Mitochondrial alterations, oxidative stress and neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disorder characterized by the progressive deterioration of neuronal networks. The primary cause and sequence of its progression are only partially understood but abnormalities in folding and accumulation of insoluble proteins such as beta-amyloid and Tau-protein are both associated with the pathogenesis of AD. Mitochondria play a crucial role in cell survival and death, and changes in mitochondrial structure and/or function are related to many human diseases. Increasing evidence suggests that compromised mitochondrial function contributes to the aging process and thus may increase the risk of AD. Dysfunctional mitochondria contribute to reactive oxygen species which can lead to extensive macromolecule oxidative damage and the progression of amyloid pathology. Oxidative stress and amyloid toxicity leave neurons chemically vulnerable. The mitochondrial toxicity induced by beta-amyloid is still not clear but may include numerous mechanisms, such as the increased permeability of mitochondrial membranes, the disruption of calcium homeostasis, the alteration of oxidative phosphorylation with a consequent overproduction of reactive oxygen species. Other mechanisms have been associated with the pathophysiology of AD. Inflammatory changes are observed in AD brain overall, particularly at the amyloid deposits, which are rich in activated microglia. Once stimulated, the microglia release a wide variety of pro-inflammatory mediators including cytokines, complement components and free radicals, all of which potentially contribute to further neuronal dysfunction and eventually death. Clinically, novel approaches to visualize early neuroinflammation in the human brain are needed to improve the monitoring and control of therapeutic strategies that target inflammatory and other pathological mechanisms. Similarly, there is growing interest in developing agents that modulate mitochondrial function.

A test of the nature of cosmic acceleration using galaxy redshift distortions.

Observations of distant supernovae indicate that the Universe is now in a phase of accelerated expansion the physical cause of which is a mystery. Formally, this requires the inclusion of a term acting as a negative pressure in the equations of cosmic expansion, accounting for about 75 per cent of the total energy density in the Universe. The simplest option for this 'dark energy' corresponds to a 'cosmological constant', perhaps related to the quantum vacuum energy. Physically viable alternatives invoke either the presence of a scalar field with an evolving equation of state, or extensions of general relativity involving higher-order curvature terms or extra dimensions. Although they produce similar expansion rates, different models predict measurable differences in the growth rate of large-scale structure with cosmic time. A fingerprint of this growth is provided by coherent galaxy motions, which introduce a radial anisotropy in the clustering pattern reconstructed by galaxy redshift surveys. Here we report a measurement of this effect at a redshift of 0.8. Using a new survey of more than 10,000 faint galaxies, we measure the anisotropy parameter beta = 0.70 +/- 0.26, which corresponds to a growth rate of structure at that time of f = 0.91 +/- 0.36. This is consistent with the standard cosmological-constant model with low matter density and flat geometry, although the error bars are still too large to distinguish among alternative origins for the accelerated expansion. The correct origin could be determined with a further factor-of-ten increase in the sampled volume at similar redshift.

A large population of galaxies 9 to 12 billion years back in the history of the Universe.

To understand the evolution of galaxies, we need to know as accurately as possible how many galaxies were present in the Universe at different epochs. Galaxies in the young Universe have hitherto mainly been identified using their expected optical colours, but this leaves open the possibility that a significant population remains undetected because their colours are the result of a complex mix of stars, gas, dust or active galactic nuclei. Here we report the results of a flux-limited I-band survey of galaxies at look-back times of 9 to 12 billion years. We find 970 galaxies with spectroscopic redshifts between 1.4 and 5. This population is 1.6 to 6.2 times larger than previous estimates, with the difference increasing towards brighter magnitudes. Strong ultraviolet continua (in the rest frame of the galaxies) indicate vigorous star formation rates of more than 10-100 solar masses per year. As a consequence, the cosmic star formation rate representing the volume-averaged production of stars is higher than previously measured at redshifts of 3 to 4.

Oral supplements of vitamin E improve measures of oxidative stress in plasma and reduce oxidative damage to LDL and erythrocytes in beta-thalassemia intermedia patients.

Fifteen beta-thalassemia intermedia patients, not requiring chronic transfusional therapy, were monitored in order to check their antioxidant status, and the lipid oxidation products in plasma, LDL, and erythrocytes before and during a 9-month oral treatment with 600 mg/day vitamin E. The low level of vitamin E, and high level of malondialdehyde in plasma clearly tended to normalize after three months (P < .001), and were quite similar to control after six months. The abnormally low level of vitamin E in LDL and the four times higher than control basal level of conjugated dienes (LDL-CD), were not modified after three months of treatment. Significant changes of LDL-VE (P < .05) and of the basal LDL-CD (P < .001) were evident after six months. LDL-VE was within the normal range after nine months, whereas LDL-CD still appeared twice as higher than control. Plasma vitamin A, ascorbate, beta-carotene, and lycopene increased markedly at the end of the trial (P < .005). The level of vitamin E in red blood cells was normalized after six months of supplementation. A decrease of the baseline value of conjugated dienes was observed after nine months, although it remained 1.4-fold higher than control. The RBC count and hematocrit appeared higher at the end of the trial (P < .05 and P < .001, respectively). The hemoglobin value did not show variations. A shift to normal of the resistance of erythrocytes to osmotic lysis was observed. Our findings provide evidence that an oral treatment with vitamin E improves the antioxidant/oxidant balance in plasma, LDL particles, and red blood cells, and counteracts lipid peroxidation processes in beta-thalassemia intermedia patients.

Oxidative stress after moderate to extensive burning in humans.

Lipid peroxidation products, lipid antioxidants, and hematologic and blood chemistry changes were evaluated in plasma of patients after acute burning injury involving 10% (n=8), 20% (n=8), and 40% (n=5) of total body surface area (TBSA), 24 h after burning (baseline) up to 30 days after. Markedly increased plasma levels of malondialdehyde (MDA) were observed at baseline in all patients, according to the extent of the injury, then the values declined progressively. However, levels of MDA remained above normal up to 30 days even in less injured patients. On the other hand, the plasma level of conjugated diene lipid hydroperoxides was only slightly higher than control at the baseline, then dropped under the control value in all patients. Cholesterol showed a marked fall at baseline, followed by a rapidly progressive decrease, indicating a massive loss of circulating lipids by the acute thermal injury. Because of such an extensive and rapidly spreading oxidative degradation of lipids, decomposition of conjugated diene hydroperoxides, produced in early stages of the peroxidation process, occurs, so these compounds cannot be a suitable index to value lipid oxidation in burned patients. Aldehydic products of lipid peroxidation act as endotoxins, causing damage to various tissues and organs. Damage to liver and decrease of erythrocyte survival were assessed by increased plasma levels of asparate and alanine transaminases, within 7-15 days after injury, and by a decreased number of red blood cells, which remained under the normal value at 30 days. A marked decrease of lipid antioxidants, beta-carotene, vitamin A and vitamin E was observed at baseline. The level of beta-carotene remained low in all patients at the end of the 30-day observation. A complete recovery of vitamin A did not occur at 30 days post-burn, even in the patients with 10% of burned TBSA. Plasma levels of vitamin E decreased significantly in 1-7 days after burn in all patients, but these levels increased thereafter, with almost total recovery at 30 days. These data show evidence of a marked, long-lasting oxidant/antioxidant imbalance in burned patients, in accordance with the severity of the injury, which is also reflected as systemic oxidant stress.

Correlation between digestive disease and psychiatric disease: casual or causal implication?

The aim of this study was to evaluate the prevalence of psychiatric disturbances among patients affected with digestive diseases (both organic and functional) and, viceversa, the prevalence of digestive disturbances among patients with psychiatric diseases. We performed a trasversal study on: 100 patients with organic digestive diseases and 100 patients with functional digestive diseases afferent from a Gastroenterologic Ambulatory (gastroenterologic group); 50 patients afferent from a Psychiatry Service (psychiatric group) and 50 patients afferent from a General Medicine Ambulatory affected with a non gastroenterologic active problem (control group). Each patient underwent an anamnestic, laboratory and instrumental evaluation, in order to ascertain or exclude the presence of digestive symptoms and their eventual organic basis; moreover, a semistructured interview was performed aimed at identifying a psychiatric disturbance, according to DSM-IIIr criteria. Our results showed a significantly higher prevalence: 1) of psychiatric disturbances, in the gastroentorologic group versus the control group (p<0.001), especially of somatoform (p<0.05) and anxious (p<0.001) disorders; 2) of psychiatric disturbances among patients affected by functional digestive disorders versus patients affected by organic digestive disorders; 3) of gastroenterologic disorders, in the psychiatric group versus the control group (p<0.001), with a significantly higher prevalence of functional gastroenterologic syndromes in comparison the organic ones (p<0.001). The well-established bidirectional correlation between digestive functional and psychiatric disorders is a necessary but not sufficient condition to state a relationship of direct causality between the two syndromes; however we can hypothesize that the well documented neuro-hormonal alterations may cause, on clinical grounds different symptoms, that are differently interpreted by the different specialists (gastroenterologists or psychiatrists) consulted.

Cross validation of the factor structure of the 20-item Toronto Alexithymia Scale: an Italian multicenter study.

The 20-item Toronto Alexithymia Scale (TAS-20) has been shown in previous research to measure a general dimension of alexithymia with three intercorrelated factors. This study evaluated the reliability and factorial validity of an Italian translation of the TAS-20 in a group of normal adults (N = 206) and in a mixed group of medical and psychiatric outpatients (N = 642). Using confirmatory factor analyses, the previously established three-factor model of the TAS-20 was found to be replicable in both groups. In addition, the Italian TAS-20 demonstrated adequate estimates of internal reliability and test-retest reliability. Although evaluation of the convergent, discriminant, and concurrent validity of the TAS-20 is required in Italian populations, the present results support the use of the Italian translation of the scale for clinical and research purposes.

Oxidative stress and antioxidant status in beta-thalassemia major: iron overload and depletion of lipid-soluble antioxidants.

Because of continuous blood transfusions, thalassemia patients are subjected to peroxidative tissue injury by the secondary iron overload. In accordance, analysis of serum from 42 beta-thalassemia patients, aged 4 to 40 years, showed that the mean concentrations of conjugated diene lipid hydroperoxides (CD), lipoperoxides evaluated as malondialdehyde/ thiobarbituric acid (MDA/TBA) adducts, and protein carbonyls increased about twofold with respect to control. Ferritin levels were positively correlated with the amount of MDA (r = .41; P = .007) and showed a positive trend with CD (r = .31; P = .07) and protein carbonyls (r = .35; P = .054), as further evidence of the deleterious effects of high tissue iron levels. Marked changes in the antioxidant pattern were also observed in all patients. Evidence is presented of a net drop in the concentration of ascorbate (-44%), vitamin E (-42%), vitamin A(-44%), beta-carotene (-29%), and lycopene (-67%). On the other hand, an increase of uric acid and bilirubin was observed, whereas serum albumin and glutathione were in the normal range in all patients. As a result, the total serum antioxidant potential, measured as trolox equivalent antioxidant capacity appeared significantly decreased by 14%. Serum levels of vitamin E were inversely correlated with ferritin (r = -.45; P = .003), suggesting a major consumption of this antioxidant under iron overload. Nontransferrin bound iron (NTBI) was in the range 4.5 to 54.8 micrograms/dL (mean, 21.8 +/- 13.9). Although NTBI had a positive trend with ferritin (r = .37, P = .03), no clear correlation was found with either MDA or vitamin E. A mild to severe hepatic damage, as assessed by serum transaminases, was shown in 24 of 42 patients. Serum levels of vitamin E (r = -.49, P = .015), vitamin A (r = -.48, P = .016) and lycopene (r = -.47, P = .020), were inversely correlated with the levels of transminases. On the other hand, lipid-soluble antioxidants in thalassemia patients were depleted to the same extent in hepatitis C virus (HCV)-infected (31 subjects) and in HCV-uninfected (10 subjects), while in the normal range in serum from 30 nonthalassemic patients with HCV-related chronic hepatitis. These results point out that the iron-induced liver damage in thalassemia may play a major role in the depletion of lipid-soluble antioxidants. The variations of the parameters evaluated in the present study were not correlated with the age of the patients. Our results suggest that the measurement of peroxidation products, matched with evaluation of antioxidants, may be a simple measure of iron toxicity in thalessemia, in addition to the conventional indices of iron status.

Synergistic interactions between vitamin A and vitamin E against lipid peroxidation in phosphatidylcholine liposomes.

Interactions between alpha-tocopherol and all-trans retinol in suppressing lipid peroxidation were studied in a unilamellar liposomal system of phosphatidylcholine from either egg or soybean, in which peroxidation was initiated by the water-soluble azo initiator 2,2-azobis(2-amidino-propane)hydrochloride and peroxidation was measured as production of conjugated diene hydroperoxides. While all-trans retinol alone was poorly effective, the combination of all-trans retinol with alpha-tocopherol caused an inhibition period far beyond the sum of the inhibition periods observed with individual antioxidants, providing evidence of synergistic interactions. Furthermore, the inhibition rate calculated in the presence of both all-trans retinol and alpha-tocopherol, Rinh(E+A), was lower than Rinh(E) observed with alpha-tocopherol alone, suggesting that the extension of the inhibition time cannot be ascribed only to the antioxidant activity of alpha-tocopherol. The extent of synergism was linear with a molar ratio all-trans retinol/alpha-tocopherol ranging from 0.1 to 1.0, whereas a drop was observed at a ratio of 2.0. Synergistic antioxidant interactions between all-trans retinol and alpha-tocopherol were also evident when peroxidation was evaluated as production of malondialdehyde. A time course study, in which peroxidation of liposomes and depletion of antioxidants were concomitantly monitored, while showing that most of alpha-tocopherol was consumed to bring about the inhibition period, indicated that autooxidative reactions substantially contributed to the rapid depletion of all-trans retinol, when the antioxidants were allowed to act separately. On the other hand, when alpha-tocopherol and all-trans retinol were combined, the consumption of both antioxidants was significantly delayed, indicating reciprocal protection. Regeneration mechanisms cannot be accounted for by our results. The observed synergism between all-trans retinol and alpha-tocopherol does not appear as the result of specific structural interactions in the lipid bilayer. Combination of all-trans retinol with butylated hydroxytoluene, which reduced markedly all-trans retinol oxidation, resulted in a synergistic antioxidant activity greater than that observed with comparable amounts of alpha-tocopherol. In light of the known antioxidant mechanism of retinoids, the data suggest that by limiting autooxidation of all-trans retinol, alpha-tocopherol strongly promotes its antioxidant effectiveness. The concerted radical scavenging action in turn results in a synergistic protection of the lipid system against peroxidative stress and, ultimately, slows down the alpha-tocopherol consumption.

Reciprocal protective effects of all-trans retinol and alpha-tocopherol during lipid peroxidation in retinal membranes.

Interactions between vitamin A and vitamin E in suppressing lipid peroxidation were observed in bovine retinal membrane preparations submitted to peroxidative injury by the water soluble azo initiator 2,2'-azobis(2-amidino-propane) hydrochloride (AAPH). Incorporation of 0.75 nmol mg prot(-1) all-trans retinol, an amount comparable with that of the endogenous alpha-tocopherol, significantly elongated the induction time preceding the release of TBA-reactive lipid peroxidation products, and reduced the consumption rate of the endogenous alpha-tocopherol. On the other hand, all-trans retinol was not able to induce any delay to the onset of lipid peroxidation when incorporated in membranes deprived of endogenous alpha-tocopherol by exposure to UV light, although TBARS produced within 60 min decreased slightly. Consumption of all-trans retinol during peroxidation was more rapid when all-trans retinol was incorporated in membranes deprived of alpha-tocopherol than in native membranes. These data suggest that reciprocal protective effects between vitamin A and vitamin E may strongly contribute to the defence of membranes against oxidative stress.

Contribution of vitamin A to the oxidation resistance of human low density lipoproteins.

This study investigated the antioxidant contribution of vitamin A in protecting human low density lipoprotein (LDL) against copper-stimulated oxidation. The presence of small amounts of retinol (0.033 +/- 0.012 nmol/mol LDL) and retinyl palmitate (0.036 +/- 0.021 nmol/mol LDL) was routinely ascertained in the LDL. A single oral supplementation with 20,000 IU vitamin A caused a two- to three-fold increase of retinol and retinyl palmitate in the LDL isolated 8 h after the supplementation. In comparison to autologous-control LDL, vitamin A-enriched LDL were more resistant to oxidation, as expressed both by a clear delay in the onset of lipid peroxidation and by a reduction of the rate of conjugated diene hydroperoxide production during the propagation phase. The calculated incremental increase in the lag phase produced by 1 mol retinol per mol LDL is about 1000 min, suggesting that retinol is more potent than alpha-tocopherol in LDL. Oxidation experiments carried out with LDL isolated from plasma incubated in vitro with either retinol or retinyl palmitate indicated that retinol does lengthen the lag phase, whereas retinyl palmitate can slow the rate of peroxyl chain propagation, without affecting the duration of the lag phase. Temporal disappearance of retinol and retinyl palmitate, followed in comparison with that of alpha-tocopherol and beta-carotene, indicated that the reactivity of the antioxidants with lipoperoxyl radicals was in the sequence alpha-tocopherol, retinol, beta-carotene, and retinyl esters. Although the detailed antioxidant mechanism remains to be elucidated, these results suggest that LDL-associated vitamin A can play a role in maintaining the antioxidant status of LDL during oxidative stress in vivo.

Vitamin A preserves the cytotoxic activity of adriamycin while counteracting its peroxidative effects in human leukemic cells in vitro.

Previous results from our laboratory gave evidence that safe doses of vitamin A were very effective in protecting rats from adriamycin-induced oxidative stress and lethal cardiotoxicity (Tesoriere, L. et al. (1994) J. Pharmacol. Experim. Ther. 269, 430-436). This was an incentive also to evaluate whether or not vitamin A affected the antitumor activity of adriamycin. K562 human erythroleukemia cells were exposed to adriamycin or to adriamycin plus vitamin A. Presence of 2.5 to 15 microM all-trans retinol in the cell culture did not impair the cytotoxicity of adriamycin. Rather, an enhanced cell death was observed when cell colony was exposed to both compounds. Additional assays showed that all-trans retinol counteracted the lipoperoxide formation, assayed as malondialdehyde, induced in cell cultures by the redox cycling activity of adriamycin. These data strongly encourage a new therapeuthical approach with safe doses of vitamin A as an adjuvant in cancer chemotherapy.

Effect of vitamin A administration on resistance of rat heart against doxorubicin-induced cardiotoxicity and lethality.

The peroxyl radical-scavenging activity of vitamin A has been exploited to obtain protection against peroxidative damages induced in rat heart by administration of an acute dose of doxorubicin (10 mg/kg, in vein). Peroxidative lesions were evaluated by both biochemical and histological assays, 48 hr after the injection of doxorubicin. Heart tissue from rats receiving doxorubicin showed a marked increase of protein carbonyl levels, and of membrane conjugated dienes, as well as a decrease of membrane protein thiols. Abnormal chemistries, including a large increase of the activity of serum lactate dehydrogenase and creatine phosphokinase, an index of the myocardial damage caused by doxorubicin, were also observed. Pretreatment of rats with 25 I.U./kg b.wt. of vitamin A, once a day for 2 days, before injecting doxorubicin, substantially reduced the peroxidative damage to heart lipids and proteins, and markedly lowered the serum values of lactate dehydrogenase and creatine phosphokinase to values close to those of control rats. The significant prevention of doxorubicin-induced cardiomyopathy by vitamin A was evident from the histopathological pattern observed after light microscopy. The dosage of vitamin A useful to obtain the protective effect appears safe and does not injure the liver, as indicated by light microscopy of the tissue. A survival study, carried out by injecting rats with a single injection of 10 mg/kg of doxorubicin, showed that pretreatment with 25 I.U. of vitamin A per kg significantly increased survival rate of the animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidant activity of all-trans-retinol in homogeneous solution and in phosphatidylcholine liposomes.

A kinetic quantification of the lipoperoxyl radical-scavenging activity of all-trans-retinol has been carried out in homogeneous solution, when radicals were produced from the oxidation of methyl linoleate in methanol, initiated by the lipid-soluble 2,2'-azobis (2,4-dimethylvaleronitrile) (AMVN) as well as in a soybean phosphatidylcholine membrane model, in which peroxidation was induced either by AMVN or the hydrophylic 2,2'-azobis(2-amidinopropane)hydrochloride (AAPH). The physical microenvironment contributes to the determination of antioxidant efficiency of all-trans-retinol. In homogeneous solution the kinetic constant kinh is 3.5 x 10(5) M-1 s-1 and appears of the same order of magnitude as the inhibition constant measured for alpha-tocopherol under the same experimental conditions. Nevertheless, despite its very high chemical reactivity toward lipoperoxyl radicals, the overall antioxidant efficiency of all-trans-retinol in this system appears quite limited, since the evaluated stoichiometric factor is 0.21. When the polyenoic chain of all-trans-retinol is incorporated into a phosphatidylcholine lipid bilayer, the antioxidant efficiency depends on the site of peroxyl-radical production. The highest lipoperoxyl radical-scavenging activity is measured when radicals are generated by AHVN inside the bilayer multilamellar liposomes. Under these conditions, the relative antioxidant efficiency is similar to that of alpha-tocopherol, and the stoichiometric factor is 3.1. When radicals are generated by AAPH in the aqueous phase of an unilamellar liposomal system, the antioxidant effectiveness of all-trans-retinol appears reduced and lower than that measured with equivalent amounts of alpha-tocopherol. Synergistic antioxidant effects between all-trans-retinol and alpha-tocopherol are observed when both antioxidants are simultaneously incorporated into unilamellar liposomes in which peroxidation is induced by AAPH. This suggests that all-trans-retinol may interact with tocopheroxyl radicals, thereby regenerating alpha-tocopherol. This interaction, which may be related to molecular features and to the relative location of the antioxidants in the bilayer, could provide an effective antioxidant system that may be of great importance in vivo.

Vitamin A inhibits doxorubicin-induced membrane lipid peroxidation in rat tissues in vivo.

The antioxidant activity of vitamin A against lipid peroxidation induced by doxorubicin in rat tissues in vivo was investigated. A single ip injection of doxorubicin (30 mg/kg body wt) markedly raised the level of peroxidated lipids measured as TBARS and conjugated dienes in heart and brain membrane preparations. Other tissues, such as retina and liver, did not show any increase of lipid peroxides over control values. Pretreatment of rats with two daily subcutaneous injections of retinol palmitate (0.25 g/kg body wt), for 2 days, before injecting doxorubicin, inhibited peroxidation of heart and brain membrane lipids. The antioxidant action of vitamin A does not appear to be mediated by enhancement of antioxidant enzyme activities committed to detoxify oxygen radicals. Superoxide dismutase and catalase, measured in heart and brain cytosol, were not affected by the vitamin A treatment. On the contrary, a slight increase of catalase activity was observed in heart and brain cytosol from rats that had been treated with doxorubicin. Excess vitamin A may be localized in membranes. Appreciable increase of retinyl esters and retinol was measured in membrane preparations from rats that had been treated with vitamin A, with respect to control animals. Brain and heart membrane preparations from rats receiving vitamin A, assayed in vitro in the presence of an Fe3+ ascorbate induction system, showed a delay at the beginning of the lipid peroxidation and generated lesser amounts of TBARS, with respect to membranes from control rats. Thus, the increase of vitamin A within cell membranes results in an increased resistance of membrane lipids to peroxidation, both endogenously produced and induced in vitro. These results may be consistent with the hypothesis that vitamin A may act as a physiological antioxidant in cell membranes where it is localized.

[Severe megaloblastic anemia in child breast fed by a vegetarian mother]. / Anémie mégaloblastique sévère chez un enfant allaité par une mère végétarienne.

The case of a 15-month-old, strictly breast-fed infant whose mother had been following a vegetarian diet for ten years is reported. The infant had severe megaloblastic anemia with an arrest in growth, hypotonia, and failure of psychomotor development. The very low levels of vitamin B12 in the infant's serum and mother's milk confirmed the diagnosis. Management of such cases consists in administration of vitamin B12 supplements, with a blood transfusion if needed. Other concomitant deficiencies should be looked for. The outcome is rapidly favorable. The patient reported here is now four years of age and has normal statural growth and psychomotor development.

All-trans to 11-cis retinol isomerization in nuclear membrane fraction from bovine retinal pigment epithelium.

Isomerization of all-trans to 11-cis retinol has been studied in a membrane preparation from the nuclear fraction of bovine retinal pigment epithelium. When the nuclear membrane preparation deprived of endogenous retinoids is incubated with 4.5 microM all-trans-retinol, the mean value calculated for the isomerase activity is 1.32 nmol 11-cis retinol formed hr-1 mg protein-1. Simultaneous formation of all-trans and 11-cis retinyl esters is also observed in the nuclear preparation. When assayed under the same experimental condition, RPE 150,000 g post-nuclear sediment shows about 70% of the isomerase activity found in the nuclear membrane fraction. Treatment of the nuclear membrane fraction with 0.5% (w/v) CHAPS produces a 200,000-g supernatant retaining 80% of the total isomerase activity and leads to a modest purification of the enzyme activity. Apparent values for Km and Vmax of the solubilized enzyme are 1.6 microM and 2.5 nmol 11-cis retinol formed h-1 mg protein-1, respectively. Bovine serum albumin and beta-lactoglobulin effectively stimulate the isomerization reaction. The mechanism underlying this activating effect remains unclarified at present. Some hypotheses are discussed.

Distribution of vitamin A compounds in bovine eyes after bleaching adaptation.

A seasonal increase in the amount of bleached rhodopsin caused, in living animals, by the seasonal increase of the intensity of sunlight in the early morning before the calves are killed, was verified in the bovine eyes subjected to the present study. This was used as a means of assaying distribution and isomer composition of esterified and unesterified retinol in eyes from animals light-adapted to a different extent under environmental conditions. The progressive increase of bleached rhodopsin results in a parallel increase of all-trans-retinol in retina and of both all-trans- and 11-cis-retinyl esters in pigment epithelium. Analytical subcellular fractionation of RPE homogenate reveals that retinyl esters accumulate without an exclusive subcellular localization in nuclear, mitochondrial/lysosomal and microsomal fractions. Whatever the amount of bleached rhodopsin, only small and constant amounts of retinyl esters are found in the soluble fraction of RPE, entirely under the all-trans configuration. When a considerable portion of rhodopsin is bleached (about 70%), substantial amounts of all-trans-retinol, along with minor amounts of 11-cis-retinol, accumulate in RPE subcellular organelles. The in vitro bleaching of bovine eyes results in a distribution of retinoids between retina and RPE which appears different from that detected in eyes naturally bleached to the same extent.

[De-nol in NSAID-induced gastroduodenal lesions]. / DE-NOL nelle lesioni gastroduodenali indotte da FANS.

It is well known that prolonged use of Non Steroidal Anti-inflammatory Drugs (NSAIDs) can trigger gastroduodenal lesions and/or their complications, even in the absence of any dramatic painful and dyspeptic symptomatology. The paper reports the results of a double-blind study carried out with Colloidal Bismuth Subcitrate (CBS, DE-NOL), an antiulcer drug with cytoprotective activity, versus ranitidine (RN) with the aim of assessing its therapeutic efficacy in promoting healing of either gastric or duodenal ulcers induced by NSAIDs. It is concluded that the efficacy of DE-NOL is comparable to that of RN, although some minor differences in healing rates were observed: these being in favour of DE-NOL in the gastric ulcer patients and in favour of RN in the duodenal ulcer patients, respectively. In addition, it is stated that in patients undergoing chronic treatment with NSAIDs the use of cytoprotective drugs as a preventive treatment as well as periodic endoscopic surveillance are more useful and rational in order to combat the onset of NSAIDs-induced side-effects, given the frequent paucity of symptomatology following the occurrence of gastroduodenal lesions.

[Alizapride in upper digestive endoscopy. A double-blind study vs metoclopramide and placebo]. / L'alizapride in endoscopia digestiva superiore. Studio in doppio cieco contro metoclopramide e contro placebo.

In order to assess the antiemetic properties of alizapride in the specific context of premedication for endoscopy, a double blind test was conducted on 100 patients against both metoclopramide and a placebo. Efficacy was assessed on the basis of the following parameters: technical judgement of the endoscopist; assessment of evident signs of "discomfort" by an outside observer; comparative judgement (better, worse, same) of the patient's condition after the two endoscopies performed. In the case of the first two parameters, alizapride proved significantly more effective than the control substances. The patients themselves only expressed a significant preference for alizapride vis-à-vis the placebo. It is concluded that given its efficacy and the absence of side effects, alizapride is of value in premedication for endoscopy.