Human Aldehyde Dehydrogenase: Kinetic Identification of the Isozyme for Which Biogenic Aldehydes and Acetaldehyde Compete

Michaelis constants and maximal velocities for phenylacetaldehyde (a metabolite of phenylethylamine), 3,4-dihydroxyphenylacetaldehyde (a metabolite of dopamine), 5-hydroxyindole acetaldehyde (a metabolite of serotonin), and 3,4-dihydroxyphenylglycolaldehyde (a metabolite of epinephrine and norepinephrine) have been determined for both cytoplasmic (E1) and mitochondrial (E2) isozymes of human liver aldehyde dehydrogenase (EC 1.2.1.3). Kinetic constants with biogenic aldehydes have never been previously determined for individual homogeneous isozymes of aldehyde dehydrogenase from any species. Mathematical treatment of these constants suggests that competition with acetaldehyde during alcohol metabolism would severely inhibit dehydrogenation of biogenic aldehydes with the mitochondrial and not the cytoplasmic isozyme of human liver aldehyde dehydrogenase.     

Aripiprazole augmentation in treatment-resistant depression.

BACKGROUND: Evidence is accumulating to support the use of atypical neuroleptics as adjunctive treatment for refractory mood disorders, although there are currently no published data on the efficacy of an atypical neuroleptic in treatment-resistant depression when a previous trial of drug from the same class has failed. The authors hypothesized that aripiprazole would be efficacious in augmenting antidepressant treatment in resistant patients with non-psychotic unipolar depression who had previously failed a trial of another atypical neuroleptic. METHODS: This study was a retrospective chart review of the efficacy of aripiprazole augmentation in 30 treatment-resistant unipolar depression patients who had failed multiple previous antidepressant trials and had also failed augmentation with at least one other atypical neuroleptic. Prospective Global Assessment of Functioning and Clinical Global Impressions-Improvement scores were completed on each patient throughout treatment. RESULTS: Utilizing an intent-to-treat analysis (including 9 patients who dropped out prior to completion of 6 weeks), 46.7% (14/30) patients were rated much improved or very much improved with treatment. This improvement negatively correlated with Thase-Rush staging of treatment resistance. GAF scores also showed a significant improvement. Six of the 14 patients who initially improved subsequently relapsed (yielding a long-term net response rate of 26.7%). CONCLUSION: Aripiprazole may be effective as an antidepressant augmentation agent in highly treatment resistant patients who had failed a prior trial of another atypical neuroleptic.     

Quantitation of photochemically induced focal cerebral ischemia in the rat

This study was carried out with a recently developed model of focal cerebral ischemia in the rat based on the photochemical induction of thrombotic stroke using the dye Rose Bengal. We examined the change in the volume of the lesion and brain water content, in separate groups of rats, at different times (1, 4, 24, 72, and 168 h) after the induction of the ischemic lesion. The volume of ischemic damage increased rapidly between 1 and 24 h after the ischemic insult and decreased between 24 and 168 h. The lesion at 168 h was significantly larger than that following 1 h of ischemia and similar to that obtained at 4 h, suggesting that the maximum extent of tissue damage (without the involvement of significant edema) was reached within the first 4 h in this model. The enlargement of the lesion after 4 h correlated closely with changes in brain water content.     

Amyotrophic lateral sclerosis patient antibodies label Ca2+ channel α1 subunit

Sporadic amyotrophic lateral sclerosis is an idiopathic human degenerative disease of spinal cord and brain motor neurons. Prior studies demonstrated that most patients with amyotrophic lateral sclerosis posses immunoglobulins that bind to purified L-type voltage-gated calcium channels, that titers of anti–voltage-gated calcium channel antibodies correlate with disease progression rates, and that amyotrophic lateral sclerosis patient-derived antibodies (ALS IgG) produce electrophysiological changes in the function of voltage-gated calcium channels. Using Western transfer immunoblots and enzyme-linked immunosorbent assays, the calcium ionophore–forming α₁ subunig of the voltage-gated calcium channel is now identified as the major voltage-gated calcium channel antigen to which ALS IgG binds. Additionally, the binding of an L-type voltage-gated calcium channel α₁ subunit–directed monoclonal antibody, which itself mimics the effects of ALS IgG on skeletal muscle voltage-gated calcium channel currents, is selectively prevented by preaddition of ALS IgG. Voltage-gated calcium channel–binding IgG from patients with Lambert-Eaton myasthenic syndrome appears to be differentiated from ALS IgG by the reactivity of the former to both α₁ and β subunits of the calcium channel. These assays provide further evidence linking amyotrophic lateral sclerosis to an autoimmune process, and suggest one means to differentiate immunoglobulins from patients with amyotrophic lateral sclerosis from those of patients with another autoimmune disease expressing calcium channel antibodies.     

Common bile duct calculi: updated experience with dissolution with methyl tertiary butyl ether

The authors describe their experience with methyl tertiary butyl ether (MTBE) in a larger series of patients than previously reported in order to acquaint physicians with both its effectiveness for dissolution of common bile duct calculi and the limitations of its use. Ten patients with 13 biliary calculi underwent percutaneous stone dissolution treatment with the experimental cholesterol solvent, MTBE. Three stones completely dissolved within 30 minutes, seven were reduced in size, and three were visibly unaffected. All stones not completely dissolved were easily extracted by means of a stone basket except for one in a patient taken to surgery. Although MTBE perfusion is an effective technique for management of biliary calculi, practitioners should be aware that its use is quite time consuming and its odor difficult to control.     

Disposition of oral and intravenous pravastatin in MRP2-deficient TR- rats.

The aim of this study was to characterize the role of the efflux transporter Mrp2 (Abcc2) in the pharmacokinetics of orally and intravenously administered pravastatin in rats. Eight Mrp2-deficient TR- rats and eight wild-type rats were given an oral dose of 20 mg/kg pravastatin. Four TR- animals and four wild-type animals were studied after intravenous administration of pravastatin (5 mg/kg). The TR(-) rats showed a 6.1-fold higher mean area under the plasma concentration-time curve (AUC) of pravastatin (p < 0.001) after oral administration and a 4.7-fold higher AUC (p < 0.01) after intravenous administration of pravastatin as compared with the wild-type animals. The mean systemic (total) clearance of pravastatin was 4.6-fold higher (39.2 versus 8.50 l/h/kg, p < 0.001) and the mean V 4.3-fold higher (14.1 versus 3.29 l/kg, p < 0.01) in the wild-type rats. The mean renal clearance of pravastatin in the TR(-) rats was 16.5-fold increased as compared with the wild-type animals (0.695 versus 0.042 l/h/kg, p < 0.05). The increased systemic exposure to oral pravastatin in the TR- rats was associated with a greater inhibitory effect on 3-hydroxy-3-methylglutaryl CoA reductase, as shown by smaller lathosterol to cholesterol concentration ratios. These results suggest that the reduced biliary pravastatin excretion in the Mrp2-deficient TR- rats is partly compensated for by increased urinary excretion of pravastatin. Furthermore, intestinal Mrp2 does not appear to play a major role in the oral absorption of pravastatin in normal rats.     

Knochenersatz durch Kallusdistraktion an der unteren Extremität

Successful treatment of posttraumatic chronic osteitis is often only achieved at the cost of some degree of bone loss. Various procedures for segmental transfer based on Ilizarov’s callus distraction technique have become established for reconstruction of extensive bony substance defects in recent years. Technically, both extramedullary and intramedullary procedures are available for the achievement of such a segmental transfer. Various factors must be taken into account when it is necessary to decide whether segmental transfer by means of a ring fixator, a unilateral fixateur externe or an intramedullary force carrier in combination with a fixateur externe or tension wires as the transfer system is indicated. These include how long the history of osteitis already is, how extensive it is, time taken for successful treatment of infection, soft tissue situation, resulting length of the defect following resection, and the patient’s age, together whether there are any patient-specific risk factors or comorbidities. In this paper an algorithm for deciding on the specific situations in which the different techniques of segmental transfer are indicated is discussed on the basis of many years of clinical experience in postinfectious defects on the lower extremities.     

Development of cholinergic retinal neurons from embryonic chicken in monolayer cultures: stimulation by glial cell-derived factors

In recent years evidence has indicated that, like the PNS, the development of the CNS is influenced by neuronotrophic polypeptide factors. In the present study, cultures of dissociated retinal neurons from 8-d-old chicken embryos were used to investigate the role of neuronotrophic factors (NTF) in the development of the neural retina. CAT, which in vivo is located in amacrine cells of the retina, served as a marker for studying the in vitro development of cholinergic retinal neurons. Differentiation of cholinergic cells under control conditions was indicated by a 10-fold increase of enzyme activity during a 7-d culture period. Addition of media conditioned by high-density retinal cultures resulted in a further stimulation of CAT activity by 100-400%. The CAT-stimulating activity was associated with a high-molecular-weight component of the retina conditioned medium (RCM) and was sensitive to protease treatment, but was not affected by other hydrolytic enzymes. The putative cholinergic factor was secreted by retinal cultures virtually free of neurons, suggesting that it is mainly produced by Müller cells. CAT-stimulating activity was also present in extracts from embryonic chicken retinae and medium conditioned by rat retinal cultures. NGF, anti-NGF antiserum, extracts from chicken brain tissues, and a number of other extracts and conditioned media, all known to contain neuronotrophic activities, were found to have no influence on cholinergic development in chicken retinal cultures. An extract from non-retinal eye tissue containing ciliary neuronotrophic factor (CNTF) stimulated CAT activity to the same extent as did RCM.(ABSTRACT TRUNCATED AT 250 WORDS)