Exploring the underwater life in transitional environments: Benthic foraminifera, ostracods, and dinoflagellate cysts - Biotic trends and EcoQS assessment in the Mar Piccolo of Taranto (Ionian sea, southern Italy).

Coastal areas have historically thrived as centers of human activities due to their resources, economic opportunities, and natural allure. The rapid growth of coastal populations has however brought forth a multitude of challenges to tackle, with pollution emerging as a significant and far-reaching issue. Our study focuses on the Mar Piccolo of Taranto (Ionian Sea, Southern Italy), a lagoon-like coastal basin (separated in two sub-basins) that, since decades, has been heavily affected by human activities and aquaculture, leading to environmental deterioration. Although past studies have looked at environmental conditions in the Mar Piccolo from a chemical perspective, the biological component (e.g., biological indicators) has been mostly neglected. In this study, we firstly aim to examine the distribution and diversity of foraminifera, ostracods, and dinoflagellate cysts in December 2016 and compare our findings with data collected in December 2011. Foraminiferal and ostracod communities exhibit similar patterns in the two sampling campaigns, while the communities of encysted dinoflagellates show differences concerning both densities and diversity. Then, we evaluate the Ecological Quality Status (EcoQS) using ecological indices. While the indices in the inner basin appear to reflect an actual ecological degradation, they yield conflicting results in the outer basin. In the outer basin, indeed, the indices overestimate the EcoQS. This study highlights the potential of these indices for characterizing the EcoQS but emphasizes the need for improvements in their reliability. This research also contributes to a more holistic understanding of environmental condition in the Mar Piccolo and underscores the importance of integrating biological quality elements into ecosystem management and remediation strategies.

Tobacco use in first-episode psychosis, a multinational EU-GEI study.

BACKGROUND: Tobacco is a highly prevalent substance of abuse in patients with psychosis. Previous studies have reported an association between tobacco use and schizophrenia. The aim of this study was to analyze the relationship between tobacco use and first-episode psychosis (FEP), age at onset of psychosis, and specific diagnosis of psychosis. METHODS: The sample consisted of 1105 FEP patients and 1355 controls from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We assessed substance use with the Tobacco and Alcohol Questionnaire and performed a series of regression analyses using case-control status, age of onset of psychosis, and diagnosis as outcomes and tobacco use and frequency of tobacco use as predictors. Analyses were adjusted for sociodemographic characteristics, alcohol, and cannabis use. RESULTS: After controlling for cannabis use, FEP patients were 2.6 times more likely to use tobacco [p ⩽ 0.001; adjusted odds ratio (AOR) 2.6; 95% confidence interval (CI) [2.1-3.2]] and 1.7 times more likely to smoke 20 or more cigarettes a day (p = 0.003; AOR 1.7; 95% CI [1.2-2.4]) than controls. Tobacco use was associated with an earlier age at psychosis onset (ß = -2.3; p ⩽ 0.001; 95% CI [-3.7 to -0.9]) and was 1.3 times more frequent in FEP patients with a diagnosis of schizophrenia than in other diagnoses of psychosis (AOR 1.3; 95% CI [1.0-1.8]); however, these results were no longer significant after controlling for cannabis use. CONCLUSIONS: Tobacco and heavy-tobacco use are associated with increased odds of FEP. These findings further support the relevance of tobacco prevention in young populations.

Adolescente con síndrome de down y psoriasis severa. veintidos meses de tratamiento con etanercept / Severe psoriasis in a down's syndrome adolescent patient. twenty two months of treatment with etanercept

RESUMEN Reportamos el caso de un paciente de 15 años de edad, con síndrome de Down y psoriasis desde los 2 años. La prevalencia de esta enfermedad en los pacientes con síndrome de Down, varía de 2 al 8% según la literatura consultada. Su cuadro comenzó a muy temprana edad, padeciendo cinco severos cuadros de eritrodermia, que requirieron internación. Durante los últimos 22 meses ha sido tratado con etanercept, reduciendo su PASI de 27 a 2,8 con significativa mejora en su calidad de vida.

SUMMARY We present a 15 years old patient with Down´s syndrome and psoriasis since age 2. Prevalence of psoriasis in patients with Down´s syndrome varies between 2 and 8%. In the case that concerns us, psoriasis started at an early age and suffered five severe erythrodermal events, which required impatient treatment. During the past 22 months the patient has been treated with etanercept, reducing his PASI from 27 to 2.8, hence improving his life quality.

GPCR heteromers and their allosteric receptor-receptor interactions.

The concept of intramembrane receptor-receptor interactions and evidence for their existences were introduced in the beginning of the 1980's, suggesting the existence of receptor heterodimerization. The discovery of GPCR heteromers and the receptor mosaic (higher order oligomers, more than two) has been related to the parallel development and application of a variety of resonance energy transfer techniques such as bioluminescence (BRET), fluorescence (FRET) and sequential energy transfer (SRET). The assembly of interacting GPCRs, heterodimers and receptor mosaic leads to changes in the agonist recognition, signaling, and trafficking of participating receptors via allosteric mechanisms, sometimes involving the appearance of cooperativity. The receptor interface in the GPCR heteromers is beginning to be characterized and the key role of electrostatic epitope-epitope interactions for the formation of the receptor heteromers will be discussed. Furthermore, a "guide-and-clasp" manner of receptor-receptor interactions has been proposed where the "adhesive guides" may be the triplet homologies. These interactions probably represent a general molecular mechanism for receptor-receptor interactions. It is proposed that changes in GPCR function (moonlighting) may develop through the intracellular loops and C-terminii of the GPCR heteromers as a result of dynamic allosteric interactions between different types of G proteins and other receptor interacting proteins in these domains of the receptors. The evidence for the existence of receptor heteromers opens up a new field for a better understanding of neurophysiology and neuropathology. Furthermore, novel therapeutic approaches could be possible based on the use of heteromers as targets for drug development based on their unique pharmacology.

Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer.

Estrogen effects on mammary epithelial and breast cancer (BC) cells are mediated by the nuclear receptors ERα and ERß, transcription factors that display functional antagonism with each other, with ERß acting as oncosuppressor and interfering with the effects of ERα on cell proliferation, tumor promotion and progression. Indeed, hormone-responsive, ERα+ BC cells often lack ERß, which when present associates with a less aggressive clinical phenotype of the disease. Recent evidences point to a significant role of microRNAs (miRNAs) in BC, where specific miRNA expression profiles associate with distinct clinical and biological phenotypes of the lesion. Considering the possibility that ERß might influence BC cell behavior via miRNAs, we compared miRNome expression in ERß+ vs ERß- hormone-responsive BC cells and found a widespread effect of this ER subtype on the expression pattern of these non-coding RNAs. More importantly, the expression pattern of 67 miRNAs, including 10 regulated by ERß in BC cells, clearly distinguishes ERß+, node-negative, from ERß-, metastatic, mammary tumors. Molecular dissection of miRNA biogenesis revealed multiple mechanisms for direct regulation of this process by ERß+ in BC cell nuclei. In particular, ERß downregulates miR-30a by binding to two specific sites proximal to the gene and thereby inhibiting pri-miR synthesis. On the other hand, the receptor promotes miR-23b, -27b and 24-1 accumulation in the cell by binding in close proximity of the corresponding gene cluster and preventing in situ the inhibitory effects of ERα on pri-miR maturation by the p68/DDX5-Drosha microprocessor complex. These results indicate that cell autonomous regulation of miRNA expression is part of the mechanism of action of ERß in BC cells and could contribute to establishment or maintenance of a less aggressive tumor phenotype mediated by this nuclear receptor.

The effect of age and sex on facial mimicry: a three-dimensional study in healthy adults.

To assess sex- and age-related characteristics in standardized facial movements, 40 healthy adults (20 men, 20 women; aged 20-50 years) performed seven standardized facial movements (maximum smile; free smile; "surprise" with closed mouth; "surprise" with open mouth; eye closure; right- and left-side eye closures). The three-dimensional coordinates of 21 soft tissue facial landmarks were recorded by a motion analyser, their movements computed, and asymmetry indices calculated. Within each movement, total facial mobility was independent from sex and age (analysis of variance, p>0.05). Asymmetry indices of the eyes and mouth were similar in both sexes (p>0.05). Age significantly influenced eye and mouth asymmetries of the right-side eye closure, and eye asymmetry of the surprise movement. On average, the asymmetry indices of the symmetric movements were always lower than 8%, and most did not deviate from the expected value of 0 (Student's t). Larger asymmetries were found for the asymmetric eye closures (eyes, up to 50%, p<0.05; mouth, up to 30%, p<0.05 only in the 20-30-year-old subjects). In conclusion, sex and age had a limited influence on total facial motion and asymmetry in normal adult men and women.

Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology.

Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson's disease, schizophrenia and drug addiction or drug dependence may substantially build on the existence of intramembrane receptor-receptor interactions within dopamine receptor containing receptor mosaics (RM; dimeric or high-order receptor oligomers) where it is believed that the dopamine D(2) receptor may operate as the 'hub receptor' within these complexes. The constitutive adenosine A(2A)/dopamine D(2) RM, located in the dorsal striato-pallidal GABA neurons, are of particular interest in view of the demonstrated antagonistic A(2A)/D(2) interaction within these heteromers; an interaction that led to the suggestion and later demonstration that A(2A) antagonists could be used as novel anti-Parkinsonian drugs. Based on the likely existence of A(2A)/D(2)/mGluR5 RM located both extrasynaptically on striato-pallidal GABA neurons and on cortico-striatal glutamate terminals, multiple receptor-receptor interactions within this RM involving synergism between A(2A)/mGluR5 to counteract D(2) signaling, has led to the proposal of using combined mGluR5 and A(2A) antagonists as a future anti-Parkinsonian treatment. Based on the same RM in the ventral striato-pallidal GABA pathways, novel strategies for the treatment of schizophrenia, building on the idea that A(2A) agonists and/or mGluR5 agonists will help reduce the increased dopaminergic signaling associated with this disease, have been suggested. Such treatment may ensure the proper glutamatergic drive from the mediodorsal thalamic nucleus to the prefrontal cortex, one which is believed to be reduced in schizophrenia due to a dominance of D(2)-like signaling in the ventral striatum. Recently, A(2A) receptors also have been shown to counteract the locomotor and sensitizing actions of cocaine and increases in A(2A) receptors have also been observed in the nucleus accumbens after extended cocaine self-administration, probably representing a compensatory up-regulation to counteract the cocaine-induced increases in dopamine D(2) and D(3) signaling. Therefore, A(2A) agonists, through antagonizing D(2) and D(3) signaling within A(2A)/D(2) and A(2A)/D(3) RM heteromers in the nucleus accumbens, may be found useful as a treatment for cocaine dependence. Furthermore, antagonistic cannabinoid CB(1)/D(2) interactions requiring A(2A) receptors have also been discovered and possibly operate in CB(1)/D(2)/A(2A) RM located principally on striatal glutamate terminals but also on some ventral striato-pallidal GABA neurons, thereby opening up a new mechanism for the integration of endocannabinoid, DA and adenosine mediated signals. Thus, A(2A), mGluR5 and/or CB(1) receptors can form integrative units with D(2) receptors within RM displaying different compositions, topography and localization. Also galaninR/5-HT(1A) RM probably participates in the transmission of the ascending 5-hydroxytryptamine neurons, where galanin receptors antagonize 5-HT(1A) recognition and signaling. Subtype specific galanin receptor antagonists may therefore represent novel antidepressant drugs. These results suggest the importance of a complete understanding of the function of these RM with regard to disease. Ultimately receptor-receptor interactions within RM that modify dopaminergic and serotonergic signaling may give new strategies for treatment of a wide range of diseases associated with altered dopaminergic and serotonergic signaling.

Role of c-Fos protein on glutamate toxicity in primary neural hippocampal cells.

The hippocampus is extremely sensitive to microenvironmental signals and toxic events, including massive glutamate release. Despite the extensive literature related to the cascade of molecular events triggered in postsynaptic neurons, the distinction between proapoptotic and survival pathways is still being discussed. In this study, we have investigated the role of c-Fos in glutamate-induced toxicity in primary cultures of hippocampal neurons by using antisense oligonucleotide (ASO) technology. Exposure of cells (5 days in vitro; DIV) to glutamate 0.5 mM for 24 hr caused massive nuclear alteration. An increase in the number of caspase-3-positive cells was also observed 24 hr after glutamate treatment. The expression of c-fos and c-jun immediate-early genes was increased 30 min after glutamate exposure. The study of c-Fos and c-Jun protein expression revealed an increase in the number of cells positive for both antibodies. To investigate whether the expression of c-Fos protein after glutamate treatment was related to cell death activation or cell survival pathways, cells were exposed to 5 microM of c-fos ASO at 4 DIV, 24 hr before glutamate treatment. The presence of the ASO in the medium significantly decreased the number of altered nuclei, and this was associated with a significant reduction in the number of c-Fos-positive cells after glutamate treatment. Exposure of cells to the c-fos ASO under the conditions described above decreased caspase-3 immunostaining induced by glutamate. These results suggest that the synthesis of c-Fos protein after glutamate exposure favors cell death pathway activation in which caspase-3 is also involved.

Striatal plasticity at the network level. Focus on adenosine A2A and D2 interactions in models of Parkinson's Disease.

Behavioral and microdialysis studies have been performed on antagonistic A(2A)/D(2) interactions in animal models of Parkinson's Disease. The behavioral analysis involved studies on locomotor activity in reserpinized mice, haloperidol-induced catalepsy in rats and rotational behavior in rats with unilateral 6-OHDA lesions of the ascending DA pathways (Ungerstedt model). Dual probe microdialysis studies were indirectly performed on the striatopallidal GABA neurons by studying extracellular glutamate levels in the striatum and globus pallidus of the awake freely moving rat. The striatum was perfused with A(2A) and/or D(2) agonists via reverse microdialysis. The results show that the A(2A) antagonists SCH58261 and KF17837 can increase locomotor activity in reserpinized mice and produce contralateral rotational behavior only after administration of subthreshold doses of l-DOPA or the D(2) like agonist quinpirole. Furthermore, antagonizing the A(2A) receptor (R) reduced haloperidol induced catalepsy. The behavioral results underline the view that A(2A) antagonists act by blocking A(2A) R in A(2A)/D(2) heterodimers where A(2A) R inhibits the D(2) R transduction and D(2) inhibits the adenylate cyclase (AC) activated by A(2A) R. The microdialysis studies show that the A(2A) agonist CGS21680 striatally coperfused with the D(2) agonist quinpirole more potently counteract the D(2) agonist (quinpirole) induced reduction of pallidal glutamate levels in the DA denervated vs the control striatum indicating an enhancement of the inhibitory A(2A)/D(2) interaction. In the DA denervated but not in the control striatum the A(2A) agonist CGS21680 could strongly increase striatal glutamate levels, indicating an increased receptor signaling in the A(2A) R located on the striatal glutamate terminals, where also D(2) like R exist, here probably as D(4). Thus, the signaling of this A(2A) R may be set free by the loss of D(4) tone on the AC activated by A(2A) in this postulated A(2A)/D(4) heteromer on the glutamate terminals. Taken together, the results indicate that the antiparkinsonian actions of A(2A) antagonists probably are produced by blockade of A(2A) R in the A(2A)/D(2) heterodimers mainly located in the striatopallidal GABA neurons.

Pharmacokinetics and efficacy of ropivacaine continuous wound instillation after joint replacement surgery.

BACKGROUND: As continuous wound instillation with local anaesthetic has not been evaluated after hip/knee arthroplasties, our study was designed to determine whether this technique could enhance analgesia and improve patient outcome after joint replacement surgery. METHODS: Thirty-seven patients undergoing elective hip/knee arthroplasties under spinal block were randomly assigned to two analgesia groups. Group M received continuous i.v. infusion of morphine plus ketorolac for 24 h. Then, a multi-hole 16 G catheter was placed subcutaneously and infusion of saline was maintained for 55 h. Group R received i.v. saline. Thereafter the wound was infiltrated with a solution of ropivacaine 0.5% 40 ml, then a multi-hole 16 G catheter was placed subcutaneously and an infusion of ropivacaine 0.2% 5 ml h(-1) was maintained for 55 h. Visual analogue scale scores were assessed at rest and on passive mobilization by nurses blinded to analgesic treatment. Total plasma ropivacaine concentration was measured. RESULTS: Group R showed a significant reduction in postoperative pain at rest and on mobilization, while rescue medication requirements were greater in Group M. Total ropivacaine plasma concentration remained below toxic concentrations and no adverse effects occurred. Length of hospital stay was shorter in Group R. CONCLUSION: Infiltration and wound instillation with ropivacaine 0.2% is more effective in controlling postoperative pain than systemic analgesia after major joint replacement surgery.

Digital cineradiographic swallow study: our experience.

PURPOSE: Swallowing disorders can be secondary to different types of diseases in which, at least initially, patients succeed in establishing voluntary or involuntary compensatory mechanisms that enable them to maintain a sufficient nutritional state. When the compensatory mechanisms become insufficient massive food aspiration into the airways can occur and suffocation may prove to be the main pathology. It has been calculated that in the USA about 8,000-10,000 people die each year due to suffocation. The dynamic radiological examination of swallowing is considered important not only for diagnosis, but also for planning a rehabilitation therapy and type of nutrition for the patient and for verifying the results of the therapy. The aim of this study is to analyse the results of our experience in the use of the digital cineradiography system to evaluate patients with normal and pathological swallowing. MATERIALS AND METHODS: We reviewed the digital cineradiography of 220 patients that at no time had undergone surgery and presented no organic pharyngeal or oesophageal disease (excluding hiatus hernia). All the exams followed a standard protocol that included the dynamic evaluation of the larynx, soft palate, pharynx, and gastro-oesophageal junction with a cineradiographic sequence of 12 frames/second with a 512x1024 matrix. There was also an archive of the film in a post-processing console. The patients received single photograms (printed on laserfilm), videotape recordings or CD-ROM of the dynamic exam. RESULTS: 137 (62%) of the patients did not present swallowing alterations although only 7 patients had a negative examination. In 35 cases hiatus hernia was appreciable while in 69 cases the hernia was associated with gastro-oesophageal reflux. In 23 cases aspecific functional disorders of the oesophagus were demonstrated and in 3 cases achalasia. The remaining 83 patients (38%) (37 males and 46 females, average age 57.02 yrs) presented alterations of the oral and/or pharyngeal stages of swallowing: reduction in soft-palate motility (2 cases), unilateral paralysis of the vocal chords (1 case), incontinence of the bolus during the oral stage (8 cases), lingual movement anomalies (4 cases), subepiglottic penetration (62 cases), asymmetric epiglottic tilt, aspiration of the contrast medium in the airway (17 cases), reduction of laryngeal and hyoid bone movement (9 cases), bolus retained in the valleculae and pyriform sinus (13 cases), cricopharyngeal spasm (6 cases), pharyngeal paralysis (1 case); hiatus hernia was also evident in 20 cases and gastro-oesophageal reflux was associated in 13 of them. Overall, 36% of the cases presented an isolated form while 64% of the cases presented a complex dysfunction with several simultaneous alterations. DISCUSSION AND CONCLUSIONS: The videofluorographic swallow study is an important step in the diagnostic evaluation of a dysphagic patient not only as regards the analysis of the main alteration and its capacity to confirm the presence or absence of contrast medium aspiration in the airway, but also because it provides important information on rehabilitation and nutritional orientation (oral/no oral), as well as on the results of the therapy. The recent diffusion of the digital X-ray equipment has made possible its use for the study of the organic and functional diseases of the upper alimentary tract. Currently a standard protocol for the study of swallowing with digital fluorography is not available. The technique we applied, already verified in a significant number of dysphagic patients, has allowed us to distinguish patients with normal swallowing from those with disorders of the oral and pharyngeal stage, and thus to identify disturbance and establish an appropriate rehabilitation treatment.

Plasma dopamine concentration and effects of low dopamine doses on urinary output after major vascular surgery.

To evaluate plasma dopamine concentration and the effects of low doses infusion on urinary output after abdominal vascular surgery in patients with renal function impairment we performed a prospective clinical study. Twenty hemodynamically stable patients (mean age 66.6 years), with serum creatinine concentration < 2 mg %, who undergoing general anesthesia for major vascular surgery participated. A low dose of dopamine (3 micrograms/kg/min) was administrated to patients with postoperative protracted urinary output < 0.5 ml/kg/hr for at least eight hours. Plasmatic determinations were taken at T0 (no dopamine administration), when urinary output began to increase, or if not, after two hours (T1), at eight (T2), and 24 (T3) hours after the beginning of infusion. After 24 hours the dopamine infusion was stopped and the patient's plasmatic level was measured four hours later (T4). Dopamine plasma concentrations were measured using high-performance liquid chromatography. Plasma dopamine concentration increased in all patients and reached a steady state at T2 (T2 = 76.41 +/- 16.84 ng/ml). Dopamine induced a concentration-dependent increase in urinary output (T0 = 0.45 +/- 0.14; T1 = 1.49 +/- 1.11; T2 = 2.34 +/- 1.44; T3 = 1.57 +/- 0.57; T4 = 0.85 +/- 0.7 ml/kg/hr). Three patients did not have an enhanced urinary output after dopamine infusion; they did have a prolonged clamping time and operation time (162 +/- 24 and 570 +/ 30 min, respectively). We conclude that low dose dopamine induces a dose-dependent increase of urinary output. This phenomenon also has been found in patients when their plasma concentration had not yet reached the steady-state. Lack of responsiveness to dopamine suggests a renal function impairment probably due to the prolonged aortic clamping time.

Drug use by the elderly in Italy.

OBJECTIVES: To evaluate drug consumption in the elderly aged 75 years or more living at home. DESIGN: Cross-sectional study. SETTING: Old-old (i.e., > or = 75 y) people living in central Turin, a city in northern Italy. PARTICIPANTS: Thirty-four general practitioners (GPs), with 50 or more old-old people in their patient list, randomly chosen among the GPs working in the Unità Socio-Sanitaria Locale I (Local Health Unit I) of Turin; 261 old-old people (135 men and 126 women) randomly selected from the practice records. METHODS: Data were collected by the GP through a structured questionnaire during an office visit and by a social worker in a home interview within 14 days of the GP visit. GPs were asked to record every diagnosis and drug currently taken by the patient; social workers were trained in the administration of a structured questionnaire exploring sociodemographic variables, drug use (following the medication inventory strategy), disability, cognitive functions, and depressive symptoms. RESULTS: Nearly all subjects (95% of the women and 91% of the men) were taking at least 1 drug. The overall number of drugs recorded was 917 (47.1% for men and 52.9% for women), of which 172 (18.8%) were not reported by the GP but were recorded during the social worker's visit. The mean number of drugs was 3.2 for men and 3.8 for women, with a statistically significant difference (p = 0.02), while the mean number of diagnoses was 2.3 and 2.6, respectively. The study of correlates of drug consumption showed a strong association with number of diagnoses at univariate analysis (p < 0.0001, with a linear correlation coefficient of 0.64). No multivariate model showed a clear superiority over the simple one containing only the number of diagnoses in predicting the total number of drugs taken. Cardiovascular, nervous system, and alimentary tract drugs were the most frequently used. A total of 107 subjects (41%) were taking at least 1 unreported drug. CONCLUSIONS: Our study shows high drug consumption among old-old people, with nearly 20% of drugs taken not reported by the GP. These results emphasize the need for an essential therapeutic approach in old-old people, prescribing only drugs of scientifically proven efficacy. Furthermore, the GP must make more effort when collecting a drug history from old-old patients.

Soluble CD30 antigen in human colostrum.

It is now well established that the CD30 glycoprotein is a surface antigen expressed by activated T cells producing T-helper (Th)-2-type lymphokines. Mounting laboratory evidence, however, suggests that CD30 expression is not confined to a functionally restricted subset of T cells, but also identifies activated cells with a Th-1 and Th-0 pattern of cytokine secretion. CD30-bearing T lymphocytes release a soluble form of the molecule (sCD30), which can be detected both in vitro and in vivo. In the present study, very high levels of sCD30 were found in colostrum from 20 puerperal women, but not in autologous and heterologous (nonpregnant women) blood samples. These data strongly support an involvement of CD30+ T cells in the immune processes which take place at the level of the mammary gland during pregnancy and lactation. Passively transferred immune components such as immunoglobulins, cytokines, macrophages, natural killer cells, granulocytes and memory/activated T cells, all of which may help the baby to fight off infections, have been revealed in human breast milk. However, how Th-2-type cytokine-secreting T cells or other T-cell types help to endow the congenitally immunocompromised newborn infant with extrinsic immunological support remains an open question.

5-Hydroxytryptamine-mediated effects of nicotine on endogenous GABA efflux from guinea-pig cortical slices.

1. The effect of nicotine on endogenous basal GABA outflow was studied in guinea-pig cerebral cortex slices. 2. Nicotine 1.86-18.6 mumol l-1 significantly decreased the basal, tetrodotoxin-sensitive GABA efflux, whereas at higher concentrations (186-620 mumol l-1) nicotine increased it. The inhibition was prevented by mecamylamine while the facilitation was blocked by mecamylamine, (+)-tubocurarine and tetrodotoxin. 3. The effect of nicotine was due to an indirect 5-hydroxytryptaminergic action. In fact, MDL 72222 (1 mumol l-1) completely prevented the alkaloid inhibition and methysergide (1 mumol l-1) reversed the facilitation into inhibition; concomitant treatment with methysergide and MDL 72222 antagonized the effect of nicotine at 186 mumol l-1 4. Lower concentrations of 5-HT (3-10 mumol l-1) decreased, whereas higher concentrations (30-100 mumol l-1) increased, spontaneous GABA outflow. The inhibition of GABA efflux was prevented by MDL 72222 whereas the facilitation was reversed by methysergide (1 mumol l-1) into inhibition, and prevented by MDL 72222 1 mumol l-11. 5. These results suggest that, by activating nicotinic receptors present on 5-hydroxytryptaminergic terminals, nicotine releases 5-HT which, in turn, inhibits or increases the secretory activity of cortical GABA interneurones via 5-HT3 and methysergide-sensitive receptors, respectively.

Change in prescribing patterns of general practitioners in Italy before and after the Reform Drug Act. A case study of changes in the city of Turin.

As of 1 January 1994, the introduction of a new classification of the drugs to be reimbursed by the National Health Service was approved by the Italian parliament in order to limit expenditure on pharmaceutical agents. This has set off a 'cultural revolution', unprecedented in Italy. The criteria that inspired the expert group charged with attributing drugs to different classes (Class A: essential, free of charge drugs; Class B: drugs to be paid for 50% by the patient; Class C: drugs to be paid entirely by the patient) were principally scientific rather than merely economic or administrative. Expectedly, the creation of Class C (drugs not reimbursed by the National Health Service on account of their insufficiently proven clinical effectiveness, or their unfavourable cost/benefit ratio with respect to therapeutically equivalent agents) has provoked remarkable changes in general practitioners' prescription options, particularly given the fact that many of these drugs were among the most prescribed in Italy. A database including the prescriptions of about 940 general practitioners, dispensed through the 280 community pharmacies of the city of Turin, has been analysed for a comparative sample of time periods in 1993 and 1994, in order to quantify the changes that occurred and to qualify them with respect to more relevant therapeutic groups and sentinel drugs.

Effect of acute and subchronic nicotine treatment on cortical efflux of [3H]-D-aspartate and endogenous GABA in freely moving guinea-pigs.

1. The [3H]-D-aspartate preloading of the parietal cortex of freely moving guinea-pigs equipped with epidural cups makes it possible to investigate drug effects on the efflux of this radiolabel, assumed as a marker of the glutamatergic structures underlying the cup. In the same model, the efflux of [3H]-gamma-aminobutyric acid ([3H]-GABA) and endogenous GABA can be measured. 2. Nicotine, 0.9-3.6 mg kg-1, s.c., or 3-5 micrograms, i.c.v., increased the efflux of [3H]-D-aspartate but reduced that of GABA. 3. These effects were mediated through mecamylamine-sensitive receptors but the ganglionic blocking agent was devoid of any primary activity. 4. The inhibition of GABA efflux induced by nicotine 3.6 mg kg-1, s.c., was abolished by methysergide 2 mg kg-1, i.p. and was reduced by naloxone 3 mg kg-1, i.p. pretreatment, suggesting the involvement of tryptaminergic and opioid systems. In contrast, muscarinic and catecholamine antagonists were ineffective. 5. Chronic treatment with nicotine (3.6 mg kg-1, twice daily for 16 days) reduced the facilitatory effect of [3H]-D-aspartate and abolished the inhibition of endogenous GABA efflux. 6. A slight increase in the number of nicotinic binding sites (by use of [3H]-nicotine as ligand) was found in the neocortex of chronically treated guinea-pigs. 7. The higher degree of tolerance to chronic nicotine treatment shown by GABA as compared with [3H]-D-aspartate efflux suggests that adaptative changes of the inhibitory neuronal pools prevail. This may contribute to the reinforcing and addictive properties of nicotine.