Glutathione ester protects against hydroxynonenal-induced loss of auditory hair cells.

OBJECTIVE: Test the ability of glutathione monoethyl ester (GSH(e)) to protect auditory hair cells against the ototoxic effects of 4-hydroxy-2,3-nonenal (HNE). STUDY DESIGN AND SETTING: Organ of Corti explants were either untreated or treated with one of a series of four concentrations of GSH(e) for one day, then exposed to HNE. Counts of FITC-phalloidin-labeled hair cells determined both HNE ototoxicity and GSH(e) otoprotection. RESULTS: HNE was toxic to hair cells at physiologically relevant levels, eg, 400 muM, and GSH(e) provided a significant level of protection against HNE ototoxicity (P < 0.05) at all levels tested, ie, 1.16 to 9.3 mM. CONCLUSION: GSH(e) protects auditory hair cells from damage and loss initiated by a naturally occurring ototoxic molecule, ie, HNE (a by-product of oxidative stress). SIGNIFICANCE: Treatment with GSH(e) may be an effective therapy to protect the cochlea against the adverse effects of traumas (eg, electrode insertion) that generate oxidative stress.     

Negative symptoms,defect state and Huber's basic symptoms: A comparison of the concepts

Comparing Crow's schizophrenia model with the defect state and Huber's basic symptoms shows that this model is an oversimplification of the complex reality of schizophrenic outcomes. The concept of negative symptoms is undermined by several factors, such as differing definitions, other confounding cross-sectional variables (e.g., akinesia and depression), short follow-ups and lack of confirmation by factorial analysis. The longitudinal concept of a defect state, which has been used in long-term follow-up studies, includes enduring symptoms currently classified as positive and negative. Huber's conceptualization of basic symptoms describes prodromal and enduring residual symptoms of schizophrenia associated with structural brain abnormalities. The overlap and lack of equivalence of these concepts and the limited empirical evidence does not allow firm conclusions. New longitudinal studies using clinical, psychosocial, and neuropsychological measures are needed to understand the natural history and etiology of the defect state.The authors are affiliated with the Medical College of Pennsylvania/EPPI, Philadelphia, PA. William H. Wilson, M.D., is currently at Oregon Health Sciences University, Portland, OR.     

Regulation of neurotransmitter enzyme by quisqualate subtype glutamate receptors in cultured cerebellar and hippocampal neurons

The possible involvement of ionotropic and metabotropic quisqualate (QA) receptors in neuronal plasticity was studied in cultured glutamtergic cerebellar or hippocampal cells in terms of the specific activity of phosphate-activated glutaminase, an enzyme important in the synthesis of the putative neurotransmitter pool of glutamate. When cerebellar of hippocampal neurons were treated with QA, it elevated the specific activity of glutaminase in a dose-dependent manner. The half-maximal effect was obtained at about 0.1 μM, the maximum increase was at about 1 μM, but levels higher than 10 μM QA produced progressive reduction in glutaminase activity. In contrast, QA had little effects on the activities of lactate dehydrogenase and aspartate aminotransferase and the amount of protein, indicating that the increase in glutaminase was relatively specific. The QA-mediated increase in glutaminase was mimicked by the ionotropic QA receptor agonist -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; EC₅₀, about 0.5 μM), but not by the metabotropic QA receptor agonist trans-(±)-1-aino-cyclopentyl-1,3,dicarboxyalte (t-ACPD; up to 0.5 mM). The specific ionotropic QA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) inhibited QA- and AMPA-mediated increases in glutaminase activity in a dose-dependent manner, whereas other glutamate receptor antagonists, -2-amino-5-phosphonovalerate, γ- -glutamyl aminomethyl sulphonic acid and γ- -glutamyl diethyl ester were ineffective. The elevation of neurotransmitter enzyme was Ca²⁺-dependent. The increase in Ca²⁺ influx essentially through the activation of L-type voltage-operated Ca²⁺ channels, and not the mobilization of internal Ca²⁺ stores, was responsible for these QA receptor-mediated long-term plastic changes in hippocampal and cerebellar neurons.     

Breast Cancer-Associated Antigen Ca 15.3 In Liver Cirrhosis

The tumor marker CA 15.3 was studied in 85 patients with liver cirrhosis. Nine patients (10.6%) had abnormal levels of CA 15.3 with the highest values in cases of Child's C patients. However, Child's classes were not significantly associated with the level of the antigen. We found significant correlations with some laboratory tests, especially IgA. All patients with an elevated CA 15.3 value also had abnormal levels of IgA, and multivariate analysis showed that IgA was the only independent factor associated with CA 15.3. Although IgA is a marker of alcoholic liver disease, other markers of alcoholism were not associated with CA 15.3. Cytolysis and cholestasis were not significantly associated with the CA 15.3 level, but liver dysfunction seemed to be involved. Liver disease does not substantially limit the usefulness of CA 15.3 in the cancer patient who also has liver cirrhosis, since both the percentage of abnormal values and the elevation of the serum levels are moderate in cirrhotic patients.     

The renal dopamine receptors.

Dopamine is an endogenous catecholamine that modulates many functions including behavior, movement, nerve conduction, hormone synthesis and release, blood pressure, and ion fluxes. Dopamine receptors in the brain have been classically divided into D1 and D2 subtypes, based on pharmacological data. However, molecular biology techniques have identified many more dopamine receptor subtypes. Several of the receptors cloned from the brain correspond to the classically described D1 and D2 receptors. Several D1 receptor subtypes have been cloned (D1A, D1B, and D5) and are each coupled to the stimulation of adenylyl cyclase. The D2 receptor has two isoforms, a shorter form, composed of 415 amino acids, is termed the D2short receptor. The long form, called the D2long receptor, is composed of 444 amino acids; both are coupled to the inhibition of adenylyl cyclase. The D3 and D4 receptors are closely related to, but clearly distinct from, the D2 receptor. They have not yet been linked to adenylyl cyclase activity. Outside of the central nervous system, the peripheral dopamine receptors have been classified into the DA1 and DA2 subtypes, on the basis of synaptic localization. The pharmacological properties of DA1 receptors roughly approximate those of D1 and D5 receptors, whereas those of DA2 receptors approximate those of D2 receptors. A renal dopamine receptor with some pharmacological features of the D2 receptor but not linked to adenylyl cyclase has been described in the renal cortex and inner medulla. In the inner medulla, this D2-like receptor, termed DA2k, is linked to stimulation of prostaglandin E2 production, apparently due to stimulation of phospholipase A2. Of the cloned dopamine receptors, only the mRNA of the D3 receptor has been reported in the kidney. The DA1 receptor in the kidney is associated with renal vasodilation and an increase in electrolyte excretion. The DA1-related vasodilation and inhibition of electrolyte transport is mediated by cAMP. The role of renal DA2 receptors remains to be clarified. Although DA1 and DA2 receptors may act in concert to decrease transport in the renal proximal convoluted tubule, the overall function of DA2 receptors may be actually the opposite of those noted for DA1 receptors. Dopamine has been postulated to act as an intrarenal natriuretic hormone. Moreover, an aberrant renal dopaminergic system may play a role in the pathogenesis of some forms of hypertension. A decreased renal production of dopamine and/or a defective transduction of the dopamine signal is/are present in some animal models of experimental hypertension as well as in some forms of human essential hypertension.     

Computed tomography in gunshot wounds to the neck: Can we predict vascular injury?

The purpose of this study was to evaluate the ability of helical computed tomography (CT) to detect arterial injuries in gunshot wounds to the neck. In a blinded retrospective review, 54 helical CT scans of the cervical spine were evaluated for bullet/bone fragments, subcutaneous air, bullet path, hematoma, spine fractures, and pharyngoesophageal compromise. The distance of fragments to a major vessel was calculated. CT findings that correlated significantly with major arterial injury included the presence of fragments (bullet/bone) close to a major vessel (2.5 mm) and spine fractures. Visualizing fragments <5 mm from a vessel or a transcervical bullet trajectory predicted 12 of 13 major arterial injuries. We conclude that CT clearly depicts anatomic damage. Specific findings, such as the location of fragments and bullet trajectory adjacent to a vessel and spine fractures, indicate a higher probability of vascular damage, thus directing more definitive evaluation.     

Sleep complaints and their relation with drug treatment in patients suffering from Parkinson's disease.

The aim of this research was to quantify sleep problems in patients suffering from Parkinson's disease by means of the new Parkinson's Disease Sleep Scale (PDSS) and to correlate such problems with the possible influence of current drug treatment. A total of 70 patients (36 men and 34 women) with a diagnosis of Parkinson's disease were enrolled. Their mean age was 69.7 +/- 8.2 years, and duration of disease was 7.4 +/- 4.8 years. All patients completed the PDSS and the Unified Parkinson's Disease Rating Scale (UPDRS Parts I-IV). Drug consumption and doses were registered. The mean score on the PDSS scale was 109.23 +/- 19.75 and on the UPDRS III scale was 25.24 +/- 11.35. The lowest scores were obtained in Item 3 (sleep fragmentation): 5.53 (2.46); and in Item 8 (nocturia): 5.75 (2.91). There was a weak correlation between the PDSS and UPDRS III (cc = -0.355, P = 0.003), PDSS and UPDRS I (cc = -0.272, P = 0.02), and PDSS and UPDRS IV (cc = -0.416, P < 0.001). Motor conditions, mental state, and drug complications influence sleep quality. Although this effect was significant, it was not of a great magnitude. Dopaminergic drugs did not increase daytime sleepiness. As a whole, sleep quality in patients who took dopaminergic agonists did not differ from that of patients who took levodopa in monotherapy.