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We study the establishment probabilities of locally adapted mutations using a multi-type branching process framework. We find a surprisingly simple and intuitive analytical approximation for the establishment probabilities in a symmetric two-deme model under the assumption of weak (positive) selection. This is the first analytical closed-form approximation for arbitrary migration rate to appear in the literature. We find that the establishment probability lies between the weak and the strong migration limits if we condition the origin of the mutation to the deme where it is advantageous. This is not the case when we condition the mutation to first occur in a deme where it is disadvantageous. In this case we find that an intermediate migration rate maximizes the probability of establishment. We extend our results to the cases of multiple demes, two demes with asymmetric rates of gene flow, and asymmetric carrying capacities. The latter case allows us to illustrate how density regulation can affect establishment probabilities. Finally, we use our results to investigate the role of gene flow on the rate of local adaptation and identify cases in which intermediate amounts of gene flow facilitate the rate of local adaptation as compared to two populations without gene flow., (Copyright © 2018 by the Genetics Society of America.)

Suicidality is a continuum ranging from ideation to attempted and completed suicide, with a complex etiology involving both genetic heritability and environmental factors. The majority of suicide events occur in the context of psychiatric conditions, preeminently major depression and bipolar disorder. The present study investigates clinical factors associated with suicide in a sample of 553 mood disorder patients, recruited within the 'Psy Pluriel' center, Centre Européen de Psychologie Médicale, and the Department of Psychiatry of Erasme Hospital (Brussels). Furthermore, genetic association analyses examining polymorphisms within COMT, BDNF, MAPK1 and CREB1 genes were performed in a subsample of 259 bipolar patients. The presence or absence of a previous suicide attempt and of current suicide risk were assessed. A positive association with suicide attempt was reported for younger patients, females, lower educated, smokers, those with higher scores on depressive symptoms and higher functional disability and those with anxiety comorbidity and familial history of suicidality in first- and second-degree relatives. Anxiety disorder comorbidity was the stronger predictor of current suicide risk. No associations were found with polymorphisms within COMT and BDNF genes, whereas significant associations were found with variations in rs13515 (MAPK1) and rs6740584 (CREB1) polymorphisms. From a clinical perspective, our study proposes several clinical characteristics, such as increased depressive symptomatology, anxiety comorbidity, functional disability and family history of suicidality, as correlates associated with suicide. Genetic risk variants in MAPK1 and CREB1 genes might be involved in a dysregulation of inflammatory and neuroplasticity pathways and are worthy of future investigation.

The design and synthesis of enhanced membrane-intercalating biomaterials for drug delivery or vascular membrane targeting is currently challenged by the lack of screening and prediction tools. The present work demonstrates the generation of a Quantitative Structural Activity Relationship model (QSAR) to make a priori predictions. Amphiphilic macromolecules (AMs) "stealth lipids" built on aldaric and uronic acids frameworks attached to poly(ethylene glycol) (PEG) polymer tails were developed to form self-assembling micelles. In the present study, a defined set of novel AM structures were investigated in terms of their binding to lipid membrane bilayers using Quartz Crystal Microbalance with Dissipation (QCM-D) experiments coupled with computational coarse-grained molecular dynamics (CG MD) and all-atom MD (AA MD) simulations. The CG MD simulations capture the insertion dynamics of the AM lipophilic backbones into the lipid bilayer with the PEGylated tail directed into bulk water. QCM-D measurements with Voigt viscoelastic model analysis enabled the quantitation of the mass gain and rate of interaction between the AM and the lipid bilayer surface. Thus, this study yielded insights about variations in the functional activity of AM materials with minute compositional or stereochemical differences based on membrane binding, which has translational potential for transplanting these materials in vivo. More broadly, it demonstrates an integrated computational-experimental approach, which can offer a promising strategy for the in silico design and screening of therapeutic candidate materials.

Wearable systems capable to capture vital signs allow the development of advanced medical applications. One notable example is the use of surface electromyography (EMG) to gather muscle activation potentials, in principle an easy input for prosthesis control. However, the acquisition of such signals is affected by high variability and ground loop problems. Moreover, the input impedance influenced in time by motion and perspiration determines an offset, which can be orders of magnitude higher than the signal of interest. We propose a wearable device equipped with a digitally controlled Analog Front End (AFE) for biopotentials acquisition with zero-offset. The proposed AFE solution has an internal Digital to Analog Converter (DAC) used to adjust independently the reference of each channel removing any DC offset. The analog integrated circuit is coupled with a microcontroller, which periodically estimates the offset and implements a closed loop feedback on the analog part. The proposed approach was tested on EMG signals acquired from 4 subjects while performing different activities and shows that the system correctly acquires signals with no DC offset.

Modafinil, (RS)-2-(diphenylmethylsulfinyl)acetamide derivative (Modiodal, Provigil), is a vigilance-promoting agent which reduces sleep episodes by improving wakefulness. It is approved by the USA FDA for narcolepsy, shiftwork sleep disorder and obstructive sleep apnoea with residual excessive sleepiness despite optimal use of continuous positive airway pressure. Unlike classical psychostimulants such as amphetamine and amphetamine-like compounds, the awaking effect of modafinil is not associated with a disturbance of nighttime sleep, tolerance, and sensitization. Its precise mechanism of action is still unclear. In animal studies, modafinil and its analogues have been shown to modify dopaminergic, noradrenergic, glutamatergic, GABAergic, serotoninergic, orexinergic, and histaminergic pathways. Besides the approved use in sleep disorders, modafinil has been investigated for the treatment of fatigue, impaired cognition and some symptoms in a number of other disorders. In particular, clinical studies seem to indicate that the drug could be particularly successful in the treatment of depression and its use in major depressive and bipolar disorders, has been suggested. However, the molecular mechanisms underlying this possible effect are still unknown. The present review firstly summarizes the structure-activity relationship studies and the mechanism of action of modafinil and its related compounds. Then, it focuses on data demonstrating that modafinil interacts with serotonin neuronal activity in rat frontal cortex and dorsal raphe nucleus, two brain areas linked together and involved in depression. Preclinical and clinical evidence of a positive interaction between modafinil and classical antidepressant drugs, is also summarized.

The role that the tridecapeptide neurotensin (NT) plays in the modulation of the aminoacidergic transmission is analyzed in different rat brain regions. NT exerts its effects through the activation of different receptor subtypes, NTR1, NTR2 and NTR3. The contribution of NTR1 receptor in modulating and reinforcing glutamate signalling will be shown including the involvement of interactions between NT and N-methyl-D-aspartate (NMDA) receptors. Extracellular accumulation of glutamate and the excessive activation of glutamate receptors, in particular NMDA receptors, is known to represent an important factor in the induction of glutamate-mediated neuronal damage occurring in Parkinson's disease and in pathologic events such as hypoxia and ischemia. An enhancing action of NT on glutamate-induced neurodegenerative effects is shown and NTR1 receptor antagonists could therefore become novel pharmaceutics in the treatment of neurodegenerative disease.

The neurobehavioral and neurochemical effects produced by prenatal methylmercury exposure (8 mg/kg, gestational-days 8 or 15), were investigated in rats. On postnatal day 40, animals exposed to methylmercury and tested in the open field arena, showed a reduction in the number of rearings, whereas the number of crossings and resting time was not altered with respect to the age-matched control rats. The methylmercury-exposed groups showed a lower level of exploratory behavior as well as an impairment in habituation and working memory when subjected to the novel object exploration task. The neophobia displayed by methylmercury-exposed rats is unlikely to be attributed to a higher degree of anxiety. Prenatal methylmercury exposure did not affect motor coordination or motor learning in 40-day-old rats subjected to the balance task on a rotating rod, and it did not impair the onset of reflexive behavior in pups screened for righting reflex, cliff aversion and negative geotaxis. In cortical cell cultures from pups exposed to methylmercury during gestation, basal extracellular glutamate levels were higher, whereas the KCl-evoked extracellular glutamate levels were lower than that measured in cultures from rats born to control mothers. In addition, a higher responsiveness of glutamate release to N-methyl-D-aspartic acid receptor activation was evident in cortical cell cultures from pups born from methylmercury-treated dams than in cultures obtained from control rats. The present results suggest that acute maternal methylmercury exposure induces, in rat offspring, subtle changes in short-term memory as well as in exploratory behavior. These impairments seem to be associated to alterations of cortical glutamatergic signaling.

The tridecapeptide neurotensin has been demonstrated to increase glutamate release in discrete rat brain regions, leading to the hypothesis of a possible involvement of the peptide in neurodegenerative pathologies. The role of neurotensin in modulating glutamate excitotoxicity and the possible neuroprotective action of the neurotensin receptor antagonist SR48692 were investigated in primary cultures of mesencephalic neurons by measuring [(3)H]dopamine uptake and tyrosine hydroxylase immunocytochemistry 24 hr after glutamate treatment. The exposure to glutamate (30 and 100 microM, 10 min) decreased [(3)H]dopamine uptake into mesencephalic neurons. Neurotensin (10 and 100 nM), added before glutamate (30 microM) exposure, significantly enhanced the glutamate-induced reduction of [(3)H]dopamine uptake. In addition, the peptide (10 nM) also significantly enhanced the effect of 100 microM glutamate. The effects of neurotensin were counteracted by the neurotensin receptor antagonist SR48692 (100 nM) and by the protein kinase C inhibitor calphostin C. The exposure to 100 microM, but not 30 microM, glutamate significantly reduced the number of tyrosine hydroxylase-immunoreactive cells, and neurotensin (10 nM) significantly enhanced this effect. SR48692 (100 nM) prevented the neurotensin-induced action. These findings support the view of a possible pathophysiological role of neurotensin in mesencephalic dopamine neuronal function. Furthermore, selective neurotensin antagonists in combination with conventional drug treatments could provide a novel therapeutic approach for the treatment of neurodegenerative disorders, such as Parkinson's disease., (Copyright 2002 Wiley-Liss, Inc.)

The effects of the cannabinoid receptor agonist WIN 55,212-2 (0.1-5 mg/kg i.p.) on endogenous extracellular gamma-aminobutyric acid (GABA) levels in the cerebral cortex of the awake rat was investigated by using microdialysis. WIN 55,212-2 (1 and 5 mg/kg i.p.) was associated with a concentration-dependent decrease in dialysate GABA levels (-16% +/- 4% and -26% +/- 4% of basal values, respectively). The WIN 55,212-2 (5 mg/kg i.p.) induced-inhibition was counteracted by a dose (0.1 mg/kg i.p.) of the CB(1) receptor antagonist SR141716A, which by itself was without effect on cortical GABA levels. These findings suggest that cannabinoids decrease cortical GABA levels in vivo, an action that might underlie some of the cognitive and behavioral effects of acute exposure to marijuana., (Copyright 2001 Wiley-Liss, Inc.)

The effects of the cannabinoid receptor agonist WIN 55,212-2 on endogenous extracellular glutamate levels in the prefrontal cortex of the awake rat and in primary cultures of rat cerebral cortex neurons were investigated. In the prefrontal cortex WIN 55,212-2 (0.1 and 1 mg/kg i.p.) increased dialysate glutamate levels from of the awake rat, while the lower (0.01 mg/kg) and the higher (2 mg/kg) doses were ineffective. Furthermore, the WIN 55,212-2 (0.1 mg/kg)- induced increase of dialysate glutamate levels was counteracted by pretreatment with the selective CB(1) receptor antagonist SR141716A (0.1 mg/kg i.p.) and by the local perfusion with a low-calcium Ringer solution (Ca(2+) 0.2 mM). In primary cultures of rat cerebral cortex neurons, WIN 55,212-2 (0.01--100 nM) increased extracellular glutamate levels, displaying a bell-shaped concentration-response curve. The facilitatory effect of WIN 55,212-2 (1 nM) was fully counteracted by SR141716A (10 nM), by the replacement of the normal Krebs Ringer-bicarbonate buffer with a low Ca(2+) medium (0.2 mM) and by the IP(3) receptor antagonist xestospongin C (1 microM). These in vivo and in vitro findings suggest an increase in cortical glutamatergic transmission by CB(1) receptors, an effect that may underlie some of the psychoactive and behavioural actions of acute exposure to marijuana.

We employed dual probe microdialysis in the nucleus accumbens and ipsilateral ventral pallidum of the halothane anaesthetized rat to investigate the effect of intra-accumbens perfusion with the sulphated octapeptide cholecystokinin (CCK-8S, 10-1000 nM, 60 min) alone and in the presence of the selective CCK1 and CCK2 receptor antagonists L-364,718 (10 and 100 nM) and PD134308 (10 nM), tetrodotoxin (TTX, 1000 nM) and the GABA(A) receptor antagonist bicuculline (1000 nM), on dialysate GABA levels in the ventral pallidum. Intra-accumbens perfusion with the 100 and 1000 nM concentration of CCK-8S was associated with a significant decrease (-16+/-3% and -23+/-3% vs basal, respectively) in ventral pallidum GABA levels. The CCK-8S (1000 nM) induced decrease in ventral pallidal dialysate GABA levels was abolished when PD134308, TTX and bicuculline, but not L-364,718, were included into the perfusion medium of the accumbens probe. The data indicate that nucleus accumbens CCK-8S exerts a CCK2 receptor mediated inhibition of ventral pallidal GABA levels. Furthermore, the TTX and bicuculline sensitivity of this effect suggests that this is possibly mediated via CCK2 receptors probably located on local GABA interneurons.

In the present study, we employed in vivo microdialysis in the frontal cortex of the awake rat to investigate the effects of acute and short-term (twice daily, 3 days) lithium chloride administration (1, 2, and 4 meq/kg, s.c.) on local dialysate glutamate and GABA levels. Acute lithium (1 meq/kg) failed to influence cortical glutamate levels while the higher (2 and 4 meq/kg) doses increased (+38 +/- 6% of basal levels) and reduced (-27 +/- 4%) cortical glutamate levels, respectively. Cortical GABA levels were affected by acute lithium only at the highest 4 meq/kg dose (+62 +/- 6%). Furthermore, these effects were prevented by tetrodotoxin (1 microM) and low-calcium (0.2 mM) medium perfusion. Following short-term administration, lithium increased (+58 +/- 4%) cortical dialysate glutamate levels at the 1 meq/kg dose, was ineffective at 2 meq/kg, while the effect of the 4 meq/kg dose was similar to that observed after acute administration. Interestingly, intracortical perfusion with the GABA(B) receptor antagonist CGP 35348 (100 microM) reversed the acute lithium (4 meq/kg)-induced decrease in glutamate levels. Taken together, these findings indicate a differential dose and duration dependent effect of lithium on cortical dialysate glutamate levels involving both a direct enhancement and an indirect inhibition that is mediated via an activation of local GABA(B) receptor. These findings may be relevant for the therapeutic effects of the drug., (Copyright 2000 Wiley-Liss, Inc.)

A high sensitivity bioassay able to recognise small amounts of paralytic and amnesic toxins in algal acetic extracts is described. The method is based on the measure of intracellular [Ca(2+)](i) in primary cultures of rat cortical neurones preloaded with Fura-2 and submitted to electrical field stimulation. Under normal conditions the basal [Ca(2+)](i) level was about 50-100 nM and was nearly doubled during the peaks induced by trains of electrical pulses at 10 Hz for 10 s. Saxitoxin (STX) 3.5 nM and tetrodotoxin (TTX) 24 nM halved the peaks height without affecting basal [Ca(2+)](i). Conversely, domoic acid increased the basal [Ca(2+)](i) (EC(50)=3. 7 microM) and decreased the calcium peaks (EC(50)=7.3 microM). CNQX (a competitive antagonist of AMPA/KA receptors) at 10 microM shifted to the right by a factor of 3 the concentration-response curves of domoic acid. The extracts of non-toxic algae were well tolerated by up to 10 microg protein/ml, whereas extracts of Alexandrium lusitanicum at 1-4 microg protein/ml reduced [Ca(2+)](i) peaks and increased basal calcium levels. This toxic effect of A. lusitanicum was unexpected since parallel HPLC analysis showed only the presence of gonyautoxins, known to act like saxitoxin. Therefore, the bioassay on rat cortical neurones revealed a complex composition of the toxins present in A. lusitanicum. The relevance of fluorimetric detection of [Ca(2+)](i) in primary neuronal cultures in the evaluation of algal risk is stressed.

The effect of nicotine on basal and electrically evoked (20 Hz for 20 sec) [(3)H]D-aspartate efflux (assumed as an index of transmitter release) was studied in rat cerebellar granule primary cultures. Nicotine (10-100 nM) increased the basal efflux two to three times and concentration-dependently enhanced the electrically evoked efflux up to ten times. Higher drug concentration (1 microM) underwent rapid desensitization. Facilitation of the efflux was similarly reduced by the nicotinic acetylcholine receptor antagonists, alpha-bungarotoxin and mecamylamine, suggesting the involvement of at least two receptor subtypes containing and lacking alpha(7) subunits, respectively. Since the increased efflux induced by nicotine in granule cells kept at rest or depolarized by KCl 15 mM was antagonized by tetrodotoxin, the involvement of sodium channels by receptors located at preterminal sites was suggested. Taken together, these findings emphasize the role of the cholinergic input in granule cell function and in glutamatergic signaling., (Copyright 2000 Wiley-Liss, Inc.)

In order to evaluate the risk connected with hand-arm vibration exposure and associated disorders of the peripheral nervous system a study was made to assess the relationship between nervous symptoms and laboratory data to determine the kind of disorder. 40 male subjects with hand-arm vibration exposure for more than 5 years and nervous symptoms of the hands for more than 1 year and 2 control groups of non-symptomatic non-exposed subjects were considered. An electroneurophysiological study of the exposed subjects revealed 18 nerve conduction speed changes (12 median nerve, 4 ulnar nerve, 2 median and ulnar nerve), most of which were sensitivity-motor changes; only 9 Carpal Tunnel Syndromes were diagnosed. Some statistically significant differences between exposed subjects with negative results of the electroneurophysiological study and non-exposed subjects were observed. Prolonged vibration exposure seems to induce a hand-arm nerve suffering, initially with a progressive nerve conduction speed change and non-specific symptoms, but subsequently a peripheral nervous system disorder associated or not to a Carpal Tunnel Syndrome may occur.

The ability of modafinil (Modiodal) to protect cortical neurons from glutamate-induced degeneration was evaluated by measuring electrically evoked [3H]GABA release and [3H]GABA uptake in primary cerebral cortical cultures. In normal cells, electrical stimulation (10 Hz, 2 min) increased [3H]GABA release (FR-NER St1 = 0.77+/-0.14; St2/St1 ratio = 0.94+/-0.02). The exposure of sister cells to glutamate, reduced electrically evoked [3H]GABA release (FR-NER St1 = 0.40+/-0.05; St2/St1 ratio = 0.60+/-0.08). Modafinil (0.3-1 microM) prevented the glutamate-induced reduction of the St2/St1 ratio (0.85+/-0.11; 0.88+/-0.05, respectively). A similar protective effect was observed for [3H]GABA uptake. These findings suggest that modafinil may be neuroprotective in that it attenuates glutamate-induced excitotoxicity in cortical neurons.

In the present study the [3H]GABA release in the rat cerebral cortex primary cultures, kept at rest or electrically stimulated, was measured. In addition, the development of excitotoxic cell damage caused by pretreating the cells for 10 min with increasing glutamate concentrations (10-300 microM) was examined 2 and 24 h after the insult. Cellular injury was quantitatively assessed by measuring the electrically-evoked [3H] GABA release, the [3H] GABA uptake, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide staining. Trains of electrical pulses at different frequencies (2, 5, 10, and 20 Hz) applied to the cultures elicited a [3H]GABA release which was frequency related, Ca++-dependent, and tetrodotoxin sensitive. Either 2 or 24 h after glutamate exposure, the electrically evoked [3H]GABA release was reduced by glutamate in a concentration dependent manner, while [3H]GABA uptake and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide staining appeared less sensitive. The N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and metabotropic receptor antagonists were tested on 100 microM glutamate-exposed cells and a prominent N-methyl-D-aspartate receptor-mediated component was observed. The present findings indicate that the electrically-evoked [3H]GABA release from cerebral cortical cells could represent a useful approach not only to study the spike-triggered neurosecretion but also to the neuronal damage caused by glutamate, as well as to test potential neuroprotective compounds.

Glutamate-induced changes in intracellular free Ca++ concentration ([Ca++]i) were recorded in resting and electrically-stimulated primary cultures of rat cerebral cortical cells, employing the Ca++ indicator Fura 2. A brief (10 min) exposure to glutamate led to a concentration-dependent basal [Ca++]i increase, measured 30 min after glutamate removal. In order to unmask more subtle modifications in [Ca++]i movements associated with neurosecretion, the glutamate effect was also studied in electrically-stimulated cells. The application of trains (10 s) of electrical pulses (intensity 30 mA, duration 1 ms) induced frequency-related Na+- and Ca++-dependent [Ca++]i transients. A 5 min treatment with 50 microM glutamate reduced to 48% the electrically-evoked [Ca++]i transients, evaluated 30 min after glutamate challenge. The neuroprotective effect of sodium 4,6-dichloro-3-[(E)-3-(N-phenyl)propenamide]indole-2-carboxylate (GV150526A), a new indole derivative with high affinity and selectivity for the glycine site of the NMDA receptor-channel complex, was compared with that of DL-2-amino-5-phosphonopentanoic acid (AP5), ifenprodil, 7-chlorokynurenic acid and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline (NBQX) on glutamate-induced [Ca++]i changes in resting and electrically-stimulated cells. In both experimental conditions, GV150526A showed to be the most potent compound. Moreover, GV150526A and 7-chlorokynurenic acid were 2-3 times more active in stimulated neurons than in resting neurons, indicating a major involvement of the glycine site in the protection of the cells kept in an active state.

The paper describes a case of chronic interstitial lung disease due to exposure to hard metals, with progressive global respiratory insufficiency, treated with single lung transplant. Clinical conditions improved gradually after the operation and after more than two years the patient was in good health and had resumed an almost normal life and relationships.

After more than 39 years of practice, a dentist showed Raynaud's phenomenon of the hand exposed to vibrations generated by dental instruments. Other possible occupational, pharmacological and systemic disease factors that could cause Raynaud's phenomenon were excluded. Since it has been reported in the literature that dentists and dental technicians could exceed the permissible limits for vibrations, an occupational etiology of this case is suggested on the basis of logical reasoning.

Little is known about the distribution of IgG-bearing cell subpopulations in normal liver and their possible changes in disease conditions. We developed an immunohistochemical method that proved suitable and accurate for the identification and characterization of IgG-bearing cells and their subpopulations in liver specimens. The method uses specific monoclonal antibodies on serial mirror liver sections. We applied this method to four normal liver tissue specimens and 25 liver biopsy samples of chronic hepatitis of viral etiology. Only rare IgG-bearing cells could be observed in the portal tracts of normal liver specimens. In contrast, a dense infiltrate of such cells was seen in liver specimens from patients with chronic viral hepatitis. The density of IgG-bearing cells in such patients ranged from 6 to 20 cells x 10(-4) micron2 in the different specimens (mean = 11 x 10(-4) micron2). The increase in IgG-bearing cells did not appear to be related to the histological diagnosis, to the degree of histological inflammatory activity or to the type of viral infection. The major population of IgG-bearing cells consisted of IgG1-positive cells (68%); IgG2- (17%), IgG3- (8%) and IgG4 (7%)-bearing cells represented only minor fractions. The increased prevalence of IgG1-bearing cells observed in chronic hepatitis but not in normal liver specimens suggests that these findings may reflect an activation of antibody production directed toward viral antigens or antigenic structures of self. The identification of the antigenic specificities of the antibodies produced by IgG-bearing cells might provide important clues in understanding the pathogenesis of chronic viral hepatitis.

The importance of non-malignant pleural fibrosis in asbestosis in relation to respiratory function is still open to debate because of the differing results obtained in studies of different population groups. In the present study we selected 50 subjects with occupational exposure to asbestos presenting mono- or bilateral pleural fibrosis at X-ray but without lung impairment. Each subject underwent bronchial lavage and ventilatory function tests. The subjects were divided into 4 groups on the basis of the degree of pleural alterations according to the ILO Classification of Pneumoconioses. The results revealed that the mean values of CV and FEV1 in each group were within physiological limits. Moreover, analysis of the type of lung function showed a normal situation in 64% and restricted function in 28% of the cases. The prevalence of the latter finding was not correlated to the severity of pleural fibrosis in the various groups. Also, comparison between severity of pleural fibrosis and number of asbestos bodies/ml of BAL liquid on the one hand and frequency of alveolitis on the other did not reveal any relationship. Therefore, the onset of pleural fibrosis appears to be independent of the quantity of inhaled asbestos fibres and due to different mechanisms from those leading to lung fibrosis. In practice, a correct interpretation of the presence of pleural fibrosis from a clinical and prognostic viewpoint also requires other investigations such as BAL and a complete respiratory function study.

The authors studied 10 patients with non-insulin-dependent diabetes mellitus and 5 controls matched for age, sex, blood lipids, and smoking habit. The two groups were also comparable for hemorheologic characteristics as evaluated by viscosimetry on whole blood, plasma and serum, erythrocyte filtration and aggregation. The microcirculation was studied in the subjects of both groups by microalbuminuria determination, retinal fluorangiography, and capillaroscopic examination of the bulbar conjunctive and nail folds. None of the patients presented microalbuminuria values higher than the upper limit of normal (20mg/24h). Fluoroangiographic alterations were observed in 4 patients, and all 10 presented capillaroscopic alterations at the bulbar conjunctiva (microaneurysms, erythrocyte aggregates) and nail folds (more frequently of the fingers than toes). Similar alterations were detected in controls. Thus these abnormalities seem independent of hemorheologic values.

Although the risks connected with occupational exposure to asbestos and its numerous industrial uses are widely known, it still happens that instances of exposure with high potential risk are discovered. A detailed study of a worker suffering from silicosis and asbestosis who had worked for many years in a firm dealing with the recovery and re-use of used jute sacks also containing asbestos, revealed the existence of a real asbestosis risk in the firm, with the result that other workers in the same firm were studied. A total of 22 subjects were studied, 17 of whom also underwent bronchoalveolar lavage (BAL) and determination of the cellular composition of the recovery liquid in order to establish the presence of asbestous alveolitis. The age of the subjects ranged between 39 and 75 years (x = 56.36), length of service in the firm ranged between 2 and 18 years (x = 9.27), time between start of exposure and clinical examination varied between 29 and 50 years (x = 40.27). The 22 subjects were divided into 3 groups on the basis of the radiological examinations: 1) 8 cases were negative (36.36%); 2) 8 cases had pleural alterations only (36.36%); 3) 6 cases had interstitial lung disease (with and without pleural lesions) (27.27%). Of the 17 subjects who underwent BAL, 7 were in the first group, 7 in the second and 3 in the third. Among these 17 subjects BAL showed absence of alveolitis in all subjects of the first group, diagnosis of alveolitis in only some of the second group, and in all of the third group.(ABSTRACT TRUNCATED AT 250 WORDS)

Flunarizine, a long-acting calcium antagonist, was studied in patients with peripheral vascular disease in order to assess its effects on blood viscosity, erythrocyte deformability, platelet activity and some clinical parameters. A randomized double-blind study was performed; all patients were given a standard diet, invited to abstain from smoking and to carry out a regular daily exercise (walking). After a 2-month run-in period the patients were divided into two groups: one was treated with flunarizine 10 mg/day and the other with placebo. The group treated with flunarizine presented marked and significant reduction of erythrocyte filtration time and blood viscosity and an improvement of the treadmill-free interval with a correlation between the parameters considered.

The etiologic definition of an occupational disease should be achieved via an accurate differential diagnosis. A careful assessment of any clinical features that are atypical or unusual for the disease in question can sometimes lead to the identification of other morbid states that are either hidden or show few symptoms, and may or may not interfere with the occupational picture. The case described is of a man who, after working for 10 years with vibrating tools, developed a vibration disease with typical circulatory alterations in the hands and osteoarticular and neurological alterations. However, the appearance of a necrotic ischaemic lesion at the tip of the second finger of the right hand and signs of sclerodactylia in the second finger of both hands led us to suspect the presence of another concomitant disease. The finding of anticentromere antibodies suggested the presence of a CREST syndrome, which is a serologic variant of diffuse scleroderma. More in-depth investigations and examination of the state of other organs and apparatuses confirmed the diagnostic suspicion, with evidence of impairment also of the cardio-pulmonary system. The presence of the CREST syndrome was interpreted as a state of hypersusceptibility to the traumatic action of vibrating tools on the vascular system.

Serum levels of bilirubin and of other four enzymes known to be elevated in liver diseases were measured preoperatively and controlled on the first and fourth postoperative day in 14 children with chronic liver disease and anesthetised for liver biopsy using Ketamine (7 patients, group A) or other drugs (group B). Serum levels of gamma GT, Ph. Alk, direct and indirect bilirubin show neither significant variations nor differences between the two groups of patients. SGOT and SGPT basal levels were similar in the two groups and were rather two-fold the normal values. At the first postoperative day, in group B only SGOT levels increased significantly. Moreover, their increase over the basal levels monitored at the first day was significantly lower in the group of patients anesthetised with Ketamine than in group B. In group A, SGPT values were constant showing a small, non significant decrease, while in group B, above levels present a significant increase at the postoperative day and a significant difference between the two groups. At the fourth day, SGOT and SGPT differences versus basal values were not significant. Our experience shows that - as known by normal subjects - Ketamine has no hepatic toxicity in pediatrics patients affected by chronic liver disease, too. Finally, our study suggests that Ketamine must be used in hepatopath children whenever they have to be submitted to total anesthesia.