under control in post-mitotic systems. Derangements in neural networks affect neuronal populations at large. Therefore, failure to retain synaptic connectivity is linked to dysfunction and often followed by neuronal death. Loss of neurons is a predominant feature of neurodegenerative disease. Nevertheless, neuronal cell death is not an obligate requirement for neural dysfunction at the level of distributed circuits or local circuits. Although more or less wide spread neuronal loss can occur after acute insults such as brain ischemia or invasion of the brain by pathogens, neuronal death is a hallmark of end-stage neurodegenerative and psychiatric disease. The relative contributions made by loss of synaptic connectivity versus cell death for these diseases are still debated. Here these processes are discussed in relation to acute and chronic CNS disorders.     

Failure to report attempts to quit smoking

Introduction

Accurately assessing quit attempt history is important to develop population estimates of cessation and to increase our understanding of smoking trajectories. Thus, the current study investigated failure to report quit attempts as a function of length of quit attempt by time since quit attempt over the past year.

Methods

The present study used data from the Smoking Toolkit Study, a series of population-based surveys of smokers and recent ex-smokers in England aged 16 years and older. Among the 11,772 smokers identified at baseline (24.4% of the total sample), this study focused on the 4234 participants (36.0% of current smokers) who reported between one and three quit attempts in the past year.

Results

There was a strong trend for quit attempts that lasted for shorter periods of time to fail to be reported. After three months, 90.1% of those lasting less than one day, 63.7% of those lasting between a day a one week, and 38.9% of those lasting between one week and one month failed to be reported.

Conclusion

A large proportion of unsuccessful quit attempts fail to be reported, particularly if they only last a short time or occurred longer ago. Therefore, population estimates of quit attempts based on retrospective data may be considerable underestimates and estimates of the success of quit attempts may be overestimates. Future research is needed to establish whether there is differential reporting of quit attempts as a function of features of attempts such as use of cessation aids.     

Targeting of therapeutic agents to bone to treat metastatic cancer

The three main organs affected by metastasis of all cancers include lungs, liver, and bone. Clinical confirmation of tumor spread to these organs is a negative prognostic sign that marks the stage when disease is rarely curable. Today, treatment of bone metastases is primarily palliative. The aims of treatment are to relieve pain, prevent development of pathologic fractures, improve mobility and function, and if possible, prolong survival. Significant improvements in our understanding of tumor biology along with early tumor detection has led to the discovery of few innovative approaches aimed to treat bone metastases. The most promising treatment modalities include combination of anti-cancer therapies (surgery, radiation therapy, citostatic therapy) with bone antiresorptive therapies (bisphosphonate) that specifically target osteoclasts, bone resorbing cells. The osteoclast, whose increased activity is induced by the tumor, is responsible for the deterioration of bone mass and structure along with the release of grow factors that feed back and support further tumor growth. The current pharmaceutical approach is to target bone metastases by developing drugs that specifically target tumor cells in bone in addition to bone stroma since skeletal metastases are more resistant to treatment, present the highest bulk of tumor mass in the body, serve as site for secondary spread of tumor cells, and are associated with significant morbidity. There is a real need for a more effective modified release of newer anti-cancer drugs such as gene therapy and immunotherapy by using established and novel delivery platforms that will improve therapy and reduce side effects as a result of more appropriate plasma profiles. Overall, however, developments regarding treatment of cancer metastases to bone are encouraging. The scope of future advancements is immense and includes innovative therapeutics and delivery systems aimed to improve skeletal affinity, selectivity, and efficacy of drugs.     

Environmental Chemicals: From the Environment to Food,to Breast Milk,to the Infant

Food is a source of exposure to many environmental chemicals found in human milk and other biological specimens. Ingestion of foods containing high amounts of animal fat is the main route of human exposure to lipophilic chemicals, such as persistent organic pollutants, which tend to bioaccumulate in the lipid compartment. Bioaccumulation results in increased exposure of these chemicals for humans, but particularly to breastfeeding infants, who are at the top of the food chain. The extent to which food contributes to a person's overall exposure depends on individual dietary habits and the concentrations of chemical residues in the food. These, in turn, are affected by (1) application methods, (2) properties and amounts of the chemical, and (3) preparation, handling, and the properties of the food. Once the food is ingested by the lactating woman, the chemical's pharmacokinetics and the transport mechanisms producing the movement of solutes across mammary alveolar cells determine the passage of chemicals from the blood to the milk. Thus, several factors affect the presence in human milk of environmental chemicals from dietary sources.     

Environmental chemicals: from the environment to food, to breast milk, to the infant

Food is a source of exposure to many environmental chemicals found in human milk and other biological specimens. Ingestion of foods containing high amounts of animal fat is the main route of human exposure to lipophilic chemicals, such as persistent organic pollutants, which tend to bioaccumulate in the lipid compartment. Bioaccumulation results in increased exposure of these chemicals for humans, but particularly to breastfeeding infants, who are at the top of the food chain. The extent to which food contributes to a person's overall exposure depends on individual dietary habits and the concentrations of chemical residues in the food. These, in turn, are affected by (1) application methods, (2) properties and amounts of the chemical, and (3) preparation, handling, and the properties of the food. Once the food is ingested by the lactating woman, the chemical's pharmacokinetics and the transport mechanisms producing the movement of solutes across mammary alveolar cells determine the passage of chemicals from the blood to the milk. Thus, several factors affect the presence in human milk of environmental chemicals from dietary sources.     

Tolerance to ethanol and cross-tolerance to pentobarbital and barbital

A chronic regimen of ethanol by intubation, which produced clear tolerance to ethanol-induced hypothermia, ataxia and narcosis, produced only a marginal degree of cross-tolerance to these effects of pentobarbital. The lack of appreciable cross-tolerance to pentobarbital-induced hypothermia and ataxia was also observed over a wide range of test doses. However, cross-tolerance to barbital was observed after chronic treatment with ethanol. Increased rate of drug biotransformation did not contribute significantly to the observed tolerance and cross-tolerance. The difference in the extent of cross-tolerance between ethanol and the two barbiturates is consistent with the hypothesis that there is a degree of specificity in the sites of action of ethanol and other sedative-hypnotic drugs.     

Introduction to Special Issue: Translational Research to Help Parents Respond to Adolescent Substance Use Problems

Parents experience a variety of challenges when they are confronted with the fact that their adolescent child is drinking alcohol or using other substances. This special issue is focused on the work being conducted at the National Institute on Drug Abuse (NIDA)-funded Parents Translational Research Center (PTRC) at the Treatment Research Institute in Philadelphia. By translating scientific evidence and elements of proven clinical interventions into practical tools for parents, the work of the PTRC aims to assist parents with intervening early, finding appropriate services, and facilitating treatment entry for their substance-using child.     

Mild hypertension: to treat or not to treat?

In the second half of this century, morbidity and mortality from cardiovascular disease has reached epidemic proportions. The major risk factor associated with cardiovascular disease has been found, from various epidemiological studies, to be elevated blood pressure. Therefore, a lot of energy has been expended in prospective therapeutic trials in attempting to detect whether treatment of high blood pressure is beneficial. In severe hypertension, where the risk to the individual is considerable, this benefit has been demonstrated with relative ease. However, it has not yet proven possible to show conclusive benefit of treatment in the mild group of hypertensives, which form the vast majority of patients seen in general practice. A different approach has been advocated where account is taken of other coincidental cardiovascular risk factors; their presence or absence should help the clinician decide whether to treat or not to treat in the individual case.     

浅谈胎盘早剥的早期诊断以及如何处理

目的主要就是分析并且探讨针对胎盘早剥的早期诊断以及处理的方法。方法通过回顾性分析,选取2009年初～2012年末期间所收治的100例胎盘早剥患者的病例资料,对该疾病的发病病因、临床表现以及分娩分析进行简要的统计分析。结果这100例中有30例是因为孕妇血管疾病而导致的胎盘早剥,占据了30％的比例。有30例是因为宫腔内压力突然降低从而导致胎盘早剥。同样也是占据30％的比例,还有的就是20例是因为外伤所造成的,占据的比例是20％,剩下的20例,是由于其他的原因所造成的胎盘早剥。在胎盘早剥的早期症状中,主要就是有着阴道出血、腰腹痛、胎音消失等等,在这些症状中,因为阴道出血而导致的比例就有着60％,因为腰腹痛而导致的比例就有15％,因为胎音消失而导致的比例就有着25％。这100例的患者中,在分娩的方式上,63例的患者选择剖宫产,所占的比例是63％,选择采用阴道分娩方式的患者有37例,所占的比例是37％,P〈0．05,差异具有统计学意义。结论对胎盘早剥的致病因素以及患者在临床的表现进行了主要的分析以及研究,如果能够近早采取确诊以及分娩的方式上采取合适自己的方法,是能够将围产儿的死亡率降低到一定程度的。     

Planning survival studies to compare a treatment to an active control

Rubinstein et al (1) presented a procedure for determining the required duration of accrual for a clinical trial comparing the survival distributions of two treatments using a classical hypothesis testing formulation. Here their testing procedure is modified in two ways. First, the asymptotic variances used in computation of the probabilities of type I and type II errors are based on the values of the parameters specified by the null and alternative hypotheses, respectively. Second, the null hypothesis is modified for situations where it is desired to show that the experimental treatment is better or not much worse than the control.     

Using microarrays to predict resistance to chemotherapy in cancer patients

Chemotherapy resistance remains a major obstacle to successful treatment and better outcome in cancer patients. The advent of whole genome experimental strategies, such as DNA microarrays, has transformed the way researchers approach cancer research. There is considerable hope that microarray technology will lead to the identification of new targets for therapeutic intervention, a better understanding of the disease process, and, ultimately, to higher survival rates and more personalized medicine. The question at hand is what is the best approach to apply these new technologies to the study of anticancer drug resistance, and how can the results obtained in the laboratory be quickly moved to a clinical setting? This review offers an overview of the microarray technology, including its recently associated strategies, such as array comparative genomic hybridization and promoter arrays. It also highlights some recent examples of microarray studies, which represent a first step toward a better understanding of drug resistance in cancer and, ultimately, personalized medicine.     

Extensions to the Visual Predictive Check to facilitate model performance evaluation

The Visual Predictive Check (VPC) is a valuable and supportive instrument for evaluating model performance. However in its most commonly applied form, the method largely depends on a subjective comparison of the distribution of the simulated data with the observed data, without explicitly quantifying and relating the information in both. In recent adaptations to the VPC this drawback is taken into consideration by presenting the observed and predicted data as percentiles. In addition, in some of these adaptations the uncertainty in the predictions is represented visually. However, it is not assessed whether the expected random distribution of the observations around the predicted median trend is realised in relation to the number of observations. Moreover the influence of and the information residing in missing data at each time point is not taken into consideration. Therefore, in this investigation the VPC is extended with two methods to support a less subjective and thereby more adequate evaluation of model performance: (i) the Quantified Visual Predictive Check (QVPC) and (ii) the Bootstrap Visual Predictive Check (BVPC). The QVPC presents the distribution of the observations as a percentage, thus regardless the density of the data, above and below the predicted median at each time point, while also visualising the percentage of unavailable data. The BVPC weighs the predicted median against the 5th, 50th and 95th percentiles resulting from a bootstrap of the observed data median at each time point, while accounting for the number and the theoretical position of unavailable data. The proposed extensions to the VPC are illustrated by a pharmacokinetic simulation example and applied to a pharmacodynamic disease progression example.     

Strategies to optimize siRNA delivery to hepatocellular carcinoma cells

Introduction: hepatocellular carcinoma (hcc) is the predominant form of primary liver cancer and the second leading cause of cancer-associated mortality worldwide. available therapies for hcc have limited efficacy due to often late diagnosis and the general resistance of hcc to anti-cancer agents; therefore, the development of novel therapeutics is urgently required. small-interfering rna (sirna) molecules are short, double-stranded rnas that specifically recognize and bind the mrna of a target gene to inhibit gene expression. despite the great therapeutic potential of sirnas towards many human tumors including hcc, their use is limited by suboptimal delivery.

Areas covered: In this review, we outline the current data regarding the therapeutic potential of siRNAs in HCC and describe the development of effective siRNA delivery systems. We detail the key problems associated with siRNA delivery and discuss the possible solutions. Finally, we provide examples of the various siRNA delivery strategies that have been employed in animal models of HCC and in human patients enrolled in clinical trials.

Expert opinion: Despite the existing difficulties in siRNA delivery for HCC, the increasing scientific attention and breakthrough studies in this field is facilitating the design of novel and efficient technical solutions that may soon find practical applications.     

The ubiquitin-proteasome system and assays to determine responses to inhibitors

Importance of the field: Proteasome inhibition is an important therapeutic modality. Additionally, given the toxicities of direct proteasome inhibition, interest is increasing in modulating the ubiquitin ligases in the ubiquitin-proteasome system (UPS). Areas covered in this review: A detailed examination of the ubiquitin-proteasome pathway and an examination of methods of inhibiting this pathway from a variety of targets including the proteasome, the ubiquitin ligases and molecular biology techniques. Special attention is given to the assays used to measure modulation of the ubiquitin-proteasome pathway. What the reader will gain: A thorough examination of the UPS and its role in cells and disease and an overview of several assays for analyzing the effect of inhibitors on the UPS. Significant detail is given to assays of the ligase system and molecular approaches. These assays have their own advantages and disadvantages and will allow investigators to make informed choices on investigating the UPS. Take home message: Interrupting the UPS can have profound consequences for cellular health and disease progression. The ubiquitin-proteasome pathway contains multiple activities that cannot be definitively assayed by a single technique. Assaying the UPS requires investigators to use multiple corroborating techniques and avoid confounding issues within each technique.