The effects of age on the pharmacokinetics and biotransformation of theophylline in vivo and in vitro in the Mongolian gerbil (Meriones unguiculatus). The effect of post maturational aging on the in vivo disposition of theophylline was examined in the Mongolian gerbils (Meriones unguiculatus) aged 30-39 (old), 12-18 (middle-aged) and 3 (young) months following a 20 mg/kg i.p. dose. Biotransformation of theophylline was also examined in liver microsomes from non-induced and 3-methylcholanthrene induced gerbils. Analysis of theophylline plasma kinetics showed decreased clearance, increased half-life and increased volume of distribution in old vs. young animals. Clearance to the 1,3-dimethyluric acid metabolite was similar for all age groups, while clearance to the 1-methyluric acid metabolite was significantly lower in the middle-aged group compared to that of young and old gerbils. Urinary recovery of 1-methylurate was increased in old vs. young and middle-aged animals while recovery of theophylline was decreased. 3-Methylcholanthrene induction resulted in decreased recovery of theophylline and increased recovery of 1,3-dimethylurate and 1-methylurate in young and middle-aged gerbils compared to non-induced controls. Decreased microsomal protein content was observed in old vs. young and middle-aged gerbils and an age-related decrease in cytochrome P-450 content (nmol P-450/g liver) was also observed. The rate of dimethylurate formation was decreased 37% in microsomes from old vs. young and middle-aged gerbils. 3-Methylcholanthrene administration resulted in a 2- and 1.5-fold increase in the rate of 1,3-dimethylurate formation in young and middle-aged gerbils, respectively. The results of these experiments indicate that the Mongolian gerbil may be useful for the study of the biochemical mechanisms underlying age-related changes in the biotransformation and kinetics of theophylline.


Plasmic membranes of hepatocytes and adrenocorticocytes in rats of different ages: effect of testosterone. Experiments on adult (6-8-month-old and 26-28-month-old) Wistar rats revealed the hyperpolarization of plasmic membranes and activation of Na,K-ATPase of adrenocorticocytes in animals of both age groups and of hepatocytes of adult rats. No effect of testosterone was observed on the level of membrane potential and the activity of Na,K-ATPase of hepatocytes of old rats. The effect of testosterone was prevented by inhibitors of protein biosynthesis (actinomycin D and cycloheximide) and a specific inhibitor of Na,K-ATPase (ouabain), but not by K(+)-channel blocker 2-aminopyridine. Testosterone was assumed to synthesize the specific factor, capable of activating Na,K-ATPase of plasmic membranes. The cytosole of hepatocytes and the blood serum of adult testosterone-treated rats activated the Na,K-ATPase of isolated plasmic membranes of hepatocytes of adult and old intact rats. During aging there was a decrease in the capacity of cells to synthesize the specific factor, which activated Na,K-ATPase of plasmic membranes.


Age-related morphological and morphometrical changes in parvalbumin- and calbindin-immunoreactive neurons in the rat hippocampal formation. Parvalbumin (PV)- and calbindin (CaBP)-immunostaining in the hippocampal formation of 3-, 11- and 28-month-old Wistar rats was studied using monoclonal antibodies. A quantitative analysis of the densities, cross-sectional areas, length and number of processes of PV-immunoreactive neurons in the hippocampal dentata and CA1 areas of the three age groups was employed. Marked age-related changes in the morphological appearance and in the quantitative parameters characterizing the PV-immunoreactive neurons in both hippocampal regions were observed. The intensity of CaBP-immunostaining of the hippocampal principle cells and interneurons remained the same but the immunoreactive fibers were structurally altered in aging.


Homeostasis between lipid peroxidation and antioxidant enzyme activities in healthy human aging. In healthy people the plasma malondialdehyde increases with age, however there is a simultaneous rise in the activities of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase in red blood cells, although both enzymes show a biphasic behaviour, that is, reaching the lowest values at 40-50 years of age to rise remarkably later on. No significant changes were found in the case of glutathione peroxidase but the age-dependent behaviour is similar to the other enzymes mentioned above. The activity of glutathione reductase shows a clear increase depending on age, up to middle age, with or without flavin adenine dinucleotide. We conclude that the increase in the activities of the anti-oxidant enzymes of the red blood cells during aging, could be interpreted as a positive feedback mechanism in response to rising lipid peroxidation. Consequently, from the point of view of the parameters used the homeostasis between the production of free radicals and anti-oxidant systems seems to be maintained in the common, normal aging pattern.


Pretreatment with aldosterone or corticosterone blocks the memory-enhancing effects of nimodipine, captopril, CGP 37,849, and strychnine in mice. Oral pretreatment with aldosterone or corticosterone blocked the memory-enhancing effects of the calcium antagonist nimodipine, the ACE inhibitor captopril, the NMDA blocker CGP 37,849, and the glycine antagonist strychnine in a passive-avoidance test in mice. The memory-disturbing effects of phenobarbitone, diazepam, CGP 37,849 and scopolamine were not influenced by the hormonal pretreatment. These findings could indicate the involvement of a steroid-sensitive mechanism in drug-induced improvement of memory. In the light of clinical observations showing elevated cortisol levels in Alzheimer patients, the results might also explain why only a limited number of these patients respond to therapy with memory enhancers.


Control of turning behavior under apomorphine by sensory input from the face. It has been shown that peripheral manipulation of sensory input by removal of vibrissae on one side of the rat's face induces turning behavior which is directed towards the contralateral vibrissae-intact side, under the influence of the dopamine receptor agonist apomorphine. In the present experiment, we examined whether rats under apomorphine turn towards the side with more sensory input, or simply away from the manipulated side. Thus, an experimental manipulation was designed to increase sensory input. Sensory stimulation was applied by attaching a clip into the fur on one side of the face. Rats injected with apomorphine in doses of 0.5-5.0 mg/kg (but not with 0.05 mg/kg or vehicle) exhibited turning behavior towards the side of the clip. This sensory stimulation was also found to influence spontaneous behavioral asymmetries. These results show that an imbalance in sensory input is sufficient to produce turning under apomorphine.


Effects of anxiolytic and antidepressant drugs on long-lasting behavioural deficits resulting from one short stress experience in male rats. Exposure of male Wistar rats to one single session of ten inescapable footshocks induces changes in the behavioural responses to environmental stimuli as measured in the "noise test" 14 days later. Shocked (S) rats showed decreased locomotion and rearing during the first 3 min of exposure to a novel environment compared to control (C) rats. When the 85 dB background noise was switched off a marked immobility response emerged in S rats, concomitant with a further decrease in locomotion and rearing. In response to noise off, C rats showed hardly any immobility and a much smaller reduction in locomotion and rearing compared to S rats. These long-lasting changes in behaviour were not reversed by acute treatment with the antidepressants fluvoxamine (3.0-30.0 mg/kg) and desmethylimipramine (DMI, 2.5-10.0 mg/kg) injected IP 30 min before the noise test on day 14 following the shock session. Chronic treatment (day 1 to day 14) with fluvoxamine or DMI did not reverse the behavioural deficits induced by shock exposure. Diazepam (0.6-5.0 mg/kg) administered acutely only reversed the effects of shock on locomotion during the first 3 min of the noise test. Chronic treatment with diazepam normalized the shock-induced decrease in locomotion and attenuated the rearing decrease during the first 3 min of the test, and partially restored shock-induced changes in behavioural response to switching off the noise. The most potent drug in this study was the 5-HT1A receptor agonist flesinoxan (0.3-3.0 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)


Differential antagonism of the effects of dopamine D1-receptor agonists on feeding behavior in the rat. A series of experiments was conducted to examine the effects of dopamine D1 receptor agonists on food intake in rats. In the first experiment, the D1 agonist SKF 38393 (3.0-30.0 mg/kg) dose-dependently suppressed feeding during a 40 min food-access period, both in food-deprived rats and in non-deprived rats fed a highly palatable diet. Non-deprived rats were more sensitive to these effects of SKF 38393. Using the limited-access, food-deprivation procedure, a comparison was made between the anorectic effects of three D1 agonists with differing intrinsic efficacies and receptor selectivities. Rank order of potencies for reducing food intake was SKF 82958 > SKF 77434 > SKF 38393 (ED50 values: 0.7, 3.6 and 15.7 mg/kg, respectively). Dose-related, surmountable antagonism by the D1 antagonist SCH 23390 (0.01 and 0.03 mg/kg) was only obtained with SKF 82958 (0.1-10.0 mg/kg). In contrast to the other compounds, the effects of SKF 38393 were not appreciably altered by the D1 antagonist. The effects of SKF 82958 were also antagonized by the D2 receptor antagonist spiperone (0.05 and 0.1 mg/kg), although not in a dose-dependent manner. The present results support a role for D1 receptors in central feeding mechanisms. They also suggest that the effects of SKF 38393 on feeding may not be mediated exclusively by the D1 receptor and, further, that SKF 38393 may not serve well in behavioral studies as a prototypical D1 agonist. The results also demonstrate the need for comparisons among several compounds in studies of D1 mediated behavioral effects.


Increased [3H] raclopride binding sites in postmortem brains from schizophrenic violent suicide victims. The specific binding of the D2-dopamine receptor antagonist radioligand [3H] raclopride was quantitated in the postmortem caudate and frontal cortex from schizophrenic suicide victims and control subjects. In schizophrenic suicides the density of binding sites (Bmax) was higher (40%, P < 0.05) in the caudate, whereas it did not change in the cortex as compared to those in controls. The apparent dissociation constants (KD) were also found increased both in caudate (24%) and cortex (75%) from schizophrenics, but these apparent decreases in receptor affinity did not reach statistical significance. The mean Bmax value in drug-free schizophrenic suicides (n = 3) did not differ from the Bmax value in neuroleptic drug-treated schizophrenics (n = 7) but it was found increased in respect to control subjects (n = 9). No differences in [3H] raclopride binding were observed between non-schizophrenic suicide victims (n = 4) and matched controls (n = 4), suggesting that the modifications of D2-dopamine receptors in schizophrenia are not related to suicide.


Differential effects of serotonergic and catecholaminergic drugs on ingestive behavior. The serotonergic agonists fenfluramine and fluoxetine and the catecholaminergic agonists amphetamine and phenylpropanolamine are well known to cause a reduction in intake in rats. In the studies reported here we investigated the effects of these drugs on the microstructure of licking behavior of the rat ingesting 0.4 M sucrose. The purpose was to examine the similarities in the behavioral effects within and between these two classes of anorectic agents. The serotonergic agonists fenfluramine and fluoxetine caused a reduction in intake primarily by reducing the size of bursts and clusters of licking within the test meal without affecting the duration of the meal, suggesting a reduction in the palatability of the test solution. The catecholamine agonists amphetamine and phenylpropanolamine reduced intake primarily by reducing the number of bursts and clusters without affecting their size, suggesting a fractionation in the organization of the normal pattern of ingestion. The differences between the two serotonin and the two catecholamine agonists on the microstructure of the licking behavior suggest a different effect of the two neurotransmitters on the motor system that controls ingestive behavior. The similarities between the two different agonists within each class suggests a common neurotransmitter mechanism responsible for these two different effects on the behavior of the animals.


The metabolic fate of infused L-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites. L-Tryptophan (Trp) was widely used as a natural tool for the support of serotonin-mediated brain functions and as a challenge probe for the assessment of serotonin-mediated neuroendocrine responses. The metabolic fate of the administered Trp and the kinetics of the accumulation of Trp metabolites in the circulation, however, have never thoroughly been investigated. This study describes the time- and dose-dependent alterations in the plasma levels of various Trp metabolites and large neutral amino acids after the infusion of Trp to healthy young men (1, 3 and 5 g; placebo-controlled, double-blind, cross-over study during day- and night-time). The major Trp metabolites (kynurenine, indole acetic acid and indole lactic acid) in plasma increased dose-dependently but rather slowly after Trp administration to reach their maximal plasma levels (up to 10-fold after the 5 g dose) at about 3 h p.i., and remained at an elevated level (about 5-fold) for up to 8 h. N-acetyl-Trp and 5-hydroxy-Trp rose rapidly and massively after Trp infusions, at the 5 g dose more than 200- and 20-fold, respectively, and declined rapidly to about 5-fold baseline levels within 2 h. Whole blood serotonin levels were almost unaffected by the Trp infusions. A rather slow increase of 5-hydroxyindole acetic acid was seen, reaching maximum values (3-fold at the 5 g dose) at about 2 h after the infusion of Trp. Additionally, a dose-dependent rise of circulating melatonin was observed after L-Trp infusions. The administration of L-Trp caused a depletion of the concentrations of the other large neutral amino acids and a dose dependent decrease of the ratio between plasma tyrosine and the sum of the plasma concentrations of the other large neutral amino acids. Apparently, none of the existing pathways of peripheral Trp metabolism is saturated by its substrate, Trp in men. At least some of the central effects reported after L-Trp administration may be mediated by the Trp-stimulated formation of neuroactive metabolites or by the decreased availability of tyrosine for catecholamine synthesis.


Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline. Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; however, fluoxetine and maprotiline treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 micrograms/kg) selectively reversed the recovery of sucrose drinking in antidepressant-treated stressed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action.


Scopolamine impairs delayed matching in an olfactory task in rats. The action of the cerebral cholinergic system seems to be important for remembering events over short time intervals. We decided to test this hypothesis in the rat by developing an original model of short term memory based on the olfactory sensory modality which is a major determinant in the animal behaviour. The principle of the experiment was a "delayed match-to-sample" test performed in a classical T maze divided into two compartments. In the first compartment, rats received an odorant stimulation, then, in the second, they had to discriminate between the two arms odorized differently. To receive a food reinforcement, the animals had to enter the arm signaled by the odor presented in the first part of the maze. The test was performed with (Short-term memory condition) or without (Immediate memory condition) a variable delay between the first odor sampling and the discrimination task. Both tests were performed with control and scopolamine-treated animals (0.5, 0.125 and 0.0625 mg/kg IP). An injection of scopolamine (0.5 mg/kg) impaired performances, even when no retention of the odor was required. However, lower doses (0.125, 0.0625 mg/kg) selectively altered performances in the short term memory condition. These results suggest that intact muscarinic transmission is required for an olfactory cue to be used over a short time after its presentation.


Evidence for involvement of 5-HT1C and 5-HT2 receptors in the food intake suppressant effects of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Administration of various doses of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) to rats produced dose-related decreases in 1-h food intake in the food-deprived paradigm. Pretreatment with spiperone (5-HT1A/5-HT2/D2 antagonist), propranolol or CGP361A (beta-adrenoceptor antagonists that also have binding affinities for 5-HT1A and 5-HT1B sites) and MDL-72222 (5-HT3 antagonist) did not attenuate DOI-induced suppression of food intake. In contrast, pretreatment with metergoline (5-HT1/5-HT2 antagonist) completely blocked whereas mesulergine, mianserin and ritanserin (5-HT1C/5-HT2 antagonists) partially blocked DOI's effect on food intake. On the other hand, pretreatment with MDL-72222 but not with m-chlorophenylpiperazine (m-CPP) significantly potentiated DOI-induced suppression of food intake. Furthermore, the food intake suppressant effects of various doses of DOI were found to be similar in the Fawn-Hooded (FH) rat strain as compared to the Wistar rat strain. These findings suggest that DOI-induced suppression of food intake is mediated by stimulation of both 5-HT1C and 5-HT2 receptors.


Nicotine elimination and tolerance in non-dependent cigarette smokers. Although most smokers are nicotine-dependent, recent studies suggest that some very light smokers ("chippers", who smoke fewer than five cigarettes per day) may smoke for decades without developing dependence. It was considered that slowed nicotine elimination and/or reduced nicotine tolerance might underlie chippers' ability to maintain smoking at such low levels. To evaluate this hypothesis, we studied the elimination kinetics and pharmacodynamics of nicotine in chippers and matched regular smokers. Plasma nicotine levels and cardiovascular responses were observed for several hours after subjects were administered uniform doses of tobacco smoke. Chippers did show less chronic nicotine tolerance, but only on some response measures. Their rates of nicotine elimination equaled those of regular smokers. This finding, when coupled with other data about chippers' smoking patterns and nicotine absorption, establish that chippers cannot maintain substantial plasma nicotine levels between cigarettes, and thus suggest that attempts to maintain minimal trough levels of nicotine do not underlie chippers' smoking.


Dose-dependent effect of GM1 ganglioside during development on inhibitory avoidance behaviour in mice: influence of the period of administration. Groups of C57BL/6 mice were injected intraperitoneally with GM1 monosialoganglioside at different ages during development and subsequently tested for the retention of an inhibitory avoidance task 24 h after training. Results show improvements in inhibitory avoidance retention according to the age of the animals, the doses of GM1 used and the length of treatment. The effective doses ranged from 20 mg/kg for all age groups after 7 days treatment to 280 mg/kg for 6- and 7-week old animals after pre-trial treatment. Six- and 7-week-old mice are more sensitive to GM1 treatment than 5-week-old animals and, with decreasing lengths of treatment, increasing doses of GM1 are needed to improve the performance of the animals. These findings show that short treatment durations can be effective in improving inhibitory avoidance retention as long as the doses of GM1 administered are increased and that animals are more sensitive to the treatment when they are 6 or 7 weeks of age than when they are 5 weeks old.


Effects of the 5-HT3 antagonist ondansetron on benzodiazepine-induced operant behavioural dependence in rats. This study was designed to assess whether rats made tolerant to the suppressant action on Fixed Ratio operant responding of the benzodiazepine (BZ) chlordiazepoxide (CDP) would show behavioural disruption on drug withdrawal--so-called operant behavioural dependence. In addition, the study examined the effects of the 5-HT3 antagonist ondansetron on such operant behavioural dependence. During 42 consecutive days of CDP treatment, at doses escalated from 10 to 30 mg/kg/day, marked tolerance developed to the rate-suppressant action of CDP. On subsequent days, during spontaneous withdrawal, response rates declined significantly by around 30% in animals treated with saline, although some recovery of responding was seen over successive days of withdrawal. Similar reductions in responding followed by recovery were seen in rats treated with the 5-HT3 antagonist ondansetron (0.01-0.1 mg/kg, b.i.d.). These findings demonstrate for the first time that it is possible to use operant procedures to detect spontaneous BZ withdrawal. They also suggest, in agreement with recent studies from this laboratory (Leathley and Goudie 1992), that 5-HT3 antagonists may have relatively limited utility in treating some signs of BZ dependence.


Hyperthermia induced by m-trifluoromethylphenylpiperazine (TFMPP) or m-chlorophenylpiperazine (m-CPP) in heat-adapted rats. TFMPP and m-CPP, non-selective 5-HT agonists, administered in doses of 1-20 mg/kg evoked hyperthermia in rats at a high ambient temperature (28 degrees C). The hyperthermic effect of TFMPP (10 mg/kg) or m-CPP (10 mg/kg) was dose-dependently antagonized by the 5-HT1c and 5-HT2 receptor antagonists mesulergine (0.5-4 mg/kg), ketanserin (0.6-2.5 mg/kg) and ritanserin (0.5-2 mg/kg) and by the non-selective 5-HT antagonist metergoline (0.5-1 mg/kg), or was attenuated by the 5-HT1A, 5-HT2 and dopamine receptor antagonist spiperone (3 mg/kg, but not 0.3 or 1 mg/kg). On the other hand, the 5-HT1A, 5-HT1B and beta adrenoceptor antagonists pindolol (2 mg/kg) and cyanopindolol (2 mg/kg), the 5-HT1A receptor agonist/antagonist ipsapirone (10 and 35 mg/kg) and haloperidol (0.25 and 0.5 mg/kg) showed a tendency towards enhancing the TFMPP- or m-CPP-induced hyperthermia. The 5-HT1A and alpha 1-adrenoceptor antagonist NAN-190 (1-4 mg/kg), the 5-HT3 antagonists tropisetron (0.01-1 mg/kg) and zacopride (0.5 and 1 mg/kg), the beta-blockers betaxolol (8 mg/kg) and ICI 118, 551 (8 mg/kg), which have no affinity for 5-HT receptors and prazosin (1 mg/kg), did not affect the hyperthermic effect of TFMPP or m-CPP. The hyperthermias studied were not modified, in animals with 5-HT lesion produced by p-chloroamphetamine (PCA) either. All the drugs used as putative receptor antagonists, as well as PCA, did not change or decreased (ipsapirone) the body temperature in heat-adapted rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Amperozide and clozapine but not haloperidol or raclopride increase the secretion of oxytocin in rats. The aim of the present study was to investigate whether amperozide, an antipsychotic drug which possesses anti-aggressive and anxiolytic-like properties, stimulates the secretion of oxytocin and if so, by which receptor mechanism. For this purpose, female or male Sprague Dawley rats were given amperozide (0.5, 2.5 and 5.0 mg/kg IP), ritanserin (5.0 mg/kg), raclopride (2.0 mg/kg) and prazosin (1.0 mg/kg) and were subsequently decapitated for collection of blood (30 and 120 min) after injection. Oxytocin levels were measured with radioimmunoassay. Amperozide 2.5 and 5 mg/kg increased plasma levels of oxytocin significantly (P < 0.05 and < 0.001). The effect appeared maximal about 30 min after injection of the drug and oxytocin levels were almost back to basal within 120 min. Similar effects were obtained in female and male rats as well as in animals that were freely fed or food deprived for 24 h. CSF levels of oxytocin were also increased. Ritanserin, a 5-HT2-receptor antagonist but not the D2 receptor antagonist raclopride or the alpha 1-adrenoceptor antagonist prazosin stimulated oxytocin release. In addition, clozapine, a neuroleptic with potent HT2-antagonistic properties, was a potent releaser of oxytocin, whereas haloperidol was without effect. A possible role for oxytocin in the behavioural effects of amperozide and clozapine remains to be explored.


D1/D2 dopamine and N-methyl-D-aspartate (NMDA) receptor participation in experimental catalepsy in rats. Mixed D1/D2 dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D1 DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D2 agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025-0.5 mg/kg), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D1/D2 interdependence in catalepsy and a modulatory role of D1 and D2 DA receptor stimulation on the anticataleptic effect of MK-801.


Performance of baboons under a repeated acquisition procedure during chronic oral exposure to atenolol and propranolol. Repeated acquisition behavioral performances of normotensive and renovascular hypertensive baboons were tested before, during, and following chronic oral dosing with the beta-adrenergic antagonists atenolol HCl (2.6 mg/kg/day PO), and d,l propranolol HCl (6.8 mg/kg twice daily PO) in separate studies. Each study administered active drug for 21 consecutive days preceded and followed by 14-day baseline and recovery periods, respectively. Animals pressed five keys in sequence for food reinforcement during daily experimental sessions which consisted of alternating acquisition (new sequence learning) and performance (previously learned) task components. Atenolol increased response latencies during acquisition in comparison to performance components, and during early portions of sessions. Propranolol also increased response latencies during acquisition components in early periods of sessions, but fewer dependent measures were affected, and the magnitude of increases in response latencies was smaller (12% +/- 5 SEM) as compared with atenolol (47% +/- 13). Test doses of phencyclidine HCl (PCP) increased latencies to the same degree as atenolol. PCP markedly reduced accuracy, while atenolol or propranolol did not. Blood pressures remained stable under atenolol, and decreased by approximately 10-15 mmHg under propranolol. No differences between renovascular hypertensive and normotensive baboons were found as a function of drug conditions. Drug effects were not dependent on plasma propranolol concentration.


Vitamin B-6 supplementation in elderly men: effects on mood, memory, performance and mental effort. This study evaluates the effects of vitamin B-6 supplementation (20 mg pyridoxine HCL daily for 3 months) on mood and performance in 38 self-supporting healthy men, aged between 70-79 years. Effects were compared with 38 controls who received placebo and were matched for age, plasma pyridoxal-5'-phosphate (PLP) concentration and intelligence score. Before and after drug intervention vitamin B-6 status was determined, and mood and performance were measured by means of a computerized testing system. In addition, the phasic pupil response was measured in order to assess mental effort. Positive effects of vitamin B-6 supplementation were only found with respect to memory, especially concerning long-term memory. In view of the finding that mental performance improvement and delta PLP values were most strongly correlated within an intermediate range of delta PLP, it is suggested that cognitive effects are primarily associated with a certain range of vitamin B-6 status increment. The general conclusion is that vitamin B-6 supplementation improves storage of information modestly but significantly.


Concentration of ondansetron in cerebrospinal fluid following oral dosing in volunteers. This study measured the concentrations of ondansetron in plasma and cerebrospinal fluid (CSF) in six volunteers after oral dosing to steady state. Ondansetron concentrations ranged from 39.5-147 ng ml-1 in plasma and from 2.6-15.4 ng ml-1 in CSF. There was good correlation between plasma and CSF concentrations (r = 0.89, p = 0.017). CSF concentrations were less than 15% of plasma concentrations in all cases, indicating that the rate of penetration of the blood brain barrier by ondansetron is low.


A patient with osteomalacia as single presenting symptom of gluten-sensitive enteropathy. A 59-year-old male patient presented with invalidating osteomalacia of 2.5 years' duration. The osteomalacia was caused by severe malabsorption due to gluten-sensitive enteropathy (GSE). There were no other signs or symptoms of GSE in this patient. Clinical presentation with monosymptomatic osteomalacia is very unusual. It seems that patients with GSE who undergo little exposure to the sun are at particular risk of developing overt osteomalacia. Unrecognized GSE should always be considered in the differential diagnosis of osteomalacia.


Unexplained biliary tract dilatation in lung cancer patients. Three patients, two men and one woman, diagnosed as having adenocarcinoma of the lung were found to have changes in cholestatic biochemical values, and CT scan of the abdomen demonstrated dilation of the biliary tree. Upon further evaluation using ERCP marked dilation of the biliary tree was confirmed. There was no anatomic obstruction to bile flow, no neoplastic involvement of the liver or bile ducts and no evidence of any infiltrative process or disease to explain the dilation. A paraneoplastic syndrome is proposed as the etiology of the biliary tract abnormality. Along with other more common causes, this newly described paraneoplastic syndrome should be considered in the differential diagnosis of lung cancer in patients presenting with cholestasis and biliary tract dilation.


Mammalian origins of replication.

Mammalian origins of replication. It has been almost twenty-five years since Huberman and Riggs first showed that there are multiple bidirectional origins of replication scattered at approximately 100 kb intervals along mammalian chromosomal fibers. Since that time, every conceivable physical property unique to replicating DNA has been taken advantage of to determine whether origins of replication are defined sequence elements, as they are in microorganisms. The most thoroughly studied mammalian locus to date is the dihydrofolate reductase domain of Chinese hamster cells, which will be used as a model to discuss the various methods of investigation. While several laboratories agree on the rough location of the 'initiation locus' in this large chromosomal domain, different experimental approaches paint different pictures of the mechanism by which initiation occurs. However, a variety of new techniques and synchronizing agents promises to clarify the picture for this particular locus, and to provide the means for identifying and isolating other origins of replication for comparison.


On the nature of origins of DNA replication in eukaryotes. Chromosomal origins of DNA replication in higher eukaryotes differ significantly from those of E. coli (oriC) and the tumor virus, SV40 (ori sequence). Initiation events appear to occur throughout broad zones rather than at specific origin sequences. Analysis of four chromosomal origin regions reveals that they share common modular sequence elements. These include DNA unwinding elements, pyrimidine tracts that may serve as strong DNA polymerase-primase start sites, scaffold associated regions, transcriptional regulatory sequences, and, possibly, initiator protein binding sites and inherently destabilized regions. Based on the novel organization of chromosomal origin regions, we propose a model for initiation of DNA replication in higher eukaryotes. Unwinding of duplex DNA during initiation may be uncoupled, both temporally and spatially, from DNA synthesis, resulting in transient single-stranded intermediates that function in lieu of conventional replication forks during chromosomal DNA replication. DNA synthesis begins subsequently at multiple sites within the unwound regions rather than at specific origin sequences.


Recombinant neuromuscular synapses.

Recombinant neuromuscular synapses. The developing neuromuscular junction has provided an important paradigm for studying synapse formation. An outstanding feature of neuromuscular differentiation is the aggregation of acetylcholine receptors (AChRs) at high density in the postsynaptic membrane. While AChR aggregation is generally believed to be induced by the nerve, the mechanisms underlying aggregation remain to be clarified. A 43-kD protein (43k) normally associated with the cytoplasmic aspect of AChR clusters has long been suspected of immobilizing AChRs by linking them to the cytoskeleton. In recent studies, the AChR clustering activity of 43k has, at last, been demonstrated by expressing recombinant AChR and 43k in non-muscle cells. Mutagenesis of 43k has revealed distinct domains within the primary structure which may be responsible for plasma membrane targeting and AChR binding. Other lines of study have provided clues as to how nerve-derived (extracellular) AChR-cluster inducing factors such as agrin might activate 43k-driven postsynaptic membrane specialization.


Mesoderm induction and axis determination in Xenopus laevis. In Xenopus, as in all amphibians and possibly in vertebrate embryos in general, mesoderm formation and the establishment of the dorsoventral axis depend on inductive cell interactions. Molecules involved in mesoderm induction include FGF which acts predominantly as a ventrolateral inducer, the TGF-beta homolog activin which can induce all types of mesoderm, and members of the Wnt family which have powerful dorsalizing effects. Early effects of inducer action include the activation of regulatory genes. Among such genes, particular interest is focused on three genes encoding putative transcription factors that are expressed specifically in the Spemann organizer region of the gastrula. Expression of one of these genes, goosecoid, has been shown to be sufficient to elicit the formation of a dorsal axis including head and notochord in the embryo.


Mutational analyses of lymphocyte differentiation. The site-specific recombination mechanism responsible for the assembly of antigen receptor variable region genes is only employed in lymphocyte development. Gene-targeted and other types of mutational analyses have implicated at least seven distinct gene products, some lymphoid-specific and others more generally expressed, as involved in aspects of this process. Mutation of the lymphocyte-specific activities required for VDJ recombination or mutation of the target gene segments of this process have created B and/or T cell-deficient mouse models that have provided new insights into the regulation of the VDJ recombination reaction and into how the successful achievement of this reaction at various loci helps lead lymphocytes through their early developmental program A second type of B lymphocyte-specific recombination process is involved in heavy-chain class switching; gene-targeted mutation approaches also have provided new insights into the cis-acting elements that target of this reaction to particular CH genes.


What have tissue culture studies told us about the development of oligodendrocytes? One major success of studying neural cell development in tissue culture has been the discovery of the O-2A cell. This bipotential cell generates oligodendrocytes or, under certain conditions, a type of astrocyte. This essay considers the evidence that the characteristic properties demonstrated by the O-2A cells in vitro are an accurate reflection of oligodendrocyte development in vivo.


AMP-activated protein kinase--an archetypal protein kinase cascade? Mammalian AMP-activated protein kinase is the central component of a protein kinase cascade which inactivates three key enzymes involved in the synthesis or release of free fatty acids and cholesterol inside the cell. The kinase cascade is activated by elevation of AMP, and perhaps also by fatty acid and cholesterol metabolites. The system may fulfil a protective function, preventing damage caused by depletion of ATP or excessive intracellular release of free lipids, a type of stress response. Recent evidence suggests that it may have been in existence for at least a billion years, since a very similar protein kinase cascade is present in higher plants. This system therefore represents an early eukaryotic protein kinase cascade, which is unique in that it is regulated by intracellular metabolites rather than extracellular signals or cell cycle events.


Evolution of mitochondrial genomes and the genetic code. Mitochondrial genomes are clearly marked by a strong tendency towards reductive evolution. This tendency has been facilitated by the transfer of most of the essential genes for mitochondrial propogation and function to the nuclear genome. The most extreme examples of genomic simplification are seen in animal mitochondria, where there also are the greatest tendencies to codon reassignment. The reassignment of codons to amino acids different from those designated in the so called universal code is seen in part as an expression of the reduction of the number of genes used by these genomes to code for tRNA species. The driving force for the reductive evolution of mitochondrial genomes is identified with two population genetic effects which may also be operating on populations of parasites.


Alzheimer's disease untangled.

Alzheimer's disease untangled. The last year has seen major advances in the study of Alzheimer's disease (AD). Four mutations involving amino acid substitutions in exons 16 and 17 of the amyloid precursor protein (APP) gene, have been identified which co-segregate with the disease in some families multiply affected by early onset Alzheimer's disease. These mutations are strongly suggestive of a causative role for the amyloid precursor protein in Alzheimer's disease. Despite their rarity, these mutations are important because they represent the first known cause of Alzheimer's disease. Processing of APP must be central to the pathogenesis of the disease although the precise effects of these amino acid substitutions are not understood. Work is now being undertaken to characterise the processing pathways of APP and to identify other causes of AD. The development of models of AD using the APP mutations offers the possibility of identifying drug targets and developing more effective treatments than are presently available.


The genetic control of tissue polarity in Drosophila. The cuticular surface of Drosophila is decorated by parallel arrays of polarized structures such as hairs and sensory bristles; for example, on the wing each cell produces a distally pointing hair. These patterns are termed 'tissue polarity'. Several genes are known whose activity is essential for the development of normal tissue polarity. Mutations in these genes alter the orientation of the hair or bristle with respect to neighboring cells and the body as a whole. The phenotypes of mutations in these genes allows them to be placed in three phenotypic groups. Based on their behavior in genetic mosaics, it has proved possible to determine that individual genes are required either for the generation of an intercellular polarity signal and/or the transduction of that signal to the cytoskeleton.


Phylogenetic analysis of the cadherin superfamily. Cadherins are a multigene family of proteins which mediate homophilic calcium-dependent cell adhesion and are thought to play an important role in morphogenesis by mediating specific intercellular adhesion. Different lines of experimental evidence have recently indicated that the site responsible for mediating adhesive interactions is localized to the first extracellular domain of cadherin. Based upon an analysis of the sequence of this domain, I show that cadherins can be classified into three groups with distinct structural features. Furthermore, using this sequence information a phylogenetic tree relating the known cadherins was assembled. This is the first such tree to be published for the cadherins. One cadherin subtype, neural cadherin (N-cadherin), shows very little sequence divergence between species, whereas all other cadherin subtypes show more substantial divergence, suggesting that selective pressure upon this domain may be greater for N-cadherin than for other cadherins. Phylogenetic analysis also suggests that the gene duplications which established the main branches leading to the different cadherin subtypes occurred very early in their history. These duplications set the stage for the diversified superfamily we now observe.


The molecular and cell biology of anion transport by bacteria. This article summarizes the study of anion exchange mechanisms in bacteria. Along with defining at least two different families of anion exchange, an examination of such carrier-mediated antiport reactions has led to techniques that considerably broaden the scope of biochemical methods for examining membrane proteins. Such advances have been exploited to show that anion exchange itself forms the mechanistic base of an entirely new kind of proton pump, one which may shed light on a variety of bacterial events, including methanogenesis. Perhaps most important, the study of exchange provided the final link in a chain of evidence pointing to a structural 'rhythm' that seems to characterize membrane carriers. These three issues--a biochemical tool, a new proton pump, and a common structural rhythm--are briefly examined in the context of their origins in the analysis of bacterial anion exchange.


Mitochondrial DNA and genetic disease.

Mitochondrial DNA and genetic disease. Since the human mitochondrial genome was characterised and sequenced in 1981, it has been viewed as the likely site of genetic diseases showing a maternal inheritance pattern and associated with defects of the respiratory chain, such as the mitochondrial myopathies (MMs). The properties that make it a candidate for the source of such conditions are that it encodes polypeptides involved in electron transport and that it is maternally inherited. However, several of the mtDNA diseases only fulfill one or other of these criteria: the first group of mtDNA diseases showed only sporadic deletions, and the first point mutation in Leber's Hereditary Optic Neuropathy (LHON) is not associated with a clear biochemical defect. Furthermore, it is now clear that both autosomal dominant and probably recessive nuclear genes can cause abnormalities of mtDNA. Each of these major groups will be considered in turn.


Differentiation and proliferation in mouse embryonal carcinoma cells. How cell commitment and differentiation are controlled in the early stages of embryogenesis is a problem that has long fascinated developmental biologists. Retinoic acid-induced differentiation of embryonal carcinoma cells in culture provides a model in which these questions can be explored. Recent work has yielded exciting insights into the central series of molecular changes which drives the commitment of these cells to formation of a new phenotype. Interacting with the key molecules in this central pathway is a variety of transcription factors, many of which show changes in availability and/or activity during differentiation. In various combinations, these modulate the activities of genes involved in both cell proliferation and in the production of extracellular matrix and other proteins characteristics of differentiated cells.


The sex-peptide.

The sex-peptide. Injection of a peptide of 36 amino acids into virgin Drosophila females changes their reproductive properties drastically: males are rejected and egg laying is increased. The neuronal and physiological properties of the virgin state are replaced by a new pattern of behavior and stimulation of egg production and deposition. Under natural conditions, the peptide is synthesized by the male and transferred into the female during copulation. The sex-peptide, therefore, can be considered as a pheromone. In this review, I shall limit my discussion to Drosophila melanogaster.


The hemopoietic regulators--an embarrassment of riches. A large, and growing, group of glycoprotein regulators is now recognized to control the proliferation, maturation and functional activity of the eight major families of blood cells. Each hemopoietic regulator is the product of multiple cell types and there is a puzzling redundancy of regulators able to stimulate each subfamily of hemopoietic cells. Each regulator is polyfunctional but it remains unclear how a single type of activated receptor is able to initiate the diverse cellular responses induced.


DNA triple-helix formation: an approach to artificial gene repressors? Certain sequences of double-helical DNA can be recognized and tightly bound by oligonucleotides. The effects of such triple-helical structures on DNA binding proteins have been studied. Stabilities of DNA triple-helices at or near physiological conditions are sufficient to inhibit DNA binding proteins directed to overlapping sites. Such proteins include restriction endonucleases, methylases, transcription factors, and RNA polymerases. These and other results suggest that oligonucleotide-directed triple-helix formation could provide the basis for designing artificial gene repressors. The general question of whether biological systems employ RNA molecules for recognition and regulation of double-helical DNA is discussed.


Sex-chromosome pairing and activity during mammalian meiosis. Mammalian sex chromosomes exhibit marked sexual dimorphism in behavior during gametogenesis. During oogenesis, the X chromosomes pair and participate in unrestricted recombination; both are transcriptionally active. However, during spermatogenesis the X and Y chromosomes experience spatial restriction of pairing and recombination, are transcriptionally inactive, and form a chromatin domain that is markedly different from that of the autosomes. Thus the male germ cell has to contend with the potential loss of X-encoded gene products, and it appears that coping strategies have evolved. Genetic control of sex-chromosome inactivation during spermatogenesis does not involve pairing or the presence of the Y chromosome or an intact X chromosome, and may therefore be under exogenous control by the gonad. Sex-chromosome reactivation during oogenesis and inactivation during spermatogenesis probably reflect specific meiotic events such as recombination. Understanding these phenomena may help explain other sex-related differences in genetic recombination.


DNA synthesis control in yeast: an evolutionarily conserved mechanism for regulating DNA synthesis genes? After yeast cells commit to the cell cycle in a process called START, genes required for DNA synthesis are expressed in late G1. Periodicity is mediated by a hexameric sequence, known as a MCB element, present in all DNA synthesis gene promoters. A complex that specifically binds MCBs has been identified. One polypeptide in the MCB complex is Swi6, a transcription factor that together with Swi4 also binds G1 cyclin promoters and participates in a positive feedback loop at START. The finding that Swi6 is directly involved in both START and DNA synthesis gene control suggest a model in which Swi6, activated through its participation in START, serves as the central transcription factor in coordinating late G1 gene expression. The mechanism may be conserved in all eukaryotic cells.


Mouse albino-deletions: from genetics to genes in development. Six essential genes located near the mouse albino locus have been identified as required during specific periods of development. Amongst these six, each is required either during the preimplantation stages of development, at specific times during gastrulation, within 12 hrs after birth or during juvenile development. These genes were identified as a result of extensive genetic complementation analysis using embryos homozygous for the albino deletions. Although, in principal, the associated developmental abnormalities could result from loss of multiple genes, the deletion phenotype in one case is identical to that induced by chemical mutagenesis. These results indicate that the abnormalities observed in deletion homozygotes may result from single gene loss. The deletions have proven useful not only as genetic tools to localize the position of the genes, but also as molecular entry points to the regions containing these genes. The current methodology being used to isolate candidate genes from the albino region is also reviewed here.


Control of steroid receptor function and cytoplasmic-nuclear transport by heat shock proteins. As targeted proteins that move within the cell, the steroid receptors have become very useful probes for understanding the linked phenomena of protein folding and transport. From the study of steroid receptor-associated proteins it has become clear over the past two years that these receptors are bound to a multiprotein complex containing at least two heat shock proteins, hsp90 and hsp56. Attachment of receptors to this complex in a cell-free system appears to require the protein unfolding/folding activity of a third heat shock protein, hsp70. Like the oncogenic tyrosine kinase pp60src, steroid receptors bind to this complex of chaperone proteins at the time of their translation. Binding of the receptor to the hsp90 component of the system occurs through the hormone binding domain and is under strict hormonal control. The hormone binding domain of the receptor acts as a transferable regulatory unit that confers both tight hormonal control and hsp90 binding onto chimaeric proteins. The model of folding and transport being developed for steroid receptors leads to some general suggestions regarding the folding and transport of targeted proteins in the cell.


Molecular movements in oocyte patterning and pole cell differentiation. Central to the differentiation and patterning of the Drosophila oocyte is the asymmetric intracellular localization of numerous mRNA and protein molecules involved in developmental signalling. Recent advances have identified some of the molecules mediating oocyte differentiation, specification of the anterior pole of the embryo, and determination of the embryonic germ line. This work is considered in the context of the classical model of the germ plasm as a cytoplasmic determinant for germ cell formation.


How do germ cells choose their sex? Drosophila as a paradigm. Sex determination in the germ line may either rely on cell-autonomous genetic information, or it may be imposed during development by inductive somatic signals. In Drosophila, both mechanisms contribute to ensure that germ cells are oogenic when differentiating in females and spermatogenic when differentiating in males. Some of the genes that are involved in germ line sex determination have been identified. In other species, including vertebrates, inductive signals are commonly used to determine the sex of germ cells.


E. coli hemolysin interactions with prokaryotic and eukaryotic cell membranes. The hemolysin toxin (HlyA) is secreted across both the cytoplasmic and outer membranes of pathogenic Escherichia coli and forms membrane pores in cells of the host immune system, causing cell dysfunction and death. The processes underlying the interaction of HlyA with the bacterial and mammalian cell membranes are remarkable. Secretion of HlyA occurs without a periplasmic intermediate and is directed by an uncleaved C-terminal targetting signal and the HlyB and HlyD translocator proteins, the former being a member of a transporter superfamily central to import and export of a wide range of substrates by prokaryotic and eukaryotic cells. The separate process by which HlyA is targetted to mammalian cell membranes is dependent upon fatty acylation of a non-toxic precursor, proHlyA. This is achieved by a novel mechanism directed by the activator protein HlyC, which binds to an internal proHlyA recognition sequence and provides specificity for the transfer of fatty acid from cellular acyl carrier protein.


Role of the interleukin 5 receptor system in hematopoiesis: molecular basis for overlapping function of cytokines. Interleukin 5 (IL-5) is a kind of peptide hormone released from T lymphocytes of mammals infected with microorganisms or parasites. It is an acidic glycoprotein with a molecular mass of 40 to 50 kDa that consists of a homodimer of polypeptides. It controls hematopoiesis so that it increases natural immunity. In the mouse, IL-5 acts on committed B cells to induce differentiation into Ig-producing cells and on common progenitors for CD5+ pre-B cells and CD5+ macrophages to support their survival. The antibodies secreted by CD5+ B cells seem to be responsible for the primary protection against the infection with microorganisms or parasites. It also supports the growth and/or differentiation of eosinophil precursor and mature eosinophils, which can be effective for the removal of parasites in combination with the antibodies against them. Murine IL-5 receptor (IL-5R) consists of two different polypeptide chains; alpha chain and beta chain. The IL-5R alpha chain is 60 kDa protein that binds IL-5 with low affinity. The IL-5R beta chain is a 130 kDa protein which does not bind IL-5 by itself but is necessary to form the high affinity IL-5R. The beta chain was identified by using one of the anti-IL-5R mAb and anti-IL-3R mAb as the IL-3R homologue. This beta chain is also used as the beta chain of GM-CSF receptor. This fact suggests that there is a common signaling mechanism among these cytokines and efficient cooperation among them. At the same time, these findings may explain the overlapping role of these cytokines in the development of granulocytes.


Membrane protein insertion into the endoplasmic reticulum--another channel tunnel? The synthesis of biological membranes requires the insertion of proteins into a lipid bilayer. The rough endoplasmic reticulum of eukaryotic cells is a principal site of membrane biogenesis. The insertion of proteins into the membrane of the endoplasmic reticulum is mediated by a resident proteinaceous machinery. Over the last five years several different experimental approaches have provided information about the components of the machinery and how it may function.


Is calpain activity regulated by membranes and autolysis or by calcium and calpastatin? Although the Ca(2+)-dependent proteinase (calpain) system has been found in every vertebrate cell that has been examined for its presence and has been detected in Drosophila and parasites, the physiological function(s) of this system remains unclear. Calpain activity has been associated with cleavages that alter regulation of various enzyme activities, with remodeling or disassembly of the cell cytoskeleton, and with cleavages of hormone receptors. The mechanism regulating activity of the calpain system in vivo also is unknown. It has been proposed that binding of the calpains to phospholipid in a cell membrane lowers the Ca2+ concentration, [Ca2+], required for the calpains to autolyze, and that autolysis converts an inactive proenzyme into an active protease. Recent studies, however, show that the calpains bind to specific proteins and not to phospholipids, and that binding to cell membranes does not affect the [Ca2+] required for autolysis. It seems likely that calpain activity is regulated by binding of Ca2+ to specific sites on the calpain molecule, with binding to each site eliciting a response (proteolytic activity, calpastatin binding, etc.) specific for that site. Regulation must also involve an, as yet, undiscovered mechanism that increases the affinity of the Ca(2+)-binding sites for Ca2+.


p53 loss of function: implications for the processes of immortalization and tumorigenesis. The complex process of cell immortalization and transformation is likely to involve the inactivation of growth regulatory genes. Mutations (deletions, missense mutations) in the p53 gene are the most frequently observed genetic alteration in human tumors, making p53 a candidate for a cellular protein involved in the control of cell growth. Two recent studies have examined the role of p53 in immortalization and tumorigenesis. In the first study, p53 expression was examined in both mortal and immortal chick embryo fibroblasts. All mortal clones expressed p53 but the loss of wild-type p53 expression was observed in every immortal cell line examined. In the second study, a line of mice carrying two null p53 alleles has been created and characterized. Although these mice develop normally, they show a predisposition to develop a variety of neoplasms at an early age (< 6 months). Although it is unclear whether p53 regulates the same, different, or overlapping pathways in the two experimental systems, these data demonstrate that p53 function is critical for the maintenance of normal growth control and support the current classification of p53 as a growth suppressive or tumor suppressor gene.


Genes, genes and more genes in the human major histocompatibility complex. The human major histocompatibility complex (MHC), on the short arm of chromosome 6, represents one of the most extensively characterised regions of the human genome. This approximately 4 Mb segment of DNA contains genes encoding the polymorphic MHC class I and class II molecules which are involved in antigen presentation during an immune response. Recently the whole of the MHC has been cloned in cosmids and/or yeast artificial chromosomes (YACs) and large portions have been characterised for the presence of novel genes. Many unrelated genes, both housekeeping and tissue specific, have been identified and the gene density in some regions is now approaching one gene every few kilobases. Some of the novel genes encode proteins involved in the intracellular processing and transport of antigens that are presented by MHC class I molecules. Others, however, have no obvious role in the immune response. The MHC is located in the chromosome band 6p21.3 which is a Giemsa (G)-light band. The detection of such a large number of functional genes (at least 70) in this region is compatible with the idea that both housekeeping and tissue-specific genes are localised predominantly in G-light bands.


All animals develop from a blastula: consequences of an undervalued definition for thinking on development. An early embryo becomes a blastula at the moment that its constituent cells become organised into a simple epithelium. Epithelial folding and compartmentation are essential elements of animal development. All the different cell types--epithelial and other ones--of which a differentiated organism consists differ in their plasmamembrane-cytoskeletal complex but they are assumed to have an identical genome. The hypothesis is put forward that, perhaps, the basic mechanism underlying differentiation can be defined as the generation of cells which have an identical genome but which differ in their plasmamembrane-cytoskeletal complex and which, because of these differences, can engage in differential protein synthesis-physiology.


HNF1, a homeoprotein member of the hepatic transcription regulatory network. Numerous liver specific genes are transcriptionally activated by the binding to their promoter or enhancer of Hepatic Nuclear Factor 1 (HNF1). HNF1 contains a variant homeo-domain and binds to DNA as either a homodimer or a heterodimer with the vHNF1 protein. Surprisingly, HNF1 is not restricted to hepatocytes but is expressed in epithelial cells of several endoderm derived organs and in mesoderm derived kidney tubules. Hence, HNF1 alone can not account for the differentiated state of the hepatic cells. In fact, several other liver-enriched transcription factors have been cloned. The hepatic phenotype could result from the combinatorial expression of these regulators. Possible involvement of these trans-acting factors in liver organogenesis and hepatic differentiation is discussed.


The mechanism of receptor-mediated endocytosis: more questions than answers. Receptor-mediated endocytosis occurs via clathrin-coated pits and is therefore coupled to the dynamic cycle of assembly and disassembly of the coat constituents. These coat proteins comprise part, but certainly not all, of the machinery involved in the recognition of membrane receptors and their selective packaging into transport vesicles for internalization. Despite considerable knowledge about the biochemistry of coated vesicles and purified coat proteins, little is known about the mechanisms of coated pit assembly, receptor-sorting and coated vesicle formation. Cell-free assays which faithfully reconstitute these events provide powerful new tools with which to elucidate the overall mechanism of receptor-mediated endocytosis.


The interaction of transcription factors with nucleosomal DNA. Nucleosome positioning is proposed to have an essential role in facilitating the regulated transcription of eukaryotic genes. Some transcription factors can bind to DNA when it is appropriately wrapped around the histone core, others cannot bind due to the severe deformation of DNA structure. The staged assembly of nucleosomes and positioning of histone-DNA contacts away from promoter elements can facilitate the access of transcription factors to DNA. Positioned nucleosomes can also facilitate transcription through providing the appropriate scaffolding to bring regulatory factors bound at dispersed sites into juxtaposition.


Position effect variegation and chromatin proteins. Variegated phenotypes often result from chromosomal rearrangements that place euchromatic genes next to heterochromatin. In such rearrangements, the condensed structure of heterochromatin can spread into euchromatic regions, which then assume the morphology of heterochromatin and become transcriptionally inactive. In position-effect variegation (PEV) therefore, gene inactivation results from a change in chromatin structure. PEV has been intensively investigated in the fruitfly Drosophila, where the phenomenon allows a genetic dissection of chromatin components. Consequently, many genes have been identified which, when mutated, act as dominant modifiers (suppressors or enhancers) of PEV. Data available already demonstrate that genetic, molecular and developmental analysis of these genes provides an avenue to the identification of regulatory and structural chromatin components, and hence to fundamental aspects of chromosome structure and function.


The biology of hepatocyte growth factor/scatter factor. Hepatocyte growth factor, a potent mitogen for epithelial and other cell types, and scatter factor, a stimulant of epithelial cell motility are identical. In addition to these mitogenic and motogenic functions, the factor has been shown to be an epithelial morphogen and also has antiproliferative effects in some cancer cell lines. The membrane receptor for hepatocyte growth factor/scatter factor has been identified as the c-met proto-oncogene product.


Mucins: structure, function, and associations with malignancy. Mucins are a family of high molecular weight, highly glycosylated glycoproteins found in the apical cell membrane of human epithelial cells from the mammary gland, salivary gland, digestive tract, respiratory tract, kidney, bladder, prostate, uterus and rete testis. Increased synthesis of the core protein and alterations in the carbohydrates attached to these glycoproteins are believed to play important roles in the function and proliferation of tumour cells. Aberrant glycosylation leads not only to the production of novel carbohydrate structures, but also to the exposure of the core peptide. These novel epitopes may be candidates for diagnosis or therapy, by using either synthetic mucin fragments as vaccines, or monoclonal antibody-based reagents which detect these structures.


Reverse genetics of Caenorhabditis elegans. It is somewhat ironic that animals that are the prime choice for detailed genetic analysis, such as the fruit fly and the nematode, have thus far been largely refractory to reverse genetic analysis. Their detailed genetic map, and small genome size have made them subjects of ambitious genome analysis projects, but there is still no strategy to introduce desired changes into their genomes by homologous recombination. Some alternative approaches have recently become available; this review describes possibilities and unsolved problems for reverse genetics in the nematode Caenorhabditis elegans. The transposon Tc1 could prove to be very useful for the isolation of knock out mutants, and possibly also for introduction of more subtle alterations.


Cell transplantation and gene therapy in muscular dystrophy. Duchenne's muscular dystrophy (DMD), which affects 1/3500 live male births, involves a progressive degeneration of skeletal and cardiac muscle, leading to early death. The protein dystrophin is lacking in DMD and present, but defective, in the allelic, less severe, Becker muscular dystrophy and is also missing in the mdx mouse. Experiments on the mdx mouse have suggested two possible therapies for these myopathies. Implantation of normal muscle precursor cells (mpc) into mdx skeletal muscle leads to the conversion of dystrophin-negative fibres to -positive, with consequent improvement in muscle histology. Direct injection of dystrophin cDNA into skeletal or cardiac muscle also gives rise to dystrophin-positive fibres. Although both appear promising, there are a number of questions to be answered and refinements to be made before either technique could be considered possible as treatments for myopathies in man.


Heparin binding site, conformational change, and activation of antithrombin. Alignment of the heparin-activated serpins indicates the presence of two binding sites for heparin: a small high-affinity site on the D-helix corresponding in size to the minimal pentasaccharide heparin, and a longer contiguous low-affinity site extending to the reactive center pole of the molecule. Studies of the complexing of antithrombin and its variants with heparin fractions and with reactive center loop peptides including intermolecular loop-sheet polymers all support a 3-fold mechanism for the heparin activation of antithrombin. Binding to the pentasaccharide site induces a conformational change as measured by circular dichroism. Accompanying this, the reactive center becomes more accessible to proteolytic cleavage and there is a 100-fold increase in the kass for factor Xa but only a 10-fold increase for thrombin, to 6.4 x 10(4) M-1 s-1. To obtain a 100-fold increase in the kass for thrombin requires in addition a 4:1 molar ratio of disaccharide to neutralize the charge on the extended low-affinity site. Full activation requires longer heparin chains in order to stabilize the ternary complex between antithrombin and thrombin. Thus, addition of low-affinity but high molecular weight heparin in conjunction with pentasaccharide gives an overall kass of 2.7 x 10(6) M-1 s-1, close to that of maximal heparin activation.


Five specificity patterns of (1----3)-alpha-L-fucosyltransferase activity defined by use of synthetic oligosaccharide acceptors. Differential expression of the enzymes during human embryonic development and in adult tissues. The use of synthetic trisaccharides as acceptors led to the definition of five main (1----3)-alpha-L-fucosyltransferase activity patterns in human adult tissues: (I). Myeliod cells, granulocytes, monocytes, and lymphoblasts, transfer an alpha-L-fucopyranosyl group to O-3 of a 2-acetamido-2-deoxy-D-glucosyl residue of H blood-group Type 2 oligosaccharide [alpha-L-Fucp-(1----2)-beta-D-Galp-(1----4)-beta-D-GlcpNAc----R] with Mn2+ as activator. (II) Brain has the same acceptor specificity pattern as myeloid cells, but can also use Co2+ as activator. (III) Plasma and liver transfer an alpha-L-furopyranosyl group to H blood-group Type 2 and to sialyl-N-acetyllactosamine [alpha-NeuAc-(2----3)-beta-D-Galp-(1----4)-beta-D-GlcpNAc----R]. (IV) Intestine, gall bladder, kidney, and milk have the same activity as (III), but also transfer an alpha-L-fucopyranosyl group to O-4 of a 2-acetamido-2-deoxy-D-glucose residue of H blood-group Type 1 [alpha-L-Fucp-(1----2)-beta-D-Galp-(1----3)-beta-D-GlcpNAc----R] and sialyl Type 1 [alpha-NeuAc-(1----3)-beta-D-Galp-(1----3)-beta-D-GlcpNAc----R]. (V) Stomach mucosa is not able to use sialyl-N-acetyllactosamine, but can transfer an alpha-L-fucopyranosyl group to the other Type 1 and Type 2 acceptors. Unlike in adult tissue, a single myeloid-like pattern of (1----3)-alpha-L-fucosyltransferase activity was found at early stages of development in all tissues tested. This embryonic enzyme is later progressively replaced by enzymes or mixtures of enzymes having the corresponding adult patterns of enzyme expression. All lymphoblastoid cell lines and half of the tumor epithelial cell lines tested expressed the myeloid-like pattern of enzyme found in normal embryonic tissues. The remaining tumor epithelial cell lines expressed different forms of (1----3/4)-alpha-L-fucosyltransferase acceptor specificity patterns.


Varicella-zoster virus open reading frame 61 protein is functionally homologous to herpes simplex virus type 1 ICP0. The varicella-zoster virus (VZV) open reading frame 61 (ORF61) protein is thought to be the homolog of herpes simplex virus type 1 (HSV-1) ICP0, based on gene location and limited amino acid homology. However, HSV-1 ICP0 trans activates HSV-1 genes, while VZV ORF61 protein trans represses the function of VZV trans activators on VZV promoters in transient expression assays. To investigate the functional relatedness of HSV-1 ICP0 and VZV ORF61 protein, we established Vero and MeWo cell lines which stably express VZV ORF61 under the control of a metallothionein promoter and performed complementation studies with an HSV-1 ICP0 deletion mutant (7134). Mutant 7134 is impaired for plaque formation and replication at a low multiplicity of infection in cell culture, but these defects were complemented by up to 200-fold in Vero cell lines expressing VZV ORF61. Likewise, the efficiency of plaque formation was improved by up to 100-fold in MeWo cell lines expressing VZV ORF61. A cell line expressing another VZV immediate-early gene product (ORF62) was unable to complement mutant 7134. HSV-1 mutants which are deleted for other HSV-1 immediate-early gene products (ICP4, ICP27) were unable to grow in VZV ORF61-expressing cell lines. These results indicate that, despite marked differences in their sequences and in effects on their cognate promoters in transient expression assays, VZV ORF61 protein is the functional homolog of HSV-1 ICP0.


Quinolone antibacterial agents. Synthesis and structure-activity relationships of a series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)quinolones. Highly soluble quinolone prodrugs with in vivo pseudomonas activity. A series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1,8-naphthyridine-3-carboxylic acids, 1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids, 1-cyclopropyl-6-fluoro-3-quinolinecarboxylic acids, and 5-amino-1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids have been prepared and evaluated for comparative antibacterial activity. Compounds were prepared by acylation of the 3-amino group of the pyrrolidine with common amino acids using standard peptide chemistry. This series has been compared with the parent compounds for antibacterial activity in vitro and in vivo as well as for comparative solubility. The amino acid analogues were less active in vitro, but had equal or increased efficacy in vivo. Indeed, it was proven that these compounds, which were stable to acid and base under the reaction conditions for their preparation, were rapidly cleaved in serum to give the parent quinolones. The amino acid derivatives showed a 3-70 times improved solubility when compared to the parent compounds. The most active compound of the series was [S-(R*,R*)]-7-[3-[(2-amino-1-oxopropyl)-amino]-1-pyrrolidinyl]-1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (PD 131112).


Mallory-Weiss tears occurring during endoscopy: a report of seven cases. Mallory-Weiss tears occurring during the course of upper gastrointestinal endoscopy are apparently rare. The present report describes seven cases of iatrogenic gastro-oesophageal tears encountered during 10,000 endoscopic examinations over a period of six years. Five of the seven patients were female and six patients were aged 75 years or older. Six patients had hiatal hernias. The site of the mucosal tear was similar in all patients, extending from a V-shaped breach at the gastro-oesophageal junction inferiorly along the lesser curve for a variable distance of up to 8 cm. Neither retching nor struggling during the procedure contributed to the development of the lesion in any of the patients. One patient suffered from a haematemesis which required transfusion, and in a further patient the tear resulted in a haematemesis and gastric perforation necessitating laparotomy. The study indicates that Mallory-Weiss tears complicating endoscopy occur especially in elderly, female patients with hiatal hernias. The importance of admitting patients with this complication to hospital for overnight observation is recommended in view of the possible development of haemorrhage or perforation.


[Primary leiomyosarcoma of the left renal vein]. The authors report a case of leiomyosarcoma of the left renal vein. Because of its retroperitoneal position, this exceptional tumour was responsible for few symptoms. Complementary investigations (CT scan, ultrasonography, arteriography) often do not confirm the diagnosis. Complete surgical excision combined with complementary treatment can ensure long-term survival.


[Rheumatic complaints and diseases in ex-prisoners of war in Croatia in 1991. A review of medical prognosis for work capacity]. The results are presented of an examination of the locomotor system in 48 ex-prisoners of war, previously maltreated in prison camps in Serbia and occupied areas of Croatia. They were part of a group of 508 prisoners of war, examined in the Clinic for Infectious Diseases in Zagreb. They were all male, aged 33.9 +/- 11.56 years, in whom, after the first medical examination a rheumatological examination was indicated because of disorders of the locomotor system. Only 16.7% of the subjects had not been physically maltreated. Blows to the lumbo-sacral spine were the most frequent (43.7%), shoulders (33.4%) and the head (27.0%). Earlier rheumatic disorders were reported by 41.7% of the ex prisoners, and during the examination in our Rheumatological clinic 70.8%. In 21% of the ex-prisoners the rheumatological disorders started as a direct consequence of maltreatment in the prison camps. In one of the ex-prisoners acquisition of ankylosis spondylitis occurred and in another uric arthritis. In 50% of the ex-prisoners a marked reduction in work ability was confirmed. Disability retirement was proposed for two ex-prisoners. Optimal health treatment is discussed and medical prognosis of work ability.


[The effect of gold salts on rheumatoid factor dynamics in patients with rheumatoid arthritis]. The aim of research was to establish effect of gold-salts (under protected name "Tauredon" Byk Gulden) on the dynamics of rheumatoid factor, decreed with Waaler-Rose test, at patients with rheumatoid arthritis. Following the dynamics of rheumatoid factors was performed during 6 months continued application of "Tauredon" on a group of patients with certain diagnosis of rheumatoid arthritis. The group consisted of 8 men and 35 women, with age profile of 50 years. With continuous observation of patients and their laboratory findings (Waaler-Rose test) in regular time intervals it was found out that "Tauredon" has significant influence on oscillation of rheumatoid factor, decreed by the method of hemaglutination of sheep erythrocytes.


[Radiologic changes in the costovertebral and costotransverse joints and functional changes in the thoracic spine in ankylosing spondylitis]. Radiological, morphological and functional changes of the thoracic spine together with costovertebral and costotransversal joint involvement were studied in patients with ankylosing spondylitis. While radiological changes were found in all patients, in 74% they were of inflammatory origin. Radiological abnormalities were more prominent in patients with a more severe clinical course and a relatively short duration of the disease. As many as 95% of patients exhibited functional impairment of the thoracic spine. No significant difference was observed between the duration of disease and functional impairment of the thoracic spine (t = 1.4, P > 0.05) but there was a highly significant correlation between radiological changes and functional impairment of the thoracic spine (r = 0.577, P < 0.001).


[The effect of Tauredon on the development of non-specific indicators of inflammatory activity in patients with rheumatoid arthritis]. The objective of this research has been to determine the effects of the gold salts Tauredon Byk Gulden on the development of non-specific parameters with regard to the inflammatory processes in patients with rheumatoid arthritis. The group being tested comprised 8 men and 35 women with a positive diagnosis of rheumatoid arthritis, their average age being 50, the average disease course 9.5 years. During a six-month continuous application of Tauredon, the following parameters were observed in regular intervals: the erythrocyte sedimentation rate, the haemoglobin level in the serum and the C-reactive protein. The statistical processing of data indicated that Tauredon significantly reduces the erythrocyte sedimentation, considerably increases the haemoglobin level in the serum and significantly decreases the C-reactive protein value.


[Critical review of images of the lumbosacral part of the spine in patients with low back pain]. A comparative analysis of X-ray images of lumbar spine both in the standard positions (dorsal and profile image) and upright position has been performed by the authors. The examination was carried--out on 33 subjects in all (17 man and 16 women). The sagital curvature of lumbar spine changes considerably in dependence of body position during the raying. Preserved lumbar lordosis was found in 31 patients X-ray images take in upright position or 94%, while lumbar lordosis in standard position was seen reduced or completely disappeared in X-ray images. The evaluation of sagital curvature degree is of almost importance in physiotherapy due to correct planning kinesiotherapeutic procedure. Only the X-ray images of an observed group patients in a upright position was showed the spondylolisthesis in one patient, stenosis of lumbar spine channel in one patient and the lesion of intervertebral disc in one patient. The authors conclude that in patients with low back pain syndrome only the X-ray images in upright position are necessary, since they provide more information to analyse both the condition and the relation between the vertebral dynamical segments.


[The effect of 6 months of treatment with Tauredon on clinical indicators in rheumatoid arthritis]. The objective of this research has been to evaluate the efficacy of Tauredon (the aqueous solution of Na-thiomalate) on the development of some clinical parameters in patients with rheumatoid arthritis. The group being tested comprised 8 men and 35 women, their average age being 50, the average duration of their illness being 9.5 years. As regards the anatomic development stage of illness, the majority of patients belonged to stage 2 (62.8%), with no patients belonging to stage 4. During the continuous six-month application of Tauredon, the following parameters have been observed: the Ritchie index, the PIP extent of the fist joints and the morning stiffness span of the small fist joints. The evaluation of the six-month treatment with Tauredon has proved its positive effect on all clinical parameters, shown in the lower value of the Ritchie index, the lower PIP extent of the fist joints as well as the shorter morning stiffness span. Further, the Tauredon effect has been seen in suppressing the inflammatory activities and in restituting the joint functions in patients with rheumatoid arthritis.


[Complement (C3 and C4) in patients with rheumatoid arthritis during 6 months of treatment with gold salts]. The aim of research was to establish effect of gold-salts under protected name "Tauredon" Byk Gulden, on the dynamics of fraction of complements C3 and C4 at patients with rheumatoid arthritis. Following the dynamics of both parameters, was performed during 6 months continued application of "Tauredon", on 8 men and 35 women with certain diagnosis. Profile of the age of patients was 50 years old. With continuous observation of patients and their laboratory findings, in regular time intervals, we found out that "Tauredon" has significant influence on increase of level of C3 in serum of patients (P = 0.006) but not in increase of fraction of complement C4 (P = 0.117).


[The effect of Na-aurothiomalate on circulating immune complex dynamics in patients with rheumatoid arthritis]. The objective of this research has been to determine the efficacy of Na-aurothiomalate, under the trade name Tauredon, on the development of circulating immune complexes (CIC) in patients with rheumatoid arthritis. During a continuous six month administering of Tauredon to a group of patients with the diagnosis of rheumatoid arthritis various parameters have been observed. The group comprised 43 patients, 8 men and 35 women, their average age being 50. By continuous observations of both the patients and their laboratory reports in regular intervals during six-month administering of Tauredon, a positive effect of Tauredon on the development of the CIC IgM values (P = 0.006) has been proved, i.e. reducing their level in the patients' serum. Owing to great individual differences in the decrease of the CIC IgG values, it has been difficult to prove the consequences of this fall (P = 0.086). The impossibility of testing the significant decrease of the CIC IgA values is due to a small number of patients with the positive CIC IgA values.


[Prevalence of rheumatoid factor in a single sampling of the urban population in Croatia]. The prevalence of rheumatoid factor (RF) in urban population was examined. A random sample was taken according to the register of voters and included 5% of the population. Among them 60% suffered from various rheumatic symptoms. Out of 500 persons invited to an examination, 231 examinees responded. None of the examinees in that moment showed signs of rheumatoid arthritis. RF is determined in serum according to Waaler-Rose and it was positive in 12 out of 231 examinees (5.2%) about equally in men and women (P > 0.05). The majority of examinees was over 50 years old. Titar RF increased with the age of the examinee, but difference is not significant (P > 0.05). RF is not only a characteristic of RA, but it could also be found during the other diseases which are accompanied by, first of all, hypergammaglobulinemia and fibrosis.


[Phagocytic activity in rheumatoid arthritis]. The phagocytic activity of leukocytes was studied in 41 patients with active rheumatoid arthritis, 24 of whom were treated with gold compounds and the remaining 17 with non-steroidal anti-inflammatory drugs. The control group comprised 137 patients with no signs of inflammatory rheumatic diseases. The mean age of patients was 54.8 years (range: 32-75) and that of the controls, 53.5 years (range: 32-75). Spontaneous mobility (P < 0.001), phagocytic activity (P < 0.001) and antibody-dependent cytotoxicity (P < 0.001) of leukocytes were significantly lower in patients with rheumatoid arthritis compared to the control group. No significant differences were observed between patients treated with gold compounds and those receiving nonsteroidal anti-inflammatory drugs with respect to mean spontaneous mobility (U = 198, P = 0.44), phagocytic activity (U = 185, P = 0.31) and antibody-dependent cytotoxicity (U = 183, P = 0.29) of leukocytes. Among patients treated with gold compounds phagocytic activity was significantly lower in those receiving TauredonR compared to those receiving AuropanR (U = 33.5, P = 0.05). The antibody-dependent cytotoxicity was comparable in patients receiving Tauredon and Auropan, respectively (U = 58.5, P = 0.48).


[Systemic allergic vasculitis: case report of a female patient with the Churg-Strauss syndrome]. A female patient with asthmatic attacks developed signs of peripheral and central nervous system involvement, cutaneous and joint manifestations, pulmonary and gastrointestinal involvement, with significant body weight loss. A blood eosinophilia was found and muscle biopsy revealed tissue infiltration by eosinophils and vasculitis. Very short interval from onset of first symptoms to appearance of vasculitis is a bad prognostic sign and probably cause of unsuccessful therapy.


[Side effects of gold salt therapy in patients with rheumatoid arthritis]. Observing the efficacy of the gold sodium thiomalate (under the trade name of Tauredon Byk Gulden) during the treatment of 43 patients with rheumatoid arthritis, a certain number of side effects have been noted and registered. The group being tested comprised 43 patients, 8 men and 35 women, average age being 50. The side effects were observed in 14 patients (32.5%), namely in one man and 13 woman, the most frequent being thrombocytopenia (20.8%), serious exacerbation of the disease (16.6%), thrombocytosis and dermatitis (12.5%). The recurrence rate of the side effects during the treatment with the gold sodium thiomalate was greater during the first (14%) and the second month (11.8%) than during the third (4.6%) and the fourth month (2.5%).


[Educational-motivational guidelines for working with parents of children with juvenile chronic arthritis]. This paper points at the role of parents in performance and supervision of out institutional treatment and rehabilitation of children suffering from juvenile chronic arthritis (JCA) dealing with educational--motivating elements in work of parents with ill child. Medical psycho-sociological and pedagogic aspects of work of parents with ill child has been presented. For each indicated educational--motivating unity parents have to be completely prepared for better and more complete than usual piling of facts and presenting in front of them unsolvable tasks and obligations. Should child's rheumatologist succeed in this a plan of individual continuous treatment and rehabilitation of each patient suffering from JCA shall meet with success.


[Results of a comparative study of the success of treatment of pain in the lumbar spine at the Moravske Toplice health spa, at the department of physical therapy and rehabilitation and at the department of rheumatology of the Maribor Teaching Hospital]. A parallel investigation of the success of treating patients with chronic low back pain has been carried out at the Moravci Spa, at the Department for Physical Therapy and Rehabilitation and at the Rheumatology Department of Maribor Teaching Hospital. One hundred patients suffering from low-back pain were given a 14-day treatment in the termomineral water (T--36 degrees C) of the Moravci Spa. A comparative group of another 100 patients also suffering from pain in the lumbar region of the spine underwent equal balneo-physical treatment in plain water (T--32 degrees C) at the Dept. for Physical Therapy and Rehabilitation and at the Dept. of Rheumatology at Maribor Teaching Hospital, Slovenia. The educational background of the two groups features a statistically significant difference (p < 0.001): the percentage of patients with lower education was higher at the Moravci Spa (67%) compared with only 46% among those treated at Maribor Teaching Hospital. Correspondingly, the difference in occupation of the two groups were similar (p < 0.005): prevalent among the patients at Moravci Spa were bluecollar workers (40%) compared with white-collar workers (27%). The percentage of white-collar workers at Maribor Teaching Hospital was 45%. The average age of the patients treated at the Moravci Spa was 46.9 +/- 9.5 years (28-77 years), at Maribor Teaching Hospital it was 45.2 +/- 8.2 years (26-71 years). There was no statistically significant difference in age (p < 0.10) between the two groups. Generalized spondylochondrosis was present in both groups, i.e. 87%; approximately 10% of the patients from both groups underwent surgical treatment of hernia disci.(ABSTRACT TRUNCATED AT 250 WORDS)


[The effect of verticalization of the resulting force (R) of weight bearing in the hip joint on morphologic characteristics of the medullary canal in the femoral shaft in patients with coxarthrosis]. An influence of verticalization of the resulting force of weight-bearing on the hip joint "R" on the morphological characteristics of the medullar canal on the proximal edge of the shaft of femur was researched. Progressive degenerative changes of the hip joint with a consequent sideways limping or changes of the collodiaphysial angle (ccd angle) were the cause of the verticalization of the resulting force "R". The analysis of patients treated and operated on The Orthopaedic Department of the General Hospital Osijek and The Orthopaedic Clinic of The Medical Faculty of The University of Zagreb. The research, undoubtedly, proved that the patients with coxarthrosis and side-ways in the hip or with changed collodiaphysial angle experienced verticalization of the resulting force of weigh-bearing of the hip joint and the proximal edge of femur which caused morphological changes of the medular canal of the shaft of femur.


[A community program to stimulate smoking cessation]. A community program to stimulate smoking cessation developed on the 1988 World No-smoking Day in the city of Barcelona (Spain) is presented. Participants in this program could make a written commitment to quit, and received support materials by mail. The results are evaluated in a sample of participants: 69% declare having quit on the specified date, and 29% do not smoke after one year.


[The revision of the organization of consultation for long-term treatment]. The growing drug dependency of developed societies has meant the uncontrolled use of drugs with the consequent medical risks and important economic repercussions. Primary health care in our country is characterized by high demand bureaucratization of clinics. Because of this, we consider it useful to rely on a prescription system for long term treatment, this being understood as a mechanism which allows the obtaining of prescriptions easily both for the patient and the doctor, control and monitoring of established chronic treatments, periodical therapy evaluations, which rely on the participation of other members of the primary health care team. In this report the model of the repeat prescription system in our health area is shown, from which the prescription can be obtained in a maximum time limit of 8 hours, the medication taken for chronic illness can be easily recognized and to make note of the date of the prescription.


[Socioeconomic level and mortality].

[Socioeconomic level and mortality]. A revision of the bibliography has been carried out, referring to the influence of people's social economic condition to the cause and age at death. Special interest was taken in collecting works carried out after the Black Report was published, taking its particular relevance into account.


[The diagnosis of basic sanitation in the Erniobea region]. The aim of this report was to identify the basic sanitary situation and that of a series of health markers, in the area of influence of our health centre. The population studied have all come from places under the census and the measuring system used was a prepared survey and also, direct observation. The information collected was verified by revising all the clinical notes of the affected people. The results found are presented, referring to the characteristics of the houses and the stables, the sanitary situation of the livestock, water supply and excrement removal, rubbish removal methods and health markers. The high number of houses without adequate installation maintenance (water, excrement...) and the high incidence of infectious diseases should be highlighted.


[The ionic composition of the atmospheric aerosols in industrial areas of the north of Spain]. Over the years 1986, 1987 and 1988 determinations of the mass concentration of total particles in suspension and of the anionic components (chlorides, nitrates and sulphates) and cationic (sodium, potassium, calcium, magnesium and ammonia) contained in these was carried out in Bilbao, Sestao and Erandio. The determination of the mass of particles was carried out by gravimetry and chemical composition by ionic chromatography. The particle concentrations in Bilbao and Sestao, over the measuring period, were higher than those in Erandio. The studies of concentrations, percentages and correlations show the existence of centres of calcium emission during one season and high levels of chlorides during all of them. Surprisingly enough, the nitrate and ammonia content for all the seasons is low in comparison with other urban and industrial centres of the peninsular inland.


[An epidemiological study of the body mass index in a school-aged population of Madrid]. A descriptive study has been carried out, to perform body mass index, between 2606 schoolchildren at Madrid, during 1986 to 1990. Observational and transversal study. The data obtained were compared by age and sex for each year, and we calculated the body mass index percentiles for each group in the study. Mean body mass index rises with age and also 90 and 95 percentiles. The 1.5% and 0.8% of children at 6 years had BMI more than 26, for male and female respectively. At age 10, this percentages were 9.5% and 11.6% for male and female, and the results for age 13 were 16.1% and 17.8% respectively.


[The epidemiology of dermatologic diseases in primary care]. With the aim of finding out the prevalence and the origin of the skin disease in primary health care, a prospective study was carried out over the period of May to October of 1989 in an urban health centre, with the support of the dermatologist and using iconographic means. The 395 cases considered made up 4.85% of all the medical examinations. A limited number of diagnoses (11) made up the majority of the medical examinations (70%). 19% were referred to the dermatologist. 23% of those diagnosed were not consulted for the patient, including two malign tumours. skin disease has a relevant place in primary health care clinics; the dermatological training of the primary health care doctor should be aimed at the most frequent diagnoses in his setting; active detection of skin lesions is very important.


[The seroprevalence of human toxoplasmosis in Córdoba]. A seroprevalency study of human toxoplasmosis was carried out in Córdoba, using indirect immunofluorescence and indirect hemagglutination. The sample of people interviewed was made up of 443 serums, 356 supposedly healthy people (mainly students) and 87, considered "high risk" (patients from the "Reina Sofia" Hospital). The positiveness obtained for the total of the sample was 43.79% with IFI and 53.59% for HAI. As regards sex of the person tested, prevalence is higher in women, with 54.36% and 70.47% with IFI and HAI respectively, in men the scores were 38.43% and 44.90% for the same tests. As far as the origin of the sample was concerned, there were 31.18% with IFI and 43.25% for HAI of the normal population, in the "high risk" sample, for both tests it was 95.40%. With both tests there are significative differences in low amounts, but not in high dilutions. We conclude that human toxoplasmosis is present and widespread in the studied population.


[Current changes in the predominant mechanisms of the transmission of brucellosis in the province of Valencia]. A descriptive epidemiological study of brucellosis in the province of Valencia was carried out over the period 1985-1988. In this report predominant transmission mechanisms and their relation with sex, age and profession variables are described. Moreover, the results obtained were compared with those from other brucellosis epidemiologies which were previously carried out in the province of Valencia. It can be seen that there is a relative increase in the direct contagion mechanism and a decrease in the indirect contagion mechanism with respect to the previous periods, which has effects on the variations of sex and profession distribution of the disease. The changes observed could be attributed to a better sanitary control of milk and diary products, mainly fresh cheese, which are very important in the transmission of the disease in the province of Valencia.