Investigations on drug produced and subjectively experienced discriminative stimuli. 2. Loperamide, an antidiarrheal devoid of narcotic cue producing actions.

By means of a new behavioral procedure effectively controlling the narcotic stimulus properties of drugs, it was found that the oral administration of fentanyl, morphine, codeine and diphenoxylate produced the narcotic cue. The new antidiarrheal loperamide did not produce this cue in rats as sensitive as being able to detect 0.005 mg/kg s.c. fentanyl. The results are discussed in terms of drug abuse liability.     

The functional state of microcirculation and autonomic regulation in young subjects with different levels of subjectively experienced psychological stress

A comprehensive comparative analysis of hemodynamics, microcirculation (the method of laser Doppler flowmetry with an occlusion test and the optical tissue oxymetry), blood circulation neurohumoral regulation (analysis of heart rate variability, HRV) in apparently healthy young subjects with different levels of subjectively experienced emotional stress has been performed. Depending on the degree of everyday stress (acute and/or chronic), the character of the autonomic regulation of blood circulation, as well as the state of the microcirculation and its regulation substantially vary. Moderate stress is accompanied by coactivation of sympathetic-parasympathetic regulatory mechanisms with augmented HRV baroreflex regulation circuits, which compensates for hemodynamic changes and is not accompanied by hypotensive reactions. An increase in the activity of neurogenic and myogenic tones of microhemodynamics in the subjects with moderate stress, which determines a high probability of blood shunting in tested tissue and decrease in relative oxygen extraction, has been discovered. Moderate levels of stress are also associated with an increase in the latency of postocclusive vasoreactive hyperemia, which is considered to be an early sign of the endothelium-mediated dysfunction of microcirculation.     

Tinnitus: distinguishing between subjectively perceived loudness and tinnitus-related distress

Objectives

Overall success of current tinnitus therapies is low, which may be due to the heterogeneity of tinnitus patients. Therefore, subclassification of tinnitus patients is expected to improve therapeutic allocation, which, in turn, is hoped to improve therapeutic success for the individual patient. The present study aims to define factors that differentially influence subjectively perceived tinnitus loudness and tinnitus-related distress.

Methods

In a questionnaire-based cross-sectional survey, the data of 4705 individuals with tinnitus were analyzed. The self-report questionnaire contained items about subjective tinnitus loudness, type of onset, awareness and localization of the tinnitus, hearing impairment, chronic comorbidities, sleep quality, and psychometrically validated questionnaires addressing tinnitus-related distress, depressivity, anxiety, and somatic symptom severity. In a binary step-wise logistic regression model, we tested the predictive power of these variables on subjective tinnitus loudness and tinnitus-related distress.

Results

The present data contribute to the distinction between subjective tinnitus loudness and tinnitus-related distress. Whereas subjective loudness was associated with permanent awareness and binaural localization of the tinnitus, tinnitus-related distress was associated with depressivity, anxiety, and somatic symptom severity.

Conclusions

Subjective tinnitus loudness and the potential presence of severe depressivity, anxiety, and somatic symptom severity should be assessed separately from tinnitus-related distress. If loud tinnitus is the major complaint together with mild or moderate tinnitus-related distress, therapies should focus on auditory perception. If levels of depressivity, anxiety or somatic symptom severity are severe, therapies and further diagnosis should focus on these symptoms at first.     

Typical dreams experienced by Chinese people.

The present study investigated the prevalence profile and frequencies of typical dream themes experienced by Chinese people. The Typical Dreams Questionnaire was administered to 348 university students in Hong Kong. The results demonstrated that the prevalence profile of the typical dream themes for the Chinese participants resembled those profiles previously reported by Western studies. In addition, the present study found large positive correlations between the rank-ordered prevalence and frequency scores of the typical dream themes. This implied that the most prevalent themes were also more likely to be the most recurrent themes and vice versa. Therefore, typical dream themes not only are shared by many people but also tend to be repeatedly experienced within a person. This result supports the postulation that typical dreams are distinguished by both their universality and recurrence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Estimation of an in vivo fitness landscape experienced by HIV-1 under drug selective pressure useful for prediction of drug resistance evolution during treatment

MOTIVATION: HIV-1 antiviral resistance is a major cause of antiviral treatment failure. The in vivo fitness landscape experienced by the virus in presence of treatment could in principle be used to determine both the susceptibility of the virus to the treatment and the genetic barrier to resistance. We propose a method to estimate this fitness landscape from cross-sectional clinical genetic sequence data of different subtypes, by reverse engineering the required selective pressure for HIV-1 sequences obtained from treatment naive patients, to evolve towards sequences obtained from treated patients. The method was evaluated for recovering 10 random fictive selective pressures in simulation experiments, and for modeling the selective pressure under treatment with the protease inhibitor nelfinavir. RESULTS: The estimated fitness function under nelfinavir treatment considered fitness contributions of 114 mutations at 48 sites. Estimated fitness correlated significantly with the in vitro resistance phenotype in 519 matched genotype-phenotype pairs (R(2) = 0.47 (0.41 - 0.54)) and variation in predicted evolution under nelfinavir selective pressure correlated significantly with observed in vivo evolution during nelfinavir treatment for 39 mutations (with FDR = 0.05). AVAILABILITY: The software is available on request from the authors, and data sets are available from http://jose.med.kuleuven.be/~kdforc0/nfv-fitness-data/.     

Dissociation of subjectively reported and behaviorally indexed mind wandering by EEG rhythmic activity

Inattention to current activity is ubiquitous in everyday situations. Mind wandering is an example of such a state, and its related brain areas have been examined in the literature. However, there is no clear evidence regarding neural rhythmic activities linked to mind wandering. Using a vigilance task with thought sampling and electroencephalography recording, the current study simultaneously examined neural oscillatory activities related to subjectively reported and behaviorally indexed mind wandering. By implementing time-frequency analysis, we found that subjectively reported mind wandering, relative to behaviorally indexed, showed increased gamma band activity at bilateral frontal-central areas. By means of beamformer source imaging, we found subjectively reported mind wandering within the gamma band to be characterized by increased activation in bilateral frontal cortices, supplemental motor area, paracentral cortex and right inferior temporal cortex in comparison to behaviorally indexed mind wandering. These findings dissociate subjectively reported and behaviorally indexed mind wandering and suggest that a higher degree of executive control processes are engaged in subjectively reported mind wandering.     

Fetal drug therapy.

Fetal drug therapy encompasses several areas, including the prevention of external genital masculinization in 21-hydroxylase deficiency syndrome (congenital adrenal hyperplasia), biochemical amelioration of methylmalonic acidemia, and biotin-responsive multiple carboxylase deficiency. The correction of cardiac arrhythmias has become relatively commonplace, and a reduction in the risks of neural tube defects is now possible with the use of preconceptual and early conceptual folic acid. Similarly, fetal function can be altered by the induction of fetal lung maturity using a number of agents; corticosteroids are the most common fetal pharmaceutic agent, and a number of other agents have also been tried. The most common route of administering pharmaceutic agents is through the mother and the placenta, although the direct administration of certain agents is becoming more common.     

Fitness benefits of polyandry for experienced females

Females often mate with several different males, which may promote sperm competition and increase offspring viability. However, the potential benefits of polyandry remain controversial, particularly in birds where recent reviews have suggested that females gain few genetic benefits from extra‐pair mating. In tree swallows (Tachycineta bicolor), we found that females with prior breeding experience had more sires per brood when paired to genetically similar social mates, and, among experienced females, broods with more sires had higher hatching success. Individual females breeding in two consecutive years also produced broods with more sires when they were more genetically similar to their mate. Thus, experienced females were able to avoid the costs of mating with a genetically similar social mate and realize fitness benefits from mating with a relatively large number of males. This is one of the first studies to show that female breeding experience influences polyandry and female fitness in a natural population of vertebrates. Our results suggest that the benefits of polyandry may only be clear when considering both the number of mates females acquire and their ability to modify the outcome of sexual conflict.     

Cytomics and drug discovery.

Pharmaceutical companies try to develop new drugs that have a high success rate of reaching the market. However, current disease models lack a strong correlation to clinical reality, because of the underestimation of the complexity and variability of clinical disease processes. This leads to high attrition rates late in drug development and soaring costs. Improvement of disease models is an important issue to reduce the high attrition rates in drug development. Using cell-based disease models, which should take into account the molecular diversity of the human cytome, will improve the predictive value of drug discovery.     

Guidelines for drug donations.

Drug donations are usually given in response to acute emergencies, but they can also be part of development aid. Donations may be given directly by governments, by non-governmental organisations, as corporate donations (direct or through private voluntary organisations), or as private donations to single health facilities. Although there are legitimate differences between these donations, basic rules should apply to them all. This common core of "good donation practice" is the basis for new guidelines which have recently been issued by the World Health Organisation after consultation with all relevant United Nations agencies, the Red Cross, and other major international agencies active in humanitarian emergency relief. This article summarises the need for such guidelines, the development process, the core principles, and the guidelines themselves and gives practical advice to recipients and donor agencies.     

Modulation of cell mutability by serum factors from volunteers who experienced head-down-tilt bed rest.

Head-down-tilt bed rest (BR) is utilized to mimic a microgravity environment. In this study, we examined whether the modulating activity of serum factors on cell mutability was changed in seventeen volunteers subjected to BR. For comparison, serum was comparatively obtained from seven volunteers who experienced the parabolic flight (PF). Cultured human cells were treated with serum and then irradiated with UV or X-ray. Mutagenicity was estimated by identification of K-ras codon 12 base substitution mutation, following PCR and differential dot-blot hybridization. Modulating activity was detected in one sample from each of post-BR and post-PF serum.     

One drug for epilepsy.

We performed prospective trials of phenytoin and carbamazepine, assisted by blood level monitoring, in untreated patients newly referred with grand mal or partial seizures, or both, to a neurological clinic. At the time of follow-up (mean 28.5 months for phenytoin; 12 months for carbamazepine) 76-88% of patients were completely controlled. Twelve per cent of the patients on each drug had further seizures, despite an optimum blood level. When the blood drug concentration was in the optimum range there was a 98% reduction in grand mal attack rate and 92-93% reduction in partial seizure rate. These results suggest that polypharmacy is largely, and possibly totally, unnecessary in newly diagnosed adult epileptics.     

Receptor alterations and drug tolerance.

A brief review of studies which have employed chronic administration of anticholinesterases, benzodiazepines, amphetamine, antidepressants, neuroleptics and opiates is presented to illustrate the deficiencies in our current knowledge about the degree to which alterations in neurotransmitter receptors can account for tolerance development to these agents. Although numerous investigators have reported alterations in receptor binding following chronic drug treatment and others have reported tolerance development, these two phenomena have seldom been studied in the same experiment. It is argued that a multidisciplinary approach is required to elucidate the role of receptor alterations in drug tolerance.     

Comparison perception of singular transcranial magnetic stimuli by subjectively electrosensitive subjects and general population controls

Transcranial magnetic stimulation of the dorsolateral prefrontal cortex by single pulses of varying field intensities was used to measure thresholds of individual perception and motor response in three groups of subjects: subjectively electrosensitive people, general population controls with a high burden of complaints related to electromagnetic field (EMF) exposure in the literature (highest decile in complaint burden), and general population controls with a low burden of complaints (lowest decile in complaint burden). The major study endpoint was the ability of the subjects to differentiate between real magnetic stimulation and a sham condition. There were no significant differences between groups in the thresholds, neither of detecting the real magnetic stimulus nor in motor response. But the three groups differed significantly in differentiating between stimulation and sham condition, with the subjectively electrosensitive people having the lowest ability to differentiate and the control group with high level of EMF-related complaints having the best ability to differentiate. Differences between groups were mostly due to false alarm reactions in the sham condition reported by subjectively electrosensitives (SES). We found no objective correlate of the self perception of being "electrosensitive." Overall, our experiment does not support the hypothesis that subjectively electrosensitive patients suffer from a physiological hypersensitivity to EMFs or stimuli. Further research should focus on disposing factors explaining the unspecific sensory hyperresponsiveness of subjectively electrosensitive subjects.     

Novel anticancer drug discovery.

There is at present, much optimism about the possibility of finding selective anticancer drugs that will eliminate the cytotoxic side effects associated with conventional cancer chemotherapy. This hope is based on uncovering many novel molecular targets that are 'cancer-specific', which will allow the targeting of cancer cells while normal cells are spared. Thus far, encouraging results have been obtained with several of these novel agents at the preclinical level, and clinical trials have begun. These targets are involved at one level or more in tumor biology, including tumor cell proliferation, angiogenesis and metastasis. Novel targets for which advances are being made include the following: growth factor receptor tyrosine kinases such as the epidermal growth factor receptor and HER-2/neu (proliferation); the vascular endothelial growth factor receptor and the basic fibroblast growth factor receptor (angiogenesis); the oncogenic GTP-binding protein Ras (especially agents targeting Ras farnesylation, farnesyltransferase inhibitors) (proliferation); protein kinase C (proliferation and drug resistance); cyclin-dependent kinases (proliferation); and matrix metalloproteinases and angiogenin (angiogenesis and metastasis). Less explored, but potentially useful targets include the receptor tyrosine kinase platelet-derived growth factor receptor, mitogen-activated protein kinase cascade oncogenes such as Raf-1 and mitogen-activated protein kinase kinase, cell adhesion molecules such as integrins, anti-apoptosis proteins such as Bcl-2, MDM2 and survivin, and the cell life-span target telomerase.     

Behavioral economics of drug self-administration. I. Functional equivalence of response requirement and drug dose

Response requirement and dose of drug per administration are two separate factors that have been demonstrated to control drug self-administration. Recent developments in behavioral economics have shown that these two factors are in fact functionally equivalent for nondrug reinforcers, as indicated by a unit-price analysis. In this review, the unit-price notion was tested for drugs as reinforcers via a re-analysis of ten drug self-administration studies. The results of the re-analysis indicated that response requirement and reinforcer magnitude, the constituents of unit price, have functionally equivalent effects on drug consumption and that a positively decelerating demand curve is produced as unit price increases. This suggests that the behavioral-economic notion of unit price is a more parsimonious explanation of the effects of response requirement and dose in drug self-administration studies, in that it integrates and describes what was previously considered to be two distinct operations.     

Apoptosis and anticancer drug resistance.

Anticancer agents induce cancer cell death through apoptosis or necrosis. As anticancer agents at low and high concentrations cause apoptosis and necrosis, respectively, cancer cells may be merely injured by an anticancer agent in apoptosis, and cell death may result from an activation of the internal constituents to induce apoptosis. Therefore, an alternation of apoptotic pathway must change the efficacy of anticancer agents. As an escape of cancer cells from apoptosis seems to be closely associated with the development of anticancer resistance, this report focuses on mechanisms of apoptosis and its association with anticancer resistance. A Bax induces apoptosis mitochondria-dependently, whereas Fas can induce apoptosis mitochondria-independently. An interaction of Bax and Bcl-2 is very important to decide cell life or death, and Bcl-2 phosphorylation may control this interaction: Paclitaxel treatment induced Bcl-2 phosphorylation and typical apoptosis, whereas hyperthermia induced not Bcl-2 phosphorylation but nuclear translocation and failed to induce apoptosis. Moreover, Fas was localized in the cytoplasm of exponentially growing cells and on the cell membrane of confluent cells. We would like to emphasize that it is very important to check the localization of constituents of apoptosis in order to evaluate the susceptibility of cancer cells to apoptosis.