The hemoglobins of Notothenia angustata, a temperate fish belonging to a family largely endemic to the Antarctic Ocean. The blood of the teleost Notothenia angustata contains a major hemoglobin (Hb 1, over 95% of the total), accompanied by a minor component (Hb 2). The two hemoglobins have identical beta chains and differ in their alpha chains. The primary structure of both hemoglobins has been established through the elucidation of the complete amino acid sequence of the three chains. The study of the oxygen-binding properties shows that Hb 1 displays the Bohr and Root effects and has high affinity for organic phosphates. N. angustata belongs to the family Nototheniidae, suborder Notothenioidei. Unlike the vast majority of nototheniid species, which live in isolation in the Antarctic Ocean and have developed cold adaptation, N. angustata inhabits the waters of southern New Zealand and is not cold adapted. Although some hematological parameters typically favour oxygen transport in a temperate environment, the hemoglobin multiplicity and structural and functional features closely resemble those of the Antarctic species of the same family and suborder. Thus, N. angustata may be considered as a link between temperate and Antarctic habitats. The hypothetical separation history of N. angustata from the Antarctic species of the same family is discussed in the light of the present findings.


Salt dependence, kinetic properties and catalytic mechanism of N-formylmethanofuran:tetrahydromethanopterin formyltransferase from the extreme thermophile Methanopyrus kandleri. N-Formylmethanofuran(CHO-MFR):tetrahydromethanopterin(H4MPT) formyltransferase (formyltransferase) from the extremely thermophilic Methanopyrus kandleri was purified over 100-fold to apparent homogeneity with a 54% yield. The monomeric enzyme had an apparent molecular mass of 35 kDa. The N-terminal amino acid sequence of the polypeptide was determined. The formyltransferase was found to be absolutely dependent on the presence of phosphate or sulfate salts for activity. The ability of salts to activate the enzyme decreased in the order K2HPO4 > (NH4)2SO4 > K2SO4 > Na2SO4 > Na2HPO4. The salts KCl, NaCl and NH4Cl did not activate the enzyme. The dependence of activity on salt concentration showed a sigmoidal curve. For half-maximal activity, 1 M K2HPO4 and 1.2 M (NH4)2SO4 were required. A detailed kinetic analysis revealed that phosphates and sulfates both affected the Vmax rather than the Km for CHO-MFR and H4MPT. At the optimal salt concentration and at 65 degrees C, the Vmax was 2700 U/mg (1 U = 1 mumol/min), the Km for CHO-MFR was 50 microM and the Km for H4MPT was 100 microM. At 90 degrees C, the temperature optimum of the enzyme, the Vmax was about 2.5-fold higher than at 65 degrees C. Thermostability as well as activity of formyltransferase was dramatically increased in the presence of salts, 1.5 M being required for optimal stabilization. The efficiency of salts in protecting formyltransferase from heat inactivation at 90 degrees C decreased in the order K2HPO4 = (NH4)2SO4 >> KCl = NH4Cl = NaCl >> Na2SO4 > Na2HPO4. The catalytic mechanism of formyltransferase was determined to be of the ternary-complex type. The properties of the enzyme from M. kandleri are compared with those of formyltransferase from Methanobacterium thermoautotrophicum, Methanosarcina barkeri and Archaeoglobus fulgidus.


Expression and secretion of wheat germ agglutinin by Saccharomyces cerevisiae. Genes encoding pre-protein and prepro-protein of wheat germ agglutinin isolectin 2 (WGA2) were chemically synthesized and expressed in the yeast Saccharomyces cerevisiae under the control of the ENO1 promoter. Yeast harboring either a pre-WGA2 or a prepro-WGA2 gene expression plasmid secreted a mature form of WGA2 into the culture medium. The amount of WGA2 secreted by the strain KS58-2Ddel, which has a ssl1 mutation causing a supersecretion of human lysozyme [Suzuki, K., Ichikawa, K. & Jigami, Y. (1989) Mol. Gen. Genet. 219, 58-64], was 20-fold greater than that secreted by the wild-type strain KK4. The recombinant WGA2 from the cells containing the prepro-WGA2 gene expression plasmid was purified to homogeneity by a three-step ion-exchange chromatography scheme. As in wheat, the N-terminal signal peptide of recombinant WGA2 purified from yeast culture was processed to form an N-terminal 5-oxoprolyl (pyroglutamyl) residue. Likewise, we found that the C-terminal pro-region of recombinant WGA2 had also been processed in yeast. Using electrospray ionization mass spectrometry, we found the processed C-terminus to be heterogeneous in both recombinant WGA2 purified from yeast and in authentic WGA2. The major component of the recombinant WGA2 contained two additional amino acids at its C-terminus compared to that of authentic WGA2. In spite of this difference in the C-terminus, the recombinant WGA2 exhibited a sugar binding activity that was indistinguishable from that of authentic WGA2.


Large intercommunity difference in cardiovascular drug consumption: relation to mortality, risk factors and socioeconomic differences. A comparison of cardiovascular drug sales and cardiovascular mortality was made between two Swedish counties (Värmland and Malmöhus) and between two rural municipalities in those counties (Torsby in Värmland and Hörby in Malmöhus). Cardiovascular drug sales (defined daily doses (DDD) per 1,000 inhabitants per day) during 1986-87 were 25% higher in Värmland than in Malmöhus county, and the age-standardized mortality of coronary heart disease (CHD) was 36% (men) and 54% (women) higher. In Torsby, age-standardized CHD mortality (1986-87) was 71% (both sexes) higher than in Hörby, and the sales of cardiovascular drugs (1978-87) were 58% higher. Statistically, every third inhabitant of Torsby took one DDD of a cardiovascular drug every day, as compared to every fifth inhabitant in Hörby. In Torsby there was a 6% higher serum cholesterol, 71% lower tap water hardness, 33% lower income, a lower educational level, a three-fold higher unemployment rate, and a different ethnic background (20% eastern Finnish ancestry), all factors assumed to promote a high CHD rate. All of these factors may contribute to the higher CHD mortality, which was in turn reflected in higher sales of cardiovascular drugs.


Flow resistance and its components in hypertensive men treated with the calcium antagonist isradipine. The components of blood flow resistance were investigated in 14 men with essential hypertension (diastolic blood pressure higher or equal to 100 mm Hg) before and after treatment with the dihydropyridine calcium antagonist-isradipine. Isradipine reduced intraarterial blood pressure by decreasing the total (placebo 5.1 U.mPa-1.s-1; isradipine 3.9 U.mPa-1.s-1), and renal (placebo 48.9 U.mPa-1.s-1, isradipine 35.4 U.mPa-1.s-1) vascular hindrance, the blood viscosity being unchanged. Arterial compliance was increased by isradipine (placebo 1.03 ml.mmHg-1; isradipine 1,25 ml.mmHg-1). The pressor response to adrenergic alpha stimulation with phenylephrine was decreased during treatment with the calcium antagonist. The compliance of the venous system was not changed by the treatment with isradipine. Haemorheological parameters were stable throughout the study but some changes in the correlations between the different rheological parameters were observed. The present study indicates that the antihypertensive effect of the dihydropyridine calcium antagonist isradipine was the result of functional modulation of the small and large arteries, the venous system and the flow properties of blood being unaffected.


Portal pressure, renal function and hormonal profile after acute and chronic captopril treatment in cirrhosis. The acute effects of captopril in cirrhosis are well known but there are few descriptions of the pattern of response to chronic administration of captopril in this disease. Nine nonuraemic cirrhotic patients with ascites and portal hypertension were studied after 1 week on fixed sodium and water intake (balance diet) and following acute and chronic treatment with captopril (three doses of 25 mg every 30 min and 75 mg.day-1 for three weeks, respectively). Whilst on the balance diet, 7/9 patients were unable to excrete the amount of sodium ingested. After the acute administration of captopril, a significant reduction was seen in arterial blood pressure (86.9 vs 77 mm Hg), with no change in the intra-hepatic pressures (free suprahepatic pressure, FSHP: 15.0 vs 12.1 mm Hg and wedged suprahepatic pressure, WSHP: 22.9 vs 20.7 mm Hg). After chronic captopril treatment, a drop was observed in portal pressure (FSHP: 9.4 mm Hg and WSHP 18.8 mm Hg, NS) and the arterial pressure returned to its basal level. The plasma aldosterone concentration decreased, whilst noradrenaline and dopamine increased significantly, the latter more than the former, leading to a reduction in the noradrenaline/dopamine ratio (14.5 vs 5.0). Seven out of nine patients showed enhanced natriuresis and the remaining two, who previously had had a positive sodium balance failed to do so. These haemodynamic, hormonal and renal changes were interpreted as evidence of blockade of angiotensin II generation by captopril, and also as a homoeostatic response by the sympathetic nervous system.


Objective evidence for tolerance, against a background of improvement, during maintenance therapy with controlled release levodopa/carbidopa. We have investigated whether the potential benefits of a controlled release formulation of levodopa (200 mg)/carbidopa (50 mg), Sinemet CR, are realised during maintenance therapy. Eight sufferers from idiopathic Parkinsonism, mean age 69.9 y, were studied: all exhibited "end of dose" effect within 4 h of a dose of their maintenance therapy with levodopa (100 mg)/carbidopa (25 mg) in a conventional release formulation, Sinemet Plus. They received, in random order, initial single dose challenges with one tablet of Sinemet Plus, one and two tablets of Sinemet CR and placebo alone, each on a separate day. After a mean of 21 weeks on maintenance therapy with Sinemet CR, subsequent single dose challenges with Sinemet CR and placebo were made. Objective measures of performance and blood sampling for assay of plasma concentrations of levodopa and the major peripheral metabolite, 3-0-methyldopa (30MD) were carried out immediately before (10.00 h) and serially until 6 h after each challenge. The overall mean stride length was significantly greater in relation to the subsequent (679 mm) than the initial (517 mm) placebo challenge. Moreover, stride length immediately before the challenges was significantly greater on the subsequent occasions. Improved performance, also seen for free walking speed, was not explained by plasma levodopa or 30MD concentrations. In the initial challenges, the mean increment in stride length achieved by active treatment, as compared with placebo, did not differ significantly between the one (210 mm) and two (235 mm) tablet doses of Sinemet CR: a maximal response had been obtained.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of treatment at night with S-1452, a thromboxane A2 receptor antagonist, on the morning rise in platelet aggregation. It is well known that platelet aggregation shows a morning rise, which may contribute to the increase in the onset of ischaemic heart diseases during the morning period. The present study was undertaken to determine whether nocturnal dosage with S-1452, a thromboxane A2 receptor antagonist, would blunt the morning rise in platelet aggregability. S-1452 50 mg or placebo were given orally to 8 healthy subjects at 10.00 h (day trial) or 22.00 h (night trial) according to a cross-over design. Plasma concentrations of S-1452 and its metabolites, bisnor-(+)-S-145 and tetranor-(+)-S-145, and platelet aggregation were determined during the 12-hour period following the dose. Mean plasma concentrations of S-1452, bisnor-(+)-S-145 and tetranor-(+)-S-145 during the absorption phase were lower after the nocturnal dose than after the morning dose. The maximum plasma concentration and area under the plasma concentration-time curve of the compounds were also lower and the time to the maximum concentration were delayed after the treatment at night. A morning rise in platelet aggregation was observed following placebo treatment. The inhibitory effect of S-1452 on platelet aggregation was observed at 3 hours and persisted for up to 9 h in both trials. The results suggest that S-1452 is absorbed more slowly after the nocturnal dose than after the morning dose. However nocturnal treatment with 50 mg S-1452 may blunt the morning rise in platelet aggregability.


Influence of food on the tyramine pressor effect during chronic moclobemide treatment of healthy volunteers. An open study was carried out to examine the effect of moclobemide, a new antidepressant reversible inhibitor of MAO-A, on the pressor response induced by oral tyramine added to meals of different lipid and protein composition, and to correlate the blood pressure increase in the tyramine test with that obtained during an exercise test. Eight healthy volunteers of both sexes participated in the study. A tyramine sensitivity and an exercise test were performed beforehand. Subjects were included if, under fasting condition, their systolic blood pressure (SBP) increased by more than 30 mmHg after administration of 400 or 600 mg tyramine. Exercise tests were performed to determine the grade of effort that corresponded to a rise in SBP of 30 mmHg. Subjects received moclobemide 600 mg/d. Starting on Day 7, each subject consumed a standardized meal (52 g lipids, 43 g proteins, 86 g carbohydrates) just before taking moclobemide. Tyramine was added to these meals in daily increasing doses of 50, 100, 150...mg until an increase in SBP > or = 30 mmHg was obtained. On moclobemide treatment, an average dose of 250 mg tyramine (range 150-400 mg) increased SBP by 36.6 mmHg. The time to reach peak SBP was longer (175 min) than in the fasting condition before the trial (40.6 min).(ABSTRACT TRUNCATED AT 250 WORDS)


Quantification of tissue distribution of antibiotics by kinetic hysteresis analysis. Distribution of antibiotics can be described by kinetic hysteresis analysis when concentrations are measured in the serum and an extravascular sampling site. By calculating the area of the hysteresis loop (a simple formula is presented), the relative amount of drug transferred to an extravascular site can be quantified. With this approach, changes in disposition characteristics can be evaluated under various pathophysiological conditions. In addition, a specific distribution coefficient may be derived for any drug when different dose levels are studied under identical conditions. Kinetic hysteresis analysis overcomes the drawback of conventional compartment model pharmacokinetic analysis, since no simultaneous fitting of two different concentration-time courses is feasible.


Penetration of tinidazole into skin blister fluid following its oral administration. Plasma and skin blister fluid concentrations of tinidazole following a single oral dose of 2 g drug, and after multiple doses of 0.25 g every 12 h, were determined. Skin blisters were produced by direct application of 0.25% cantharidin ointment to the skin. The maximum concentration in plasma of about 36 mg.l-1 was observed after about 2 h, whereas in skin blister fluid the peak occurred after about 6 h and was 30 mg.l-1. The half-life in plasma was slightly shorter than in blister fluid at 17 and 19 h, respectively, but the difference was not significant. The penetration of tinidazole into cantharidin-induced skin blister fluid, defined according to Wise as the ratio of the AUCs in blister fluid and plasma was 1.00. During routine treatment with tinidazole (0.25 g every 12 h), the concentrations in plasma and blister fluid collected before and 3 h after the morning dose exceeded the minimal inhibitory concentrations for susceptible pathogens. The results provide a pharmacokinetic basis for the proven efficacy of tinidazole in the treatment of protozoal and anaerobic infections.


Intracolonic bioavailability of human calcitonin in man. Human calcitonin (hCT) injected into the lumen of the descending colon of normal human subjects was absorbed within minutes and could be recognized intact in plasma as shown by RIA in combination with reverse-phase HPLC. The absorption was low and variable, with bioavailabilities ranging from 0.01% to 2.7% relative to intravenously administered hCT (area under the concentration-time curve). With intravenous hCT serum calcium was lowered and the fractional urinary excretion of calcium, phosphorus, sodium and chloride was significantly stimulated. With the intracolonic hCT, the fractional urinary excretions of calcium, sodium and chloride were also marginally stimulated relative to intracolonic vehicle (placebo). In conclusion, hCT is absorbed intact from the colon, but the bioavailability is low and highly variable.


Human pharmacokinetics of an analogue of atrial natriuretic factor. The pharmacokinetics of ANP-270, a 26 amino acid analogue of alpha human natriuretic factor (alpha-hANF) with a prolonged effect on isolated arterial preparations, has been studied in 40 healthy males, in a double-blind placebo controlled investigation. Placebo or ANP-270 0.3, 1.5 or 3.0 micrograms/kg were given by intravenous bolus injection, each to groups of 10 subjects. Blood samples were assayed for ANP-270 by a specific sandwich ELISA. The disappearance of ANP-270 from plasma followed a two-compartment decay, with mean distribution and elimination half-lives of 2.6 min (n = 30) and 10.6 min (n = 20), respectively. These estimates were similar to those obtained by other investigators for alpha-hANF. Their brevity explains the lack of a prolonged effect of ANP-270 in vivo compared to alpha-hANF.


Menstrual cycle effects on caffeine elimination in the human female. Increases in the levels of sex steroids due to pregnancy or oral contraceptive steroid use are known to decrease significantly the rate at which caffeine is eliminated from the body. An investigation has now been made into whether the changes in sex steroid levels that occur during normal menstrual cycling also affect the rate of caffeine elimination, especially whether hormonal shifts in the luteal phase are associated with slower elimination of caffeine. Repeated 24-hour caffeine elimination studies were conducted during the follicular and luteal phases of the menstrual cycle in 10 healthy women. Comparisons of the follicular and luteal phases revealed that systemic clearance of caffeine was slower in the luteal phase, although the t1/2 did not differ. The slowing effect was related to the proximity to onset of menstruation and to levels of progesterone. The evidence suggests that caffeine elimination may be slowed in the late luteal phase, prior to the onset of menstruation. Such a reduction would lead to increased accumulation of caffeine with repeated self-administration during the day, but the effect may be too small to be of clinical significance in the majority of women.


Exercise and the pharmacokinetics of propranolol, verapamil and atenolol. The volumes of distribution of the beta-adrenoceptor blocking agents propranolol and atenolol, and the calcium antagonist verapamil, during exercise have been investigated. Changes in the plasma concentrations of atenolol and propranolol during exhaustive exercise at 70% of maximal aerobic power were compared after 1 week of oral treatment (propranolol 80 mg b.d. and atenolol 100 mg once daily) in 12 healthy volunteers. In a second study the effect of 10 min exercise at 50% of maximal aerobic power on steady state plasma concentrations of propranolol, atenolol and verapamil was compared in 7 healthy subjects. The drugs were administered by a continuous intravenous infusion. The plasma concentration of atenolol was not changed by exercise in either study, but the plasma concentrations of propranolol and verapamil were significantly increased in both studies. However, after correction for changes in plasma volume during exercise, the plasma propranolol concentration was not significantly elevated in the second study. From the results it is concluded that exercise led to a reduction in the volume of distribution of propranolol during prolonged exercise (25 min) at 70% Wmax, which was not clearly demonstrable during 10 min exercise at 50% Wmax. The volume of distribution of verapamil was reduced during 10 min exercise at 50% Wmax. No change in the volume of distribution of atenolol during exercise could be shown. The changes in the volumes of distribution of propranolol and verapamil during exercise may contribute to preventing an increase in the half-life of these drugs in patients performing prolonged physical exercise.


Serum concentration-effect relationship of (+/-)-nicardipine and nifedipine in elderly hypertensive patients. The concentration-effect relationships of (+/-)-nicardipine and nifedipine have been investigated in hypertensive geriatric patients. Following a parallel group, randomised, double blind trial design, they received either slow release nifedipine 20 mg b.d. (n = 9) or slow release (+/-)-nicardipine 50 mg b.d. (n = 10) for 7 days. On Days 1 and 7 serum (+/-)-nicardipine and nifedipine, blood pressure and heart rate were measured 6 and 12 h after drug administration. (+/-)-Nicardipine showed significant cumulation (ca 2 x) without a corresponding decrease in blood pressure or increase in heart rate. Concentration-effect plots indicated that (+/-)-nicardipine was more potent than nifedipine but that it showed apparently comparable efficacy in reducing the blood pressure. Compared to young healthy volunteers, both drugs had a more pronounced effect in elderly patients.


Effect of propranolol on urinary prostaglandin E2 excretion and renal interlobar arterial blood flow after furosemide administration in patients with hepatic cirrhosis. The effect of propranolol on furosemide-stimulated urinary prostaglandin E2 (PGE2) excretion and renal blood flow was evaluated in 12 patients with alcoholic liver cirrhosis. Plasma and urine were collected before and 60 min after furosemide 20 mgI with or without propranolol pretreatment, and plasma renin activity (PRA), plasma aldosterone concentration (PAC), urinary excretion of PGE2 and sodium were determined. The renal interlobar arterial Pulsatility Index (PI), as an index of resistance to blood flow, was also determined before and 60 min after furosemide administration with and without propranolol pretreatment, by using a duplex Doppler ultrasound (Hitachi EUB 565). Urine volume and sodium excretion after furosemide administration were not influenced by the propranolol pretreatment. Furosemide administration significantly increased urinary PGE2 excretion, PRA and PAC, and these effects were significantly reduced by propranolol. Furosemide administration with or without propranolol significantly reduced renal interlobar arterial PI, the average reduction in PI being significantly lower after furosemide administration with propranolol pretreatment. The results demonstrate that propranolol pretreatment significantly influenced the furosemide-induced increase in urinary PGE2 excretion and renal interlobar arterial blood flow in cirrhotic patients.


Pharmacokinetics of famotidine in patients with cirrhosis and ascites. The pharmacokinetics of famotidine has been investigated in ascitic cirrhotic patients. 10 decompensated cirrhotic patients were studied (9m, 1f), who had normal renal function, and six healthy control subjects (4m, 2f), matched for age, sex and weight. Each subject received on two occasions, at least four days apart, a single oral (40 mg) or intravenous dose (20 mg) of famotidine, at 21.00 h in a randomised manner. Serial blood samples were collected and famotidine in plasma was determined by a HPLC/UV method. Plasma data were subjected to non compartmental pharmacokinetic analysis. There were no statistically significant differences in pharmacokinetic parameters between the two groups after either the intravenous or oral administration of famotidine. The findings suggest that the dose of famotidine may not require any adjustment in ascitic patients without renal failure.


Correlations between theophylline concentrations in plasma, erythrocytes and cantharides-induced blister fluid and peak expiratory flow in asthma patients. Theophylline levels in plasma, erythrocytes and cantharides-induced blister fluid (BF) have been correlated with peak expiratory flow (PEF) in asthmatic patients. Nine asthmatic men received an IV infusion of 240 mg theophylline at a constant rate for 30 min. The theophylline concentrations in erythrocytes and blister fluid were 37% and 78% of those in plasma. There was not a strong correlation between erythrocyte or blister fluid penetration and the clinical effect of theophylline.


Effect of tetracycline on mefloquine pharmacokinetics in Thai males. The kinetics of a single oral dose of mefloquine given either alone or with tetracycline has been studied in 20 healthy Thai male volunteers. There was a significantly higher maximum whole blood mefloquine concentration after coadministration with tetracycline (1600 vs 1160 ng.ml-1), as well as a significantly reduced terminal half-life (14.4 vs 19.3 days), mean residence time (11.9 vs 16.0 days) and volume of distribution at steady state (13.3 vs 19.9 1.kg-1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 7 days was significantly increased by tetracycline (6.18 vs 4.76 micrograms.ml-1.day). The changes in mefloquine disposition after tetracycline treatment are probably due to a reduction in enterohepatic recycling. The initial increase in mefloquine AUC without an apparent increase in side-effects suggests that this combination may have a place in the treatment of multi-drug resistant falciparum malaria.


Image analysis of the lens opacities induced in developing chick embryo by glucocorticoid. Glucocorticoid-induced cataracts in chick embryos were monitored by an image analysis system. Opacities in the lens visually showed a complex pattern with significant changes in the cortical and nuclear regions. An electronic image analyser produced an image in which contrast represented different zones of lens opacification in the frontal plane and documented objective lens findings such as the precise topography of the opacities, density and opacity measurements, geometric measurements of boundary surfaces and of regional areas. Parameters of lens clouding were evaluated quantitatively by measuring the optical density index and the area of the zones of clouding outlined with equi-densities. The light intensity standard graded different morphological areas of the lens into up to 256 grey levels. The data were entered and stored quantitatively into a computer. The lens images thus picked up by the TV camera and digitally stored in a frame buffer of the measuring system could be reliably transformed into a 2-D or 3-D picture of lens clouding. The approach demonstrated by the current study provides a sensitive and meaningful measure of cataractous changes for lens laboratory research.


Spatial buffering of extracellular potassium by Müller (glial) cells in the toad retina. We examined the role of Müller (glial) cells in buffering light-evoked changes in extracellular K+ concentration, [K+]o, in the isolated retina of the toad, Bufo marinus. We found evidence for two opposing Müller cell current loops that are generated by a light-evoked increase in [K+]o in the inner plexiform layer. These current loops, which are involved in the generation of the M-wave of the electroretinogram (ERG), prevent the accumulation of K+ in the inner plexiform layer by transporting K+ both to vitreous and to distal retina. In addition, under dark-adapted conditions, we found evidence for a Müller cell current loop that is generated by a light-evoked decrease in [K+]o in the receptor layer. This current loop, which is involved in the generation of the slow PIII component of the ERG, helps to buffer the light-evoked decrease in [K+]o throughout distal retina by transporting K+ from vitreous. The spatial buffering fluxes of K+ can be abolished by blocking Müller cell K+ conductance with 200 microM Ba2+. The separate contributions of the M-wave and slow PIII currents to Müller cell spatial buffering were isolated by various pharmacological treatments that were designed to enhance or suppress light-evoked activity in specific retinal neurons. Our results show that Müller cell K+ currents not only buffer light-evoked increases in [K+]o, but also buffer light-evoked decreases in [K+]o, and thereby diminish any deleterious effects upon neuronal function that could arise in response to large changes in [K+]o in the plexiform layers. Moreover, our results emphasize that spatial buffering currents generate many components of the electroretinogram.


Age-dependent loss of the C-terminal amino acid from alpha crystallin. Antiserum made against the C-terminal region of alpha-A crystallin was used to monitor the purification of a tryptic peptide containing the C-terminus of the molecule from fetal versus adult bovine lenses. Mass spectral analysis of the peptide preparations obtained from these lenses demonstrated the presence of a peptide (T20) containing an intact C-terminus from fetal lenses and the presence of an additional peptide (T20') from older lenses that contained a cleaved C-terminal serine. These results demonstrate an age-dependent processing of alpha-A crystallin in the bovine lens, resulting in removal of the C-terminal amino acid residue.


Retinal pigment epithelial cell transplantation in RCS rats: normal metabolism in rescued photoreceptors. Photoreceptor cells in Royal College of Surgeons (RCS) rats with inherited retinal dystrophy can be rescued by the transplantation of normal, wild-type retinal pigment epithelial (RPE) cells, if done before photoreceptor cell death. In the present study, we have examined several metabolic features of rescued photoreceptors and transplanted RPE cells at 2.3-3.3 months after transplantation. Rescued photoreceptors with a structurally normal RPE interface showed a rod outer segment renewal rate similar to that of normal control rats of 2.2 microns day-1, as measured in autoradiograms. Rod outer segment disc shedding had values indistinguishable from those in normal controls, as measured by the number of phagosomes in the transplanted RPE cells both during the burst of disc shedding soon after the onset of light in the morning and during the middle of the light cycle when disc shedding is low. The interphotoreceptor matrix, which is synthesized by both photoreceptors and the RPE, was distributed normally in the regions where normal-appearing photoreceptors were present underlying normal, transplanted RPE cells. Thus, the rescued photoreceptors show normal metabolic rates and normal interactions with the RPE in each of the parameters examined. These findings, combined with the previous demonstration of opsin and Na+,K(+)-ATPase expression by the rescued photoreceptors, support our interpretation that the surviving, normal-appearing photoreceptors may function normally. Moreover, transplantation of normal RPE cells reversed pathological changes in the photoreceptors that had already occurred by the time of transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)


Kinetic properties of the bovine corneal aldehyde dehydrogenase (BCP 54). The major soluble protein of bovine cornea (BCP 54: bovine corneal protein 54 kDa) was isolated successively by gel filtration, anion-exchange chromatography and chromatofocusing. The amino acid sequence of a fragment of the purified BCP 54 obtained by lysyl-endopeptidase digestion showed marked homology with tumor-associated and 2,3,7,8-tetrachloro-dibenzo-p-dioxin-inducible aldehyde dehydrogenase (AIDH). From the high similarity of BCP 54 with tumor-associated AIDH in structural form, it is suggested that BCP 54 has AIDH activity. We confirmed a high AIDH activity of BCP 54 by immunoprecipitation using a mouse anti-BCP 54 monoclonal antibody followed by a spectrophotometric assay for AIDH activity. Next we demonstrated the unique properties of the purified BCP 54 as AIDH. The major isoelectric point is 6.41. BCP 54 preferentially oxidizes aromatic aldehyde such as benzaldehyde with NAD as coenzyme, but cannot oxidize phenylacetaldehyde. After heat treatment the AIDH activity is more stable with propionaldehyde-NAD than with benzaldehyde-NADP. With propionaldehyde-NAD the pH profile shows a broad plateau from pH 6-9 followed by a sharp rise up to pH 10. In contrast, with benzaldehyde-NADP there is a sharp optimum at pH 9.0. The activity with only benzaldehyde-NADP is inhibited by p-hydroxymercuribenzoate, but is not affected by disulfiram and diethylstilbestrol. So we suggested that BCP 54 is an AIDH with kinetic properties different from the rat tumor-associated AIDH.


Proteinase K decreases Pseudomonas aeruginosa adhesion to wounded cornea. The present study was designed to obtain further information regarding the molecular nature of the corneal receptor(s) facilitating Pseudomonas aeruginosa adhesion to cornea. Scarified adult mouse corneas in organ culture were treated for 10 or 60 min with a panel of lipase-free proteases [each at 20 micrograms ml-1 or 0.22 Units (U) ml-1, activity] including trypsin, chymotrypsin, V8 protease, elastase, subtilisin A, pronase protease and proteinase K. All of these, except proteinase K treatment (20 micrograms ml-1 for 60 min), either significantly elevated or had no effect (proteinase K 20 micrograms ml-1 for 10 min) on subsequent bacterial adhesion at 60 min following topical application of the inoculum to the scarified corneal surface. Enzyme treatment times of 10, 30 or 60 min at a higher concentration (50 micrograms ml-1) of proteinase K, significantly decreased binding at 60 min after bacterial application for each enzyme treatment time. The combined effects of proteases and lipase on bacterial binding also was examined. Eyes treated with proteinase K (20 micrograms ml-1 for 1 hr) or protease-free lipase (50,000 U ml-1 for 1 hr) alone or in combination, all reduced bacterial binding, but the effect was not additive. Trypsin or lipase alone significantly enhanced or decreased binding, respectively. In contrast, trypsin (20 micrograms ml-1 for 1 hr) followed by lipase treatment (50,000 U ml-1 for 1 hr) resulted in binding which was not significantly different than phosphate-buffered saline (PBS) control binding, indicating that the trypsin exposed receptor was lipase sensitive.(ABSTRACT TRUNCATED AT 250 WORDS)


In vitro galactosylation of rhodopsin and opsin: kinetics, properties and characterization. At best, only trace amounts of galactose have been detected as constituents of rhodopsin as analysed by several laboratories. Nevertheless, the enzymatic galactosylation of rhodopsin proceeds readily in vitro, a process which can be catalysed by galactosyltransferases from several sources. Little information is available, however, concerning the properties of the in vitro reaction. We have examined characteristics of the latter process with the hope of shedding light on the capacity of the retina to carry out this reaction. Kinetic properties of the galactosyltransferases of bovine and embryonic chick retinas, bovine milk and rat liver-Golgi were examined using rhodopsin, opsin, N-acetylglucosamine and ovalbumin as exogenous acceptors. All of these studies demonstrated the very limited activity of the galactosyltransferases of the retina as compared to the milk and rat liver systems. The subcellular distribution of the galactosyltransferases of bovine retina was examined. The influence of compounds that might modulate the reaction was also examined. alpha-Lactalbumin, a modifier of the galactosyltransferase in milk, acted as a competitive inhibitor of the galactosylation of opsin. Analogs of vitamin A, shown to inhibit galactosyltransferases in other systems, did not have this effect on the galactosylation of opsin. Similarly, mixing experiments could not demonstrate the presence of endogenous material that inhibited the reaction in the retina. The conformation of the visual pigment was shown to influence the reaction. After bleaching by visible light, opsin was preferred over rhodopsin as an acceptor of galactose by the galactosyltransferases of bovine and embryonic chick retinas and by rat liver. This distinction was only minimally demonstrated by the milk enzyme. The galactosylation of ovalbumin was unaffected by conditions of light or dark by any of the enzymes. While the mode ratio of galactose to rhodopsin after catalysis by the milk enzyme was about 1.6, this ratio was only about 0.01 after reaction with the enzyme from bovine retina. The linkage of galactose in enzymatically galactosylated rhodopsin and opsin was beta(1-4).


Cell death in the rat retina after a pressure-induced ischaemia-reperfusion insult: an electron microscopic study. I. Ganglion cell layer and inner nuclear layer. In rats, a pressure-induced ischaemia-reperfusion insult can lead to retinal cell death. In order to elucidate the underlying mechanisms, we performed a qualitative study of the ultrastructural morphology of degenerating retinal cells in the ganglion cell and inner nuclear layers at several time points after the insult. Three morphologically distinct types of cell death could be individualized. Type I was characterized by progressive karyo- and cytolysis and was consistent with necrosis. Type II exhibited progressive shrinkage and condensation of the nuclear and cytoplasmic components followed by heterophagic elimination, thus resembling apoptosis. Type III was characterized mainly by homogenization of the nucleoplasm and cytoplasm and dilation of the perinuclear cisternae and endoplasmic reticulum, thus showing features of 'non-lysosomal vesiculate' cell death. This study lends support to the concept that there may exist a fair but limited number of types of cell death in the retina.


Colloid osmotic pressure of steer crystallins: implications for the origin of the refractive index gradient and transparency of the lens. The osmotic behavior of soluble cortical and nuclear steer lens crystallins was characterized by secondary osmometry for several ionic strength and pH conditions. Osmotic pressure versus protein concentration relationships were measured for pressures up to 1.15 x 10(6) dyn cm-2. At low concentrations (< 0.2 g ml-1), the osmotic pressure increased linearly with pressure, whereas for concentrations above 0.2 g ml-1, the pressure rose more sharply, giving progressively larger changes in osmotic pressure with increasing crystallin concentration. At a given ionic strength and applied osmotic pressure, the nuclear proteins attained a higher protein concentration than did the cortical proteins. For example, at the highest osmotic pressure of 1.15 x 10(6) dyn cm-2 at pH 7.6 and 0.1 M ionic strength, the observed protein concentrations were 0.43 g ml-1 for the cortical proteins and 0.52 g ml-1 for the nuclear proteins. For both cortical and nuclear steer crystallins, the pressure rose more steeply with concentration than do pressures for calf crystallins described in the literature. The impact of these developmental differences in osmotic pressure on lens transparency is discussed. Both the nuclear and cortical crystallins exhibited ionic strength-dependent shifts in their pressure-concentration behavior. At 0.02 M ionic strength, higher pressures were observed, whereas at 0.4 M ionic strength lower pressures were observed for a given protein concentration. The crystallins were also found to equilibrate to different protein concentrations at a constant osmotic pressure and 0.1 M ionic strength over a pH range of 4-9, with a maximum concentration around pH 5 for the cortical crystallins and pH 6 for the nuclear crystallins. Thus, the adult bovine cortical and nuclear soluble lens extracts are different in their osmotic properties, reflecting underlying differences in protein composition. The results of the ionic strength and pH experiments suggest that hard-sphere, electrostatic, and Donnan forces contribute to the total colloid osmotic pressure of the lens crystallins. However, near physiologic pH and ionic strength the charges of the proteins are screened to the extent that the colloid osmotic pressure exhibits only minor changes for large changes in ionic conditions. The differences in the osmotic behavior of the cortical and nuclear proteins are consistent with a model where regional variations in the colloid osmotic properties of the proteins across the lens help support the radial refractive index gradient that is present in vertebrate lenses. The importance of a radial concentration gradient of metabolites is also discussed.


Profile of messenger RNA decay in the Emory mouse lens in cataractogenesis and in aging. The Emory mouse is presumed to be a model for studies on human senile cataracts. The cataract develops in 5-8 months after birth, and it does not appear to have an osmotic component. To date, no specific metabolic lesion has been uncovered as a probable cause to this cataract. Several studies have shown that the Emory mouse undergoes accelerated aging changes, possibly leading to development of senile-type cataracts. In this study we quantitated changes that might occur in the population of various mRNAs for proteins presumed to be essential for lens transparency, and for proteins that may contribute to development of cataracts. By Northern blot hybridization analysis we quantitated the mRNAs for: alpha A-crystallin, beta B1-crystallin, gamma-crystallin, the main lens intrinsic membrane protein, MP26, and aldose reductase; all in lenses of Emory mouse early cataract strain (EMEC), and of an age-matched cataract resistant strain (CR). These measurements were done in increments of 1 month over a 6-month period, then at both 9 and 12 months. The results show that all of these mRNAs decrease with age and with development of cataracts; although in some cases the initial concentrations at 1 month appear to be lower in the EMEC than in the CR strain. The most dramatic change occurred with the MP26 mRNA. In the CR strain, MP26 mRNA maintained its high concentration for a period of about 6 months before it began its decline to the 12 month level (about 25% of the 1 month level).(ABSTRACT TRUNCATED AT 250 WORDS)


The microchemical detection of carbonic anhydrase in corneal epithelia. Carbonic anhydrase (CA) activity has been detected and quantified in the corneal epithelia of various mammalian species using a microchemical assay. The highest levels were found in the rabbit, followed by man, dog, sheep, and cat. Enzyme levels in the rabbit epithelium were approximately one-third the amount found in the endothelium, perhaps explaining earlier failures to find CA in the epithelium. Selective inactivation of CA-II in tissue homogenates with bromopyruvic acid allowed determination of CA-I/CA-II ratios. The ratios in corneal epithelia from two species (rabbit and dog) approximated that in the erythrocyte. Although CA levels in the epithelium are low they are perhaps functional in the transfer of CO2 across the cornea.


Role of primate basal ganglia and frontal cortex in the internal generation of movements. I. Preparatory activity in the anterior striatum. The purpose of these studies was to investigate neuronal activity in the basal ganglia and frontal cortex in relation to the internal generation of goal-directed movements. Monkeys performed goal-directed arm movements at a self-chosen moment in the absence of phasic stimuli providing external temporal reference. They were rewarded with a small morsel of food for each movement, although automatic or repetitive behavior was not reinforced. For reasons of comparison, animals were also trained in a delayed go no-go task in which visual cues instructed them to perform or refrain from an arm movement reaction to a subsequent trigger stimulus. This report describes the activity of neurons in the head of the caudate nucleus and rostral putamen preceding self-initiated arm movements and compares it with instruction-induced preparatory activity preceding movements in the delay task. A total of 497 caudate and 354 putamen neurons were tested in the delay task. Two types of preparatory activity were observed: (1) transient responses to the instruction cue, and (2) sustained activity preceding the trigger stimulus or movement onset. Transient responses were found in 48 caudate and 50 putamen neurons, occurring twice as often in movement ('go') as compared to no-movement ('no-go') trials, but rarely in both. These responses may code the information contained in the instruction relative to the forthcoming behavioral reaction. Sustained activity began after instruction onset and lasted until the trigger stimulus or the arm movement occurred, this being for periods of 2-7 s, 12-35 s, or up to 80 s, depending on the task requirements. This activity was seen in 47 caudate and 45 putamen neurons, was largely confined to go trials, and was unrelated to the preparation of saccadic eye movements. In some cases, this activity began as direct responses to the instruction stimulus, but in the majority of cases developed more gradually before the movement. Thus, both transient and sustained activations appear to be related to the preparation of movements. A total of 390 caudate and 293 putamen neurons were tested during self-initiated movements. Activity preceding earliest movement-related muscle activity was found in 32 caudate and 42 putamen neurons. This premovement activity began 0.5-5.0 s before movement onset (median 1160 ms), increased slowly, reached its peak close to movement onset, and subsided rapidly thereafter. It was unrelated to the preparation of saccadic eye movements. Comparisons between the two tasks were made on 53 neurons.(ABSTRACT TRUNCATED AT 400 WORDS)


Role of primate basal ganglia and frontal cortex in the internal generation of movements. II. Movement-related activity in the anterior striatum. In order to more comprehensively assess the role of the basal ganglia in the internal generation of movements, we studied the activity of neurons in the head of the caudate and in the rostral putamen in relation to the execution of movements. Monkeys performed self-initiated and stimulus-triggered arm reaching movements in separate blocks of trials. With stimulus-triggered movements, 217 striatal neurons increased their activity after the trigger stimulus (127 in caudate, 90 in putamen). Of these, 68 neurons showed time-locked responses to the trigger stimulus, with a median latency of 60 ms, that were independent of visual or auditory stimulus modalities. Three quarters of responses were conditional on a movement being performed. These responses may participate in neuronal processes through which the reception of a stimulus is translated into the execution of a behavioral reaction. Further, 44 neurons increased their activity before the earliest muscle activity without being clearly time-locked to the stimulus (148-324 ms before movement onset), 55 neurons were activated later before the movement, and 50 neurons were activated after movement onset. With self-initiated movements, 106 striatal neurons showed movement-related activity beginning up to 460 ms before movement onset (52 in caudate, 54 in putamen). Comparisons between the two types of movement were made on 53 neurons with premovement activity beginning more than 500 ms before self-initiated movements. Only one fifth of them also showed movement-related activity with stimulus-triggered movements, including trigger responses. Comparisons among 39 neurons with movement-related activity during self-initiated arm movements showed that about half of them also showed movement-related activity with stimulus-triggered movements. These data demonstrate a considerably segregated population of striatal neurons engaged in the internal generation of movements, whereas processes underlying the execution of movements appear to involve overlapping neuronal populations.


Role of primate basal ganglia and frontal cortex in the internal generation of movements. III. Neuronal activity in the supplementary motor area. This study is a part of a project investigating neuronal activity in the basal ganglia and frontal cortex and describes externally and internally induced preparatory activity in the supplementary motor area (SMA), which forms a closed neuronal loop with the striatum. Monkeys made self-initiated arm reaching movements toward a constant target in the absence of phasic external stimuli. In separate blocks of trials, animals performed in a delayed go no-go task in which an instruction cue prepared for subsequent movement or no-movement to a trigger stimulus. A total of 328 neurons were tested in the delay task. Of these, 91 responded transiently to the instruction light with a median latency of 262 ms. Three quarters of these responses were restricted to the instruction preparing for arm movement, as opposed to withholding it, and thus may be involved in movement preparation processes. Sustained activation during the instruction-trigger interval was found for 67 neurons and occurred nearly exclusively in movement trials. Activation usually increased gradually after the cue and ended abruptly upon movement onset and thus could be related to the setting and maintenance of processes underlying the preparation of movement. Time-locked responses to the trigger stimulus were found in 38 neurons and were usually restricted to movement trials (median latency 80 ms). Activity time-locked to movement execution occurred in 67 neurons, beginning up to 252 ms before movement onset. A total of 266 neurons were tested with self-initiated arm movements. Of these, 43 showed premovement activity beginning 610-3030 ms before movement onset (median 1430 ms). The activity increased slowly and reached its peak at 370 ms before movement onset. It ended before movement onset or continued until the arm began to move or reached the target. This activity appears to reflect neuronal processes related to the internal generation of movements. Two thirds of activations preceding self-initiated movements occurred in neurons not activated before externally instructed movements, suggesting a selectivity for the internal generation process. Activity related to the execution of self-initiated movements occurred in 67 neurons: it began during and up to 420 ms before movement onset and was usually not associated with premovement activity. Most of these neurons were also activated with stimulus-triggered movements, suggesting a lack of selectivity for the execution of self-initiated movements. In comparison with the striatum, more SMA neurons showed preparatory activity preceding externally instructed movements (transient 27% vs 16%, sustained 20% vs 12%) and self-initiated movements (16% vs 11%).(ABSTRACT TRUNCATED AT 400 WORDS)


Difference in receptive field features of taste neurons in rat granular and dysgranular insular cortices. Receptive fields (RFs) of 59 cortical taste neurons (35 in the granular insular area, area GI, 21 in the dysgranular insular area, area DI, and 3 in the agranular insular area, area AI) were identified in the oral cavity of the rat. The fraction of the neurons with RFs in the anterior oral cavity only was significantly larger in area GI (74.3%) than in area DI (42.9%). On the other hand, the fraction of neurons with RFs in both the anterior and posterior oral cavity was larger in area DI (42.9%) than in area GI (11.4%). On the whole, it is suggested that area GI is involved in discrimination of several taste stimuli in the oral cavity, whereas in area DI taste information originating from various regions of the oral cavity is integrated. When neurons were classified according to the best stimulus which most excited the neuron among the four basic tastes, different categories of taste neurons had RFs in different parts of the oral cavity. It is suggested that, in either taste area, different categories of taste neurons are involved in different sorts of taste coding. The majority of neurons in both areas had bilateral RFs. In area GI, neurons with RFs on single subpopulations of taste buds were significantly more numerous at the rostral region of the cortex than at the caudal region. There was no such relation between RF types and cortical localization in area DI. Otherwise, topographic representation of the oral cavity by taste neurons on the cortical surface was not obvious. RF features of taste neurons did not differ across layers in either cortical area.


Difference in taste quality coding between two cortical taste areas, granular and dysgranular insular areas, in rats. The responses of 84 taste neurons to stimulation of the oral cavity in rats were examined; most taste neurons were found in either a granular insular area (area GI; n = 55) or dysgranular insular area (DI; n = 25), and the others (n = 4) were in an agranular insular area (area AI). The fraction of neurons responding to only one of the four basic stimuli was significantly larger in area GI than in area DI. When neurons were classified by the stimulus which most excited the neuron among the four basic stimuli, every "best-stimulus category" of neurons was found in both GI and DI areas. Quinine-best and "multistimulus-type" neurons, whose responses to some non-best stimulus exceeded 90% of the maximum, were more numerous in the cortex than in the thalamocortical relay neurons. When responses were plotted against taste stimuli arranged in the order of sucrose, NaCl, HCl, and quinine along the abscissa (taste coordinate), response profiles of taste neurons often showed two peaks. The double-peaked type of response profiles were found in every best-stimulus category of neurons in both areas; though, a significantly large fraction of quinine-best neurons in area GI were of the double-peaked type. Some taste neurons in area GI (n = 21) and in area DI (n = 7) were inhibited by one to two taste stimuli, particularly by the stimuli present next to the best one along the taste coordinate. In correlation profiles--correlation coefficients between sucrose and NaCl and between HCl and quinine--pairs of stimuli which were located next to each other on the taste coordinate were significantly smaller in area GI than in area DI. It is thus highly probable that area GI plays an important role in fine taste discrimination and area DI in integration of taste information.


A comparison of monaural and binaural responses to frequency modulated (FM) sweeps in cat primary auditory cortex. Monaural and binaural single unit responses to frequency-modulated (FM) sweeps were compared in cat primary auditory cortex (AI). Both upward-directed (changing from low to high frequency) and downward-directed (changing from high to low frequency) FM sweeps were presented monaurally and binaurally at five rates of frequency modulation (referred to here as the speed of FM sweep). Two types of binaural FM sweep conditions were presented: (1) like-directed FM sweeps, in which identical FM sweeps were presented to both ears, and (2) opposite-directed FM sweeps, in which one ear was presented with one direction of FM sweep while the other ear was simultaneously presented with the opposite direction of FM sweep. In a sample of 78 cells, 33 cells were classified as EE (binaural facilitatory) and 45 were classified as EI (binaural inhibitory). Ninety-four percent of all units were sensitive to the direction and/or speed of FM sweeps. In general, under binaural stimulus conditions, EE cells responded optimally to like-directed FM sweeps, while EI cells preferred opposite-directed FM sweeps. When tested monaurally, 59% of all cells (both EE and EI) were direction selective, with the majority (76%) preferring downward-directed FM sweeps. When tested binaurally, most direction selective EE cells (60%) preferred upward-directed FM sweeps, while the majority of direction selective EI cells (71%) preferred downward-directed FM sweeps. Our analysis also allowed us to classify inhibitory responses of EI cells as either direction selective (37%) or non-direction selective (63%). For FM speed selectivity under monaural conditions, most EE cells preferred fast FM sweep rates (0.4-0.8 kHz/ms), while approximately equal numbers of EI cells preferred either slow (i.e., 0.05-0.1 kHz/ms) or fast (i.e., 0.4-0.8 kHz/ms) speeds. Under binaural conditions, the majority of EE and EI cells responded best to high speeds when tested with like-directed FM sweeps, while the preferred speed with opposite-directed FM sweeps was more broadly tuned. The results suggest the presence of binaural neural mechanisms underlying cortical FM sweep direction and speed selectivity.


How complete is physiological compensation in extrastriate cortex after visual cortex damage in kittens? Previous studies indicate that neurons in the cat's posteromedial lateral suprasylvian (PMLS) visual area of cortex show physiological compensation after neonatal but not adult damage to areas 17, 18, and 19 of the visual cortex (collectively, VC). Thus, VC damage in adults produces a loss of direction selectivity and a decrease in response to the ipsilateral eye among PMLS cells, but these changes are not seen in adult cats that received VC damage as kittens. This represents compensation for early VC damage in the sense that PMLS neurons develop properties they would have had if there had been no brain damage. However, this is only a partial compensation for the effects of VC damage. A full compensation would involve development of properties of the VC cells that were removed in the damage. The present study investigated whether this type of compensation occurs for detailed spatial- and temporal-frequency processing. Single-cell recordings were made in PMLS cortex of adult cats that had received a VC lesion on the day of birth or at 8 weeks of age. Responses to sine-wave gratings that varied in spatial frequency, contrast, and temporal frequency were assessed quantitatively. We found that the spatial- and temporal-frequency processing of PMLS cells in adult cats that had neonatal VC damage were not significantly different from PMLS cells in normal cats. Therefore, there was no evidence that PMLS cells can compensate for VC damage by developing properties that are better than normal and like those of the striate cortex cells that were damaged. We also assessed the effects of long-term VC damage in adult cats to determine whether the normal properties seen in cats with neonatal VC damage represent a compensation for abnormalities in PMLS cortex present after adult damage. In a previous study, we found that acute VC damage in adult cats has small but reliable effects on maximal response amplitude, maximal contrast sensitivity, and spatial resolution (Guido et al. 1990b). In the present study, we found that long-term VC damage in adult cats does not increase these abnormalities as a result of secondary degenerative changes. In fact, the minor abnormalities that were present after an acute VC lesion were virtually absent following a long-term adult lesion, perhaps because they were due to transient traumatic effects. Therefore, there was little evidence for abnormalities in spatial- or temporal-frequency processing following long-term adult VC damage for which PMLS cells might show compensation following long-term neonatal damage.(ABSTRACT TRUNCATED AT 400 WORDS)


Differential effects of long-term transplantation on the growth of cortical neurons containing parvalbumin or calbindin. Numerical density and morphology of the two main GABAergic neuronal classes, the parvalbumin (PV) and calbindin- (CaBP)-containing nerve cells were investigated in long-term neocortical transplants in rats. It was observed that 4 months after the transplantation both CaBP- and PV-immunoreactive neurons survive and grow in neocortical grafts. However, the numerical density of PV cells decreased to about half of the control value (host cortex), while the density of CaBP-positive cells was 25-60% of that seen in the host cortex, depending on the degree of integration of the graft. The mean diameter of PV neurons rose to double of the control value, while the size of CaBP-positive perikarya did not change. This indicates that GABAergic neurons with hypertrophic perikarya (Bragin et al. 1991a) are identical to PV neurons. On the basis of these qualitative and quantitative morphological data it is concluded that PV- and CaBP-containing GABA cells in the transplant exhibit different sensitivities to transplantation-related structural and functional alterations.


Integration of multiple sensory modalities in cat cortex. The results of this study show that the different receptive fields of multisensory neurons in the cortex of the cat anterior ectosylvian sulcus (AES) were in spatial register, and it is this register that determined the manner in which these neurons integrated multiple sensory stimuli. The functional properties of multisensory neurons in AES cortex bore fundamental similarities to those in other cortical and subcortical structures. These constancies in the principles of multisensory integration are likely to provide a basis for spatial coherence in information processing throughout the nervous system.


Regulatory aspects of nigrostriatal dopaminergic neurons. In the urethane-anesthetized rat, electrical stimulation (10 Hz, 30 s, 250 microA) of the medial forebrain bundle (MFB), at 20-min intervals over an 8-h period, combined with intracerebral microdialysis in the striatum caused: an undiminished increase in the release of dopamine (DA) with each stimulation episode; a decreased efflux of 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA) after the first stimulation only; a delayed increased efflux of DOPAC with no change in HVA; and a poststimulation depression of firing of dopaminergic neurons in the substantia nigra (before, 3.1 +/- 0.7 Hz; after, 1.9 +/- 1.0 Hz; P < 0.05). After the last stimulation episode, the release of DA declined to prestimulation values, while the increased efflux of DOPAC persisted for three more hours. After the infusion of tetrodotoxin (4.0 x 10(-7) M, 1.5 microliters, 1.0 microliters/min) into the MFB, the basal release of DA was reduced (P < 0.05), while the efflux of DOPAC and HVA was increased (P < 0.05). A model is proposed suggesting that: (1) during increased release of DA in the striatum, the metabolism of DA is decreased; (2) inhibition of nigrostriatal dopaminergic neurons is the usual cause of increased synthesis and metabolism of DA in the striatum; and (3) increased release of DA, and increased synthesis and metabolism of DA in the striatum are not causally linked and are noncoupled processes.


Experimental study and modeling of vestibulo-ocular reflex modulation during large shifts of gaze in humans. An experimental study of head-free and head-fixed gaze shifts explores the role of the vestibulo-ocular reflex (VOR) during saccadic and slow phase components of the gaze shifts. A systematic comparison of head-free and head-fixed gaze shifts in humans revealed that while the VOR is switched off as soon as the saccade starts, its function is progressively restored during the terminal phase of the saccade. The duration of this restoration period is fairly constant; therefore, the faster the gaze saccade, the sooner the VOR function starts to be restored. On the basis of these experimental data, a new eye-head coordination model is proposed. This model is an extension of the one proposed by Laurutis and Robinson (1986) where VOR gain is a function of both the dynamic gaze error signal and head velocity. This extension has also been added to another eye-head coordination model (Guitton et al. 1990). Both modified models yield simulation results comparable to experimental data. This study pinpoints the high efficiency of the gaze control system. Indeed, a fixed period of time (approximately 40 ms) is needed to restore the inhibited VOR; the gaze control system thus must have a knowledge of its own dynamics in order to be able to anticipate the end of the saccadic movement.


Effects of weak antagonist on fast elbow flexion movements in man. By using a mathematical model and experiments involving electrical simulation of antagonistic muscles, we have formed the hypothesis (Wierzbicka et al. 1986) that in one-joint movements the antagonist muscle not only provides braking torque but also controls movement time. To get additional experimental support for this hypothesis, we studied elbow flexion movements performed by patients with spinal cord injury at the C5-6 level who had relatively normal strength in their biceps muscle and little or no voluntary control of the triceps. Seven quadriplegic patients and six control subjects performed elbow flexion movements of 10 degrees, 20 degrees, and 30 degrees "as fast and accurately as possible". Despite the lack of antagonist, patients used the same "pulse height" strategy as control subjects to scale their responses with movement amplitude. However, patients' movement time was on average twice that of control subjects, and durations of both accelerative and decelerative phases of movement were increased. Movement speed and acceleration were reduced to 20-50% of the corresponding values of control subjects. Patients tended to overshoot the target to a larger extent than control subjects, particularly 10 degrees targets, with nearly twice the error. We performed the same experiments using an external torque motor to assist the weak triceps. When a constant extensor torque of 2.5 or 5 Nm was provided by the motor, patients were able to move faster, and movement accuracy improved to within the normal range. These results provide direct evidence that the lack of an antagonist has an important effect on completion time and accuracy of fast goal-directed movements.


An anisotropy of human tactile sensitivity and its relation to the visual oblique effect. The ability of humans to detect striated stimuli on the distal phalanges was found to be highly anisotropic. Observers were much more sensitive to stripes presented in the proximal-distal orientation than to stripes in any other orientation. This tactile anisotropy was contrasted with the well-known visual anisotropy in which sensitivity is greatest for stripes at the horizontal and vertical orientations. We suggest that both the tactile anisotropy and the visual anisotropy are caused by corresponding anisotropies in the distribution of preferred orientations of orientation-selective neurons with in the respective modalities.


Human ocular following responses are plastic: evidence for control by temporal frequency-dependent cortical adaptation. Optokinetic nystagmus (OKN) induced by wide-field visual stimulation was measured with and without prior adaptation to moving sinusoidal gratings. Under unadapted conditions the mean gains of the slow phases of OKN in the first 500 ms were 0.5-0.8, and the eye velocities and amplitudes had rise times with time constants of 0.1-0.2 s. By contrast, following adaptation to as little as 1 s of image motion, the magnitude of the initial gains fell and the rise times of the velocities and amplitudes increased markedly. The degree of adaptation depended on the adapting temporal frequency, the optimum adaptive frequencies being 1.7-3.4 Hz. In this range of temporal frequencies, the initial gains fell to 0.1-0.3 and the rise times for velocity and amplitude ranged from 0.4 to 7.0 s, depending on the length of the adapting period. Thus the observed changes in the time constant were up to 70-fold. Neither spatial frequency or image velocity had any marked influence on the level of adaptation. The dependence on temporal frequency rather than image velocity suggests that the motion detectors feeding the adaptive system respond to local motion-related changes in luminance. The adaptive effects were direction-selective, showing that this must also be the case for the motion detectors. The adaptive effects were observed both when the drift temporal frequency on the retina was established by artificially maintaining a fixed gaze or when the adapting temporal frequency was induced by retinal slip during OKN. Time constants for recovery from adaptation were similar to motion aftereffects measured by psychophysical and physiological methods. The results suggest a link between cortical motion adaptation and adaptive mechanisms effecting the oculomotor system.


Independent control of the digits: changes in perceived heaviness over a wide range of force. Perceived heaviness of a weight lifted by flexion of the distal joint of one digit increases when an adjacent digit concurrently lifts a weight. The present study confirmed this finding for relatively low weights (representing 3-5% maximal voluntary force) and a method was adapted to show that this effect occurs for much larger weights (20-25% maximal force). Thus, the increase in perceived heaviness is likely to operate over a wide range of muscle force generated by the hand. As perceived heaviness is biased by the magnitude of the central motor commands, these findings may reflect a lack of complete independence of motor commands to the long flexor muscles acting on the digits.


C-value paradox in angiosperm plant species. I. Sensitivity to DNase I in species with different 2C DNA content. The experimental conditions for DNAase I digestion in situ for plant nuclei have been presented. Cytophotometric measurements of DNA loss performed on Feulgen-stained nuclei of three species differing in 2C DNA, heterochromatin and condensed euchromatin contents have shown that the lower 2C DNA amount the higher is DNase I sensitivity. Heterochromatin and some fractions of euchromatin are DNase I resistant. Microdensitometric measurements along M chromosome in Vicia faba have demonstrated the sites hypersensitive to DNase I.


American women's sexual behavior and exposure to risk of sexually transmitted diseases. According to nationally representative data from the 1988 National Survey of Family Growth and the 1988 and 1989 General Social Surveys, 67% of all women aged 15-44 who have ever had intercourse have had more than one partner, 41% have had four or more, 23% six or more and 8% more than 10; 71% have had one or more nonmarital partners. Fewer than 1% of currently married women report having had more than one partner in the previous three months, compared with 13% of formerly married women and 9% of single women who are sexually active. For the most part, women with multiple partners do not have characteristics that set them apart from other women; women in all age-groups and racial or ethnic groups appear equally likely to have multiple partners while unmarried. Fifty-seven percent of women who report multiple partners have never been married, and another one-quarter are currently divorced. Twenty-one percent are teenagers, 46% are aged 20-29 and 24% are in their 30s. Between 27% and 39% of all sexually active women aged 18-44 are estimated to have had direct or indirect contact with more than one sexual partner during the preceding 12 months (including women with only one partner whose partner had multiple partners). About 20% of currently sexually active women reported using the condom, but one in five condom users had not used one at last intercourse. Once social and demographic factors are controlled, condom users with multiple partners are less likely than other condom users to have used a condom at last intercourse.


Analysis of spatial structure of thymocytes and of their contacts with thymic non-lymphoid cells. The study aimed et determining morphological relations between thymic cells and thymocytes. The studies were performed on 16 days old rats of Wistar strain. The material was processed for ultrastructural studies in a routine manner. For 50 thymocytes computer reconstruction was performed which allowed to define cell volume, volume of cell nucleus and of condensed chromatin. The value characterizing three-dimensional morphology of thymocytes provided grounds for analysis using graph theory. The stereological methods allowed to examine microarchitecture of individual thymic zones. Thymocytes in contact with dendritic cells or with macrophages were found to differ in morphology from thymocytes with no such contacts. The results indicated direct effect of dendritic cells and of macrophages on thymocytes.


Substance use and other factors associated with risky sexual behavior among pregnant adolescents. A study of the relationship between substance use and risky sexual behavior was conducted among 241 unmarried pregnant adolescents aged 17 and younger who lived in a metropolitan area in the Northwest. The respondents had comparable or higher lifetime use rates for all substances than did women in a national sample of high school seniors, even though the pregnant adolescents were younger. Ninety-four percent had used alcohol, 78% marijuana, 30% cocaine and 30% stimulants, compared with 92%, 48%, 14% and 23%, respectively, among women in the national sample. Among the pregnant adolescents, 84% had had more than one sexual partner, 39% had had a sexually transmitted disease and 60% had used contraceptives during less than half of their sexual encounters. At the bivariate level, use of cigarettes and alcohol in general and use of alcohol and drugs during sex were positively associated with risky sexual behavior. However, when other characteristics associated with risky sexual behavior--family bonding, parental monitoring, commitment to conventional values, peer associations, self-esteem and delinquent activities--were included in the multivariate analysis, the effect of substance use disappeared.


Analysis of thymocytes contacts with other thymic cells. The study aimed et defining morphological relationships between thymic stroma cells and thymocytes. The studies were conducted on 16-days old Wistar strain rats. The material was routinely processed for ultrastructural examination. On grounds of serial section analysis, types of contacts of 83 thymocytes were established, for each cell total area and areas of contact with other cells were estimated. Employing stereological techniques microarchitecture of individual thymic zones was studied. The results point to a direct influence of thymic stroma cells on thymocytes.


Parvalbumin in skeletal muscles of teleost (Tinca tinca L. and Misgurnus fossilis L.). Histochemical and immunohistochemical study. Musculatures of two fish species belonging to the suborder Cyprinoidei were examined histochemically and immunohistochemically for demonstration of mATP-ase activity and parvalbumin content, respectively. The tench lateral musculature shows a typical "acid reversal" picture of mATP-ase activity--red fibres are alkali labile, acid stable and white and white fibres are alkali stable, acid labile. In the pond loach a superficial layer of musculature is composed of alkali--and acid stable red fibres. This alkaline stability of the red fibres caused the classical "acid reversal" picture impossible to obtain. For immunohistochemical reaction a monoclonal antibody specific for parvalbumin II component of the Carp muscles (Pv Carp II) was used. Immunohistochemical results gave evidence that lateral musculatures of the two species examined possessed parvalbumin II component entirely in the fast-contracting fibres--intermediate and white. This results correlate with mATP-ase activity in the tench musculature and did not correlate in the pond loach with respect to mATP-ase alkali stable red muscle fibres in the fish. We conclude that fish muscles mATP-ase activity not always correlates with parvalbumin content in the opposite to mammalian muscles where such correlation seems to be obvious.


The effect of calcium on DNA synthesis in pea (Pisus sativus L.) roots after treatment with heavy metals. Cortex cells of the meristematic (1 mm) and differentiated (7 mm) zones of Pisus sativus L. roots after 144 h culture in distilled water (control), Ca2+ (10(-3) M) and/or Cd2+, Cr3+, Pb2+ solutions (10(-4) M, each) were subject of the present studies. Reductions in the number of nuclei incorporating 3H thymidine was observed in meristem in the presence of Cd2+ and in differentiated zone in Pb2+ treated roots. Intensity of DNA synthesis diminished after Pb2+ treatment but mostly in Cd2+ treated roots, mainly in meristem. Addition of calcium to the metal solutions caused an increase in the number of nuclei witch uptook the radioactive material in both studied root zones. Positive effect of calcium alone was visible also in the differentiated zone. Presence of calcium in the metal solutions caused a marked increase in 3H thymidine incorporation into nuclear DNA in meristem, although neutralizing calcium effect in this root zone was visible only in roots treated with Cr2+ and Pb2+. In the differentiated zone of roots growing in Cd2+ solution, calcium addition stimulated DNA synthesis but the intensity of this process was lower than in control (water).


Disturbances of mineral metabolism in teeth of rats receiving corticosteroids for 3 generations. Distribution of calcium and phosphorus was investigated with quantitative and qualitative methods in teeth of rats chronically treated with low doses of corticosteroids for 3 generations. In animals from 2nd and 3rd generation, scanning electron microscopy revealed focal lesions in enamel and dentin. The disturbances of the mineral metabolism in teeth of corticosteroid-treated rats were also reflected by abnormal calcium and phosphorus content in enamel and dentin, as assessed by X-ray microanalysis.


Fertility transition, conscious choice, and numeracy. One of the preconditions of the fertility transition, as stated by A.J. Coale, is that reproductive decisions must be within the calculus of conscious choice. It is suggested that the change in mentality which leads to family limitation includes "numeracy about children," a clear notion of what family size ought to be and the awareness of individuals of where they stand with respect to the norm. The article explores the hypothesis that numeracy about children appeared historically in various times and places, and that the conceptualization of family size was a necessary condition for adopting family limitation.


Family organization and fertility limitation in Nepal. This paper uses the family mode of organization framework to link together hypotheses relating social change to fertility limitation. Experiences in nonfamily activities are predicted to affect fertility behavior, with the outcome depending on the social, economic, and cultural context. To provide individual-level tests of hypotheses, the paper uses data from a Nepalese community which recently began dramatic family and fertility transitions. The findings show that experiences in nonfamily activities before marriage increase the odds of subsequently adopting fertility limitation in this setting. The evidence also demonstrates the importance of including measures of husbands' experiences in models of fertility decisions.


The perceived impact of child care costs on women's labor supply and fertility. In a sample of Detroit-area mothers of preschool-aged children interviewed in 1986, one-third reported that child care problems had constrained their employment. Such reports were relatively prevalent among poor women, those without relatives nearby, and those willing to entrust the care of their children to nonfamily members. Only one-tenth of the sample reported a similar child care constraint on fertility, a phenomenon unrelated to income but relatively prevalent among women with strong labor force attachment. The results suggest that policies to increase the supply of child care or to lower its cost could increase female labor supply by a substantial fraction, with an even greater rise among women most at risk of poverty and reliance on public assistance, but probably would not raise fertility significantly.


Forgone labor participation and earning due to childbearing among Norwegian women. Individual-level retrospective data from the Family and Occupation Survey of 1988 are used to assess the time diverted from gainful employment because of the presence of children in two Norwegian birth cohorts. We find that a two-child mother born in 1950, whose births occurred in her early twenties, lost 6.6 women-years up to age 37, compared to a childless woman. By matching information on registered income with the survey data, we estimate that her lost income amounts to $151,000 at 1990 prices. After taxation the loss is $98,000. Women with fewer than 12 years of schooling seem to forgo more labor market activity by reason of childbearing than do their better-educated counterparts. The pattern is less clear with respect to the loss of income.


A description of the extreme aged population based on improved Medicare enrollment data. The mortality and size of the extreme aged population can be studied most accurately with Medicare enrollment data from the Social Security Administration's Master Beneficiary Record after certain types of questionable records are eliminated. With the improved data base we find that mortality rates at the very old ages are higher than published rates, we are more confident of the reality of the race crossover, and we can estimate the number of centenarians more accurately. Furthermore, a large matched-records study shows close agreement on age at death between the Master Beneficiary Record and the death certificate.


Extreme mortality in nineteenth-century Africa: the case of Liberian immigrants. Several studies have examined the mortality of immigrants from Europe to Africa in the nineteenth century. This paper examines the level of mortality in Liberia of Africans who emigrated there from the United States. A life table is estimated from data collected by the American Colonization Society from 1820 to 1843. The analysis reflects the mortality experience of a population that is transplanted from one disease environment to another, more exacting, disease environment. The results of this analysis show that these Liberian immigrants experienced the highest mortality rates in accurately recorded human history.


Immigrant's ages and the structure of stationary populations with below-replacement fertility. A sustained regime of low fertility plus immigration yields an unusual kind of stationary population. The author demonstrates that all stationary populations have a common structure, and that the familiar replacement-level fertility population is the youngest among the many stationary populations corresponding to a particular life table. This finding has important consequences for policy because although fertility increase and immigration are equally effective at halting population decline, immigration is inferior as a means of rejuvenating low-fertility populations. In fact, an immigration-based policy could make a low-fertility population older rather than younger. The paper includes examples using U.S. and West German vital rates.


Estimates of long-term immigration to the United States: moving US statistics toward United Nations concepts. US immigration data are revised to reflect the UN demographic concept of long-term immigration. Long-term immigration is measured by the number of new immigrants (permanent resident aliens) arriving in the year, temporary migrant arrivals (nonimmigrants) who subsequently adjust to permanent resident status, arrivals of asylees and refugees, and nonimmigrants who arrive during the year and stay for more than twelve months before departing. The estimates of long-term immigration for 1983 are compared to official INS statistics on alien immigration. Significant differences emerge according to country of origin, age, and state of intended residence. A method of producing current estimates of long-term immigration is illustrated.


Operant and Pavlovian contributions to the ontogeny of pecking in ring doves. This series of experiments analyzes the role of learning in the development of pecking in ring dove squab. Experiment 1 showed that there is a high probability that parents will feed squab after a period of separation (Experiment 1). Such feedings may have been essential for producing the previous observation (Graf, Balsam, & Silver, 1985) that pecking develops normally if squab which have been separated from their parents are given a daily 20-min interaction with seed followed by an immediate return to their parents. Experiment 2 showed that exposure to seed followed by experimenter-provided feedings were sufficient for inducing adult pecking levels. Experiment 3 showed that general experience with conspecifics was not necessary for the development of pecking and that maturation alone could not account for the pecking observed in previous experiments. Experiment 4 showed that Pavlovian contingencies consisting of visual exposure to seed followed by feeding was sufficient to induce high levels of pecking. There did not appear to be an additional contribution of an operant contingency present when squab were allowed to both see and peck at seed prior to feedings in Experiment 5. However, squab must actually be given experience in handling and ingesting seeds before adult levels of pecking can be obtained. These results are discussed in terms of the developmental pathways whereby experience leads to adult behavior.


Visual discrimination and recognition of facial expressions of anger, fear, and surprise in 4- to 6-month-old infants. On the assumption that the ability to discriminate facial expressions has adaptive value to infants during early social exchanges, ethologically based theorists have argued that this ability is innate. Guided by this perspective, we investigated the ability of infants, 4-6 months old to recognize and discriminate facial expressions of anger, fear, and surprise. Results obtained with an infant-controlled habituation-recovery procedure showed that infants both discriminated and recognized these expressions when portrayed by several adult female models. In addition, infants spent more time looking at expressions of anger and surprise than at fear expressions. These results suggest that infants can abstract configurations of features that give affective meaning to facial expressions. It is suggested that the differences in habituation to each expression might be the result of their distinct functional signification for the infant.


Mobile surrogate mothers and the development of exploratory behavior and radius of action in infant long-tailed macaques (Macaca fascicularis). One of the effects of rearing young monkeys on surrogate mothers is a delay in the development of exploratory behavior. An important question is which difference between mother and surrogate mother caused this delay. We hypothesized that the mothers' carrying the infant through the environment promotes the development of exploratory behavior and the radius of action of infant macques. Using surrogate mothers, we reared 9 infants in a peer group with immobile surrogates and 10 infants in another peer group with mobile surrogates. During the 3rd to the 6th month, we observed each infant for 30 min weekly, collecting observational data on several behavioral parameters and on time spent in several areas in the cage. Results showed that exploratory behavior and an increase in radius of action developed more rapidly in the mobile-reared infants.


Behavioral selection of odor cues by young female mice affects age of puberty. Female house mice were reared from weaning at 21 days of age until first vaginal estrus in 40 1 aquaria in which they were given a choice of exposing themselves to bedding placed on opposite halves of the aquarium floor and sprayed with water or urine containing puberty-influencing chemosignals. In Experimental 1, mice housed with only male urine cues sprayed on the bedding matured significantly earlier and mice housed with only grouped female urine sprayed on the bedding matured significantly later than control mice where water was sprayed on the bedding for both halves of the aquarium. In Experiment 2, there were no significant differences in mean ages at vaginal introitus or first estrus for females reared with choices between (a) bedding sprayed with male urine versus bedding sprayed with water, (b) bedding sprayed with urine from grouped females versus bedding sprayed with water, (c) bedding sprayed with male urine versus bedding sprayed with urine from grouped females, or (d) the control condition where both sides of the aquarium contained bedding sprayed with water. Analysis of continuous video tapes of the locations of the females for Experiment 2 revealed that females chose initially to spend more time on the half of the floor with bedding that delayed puberty relative to the other side, but shifted their preference toward a more puberty-enhancing signal at about the time of first estrus. Female house mice appear to be able to exert some behavioral control over their own sexual maturation.


[Cost of fibroscopy in gastroduodenal ulcer]. The assessment of mean cost of upper GI endoscopy is of critical importance if one wants to perform pharmacoeconomic studies, especially in peptic ulcer disease (PUD). The aim of this work was to calculate such costs, based on an inquiry conducted in December 1991 in a representative sampling of 94 French gastroenterologists (GEs) (i.e. 4.3% of the whole population). Thirty-nine percent of GEs work in their office; 25% work in private and 26% in public hospitals. GEs performed 70 +/- 5 (mean +/- SEM) upper GI endoscopies per month. Fifty-nine % are performed to investigate epigastric pain; PUD was found in nearly one patient out of four. Fifteen % of the endoscopies were performed for follow-up of PUD. Upper GI endoscopy modalities varied greatly according to whether performed in GEs' office, private or public hospital. The proportion of investigations performed with biopsies was 66, 71 and 50%, respectively. Neuroleptanalgesia (or general anesthesia), was performed in 8, 49 and 4% of cases, respectively, and a 24-hour hospitalization was required in 0, 7 and 2% of cases, respectively. Sources of expenditure were evaluated according to the current fares of the French Health Care System (for GEs' office and private hospitals) and to real costs (for public hospitals). Taking into account the differences in place and modalities of realization, mean cost of upper GI endoscopy was evaluated at 1,084 FF. This cost could be used in future cost or cost/effectiveness studies of diagnostic or therapeutic strategies.


[Economic analysis of maintenance treatment with ranitidine 150 mg in duodenal ulcer]. While it is well-established that ranitidine 150 mg/day is effective in preventing recurrence and complications of duodenal ulcer, the economic impact of maintenance therapy is unknown. Socio-economic data, allowing to calculate the costs and cost-effectiveness ratio of intermittent and maintenance therapy, were prospectively obtained from a therapeutic trial in 399 duodenal ulcer patients (Mignon et al, Gastroenterol Clin Biol 1990;14:732-8). Visits and endoscopy investigations, work days lost, duration of hospital stay and drug consumption were recorded in both placebo (n = 202) and ranitidine (n = 197) groups. Each source of expenditure was evaluated using current fares and sales prices, from the point of view of both the collectivity and the French Health Care System. The costs of ranitidine strategy were less than the costs of placebo strategy, for the collectivity (2,031 and 2,823 FF per patient for one year, respectively) as well as for the French Health Care System (1,541 and 2,426 FF per patient per year, respectively). In the ranitidine group, expenditures were principally due to the drug (71%) and endoscopy investigation (24%). In the placebo group, endoscopy and hospital stay accounted for 50 and 39% of the expenses, respectively. The latter were due to the occurrence of complications in the placebo group. Sensitivity analysis disclosed that the results were unsensitive to the variations in cost hypotheses of the main expenditure sources. Cost/effectiveness analysis defined as cost per patient successfully treated showed that the cost of a "ranitidine strategy" was 2-3 times less than a "placebo strategy". Maintenance therapy for duodenal ulcer with ranitidine 150 mg/day for one year is less expensive and more cost-effective than intermittent treatment.


[Stomach adenocarcinomas: comparison between CA 19-9 and carcinoembryonic antigen for the diagnosis of recurrences after surgical treatment]. The aim of this study was to compare carcinoembryonic antigen (CEA) and CA19-9 for the detection of local recurrences and distant metastases after complete resection of gastric carcinoma. At least one postoperative measurement of CEA and CA19-9 was performed in 54 patients. Among these, 32 had recurrence (59%) with a median follow-up of 618 days. Significantly higher sensitivity was observed for CA19-9 in comparison with CEA (68.8% vs 38.2% respectively), but specificity was slightly lower (81.8% vs 95.6% respectively). Increased CEA plasma level never preceded the diagnosis of recurrence while increasing CA19-9 preceded diagnosis in 13 patients (40.6%) from 1 to 22 months (median = 4.5 months). Increasing the normal range of CA19-9 to 80 UI/mL (2.5 x N) raises the specificity to 100% with acceptable sensitivity (53.1%). This study shows that CA19-9, compare with CEA, allows diagnosis of recurrence more often and earlier in the follow-up of resected gastric cancer.


[Treatment of pseudocysts in acute pancreatitis. Retrospective study of 45 patients]. A total of 55 pancreatic pseudocysts in 45 patients with acute pancreatitis were managed between 1980 and 1990. Six patients were managed conservatively with resolution of pseudocysts in 5 patients. All pancreatic pseudocysts that disappeared were smaller than 35 mm. CT or ultrasound-guided aspiration were performed in 26 patients with a morbidity rate of 5%. Nine among 21 patients (42%) who were initially treated by percutaneous puncture were definitively cured: all pseudocysts were smaller than 55 mm. Nine patients were managed by long-term percutaneous drainage: 3 minor complications occurred and in 7 patients, no other treatment was necessary even for large pseudocysts. Endoscopic cystoenterostomy was performed in 12 patients. Only 15 pseudocysts (27%) bulged into the digestive wall, mainly of the stomach. Three complications (following 2 cystogastrostomies) occurred and one patient died after endoscopic cystogastrostomy. In 7 patients (58%), no other treatment was necessary even for large pancreatic pseudocysts. Surgery was required in 13 patients but only 4 patients underwent surgery as primary treatment. One major complication occurred and one patient died. Percutaneous drainage and endoscopic cystoenterostomy when technically feasible, are effective treatments of pancreatic pseudocysts complicating acute pancreatitis.


[Post-antibiotic diarrheas: role of Klebsiella oxytoca]. From May 1989 to January 1991, 20 patients were investigated for antibiotic-associated acute diarrhea. Colonoscopy or rectosigmoidoscopy was performed in each patient. Cultures of colonic mucosal biopsies were carried out using conventional culture grounds (cystine-lactose-electrolyte-deficient). The aim of this study was to investigate the role of a gram negative bacillus: Klebsiella oxytoca. Among the 20 patients with antibiotic-associated acute diarrhea, 11 had bloody and mucus diarrhea and colitis ranging from a right-sided hemorrhagic to diffuse acute ulcerative or erosive colitis, 7 had a grossly normal colonic appearance, while 2 had mucus diarrhea and pseudomembranous colitis. Of colonic biopsies cultures obtained from 36 control patients, 15 had a normal colonic appearance, 15 had ulcerative or crohn's colitis, 6 had well-tolerated amoxicillin therapy. Klebsiella oxytoca was never found in the 36 control patients; Klebsiella oxytoca was noted among 8/11 patients with mucus-discharging and bloody diarrhea. These results suggest that antibiotic-associated, non pseudomembranous colitis is frequently associated with Klebsiella oxytoca infection, which may be the cause of this type of colitis.


[Pathogenesis of cholelithiasis in chronic pancreatitis]. The prevalence and the pathogenesis of gallstones in patients with chronic pancreatitis have never been studied prospectively. The aim of this study was to evaluate prospectively the prevalence of gallstones with ultrasonography and to look for markers of pigment or cholesterol stone formation in gallbladder bile. Ultrasonography was performed in 39 patients and detected gallstones in 7 patients and sludge in 3. Common bile duct and intrahepatic bile duct dilatation were observed in 16 and 13 patients, respectively. Liver biopsies were obtained in 31 patients and cirrhosis was found in 4. There were calcium bilirubinate granules in 7 of the 27 bile samples examined. Cholesterol crystals were not found in any case. The nucleation time (median: 21 days) was higher in patients with chronic pancreatitis than in patients with cholesterol stones (median: 2 days) (P < 0.001) but was not different from nucleation time in patients either free of stones (median: 21 days) or with pigment stones (median: 21 days). The cholesterol saturation index was similar in patients with chronic pancreatitis and in controls. The 2 patients with chronic pancreatitis who underwent cholecystectomy had pigment stones. Calcium bilirubinate granules were more frequent in patients with intrahepatic bile ducts dilatation (P < 0.02). In conclusion, this study demonstrates a high prevalence of cholelithiasis in chronic pancreatitis patients. Pigment stone formation could be favored by cholestasis.


[Is cholecystectomy by celiovideoscopy dangerous in the initial period? Prospective study of 100 initial cases]. The aim of this study was to prospectively study the complication rate of our 100 initial laparoscopic cholecystectomies. The ultimate goal was to obtain a morbidity rate comparable to open cholecystectomy. No major complications were noticed. The conversion rate to open cholecystectomy was 8%, slightly higher in comparison with the literature. Absence of major complications could be explained by: a) indications limited to symptomatic non complicated cholelithiasis; b) assistance at the beginning of our experience of gynecologists used to laparoscopic techniques; c) conversion to open cholecystectomy in case of technical difficulties. Application of these principles allows the digestive surgeon to start laparoscopic cholecystectomy without submitting the patient to additional risks.