Determination of airway humidification in high-frequency oscillatory ventilation using an artificial neonatal lung model

Objective: Thus far only few data are available on airway humidification during high-frequency oscillatory ventilation (HFOV). Therefore, we studied the performance and efficiency of a heated humidifier (HH) and a heat and moisture exchanger (HME) in HFOV using an artificial lung model. Methods: Experiments were performed with a pediatric high-frequency oscillatory ventilator. The artificial lung contained a sponge saturated with water to simulate evaporation and was placed in an incubator heated to 37 °C to prevent condensation. The airway humidity was measured using a capacitive humidity sensor. The water loss of the lung model was determined gravimetrically. Results: The water loss of the lung model varied between 2.14 and 3.1 g/h during active humidification; it was 2.85 g/h with passive humidification and 7.56 g/h without humidification. The humidity at the tube connector varied between 34.2 and 42.5 mg/l, depending on the temperature of the HH and the ventilator setting during active humidification, and between 37 and 39.9 mg/l with passive humidification. Conclusion: In general, HH and HME are suitable devices for airway humidification in HFOV. The performance of the ventilator was not significantly influenced by the mode of humidification. However, the adequacy of humidification and safety of the HME remains to be demonstrated in clinical practice. Received: 22 September 1998 Final version received: 22 March 1999 Accepted: 23 April 1999     

Adenosine A2a receptor expression in striatal neurons: Implications for basal ganglia pathophysiology

Two dog adenosine receptors have been recently cloned. They were pharmacologically characterized as an A₁ and the A_2a receptor, respectively. The adenosine A_2a receptor is exclusively expressed in medium-sized neurons of the striatum as demonstrated by in situ hybridization. The relationships of this A_2a receptor with three major components of the striatum, enkephalin, substance P, and choline acetyltransferase, were studied in the rat. This demonstrates that the adenosine A_2a receptor is exclusively expressed by the enkephalinergic striatal neuronal subpopulation that also selectively expresses the dopamine D2 receptor. Conversely, The A_2a receptor is never detected in the substance P containing neurons or in the cholinergic neurons. This observation most probably constitutes the anatomical substratum for the preciously described A_2a-D2 receptors interactions. It also indicates that A_2a receptor is selectively express in the indirect pathway of the basal ganglia system which is hypoactive in hyperkinetic disorders such as Huntington's disease and hyperactive in hypokinetic disorders such as Parkinson's disease. The development of highly A_2a selective ligands could be therefore useful in the therapy useful in the therapy of basal ganglia degenerative diseases. © 1993 Wiley-Liss, Inc.     

Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients

Mutations in each of the five eucaryotic initiation factor 2B (eIF2B) subunits have been found in leukodystrophies of various severity: Cree leukoencephalopathy, childhood ataxia with central hypomyelination/leukodystrophy with vanishing white matter and ovarioleukodystrophy. A continuum was observed from fatal infantile forms to adult forms without neurological deterioration. Disease severity was found to correlate with the age at disease onset and the specific amino-acid substitution. In order to analyze the functional consequences of eIF2B mutations, we measured the guanine nucleotide exchange factor (GEF) activity of eIF2B in transformed lymphocytes from 30 affected patients carrying mutations in eIF2B compared to 10 unaffected heterozygotes and 22 controls without eIF2B mutations. A significant decrease of 20-70% in GEF activity was observed in all mutated cells. The severity of this decrement of GEF activity correlated with age at onset of the disease. These results suggest that a deficiency in GEF activity underlies the encephalopathy associated eIF2B-related disease. Our study demonstrates that the evaluation of the GEF activity in transformed lymphocytes represents an interesting alternative test to the systematic screening of the five EIF2B genes. This relevant cellular model may also be used to test the functional impact of different molecules on the GEF activity for future therapeutic strategies.     

The latest on leukodystrophies

PURPOSE OF REVIEW: Important advances in our understanding of genetic disorders of the white matter have been made and are discussed here. RECENT FINDINGS: It has recently been discovered that mutations in the genes encoding the five subunits of eukaryocytic initiation factor 2B (eIF2B) are the cause of vanishing white-matter disease/childhood ataxia with central hypomyelination syndrome. The extension of the clinical features of the eIF2B-related disorders to encompass both infant- and adult-onset disorders is discussed. New clinico-imaging syndromes such as hypomyelination with atrophy of the basal ganglia and cerebellum and leukoencephalopathy with brain-stem and spinal cord involvement and elevated white-matter lactate are described. Recent findings include evidence that mitochondrial fat-oxidation abnormalities may be important in the pathogenesis of adrenoleukodystrophy, and that a mutant myelin protein can cause maldistribution of other myelin proteins, causing dysmyelination, axonal damage, or both. SUMMARY: This review focuses on advances in the understanding of the role of eIF2B as a cause of a common leukodystrophy syndrome. eIF2B-related disorders have a clinical spectrum ranging from a severe, rapidly progressive congenital or early infantile encephalopathy to a slowly progressive cognitive and motor deterioration often associated with premature ovarian failure. Two newly recognized leukodystrophy syndromes are described: hypomyelination with atrophy of the basal ganglia and cerebellum, and leukoencephalopathy with brain-stem and spinal cord involvement and elevated white-matter lactate. An update is also given for adrenoleukodystrophy and myelin-protein-related disorders. This update demonstrates that an increasing number of genetic defects are being identified that may cause primary white-matter disorders.     

White matter lesions in Fabry disease occur in 'prior' selectively hypometabolic and hyperperfused brain regions

Fabry disease is an X-linked disorder associated with early onset stroke. We previously found a significantly elevated cerebral blood flow (CBF) in patients with Fabry disease. We set to determine whether elevated resting CBF in Fabry disease is primarily a cerebrovascular abnormality or is secondary to enhanced neuronal metabolism. The relationship of cerebral metabolism and blood flow to Fabry leukoencephalopathy was also investigated. We measured the global and regional cerebral metabolic rate of glucose using 18-fluoro-deoxyglucose (FDG) and PET in 16 patients with Fabry disease (7 patients with leukoaraiotic lesions and 9 without) and in 7 control subjects. MRI fluid attenuated inversion recovery (FLAIR) studies were also performed in the patient and control groups. All control subjects had normal MRI FLAIR studies with no high-signal deep white matter lesions (WML). Patients were partitioned into FLAIR lesion and non-FLAIR lesion groups. We found no evidence of cerebral glucose hypermetabolism in Fabry disease. On the contrary, significantly decreased regional cerebral glucose metabolism (rCMRGlu) was found particularly in the deep white matter in the Fabry non-lesion group and exacerbated in the lesion group. Lesion-susceptible regions were relatively hyperperfused in non-lesion patients compared to the control group. We conclude that the elevated rCBF and decreased white matter rCMRGlu indicates a dissociation between metabolism and blood flow suggesting chronic deep white matter metabolic insufficiency.     

Metal-mediated inhibition of Escherichia coli methionine aminopeptidase: structure-activity relationships and development of a novel scoring function for metal-ligand interactions

We report the discovery of thiabendazole as a potent inhibitor (K(i) = 0.4 microM) of Escherichia coli methionine aminopeptidase (ecMetAP) and the synthesis and pharmacological evaluation of thiabendazole congeners with activity in the upper nanomolar range. Elucidation of the X-ray structure of ecMetAP in complex with thiabendazole and an unrelated inhibitor that was independently described by another group showed that that both compounds bind to an additional Co(II) ion at the entrance of the active site. This unexpected finding explains the inactivity of the compounds under in vivo conditions. It also allows us to discuss the structure-activity relationships of this series of compounds in a meaningful way, based upon docking runs with an auxiliary metal ion. We describe a new scoring function for the evaluation of metal-mediated inhibitor binding that, unlike the previously used scoring function implemented in the docking program, allows us to distinguish between active and inactive compounds. Finally, conclusions for the structure-based design of in vivo-active inhibitors of ecMetAP are drawn.     

Induction of unscheduled DNA synthesis in HeLa cells by allylic compounds

Thirteen allylic compounds, mostly with close structural relationship, were tested for their ability to induce unscheduled DNA synthesis (UDS) in HeLa cells and mutations in the Ames test; 11 induced UDS in dose dependence. Allyl isothiocyanate was negative in UDS (borderline in the Ames test) and acrolein (positive in the Ames test) proved toxic to HeLa cells, therefore UDS measurement was excluded. In general, positive qualitative and quantitative correlation between UDS, Ames test and alkylating properties 9as measured in the 4-nitrobenzyl-pyridine test, NBP) were found. Among structural analogs and typical allylic compounds with various leaving groups, the amount of induced DNA repair at equimolar concentrations decreased in the same order as the mutagenic and alkylating activities in the other 2 test systems: 1,3-dichloropropene (cis) > 1,3-dichloropropene (trans) > 2,3,-dichloro-1-propene; 1-chloro-2-butene > 3-chloro-1-butene > 3-chloro-2-methyl-1-propene > allyl chloride; allyl-methanesulfonate > -iodide > -bromide > -chloride.