New insights on P2X purinoceptors

Significant advances in understanding of P_2X purinoceptor pharmacology have been made in the last few years. The limitations of nucleotide agonists as drug tools have now been amply demonstrated. Fortunately, inhibitors of the degrading ecto-ATPase enzymes are becoming available and it has become apparent that the complete removal of all divalent cations can be used experimentally in some systems to prevent nucleotide breakdown. Despite these issues, convincing evidence for P_2X receptor heterogeneity, from data with agonists, has recently been reported.A number of new antagonists at P_2X purinoceptors have also recently been described which to some degree appear to be more specific and useful than earlier antagonists like suramin. It is now apparent that suramin is a poor antagonist of ATP in many tissues because it potently inhibits ATPase activity at similar concentrations to those at which it blocks the P_2X purinoceptor.Advances in the use of radiolabelled nucleotides as radioligands for binding studies has allowed the demonstration of P_2X purinoceptors in a variety of tissues throughout the body including the brain. These studies have also provided evidence for receptor heterogeneity. Excitingly, two P_2X purinoceptor genes have been cloned but operational studies suggest that more than two types exist. The cloning studies have also demonstrated a unique structure for the P_2X purinoceptor which differentiates it from all other ligand-gated ion channel receptors. Further studies on P_2X purinoceptor operation and structure are needed to help resolve controversies alluded to regarding the characterization and classification of nucleotide receptors. Hopefully such studies will also lead to a better understanding of the physiological and pathological importance of ATP and its activation of P_2X purinoceptors. This will require the identification of better drug tools, in particular antagonists which may also provide the basis for novel therapeutic agents.     

Role of Alcohol-induced Hypothermia in Mediating the Teratogenic Effects of Alcohol in C57BL/6 J Mice

The purpose of this study was to determine the role of alcohol-induced maternal hypothermia in the teratogenic actions of alcohol. C57BL/6J mice were administered an acute dose of alcohol (5.8 g/kg orally) or isocaloric sucrose on day 10 of gestation. One half of each group was placed for 6 hr in an incubator set at 32 degrees C and the other half was housed in the incubator at room temperature (22 degrees C). As expected, acute prenatal alcohol exposure at this time of gestation was associated with decreased birth weight and an increase in limb and kidney malformations. The significant alcohol x environmental temperature interaction on these dependent variables indicated that the teratogenic insult was not attenuated, but was in fact even greater for the 32 degrees C/alcohol group. An absence of a main effect of environmental temperature indicated that the 32 degrees C environment, per se, was not teratogenic. Thus, maternal hypothermia is probably not an etiological factor in animal models of fetal alcohol syndrome. Moreover, antagonism of alcohol-induced maternal hypothermia exacerbates the teratogenic actions of alcohol observed at room temperature.     

G2019S LRRK2 mutation in familial and sporadic Parkinson's disease in Russia.

Among mutations associated with autosomal dominant and sporadic Parkinson's disease (PD) the G2019S substitution in the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequently identified. To estimate its frequency in Russia, we analyzed 208 patients with PD from the Northwestern region of Russia. Of these, 51 patients were probands from families with PD compatible with autosomal dominant inheritance. The control group represented 161 subjects without neurological disorders settled in the same region. The frequency of the G2019S mutation was greater in familial PD (2 [3.9%] of 51) than in sporadic PD (1 [0.6%] of 157). In addition, this mutation was found in the proband's father, who also had PD, in 1 PD family, and in 1 carrier without signs of PD at age 40 in another PD family. All carriers were heterozygous for the G2019S mutation and reported the Ashkenazi Jewish origin. The mutation was not found in the control group.     

Self‐reflection and self‐practice in training of Cognitive Behaviour Therapy: an overview

The present paper deals with a developing training element in cognitive behaviour therapy (CBT), the self‐practice of therapeutic techniques and the self‐exploration of the person of the therapist. Initially, the current status of this training element in CBT is discussed, and a short note on its terminology is presented. Then an overview of the most important objectives of self‐practice and self‐reflection in CBT, and the concepts and methods of practice of this element is given. The concepts focus on two major aims, the self‐exploration of the person of the therapist within and beyond his or her therapeutic practice, and the self‐application of therapeutic techniques (= self‐practice). In the second part of the paper empirical studies related to the outcome of self‐reflection and self‐practice on the development of the therapist and her or his therapeutic practice are reviewed. The few empirical studies show that trainees experience in their own view substantial professional and personal gains from this training tool, with the professional impact being more important than the personal one. The most important outcomes evaluated by subjective data from the trainees are improvements in self‐insight and self‐awareness and a better understanding of the therapist's role and the therapeutic change process. Additionally, a better understanding of CBT methods and of general therapeutic skills, such as empathy and role‐taking‐competencies, are reported by the trainees. The paper comes to the conclusion that self‐exploration and self‐practice are important components of CBT training. Consequences and recommendations for its integration into training courses for CBT are discussed as well as the necessity for more research in this area. Copyright © 2002 John Wiley & Sons, Ltd.     

Valproate potentiates and picrotoxin antagonizes the anxiolytic action of ethanol in a nonshock conflict task

The purpose of this study was to examine the effects of the indirect GABA agonist valproate and the indirect GABA antagonist picrotoxin on the anxiolytic (anti-conflict) activity of ethanol in a behavioral conflict task that does not employ electroshock. This task (negative contrast) quantifies how animals respond to an abrupt, unexpected reduction in reward. Treatment with valproate alone did not elevated depressed behavior engendered by abrupt reduction in reward. However, when administered together with a sub-effective dose of ethanol (0.5 g/kg), valproate (50-200 mg/kg) dose-dependently potentiated the anxiolytic action of ethanol. Picrotoxin (2 mg/kg) antagonized the anxiolytic effects of a larger dose of ethanol (1.0 g/kg) given alone, as well as the ability of valproate to enhance the anxiolytic effects of smaller dose of ethanol (0.5 g/kg). As such, these data support a role for GABA in mediating the anxiolytic activity of ethanol.     

Central projections of trigeminal primary afferents innervating the nasal mucosa: a horseradish peroxidase study in the rat.

The respiratory region of the nasal mucosa is innervated by the ethmoidal nerve. Chemical nociceptive stimulation of this area leads to upper airway reflexes that prevent access of noxious substances to the respiratory tract and the lungs. In the present study we examined the localization of the cell bodies of the respective primary afferent fibres within the trigeminal ganglion, as well as their central projections. In 25 rats a horseradish peroxidase-wheat germ agglutinin gel was applied to the right nasal cavity. The animals were killed after 48-72 h. For visualization of the tracer the tissue was processed according to the tetramethylbenzidine method. In the trigeminal ganglion almost all labelled cell bodies were localized in a medial band immediately caudal to the entrance of the ophthalmomaxillary branch. Transganglionic projections to the trigeminal brainstem nuclear complex were only localized in the superficial laminae of the subnucleus caudalis and in the subnucleus interpolaris, areas known to be involved in processing of nociceptive information. An additional labelled terminal field was observed in the interstitial subnucleus of the nucleus tractus solitarius, which is involved in respiratory control. These results are in favour of the hypothesis that the ethmoidal nerve in rat constitutes the afferent limb of protective upper airway reflexes since it transmits mainly nociceptive information.     

Mesodermal dysgenesis

The authors present an account on a 12-year-old girl with ectomesodermal dysgenesis of the Rieger type syndrome. The disease was manifested at the age of nine months by transient diffuse corneal opacity, while the intraocular pressure was normal. In addition to typical corneal changes and changes in the angle of the chamber other associated somatic symptoms included megalocornea, high myoptic astigmatism, cleft soft palate, hypoplasia of the upper jaw, partial anodontia, marked thoracic kyphosis, scoliosis, generalized hypermobility and taxicity of the joints and torticollis. Examination revealed an uncommon pathological karyotype 46, XX, t/1,4 (p36, q23). Cytogenetic examination of the parents and siblings of the proband did not disclose any numerical or structural aberrations. The authors reflect on possible causes of the development of the disease and on the differential diagnosis.