Effects of CNS temperature on generation and transmission of temperature signals in homeotherms a common concept for mammalian and avian thermoregulation

Neurophysiological studies on avian hypothalamic thermosensitivity have presented evidence for a higher Q₁₀ of cold than of warm signal transmission in the CNS of birds. An identical temperature dependence of central cold and warm signal transmission in mammals is suggested by considerations on the phylogeny of temperature regulation. By taking into account the experimental evidence for the existence of thermosensory afferents in the CNS of mammals and birds, being differently developed in the various sections of the neural axis and exerting quantitatively different influences on the various thermoregulatory effectors, a common concept of homeothermic thermoregulation is proposed resting on the same basic assumptions for mammals and birds. The great diversity of negative as well as positive feedback effects of CNS temperature displacements on homeothermic thermoregulation, which is particularly expressed in avian autonomic and behavioral thermoregulation and, further, certain pathophysiological conditions of disturbed thermoregulation could be accounted for by assuming quantitatively different contributions of the central thermosensory inputs to thermoregulatory effector control, but maintaining the Q₁₀ values of hypothalamic warm and cold signal transmission constant. The proposed model, while basically additive in its mathematical design, meets a number of properties described by multiplicative models of thermoregulation. It additionally generalizes these models by predicting that changes of hypothalamic temperature modify the sensitivities with which any thermoregulatory effector responds to any thermosensory input.Dedicated to Professor Dr. Dr. h. c. Rudolf Thauer on the occasion of his 75th birthday     

Interstitial loss and gain of sequences on chromosome 22 in meningiomas with normal karyotype

In nearly half of sporadic low grade meningiomas no chromosome aberration can be detected. In the majority of the other half chromosome 22 is lost. In higher grade meningiomas this loss is followed by characteristic secondary chromosome aberrations. Regarding the molecular findings in Schwannomas, homozygous loss or mutation of the NF2 gene located on chromosome 22, was supposed also to be the primary event in meningioma development. However, in nearly all high grade but in only a minority of low grade meningiomas the loss of the NF2 protein is observed. Therefore, both the hypothetical combined heterozygous loss of or inactivation of two or more tumour suppressor genes (at least one of them located on chromosome 22) or the homozygous loss of a regulatory gene on chromosome 22 different from NF2 was discussed. In search for microdeletions or/and structural recombinations of chromosome 22 we investigated primary cell cultures of 43 meningiomas by conventional G-banding (26 without, 17 with loss of chromosome 22). Twenty-seven tumours were analysed with spectral karyotyping (SKY) and 16 with fluorescence in situ hybridisation (FISH) with DNA probes for the chromosomal regions of 22q11.2, 22q11.23q12.1, 22q12.1 and 22q13.3. SKY analysis confirmed G-banding data for chromosome 22 and could specify marker chromosomes and translocations containing material from chromosome(s) 22. Confirming our assumption microdeletions on chromosome 22 were detected by FISH in 6/8 cytogenetically non-aberrant meningiomas. Surprisingly, in 2/8 cases we observed gains of the 22q13.3 and in 2/8 gains of the 22q12.1 region. Here we present first evidence for an uncommon mechanism during early meningioma development at least for a meningioma subgroup: i) duplication and translocation of sequences from chromosome 22 to different chromosomes. ii) deletion of the original sequences on chromosome 22, resulting in disomy again (only visible as translocation in metaphase FISH). iii) loss of chromosome 22.     

Relationship between the size of the capillary bed and oxidative capacity in various cat skeletal muscles

The size of the capillary bed, assessed by capillary density (CD), capillary per muscle fibre ratio (C/F), total capillary length, surface area and volume was related to the oxidative capacity, assessed by the volume density of mitochondria and O₂max in cat muscles with a different composition of glycolytic and oxidative fibres: predominantly glycolytic gracilis, purely oxidative soleus and gracilis transformed towards oxidative by chronic low frequency (10 Hz) electrical stimulation. Maximal blood flow and lactate output were measured in the muscles during isometric contractions.When capillary supply was estimated by C/F ratio, there was a close correlation between various parameters only in stimulated gracilis. The combined data of all muscles showed a significant correlation between the total volume of mitochondria, O₂max and total capillary surface area. Capillary volume showed a tight correlation with maximal blood flow in both control and stimulated gracilis, but not in soleus. Maximal blood flow was correlated withVO₂max in oxidative muscles (stimulated gracilis and soleus) but not in control glycolytic gracilis. Moreover normal gracilis did not show any relationship between the volume density of mitochondria and the size of the capillary bed. The latter was inversely correlated with the output of lactate which was greater in muscles with a lower C/P ratio.The data on gracilis indicates that the capillary bed can adapt to the increased demand for oxygen and a greater oxidative capacity induced by long-term activity imposed on a glycolytic muscle, while it may be more important for the removal of lactate in the glycolytic muscles under their normal activity. The factors involved in the regulation of blood flow in control soleus — when the morphological size of the vascular bed is not related to blood flow — are discussed.     

Memantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons

The present study examined the effect of memantine, an uncompetitive NMDA receptor antagonist, on ethanol-induced NMDA receptor up-regulation. Primary glutamatergic rat hippocampal neurons were exposed to ethanol and memantine for 5 days. The ethanol-sensitive NMDA receptor subunits NR1, NR2A and NR2B were quantified by Western immunoblot analysis. Exposure to ethanol (50 mM) caused an increase in the levels of NR1 (137 +/- 11% of untreated control, P = 0.009), NR2A (128 +/- 14%, P = 0.022) and NR2B (136 +/- 19%, P = 0.012). Coincubation with memantine (10 microM) completely blocked the ethanol-induced up-regulation of NR1 (102 +/- 4%), NR2A (95 +/- 7%) and NR2B (105 +/- 13%). No effect of memantine on NR subunit expression was observable, except for NR2A, where a decrease (79 +/- 6%, P = 0.034) was noted. Neither ethanol nor memantine alone or in combination were toxic in the concentrations tested. These results may provide a molecular explanation for beneficial effects of memantine on ethanol-induced glutamatergic hyperexcitability reflected in the ethanol withdrawal syndrome and on the development of ethanol dependence.     

In vitro assessment of dose-dependent platelet activation by polyclonal antithymocyte globulins: a flow-cytometric analysis

Polyclonal antithymocyte globulins (ATGs) are immunosuppressive drugs widely used in transplantation and hematologic disorders. Treatment with ATGs can induce side effects such as neutropenia and thrombocytopenia because of unspecific antibodies directed against nonmyeloid cells present in these preparations. Depletion, activation, and expression of adhesion molecules on platelets in vitro were studied in the whole blood of healthy volunteers by means of flow cytometry after incubation with different doses of three polyclonal ATGs. Our data show no ATG-mediated cytotoxic activity against platelets. ATGs are able to induce activation of platelets through increased expression of P-selectin and hLAMP-1 and higher percentages of gated thrombocytes expressing these molecules. Furthermore, increased expression of hLAMP-1 presented a dose-dependent pattern. ATGs induced activation and enhanced expression of adhesion molecules in unstimulated platelets. Increased adhesion may be responsible for undesirable side effects such as thrombocytopenia and reticulopenia.     

Is there a specific polysomnographic sleep pattern in children with attention deficit/hyperactivity disorder?

The aim of the study was to characterize the sleep pattern in children with attention deficit/hyperactivity disorder (ADHD). By means of polysomnography (PSG), sleep patterns were studied in 17 unmedicated preadolescent boys rigorously diagnosed with ADHD and 17 control boys precisely matched for age and intelligence. Although ADHD children did not display a general sleep alteration, major PSG data showed a significant increase in the duration of the absolute rapid eye movement (REM) sleep and the number of sleep cycles in ADHD group when compared with controls. In addition, REM sleep latency tended to be shorter in ADHD children. These results suggest that in ADHD children, a forced REM sleep initiation may produce a higher incidence of sleep cycles and may also contribute to an increased duration of the absolute REM sleep. The overall pattern of the findings implies that a forced ultradian cycling appears characteristic for the sleep in ADHD children, which may be related to alterations of brain monoamines and cortical inhibitory control accompanying the ADHD psychopathology.     

Substantial decrease of psychiatric comorbidity in chronic alcoholics upon integrated outpatient treatment - results of a prospective study

It is far from clear how comorbidity changes during alcoholism treatment. This study investigates: (1) the course of comorbid Axis I disorders in chronic alcoholics over 2 years of controlled abstinence in the outpatient long-term intensive therapy for alcoholics (OLITA) and (2) the effect of comorbid Axis I and II disorders in this group of patients on subsequent drinking outcome over a four-year follow-up. This prospective treatment study evaluates psychiatric variables of 89 severely affected chronic alcohol dependent patients on admission (t₁), month 6 (t₂), 12 (t₃) and 24 (t₄). Drinking outcomes have been analyzed from 1998 to 2002. On admission, 61.8% of the patients met criteria for a comorbid Axis I disorder, 63.2% for a comorbid personality disorder. Axis I disorders remit from t₁ (59.0% ill), t₂ (38.5%), t₃ (28.2%) to t₄ (12.8%) (p<0.0001). Anxiety disorders remit more slowly from t₁ (43.6%) to t₃ (20.5%, p=0.0086), whereas mood disorders remit early between t₁ (23.1%) and t₂ (5.1%, p=0.0387) with a slight transient increase at t₃ (10.3%). During the four-year follow-up, the cumulative probability of not having relapsed amounts to 0.59. Two predictors have a strong negative impact on abstinence probability: number of inpatient detoxifications (p=0.0013) and personality disorders (p=0.0106). The present study demonstrates a striking remission of comorbid Axis I disorders upon abstinence during comprehensive long-term outpatient alcoholism treatment. The presence of an Axis II rather than an Axis I disorder on admission strongly predicts drinking outcome over a four-year follow-up.     

Three-amino acid motifs of urocortin II and III determine their CRF receptor subtype selectivity

Corticotropin-releasing factor (CRF) and the CRF-like peptide urocortin I (UcnI) exert their activity through two different CRF receptors, CRF1 and CRF2. Recently, UcnII and UcnIII have been discovered as potential endogenous agonists selective for CRF2 known to be involved in brain functions such as learning and anxiety, as well as in cardiovascular functions. A structure-affinity relationship study using chimeric peptides was designed to characterize mouse UcnII (mUcnII) and mUcnIII further and to investigate the structural basis of their receptor subtype selectivity. In the framework of this study, mUcnII (IC50 = 4.4 nM) but not mUcnIII was identified as high-affinity ligand for the rat CRF binding protein. Such affinity had previously not been observed for the human version of this protein. On the basis of secondary structure predictions, it was hypothesized that the amino acid motifs Pro-Ile-Gly of mUcnII and Pro-Thr-Asn of mUcnIII decrease alpha-helicity and thereby impair binding to CRF1. In support of this hypothesis, binding affinity to CRF1 of the chimeric peptides [Pro11Ile12Gly13]h/rCRF, [Pro11Thr12Asn13]h/rCRF, and the corresponding rUcnI analogs was found to be decreased by three orders of magnitude, whereas binding affinity to CRF2 was much less affected. The dramatic decrease in binding affinity to CRF1 correlated with a decrease in alpha-helicity as indicated by the data of circular dichroism spectroscopy.