Selective gamma-ketoaldehyde scavengers protect Nav1.5 from oxidant-induced inactivation.

The cardiac sodium channel (SCN5A, Na(V)1.5) is a key determinant of electrical impulse conduction in cardiac tissue. Acute myocardial infarction leads to diminished sodium channel availability, both because of decreased channel expression and because of greater inactivation of channels already present. Myocardial infarction leads to significant increases in reactive oxygen species and their downstream effectors including lipoxidation products. The effects of reactive oxygen species on Na(V)1.5 function in whole hearts can be modeled in cultured myocytes, where oxidants shift the availability curve of I(Na) to hyperpolarized potentials, decreasing cardiac sodium current at the normal activation threshold. We recently examined potential mediators of the oxidant-induced inactivation and found that one specific lipoxidation product, the isoketals, recapitulated the effects of oxidant on sodium currents. Isoketals are highly reactive gamma-ketoaldehydes formed by the peroxidation of arachidonic acid that covalently modify the lysine residues of proteins. We now confirm that exposure to oxidants induces lipoxidative modification of Na(V)1.5 and that the selective isoketal scavengers block voltage-dependent changes in sodium current by the oxidant tert-butylhydroperoxide, both in cells heterologously expressing Na(V)1.5 and in a mouse cardiac myocyte cell line (HL-1). Thus, inhibition of this lipoxidative modification pathway is sufficient to protect the sodium channel from oxidant induced inactivation and suggests the potential use of isoketal scavengers as novel therapeutics to prevent arrhythmogenesis during myocardial infarction.

Oxygen-dependent DNA damage amplification involving 5,6-dihydrothymidin-5-yl in a structurally minimal system.

5,6-Dihydrothymidin-5-yl (1) was independently generated in a dinucleotide from a phenyl selenide precursor (4). Under free radical chain propagation conditions, the products resulting from hydrogen atom donation and radical-pair reaction are the major observed products in the absence of O(2). The stereoselectivity of the trapping process is dependent on the structure of the hydrogen atom donor. No evidence for internucleotidyl hydrogen atom abstraction by 1 was detected. The tandem lesion (17) resulting from hydrogen atom abstraction from the C1' position of the adjacent 2'-deoxyuridine by the peroxyl radical derived from 1 (3) is observed under aerobic conditions. The structure of this product is confirmed by independent synthesis and its transformation into a second independently synthesized product (24). Internucleotidyl hydrogen atom abstraction is effected selectively by the 5S-diastereomer of the peroxyl radical. The formation of dinucleotide 17 provides further support for the novel O(2)-dependent DNA damage amplification mechanism involving 1 reported previously (Greenberg, M. M.; et al. J. Am. Chem. Soc. 1997, 119, 1828).

Two distinct pathways of formation of 4-hydroxynonenal. Mechanisms of nonenzymatic transformation of the 9- and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals.

The mechanism of formation of 4-hydroxy-2E-nonenal (4-HNE) has been a matter of debate since it was discovered as a major cytotoxic product of lipid peroxidation in 1980. Recent evidence points to 4-hydroperoxy-2E-nonenal (4-HPNE) as the immediate precursor of 4-HNE (Lee, S. H., and Blair, I. A. (2000) Chem. Res. Toxicol. 13, 698-702; Noordermeer, M. A., Feussner, I., Kolbe, A., Veldink, G. A., and Vliegenthart, J. F. G. (2000) Biochem. Biophys. Res. Commun. 277, 112-116), and a pathway via 9-hydroperoxylinoleic acid and 3Z-nonenal is recognized in plant extracts. Using the 9- and 13-hydroperoxides of linoleic acid as starting material, we find that two distinct mechanisms lead to the formation of 4-H(P)NE and the corresponding 4-hydro(pero)xyalkenal that retains the original carboxyl group (9-hydroperoxy-12-oxo-10E-dodecenoic acid). Chiral analysis revealed that 4-HPNE formed from 13S-hydroperoxy-9Z,11E-octadecadienoic acid (13S-HPODE) retains >90% S configuration, whereas it is nearly racemic from 9S-hydroperoxy-10E,12Z-octadecadienoic acid (9S-HPODE). 9-Hydroperoxy-12-oxo-10E-dodecenoic acid is >90% S when derived from 9S-HPODE and almost racemic from 13S-HPODE. Through analysis of intermediates and products, we provide evidence that (i) allylic hydrogen abstraction at C-8 of 13S-HPODE leads to a 10,13-dihydroperoxide that undergoes cleavage between C-9 and C-10 to give 4S-HPNE, whereas direct Hock cleavage of the 13S-HPODE gives 12-oxo-9Z-dodecenoic acid, which oxygenates to racemic 9-hydroperoxy-12-oxo-10E-dodecenoic acid; by contrast, (ii) 9S-HPODE cleaves directly to 3Z-nonenal as a precursor of racemic 4-HPNE, whereas allylic hydrogen abstraction at C-14 and oxygenation to a 9,12-dihydroperoxide leads to chiral 9S-hydroperoxy-12-oxo-10E-dodecenoic acid. Our results distinguish two major pathways to the formation of 4-HNE that should apply also to other fatty acid hydroperoxides. Slight ( approximately 10%) differences in the observed chiralities from those predicted in the above mechanisms suggest the existence of additional routes to the 4-hydroxyalkenals.

Veterans Affairs Multicenter Low Vision Enhancement System (LVES) study: clinical results. Report 1: effects of manual-focus LVES on visual acuity and contrast sensitivity.

PURPOSE: The Department of Veterans Affairs LVES Study is a multicenter study to determine the effectiveness of the Low Vision Enhancement System (LVES) as a visual rehabilitation device. The purpose of this study was to explore the efficacy of the Beta 1 manual-focus LVES for improving visual acuity and contrast sensitivity. METHODS: Patients whose visual acuity was 20/80 or worse in the better eye from any disease, who did not have significant visual field loss, who had previous low vision experience and were capable of working with the LVES were enrolled in a comprehensive prospective multicenter clinical evaluation. Initially, corrected spectacle visual acuities were measured using a standardized ETDRS chart. Contrast sensitivities were also measured with spectacle correction using a standardized Peli-Robson chart. These results were then compared to the acuities and contrast sensitivity obtained with the LVES at optimal magnification. Also, visual acuities were measured using an Eschenbach 3x spectacle-mounted binocular telescope, then compared to the acuities obtained using the LVES set at the lowest magnification (3x). RESULTS: All patients who completed the study demonstrated an improvement in visual acuity, with a median improvement of six lines of Snellen equivalent acuity using the LVES. Improvement in visual acuity was the same in both ARMD and non-ARMD causes of vision loss. Mean contrast sensitivity improved in 52 of 58 patients tested, with a mean improvement of 0.49 log units. CONCLUSION: The LVES significantly improves both visual acuity and contrast sensitivity in visually impaired patients who fall within the study criteria. Up to 10-fold improvement in visual acuity and up to 1.80 log units improvement in contrast sensitivity were noted in the study group when the LVES was used.

The reactivity of the 2-deoxyribonolactone lesion in single-stranded DNA and its implication in reaction mechanisms of DNA damage and repair.

The formal C1'-oxidation product, 2-deoxyribonolactone, is formed as a result of DNA damage induced via a variety of agents, including gamma-radiolysis and the enediyne antitumor antibiotics. This alkaline labile lesion may also be an intermediate during DNA damage induced by copper-phenanthroline. Oligo-nucleotides containing this lesion at a defined site were formed via aerobic photolysis of oligonucleotides containing a photolabile ketone, and were characterized by gel electrophoresis and electrospray mass spectrometry (ESI-MS). Treatment of oligo-nucleotides containing the lesion with secondary amines produces strand breaks consisting of 3'-phosphate termini, and products which migrate more slowly in polyacrylamide gels. MALDI-TOF mass spectrometry analysis indicates that the slower moving products are formal adducts of the beta-elimination product resulting from 2-deoxyribonolactone and one molecule of amine. The addition of beta-mercapto-ethanol to the reaction mixture produces thiol adducts as well. The stability of these adducts suggests that they cannot be the labile species characterized by gel electrophoresis in copper-phenanthroline-mediated strand scission. The characterization of these adducts by mass spectrometry also provides, by analogy, affirmation of proposals regarding the reactivity of nucleophiles with the beta-elimination product of abasic sites. Finally, the effects of this lesion and the various adducts on DNA repair enzymes are unknown, but their facile generation from oligonucleotides containing a photolabile ketone suggests that such issues could be addressed.

Dementia and driving: an attempt at consensus.

The number of older drivers in Sweden will be rapidly increasing during the next decades. A possible relationship exists between the increased relative crash risk of older drivers and the prevalence of age-related diseases such as dementia. However, a clear-cut policy for evaluating driving competence in demented persons is still lacking. In recognition of this fact, the Swedish National Road Administration invited a group of researchers to formulate a consensus on the issue of driving and dementia. This consensus document is aimed at providing primary care physicians with practical advice concerning the assessment of cognitive status in relation to driving. Suggestions are based on a review of existing research and discuss the use of general and driving-specific sources of information available to the physician. Consensus was reached on the statement that a diagnosis of moderate to severe dementia precludes driving and that certain individuals with mild dementia should be considered for a specialized assessment of their driving competence.

A case study of choroideremia highlighting differential diagnosis and management with Fresnel prism therapy.

BACKGROUND: Choroideremia, along with other choroidal and retinal dystrophies, produces a progressive peripheral visual field loss. This paper highlights how to approach the optometric evaluation of a field constricted patient, how to decide if Fresnel prism therapy is appropriate and how to manage the patient if it is. METHODS: The patient described in this case report is a 36-year-old white male who presented with a diagnosis of choroideremia. On examination, the patient was found to have visual acuity of 20/40 OD and 20/30 OS. His visual fields by Goldmann perimetry were 8 degrees OD and 10 degrees OS. Treatment and management included the fitting of Fresnel prisms. RESULTS: The Fresnel prisms were utilized to successfully displace the images of objects toward the patient's central seeing visual field and to eliminate the excessive head turns that were often employed to enable him to view peripheral objects. CONCLUSIONS: Many patients with constricted visual fields can be successfully managed with the use of Fresnel prisms.

An examination of driving records in a dementia clinic.

The driving records of 249 persons referred to an outpatient dementia clinic were examined retrospectively to assess the specificity of the association between diagnosed dementia and increased traffic accidents. The clinic patients were divided into two groups: those who met criteria for dementia and those who did not. For each group, control subjects matched on age, gender, and location of residence were randomly selected from the records of all drivers in the province. The dementia sample had approximately 2.5 times the traffic crash rate of their matched control sample. The not-demented sample had approximately 2.2 times the traffic crash rate of their matched control sample. These individuals exhibited a variety of psychiatric, neurological, and medical conditions which could have affected their driving, and multiple medical problems were often present. Further clarification of the characteristics of "high risk" drivers is required if effective strategies for maximizing independence while minimizing the risk of traffic crashes are to be realized.

Choice of comparison group and findings of computerised tomography in schizophrenia.

The literature indicates that whether or not schizophrenic patients are reported to have significant lateral ventricular enlargement depends on control, and not schizophrenic-group values. This discrepancy does not result from differences in age, the ratio of males to females, the number of control subjects used in each study, or whether control groups are comprised of normal subjects or medical patients. However, medical-patient controls tend to have smaller ventricles than do normal individuals. Thus, we assessed lateral- and third-ventricle size and the degree of cortical atrophy in 30 normal volunteers, 30 medical patients, and 30 chronic schizophrenic patients. The use of a medical control group seemed to result in underestimates of ventricle and sulcal size in the normal population and, therefore, overestimates of these values in schizophrenic groups.

Neuropsychological performance in psychiatric patients with or without documented brain dysfunction.

The current study examined neuropsychological performance of schizophrenic and depressed patients with and without structural or EEG signs of brain dysfunctioning. The neuropsychological test battery was designed to sample intellectual functioning, psychomotor skills, nonverbal memory, and novel problem solving ability. Patients were classified into four groups: schizophrenics without signs of brain dysfunctioning, schizophrenics with signs of brain dysfunctioning, depressed without signs of brain dysfunctioning, and depressed with signs of brain dysfunctioning. The Trail Making Test--Parts A & B, the difference between these two components of the Trail Making Test, the World Fluency Test and a Laterality Index based on the age scale scores of the WAIS significantly discriminated between patients with and without brain dysfunction. Using these variables and a Linear Discriminant Function Analysis, we found that 84.5% of our subjects could be correctly classified. Substantially fewer patients could be correctly classified with respect to their psychiatric diagnosis (i.e., 66.7% correct classification). In fact, only the PIQ from the WAIS-R showed significant differences between the depressed and schizophrenic subjects. Poor neuropsychological performance was interpreted as showing more than the behavioral disorganization associated with psychiatric states and was felt to be related to the presence of objective signs of brain dysfunctioning.