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Background: Previous diffusion tensor imaging (DTI) studies in patients with obsessive-compulsive disorder (OCD) have reported inconsistent findings, and it is not known whether observed findings are related to abnormalities in axonal structure or myelination., Methods: In this DTI study, we investigated fractional anisotropy, as well as axial and radial diffusivity, in 21 patients with OCD and 29 healthy controls., Results: We found decreased fractional anisotropy in the body of the corpus callosum in the OCD group, which was underpinned by increased radial diffusivity., Limitations: The cross-sectional design was the main limitation., Conclusion: Our findings of increased radial diffusivity provide preliminary evidence for abnormal myelination in patients with OCD.

Background: Schizophrenia is believed to result from abnormal functional integration of neural processes thought to arise from aberrant brain connectivity. However, evidence for anatomical dysconnectivity has been equivocal, and few studies have examined axonal fiber connectivity in schizophrenia at the level of whole-brain networks., Methods: Cortico-cortical anatomical connectivity at the scale of axonal fiber bundles was modeled as a network. Eighty-two network nodes demarcated functionally specific cortical regions. Sixty-four direction diffusion tensor-imaging coupled with whole-brain tractography was performed to map the architecture via which network nodes were interconnected in each of 74 patients with schizophrenia and 32 age- and gender-matched control subjects. Testing was performed to identify pairs of nodes between which connectivity was impaired in the patient group. The connectional architecture of patients was tested for changes in five network attributes: nodal degree, small-worldness, efficiency, path length, and clustering., Results: Impaired connectivity in the patient group was found to involve a distributed network of nodes comprising medial frontal, parietal/occipital, and the left temporal lobe. Although small-world attributes were conserved in schizophrenia, the cortex was interconnected more sparsely and up to 20% less efficiently in patients. Intellectual performance was found to be associated with brain efficiency in control subjects but not in patients., Conclusions: This study presents evidence of widespread dysconnectivity in white-matter connectional architecture in a large sample of patients with schizophrenia. When considered from the perspective of recent evidence for impaired synaptic plasticity, this study points to a multifaceted pathophysiology in schizophrenia encompassing axonal as well as putative synaptic mechanisms., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Repetition of environmental sounds, like their visual counterparts, can facilitate behavior and modulate neural responses, exemplifying plasticity in how auditory objects are represented or accessed. It remains controversial whether such repetition priming/suppression involves solely plasticity based on acoustic features and/or also access to semantic features. To evaluate contributions of physical and semantic features in eliciting repetition-induced plasticity, the present functional magnetic resonance imaging (fMRI) study repeated either identical or different exemplars of the initially presented object; reasoning that identical exemplars share both physical and semantic features, whereas different exemplars share only semantic features. Participants performed a living/man-made categorization task while being scanned at 3T. Repeated stimuli of both types significantly facilitated reaction times versus initial presentations, demonstrating perceptual and semantic repetition priming. There was also repetition suppression of fMRI activity within overlapping temporal, premotor, and prefrontal regions of the auditory "what" pathway. Importantly, the magnitude of suppression effects was equivalent for both physically identical and semantically related exemplars. That the degree of repetition suppression was irrespective of whether or not both perceptual and semantic information was repeated is suggestive of a degree of acoustically independent semantic analysis in how object representations are maintained and retrieved.

We used magnetic resonance imaging to examine the effect of ethyl-eicosapentaenoic acid (E-EPA) on hippocampal T(2) relaxation time in first episode psychosis patients at baseline and after 12 weeks of follow-up. There was an increase in T(2) in the placebo group but not in the E-EPA group, suggesting a neuroprotective effect of E-EPA treatment. In addition, the smaller the increase in T(2), the greater the improvement in negative symptoms., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Whole-brain anatomical connectivity in living humans can be modeled as a network with diffusion-MRI and tractography. Network nodes are associated with distinct grey-matter regions, while white-matter fiber bundles serve as interconnecting network links. However, the lack of a gold standard for regional parcellation in brain MRI makes the definition of nodes arbitrary, meaning that network nodes are defined using templates employing either random or anatomical parcellation criteria. Consequently, the number of nodes included in networks studied by different authors has varied considerably, from less than 100 up to more than 10(4). Here, we systematically and quantitatively assess the behavior, structure and topological attributes of whole-brain anatomical networks over a wide range of nodal scales, a variety of grey-matter parcellations as well as different diffusion-MRI acquisition protocols. We show that simple binary decisions about network organization, such as whether small-worldness or scale-freeness is evident, are unaffected by spatial scale, and that the estimates of various organizational parameters (e.g. small-worldness, clustering, path length, and efficiency) are consistent across different parcellation scales at the same resolution (i.e. the same number of nodes). However, these parameters vary considerably as a function of spatial scale; for example small-worldness exhibited a difference of 95% between the widely-used automated anatomical labeling (AAL) template (approximately 100 nodes) and a 4000-node random parcellation (sigma(AAL)=1.9 vs. sigma(4000)=53.6+/-2.2). These findings indicate that any comparison of network parameters across studies must be made with reference to the spatial scale of the nodal parcellation., (Copyright 2009 Elsevier Inc. All rights reserved.)

Spatial working memory (SWM) dysfunction has been suggested as a trait marker of schizophrenia and implicates a diffuse network involving prefrontal, temporal and parietal cortices. However, structural abnormalities in both grey and white matter in relation to SWM deficits are largely unexplored. The current magnetic resonance imaging (MRI) study examined this relationship in a sample of young first-episode schizophrenia (FES) patients using a whole-brain voxel-based method. SWM ability of 21 FES patients and 41 comparable controls was assessed by the CANTAB SWM task. Using an automated morphometric analysis of brain MRI scans, we assessed the relationship between SWM abilities and both grey matter volume and white matter density in both groups. Our findings demonstrated the different directionality of the association between SWM errors and grey matter volume in left frontal regions and white matter tracts connecting these regions with temporal and occipital areas between FES patients and controls. This suggests that the substrate underpinning the normal variability in SWM function in healthy individuals may be abnormal in FES, and that the normal neurodevelopmental processes that drive the development of SWM networks are disrupted in schizophrenia.

Objective: Patients with schizophrenia show deficits in visuospatial working memory and visual pursuit processes. It is currently unclear, however, whether both impairments are related to a common neuropathological origin. The purpose of the present study was therefore to examine the possible relations between the encoding and the discrimination of dynamic visuospatial stimuli in schizophrenia., Method: Sixteen outpatients with schizophrenia and 16 control subjects were asked to encode complex disc displacements presented on a screen. After a delay, participants had to identify the previously presented disc trajectory from a choice of six static linear paths, among which were five incorrect paths. The precision of visual pursuit eye movements during the initial presentation of the dynamic stimulus was assessed. The fixations and scanning time in definite regions of the six paths presented during the discrimination phase were investigated., Results: In comparison with controls, patients showed poorer task performance, reduced pursuit accuracy during incorrect trials and less time scanning the correct stimulus or the incorrect paths approximating its global structure. Patients also spent less time scanning the leftmost portion of the correct path even when making a correct choice. The accuracy of visual pursuit and head movements, however, was not correlated with task performance., Conclusions: The present study provides direct support for the hypothesis that active integration of visuospatial information within working memory is deficient in schizophrenia. In contrast, a general impairment of oculomotor mechanisms involved in smooth pursuit did not appear to be directly related to lower visuospatial working memory performance in schizophrenia.

Objective: To investigate scanpath abnormalities during the encoding of static stimuli in schizophrenia and their interaction with visuospatial working memory (VSWM) dysfunction., Methods: Outpatients with schizophrenia and control subjects were asked to encode a static pattern for subsequent recognition after a short delay. We measured the number of correct and incorrect choices. We also assessed the number and the distribution of fixations, the scanning time in specific regions of interest (ROIs) and the head movements during the encoding of the stimuli. The distributions of fixations and scanning time in definite ROIs during the discrimination of the correct pattern from the foils were also measured., Results: Patients recognised fewer correct patterns than controls. Correct trials in patients were characterised by a specific exploration of the central part of the stimulus during its presentation, whereas this feature was absent in incorrect trials. However, the scanning time and the numbers of fixations and head movements during encoding were similar in both groups and unrelated to recognition accuracy. In both groups, correct trials were associated with a selective exploration of the correct pattern amongst the six possibilities during recognition. Furthermore, patients gave more attention to incorrect patterns with a leftmost element identical to that of the correct response and also those approximating its global structure., Conclusion: Patients showed a VSWM deficit independent of oculomotor dysfunctions and head movements during encoding. Patients' correct trials were related to specific scanning during encoding and discrimination phases. Analysis of these patterns suggests that patients try to compensate for reduced VSWM ability by using specific encoding strategies.

Aim: To investigate static and dynamic visuospatial working memory (VSWM) processes in first-episode psychosis (FEP) patients and explore the validity of such measures as specific trait markers of schizophrenia., Methods: Twenty FEP patients and 20 age-, sex-, laterality- and education-matched controls carried out a dynamic and static VSWM paradigm. At 2-year follow up 13 patients met Diagnostic and Statistical Manual (of Mental Health Disorders)--Fourth Edition (DSM-IV) criteria for schizophrenia, 1 for bipolar disorder, 1 for brief psychotic episode and 5 for schizotypal personality disorder., Results: Compared with controls, the 20 FEP patients showed severe impairment in the dynamic VSWM condition but much less impairment in the static condition. No specific bias in stimulus selection was detected in the two tasks. Two-year follow-up evaluations suggested poorer baseline scores on the dynamic task clearly differentiated the 13 FEP patients who developed schizophrenia from the seven who did not., Conclusions: Results suggest deficits in VSWM in FEP patients. Specific exploratory analyses further suggest that deficit in monitoring-manipulation VSWM processes, especially involved in our dynamic VSWM task, can be a reliable marker of schizophrenia., (© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Asia Pty Ltd.)

In the Morris water maze (MWM) task, proprioceptive information is likely to have a poor accuracy due to movement inertia. Hence, in this condition, dynamic visual information providing information on linear and angular acceleration would play a critical role in spatial navigation. To investigate this assumption we compared rat's spatial performance in the MWM and in the homing hole board (HB) tasks using a 1.5 Hz stroboscopic illumination. In the MWM, rats trained in the stroboscopic condition needed more time than those trained in a continuous light condition to reach the hidden platform. They expressed also little accuracy during the probe trial. In the HB task, in contrast, place learning remained unaffected by the stroboscopic light condition. The deficit in the MWM was thus complete, affecting both escape latency and discrimination of the reinforced area, and was thus task specific. This dissociation confirms that dynamic visual information is crucial to spatial navigation in the MWM whereas spatial navigation on solid ground is mediated by a multisensory integration, and thus less dependent on visual information.

Recent findings suggest that the visuo-spatial sketchpad (VSSP) may be divided into two sub-components processing dynamic or static visual information. This model may be useful to elucidate the confusion of data concerning the functioning of the VSSP in schizophrenia. The present study examined patients with schizophrenia and matched controls in a new working memory paradigm involving dynamic (the Ball Flight Task - BFT) or static (the Static Pattern Task - SPT) visual stimuli. In the BFT, the responses of the patients were apparently based on the retention of the last set of segments of the perceived trajectory, whereas control subjects relied on a more global strategy. We assume that the patients' performances are the result of a reduced capacity in chunking visual information since they relied mainly on the retention of the last set of segments. This assumption is confirmed by the poor performance of the patients in the static task (SPT), which requires a combination of stimulus components into object representations. We assume that the static/dynamic distinction may help us to understand the VSSP deficits in schizophrenia. This distinction also raises questions about the hypothesis that visuo-spatial working memory can simply be dissociated into visual and spatial sub-components.

Aims: Our objective was to compare the effectiveness of buprenorphine (BUP) and methadone maintenance treatment in opiate-addicted patients in a clinical nonexperimental setting., Design: We used a naturalistic observational prospective study of 24 months' duration., Setting: Subjects were enrolled and treated at a drug addiction outpatient clinic of the National Health System Local Unit in Milan, Italy., Participants: Two hundred fifty-seven subjects meeting the DSM-IV criteria for opioid dependence and opioid-seeking substitutive pharmacological treatment participated in the study., Intervention: One hundred twenty-one subjects received BUP at a mean daily dose of 11 +/- 6 mg (median = 8; range = 2-30) for a mean duration of 249 days. One hundred thirty-six subjects received methadone at a mean daily dose of 54 +/- 29 mg (median = 50; range = 4-140) for a mean duration of 267 days., Measurements: The main efficacy parameters were treatment retention rates and illicit substance abuse, as assessed by urinalysis., Findings: Retention rates were comparable in both treatment groups, but BUP-treated subjects had significantly lower rates of illicit opiate consumption (p < .0001)., Conclusions: The results confirm that, in a nonexperimental clinical practice setting, BUP is as effective as methadone in the treatment of heroin dependence, with significantly better opiate abuse control, thus possibly allowing longer and more effective treatment programs with reduced relapse rates.

The data shown here were collected with an open label prospective design from March 2001 to February 2004 while conducting routine recruitment and therapy of heroin-addicted patients. All of the data collected demonstrate the safety and efficacy of buprenorphine therapy and different characteristics observed in buprenorphine patients versus methadone patients.

In the present study we analysed the effect of endogenous sex hormones on the SCE frequencies induced in vitro by mitomycin C (MMC), a bifunctional alkylating agent producing high chromosome damage and mitotic arrest. The analysis has been performed on lymphocytes obtained at three different phases of menstrual cycle, from women with regular cycle and hormones dosage. At all phases we further analysed the effect of a post-treatment with caffeine, an agent that it is known to overrride the DNA damage checkpoints. After MMC, the cultures obtained at ovulation and luteal phases have SCE frequencies statistically higher than the cultures obtained at the progestogenic phase, showing increases of 15 and 25%, respectively. After caffeine, the MMC treated cultures which were set up at the progestogenic phase show a high potentiation of SCE frequencies (28%) whereas the treated cultures set up at ovulatory and luteal phases show little or no potentiation. These findings demonstrate that the endogenous hormones greatly modulate the SCE frequencies induced by the mutagen; they also indicate that hormones action competes with the caffeine effect. Caffeine acts by abrogating the mitotic arrest produced by DNA damage and induced cells with a higher chromosome damage into a premature mitosis. Our findings suggest that endogenous hormones could overcome the checkpoint controls activated in cells after mutagenic exposure. This action may be an epigenetic mechanism relevant in hormone carcinogenesis.

The possible effects of environmental and genetic factors on spontaneous frequencies of sister chromatid exchanges (SCEs) and cells with chromosome aberrations (CAs) in human lymphocytes were investigated by analysing 177 completed families (mother, father and at least one child). After removing the effects of methodological, biological and life-style factors by the use of multifactor analysis of variance (MANOVA), SCEs and CAs residuals were analysed by simple correlation analysis and principal component analysis. SCEs and CAs inter-familiar variability was higher than that found within families. A significant correlation was found between the average SCE frequencies shared by parents (the so-called 'midpoint parents', or 'midparent') and offspring (linear slope b=0.26+/-0.07, p<0.05), but also between mother and father (b=0.23+/-0.11, p<0.05) suggesting the presence of an effective environmental factor. The midparent-offspring correlation was found to be sustained by the mother-offspring relationship (b=0.28+/-0.08, p<0.05), being the father-offspring correlation not significant (b=0.16+/-0.11, p0.05). Concerning CAs, no statistically significant correlation between parents was found, but the strong relationship between mother and offspring was confirmed (b=0.468+/-0.11, p<0.001). The SCEs correlation between mother vs. offspring disappeared for older offspring (over 23 years old). The obtained findings strongly showed that the genetic make-up is barely detectable in the presence of domestic environment factors which are shown to play the major role in determining the interfamilial variability of SCE and CA in a general population. These results strengthen the suitability of the use of SCEs and CAs analysis in human cytogenetic surveillance for the detection of effective environmental factors.

Aims: To investigate the pharmacokinetic profile of the protease inhibitor saquinavir (SQV) after multiple doses in HIV-positive patients and to evaluate the possibility of predicting total body exposure of SQV from concentrations determined at single time points., Methods: Twenty HIV-positive patients on steady-state treatment with SQV (Hard-Gel-Capsule, Invirase(R)) were enrolled in this study. Serial blood samples were obtained during a dosing interval. SQV plasma concentrations were determined by high performance liquid chromatography (h.p.l.c.) and pharmacokinetic parameters were determined by noncompartmental techniques., Results: There was a marked interindividual variability in SQV pharmacokinetic parameters with a 11-fold variability in total systemic exposure to SQV, as expressed by AUC(0,8h) values (range: 268-3009 ng ml-1 h, CV: 69%). The oral clearance shows an interindividual CV of 75%. A strong correlation (r=0.94) was found between SQV plasma concentration at 3 h (C3 h ) and AUC(0,8h)., Conclusions: This study shows that C3 h is a good predictor for total body exposure of SQV and might be useful to predict SQV disposition in HIV-positive patients on steady-state treatment.

The capability of some metal compounds for inducing micronuclei (MN) in human lymphocytes was studied. In this investigation, Al (III), Cd (II), Hg (II), Sb (V), Te (VI), and Tl (I) salts were considered. The FISH (fluorescence in situ hybridization) technique with a centromeric probe was coupled with the MN assay in binucleated cells in order to detect both centromere-positive MN (C+ MN) due to malsegregation phenomena and centromere-negative MN (C- MN) due to chromosome breakage. The blood of two young nonsmoking male donors was employed for all experiments. In both donors, all the tested metal compounds, with the exception of Tl(2)SO(4), showed a statistically significant increase of MN compared to controls, at least at one dose. FISH analysis revealed an increase in the fraction of C+ MN for Al, Cd, and Hg compounds, and of C- MN for the Sb salt; however, this was not a statistically significant increase. A different efficiency was observed for the different metal compounds, in particular, KSbO(3) and CH(3)HgCl, which were highly genotoxic, whereas the others showed minimal effects., (Copyright 1999 Wiley-Liss, Inc.)

Patients and methods: This is a retrospective study performed on HIV-positive patients discharged from our Institution from January 1993 through December 1998 with a diagnosis of bacterial pneumonia. Cases of TB or atypical micobacterial infection were excluded from this analysis. Causative organisms were identified, when possible, by taking into account positive cultures from diverse sources (blood, sputum, pleural fluid and others). Results: In the 6-yr period we considered, 120 patients were identified. Among them, we were able to obtain clinical and imaging data on 98 cases. Focal infiltrates on chest X-ray studies were present in 87.7% of cases, 24.5% had a pleural effusion, 9.2% nodular lesions, 4.1% cavitary images and in 2 patients only hilar lymphadenopaties were noted. Causative agents resulted to be S. aureus (14 cases); P. aeruginosa (11); S. pneumoniae (6); R. equi (4); Enterobacter spp. and K. pneumoniae (3 cases each); E. coli, Peptostreptococcus spp and Enterococcus spp. (1 case each). No causative organism was isolated in 54 patients (55.1%) and the diagnosis was based on clinical and therapeutical grounds. Around half of cases (46.9%) responded well to therapy, while 11 (11.2%) died because of the lung infection. In 3 cases other opportunistic infections were the cause of death and 22 cases of relapse were recorded as well. Five patients resulted lost to follow-up. Conclusions: This retrospective study demonstrated a high prevalence of S. aureus lung infections along with the presence of otherwise rare causative organisms such as R. equi. Radiologic appearance of lung lesions did not differ substantially from the one of HIV negative patients. A relatively good response to antibiotic therapy was also noted.

Estramustine (EM) is an antineoplastic drug used in the therapy of human prostatic carcinoma. The aim of our work was to evaluate the potential aneuploidogenic activity of estramustine, by analysing its cytogenetic effects induced in human lymphocytes. To estimate the ability of EM to induce mitotic spindle disturbances, two parameters were used: the presence of c-mitoses (according to the degree of chromatid spreading and contraction) and mitotic index evaluation (increase after exposure indicating the accumulation of mitoses). EM induced c-mitoses and mitotic index increases starting from the 4 microM dose: statistically significant increases were observed up to the highest dose (40 microM). A strong correlation between c-mitoses and mitotic index increase was found. The micronucleus (MN) assay combined with the fluorescence in situ hybridization technique with a pancentromeric DNA probe was also carried out. Compared to the control, EM induced significant MN increases in binucleated lymphocytes at two doses (8-16 microM). Moreover, we found that estramustine induced significant percentages of MN with positive hybridization signal at the same doses, confirming the presence of entire chromosomes in micronuclei. Additional experiments included induction of numerical and structural chromosome aberrations, and evaluation of sister chromatid exchanges (SCE) and satellited (D- and G-group chromosomes) chromosome associations. The results of numerical chromosome aberration analysis indicated that EM was positive in inducing a statistically significant increase in aneuploid cells and/or polyploid cells at all doses tested. On the basis of these observations, EM may be defined as a typical aneuploidy inducer, whereas it was not found to increase the frequency of structural chromosome aberrations and SCE frequency.

The influence of several methodological factors on mean values of sister chromatid exchanges (SCEs) and micronuclei (MN) in peripheral lymphocytes of 1,650 subjects was analyzed. Donors belonged to a general healthy population living in Pisa and in two nearby small cities: Cascina and Navacchio (Ca-Na). Blood samples were collected over a period of 29 months and processed in three different laboratories of the some institute. Slides were analyzed by several scorers. Our data showed that lymphocyte proliferation indexes (PIs) and baseline mean values of SCEs were affected mainly by sampling period. This factor accounted for a percentage ranging from roughly 10% (Pisa) to 20% (Ca-Na) of total SCE variance and from roughly 10% (Pisa) to 13% (Ca-Na) of total PIs variance. A marginal effect was attributable to the different laboratories involved (maximum 3% for SCEs and 7% for PIs). The sampling period variable included many sources of variability such as culture media batches, fetal calf serum, PHA, BrdUrd, and seasonality. MN counts revealed a more marked dependence on processing laboratories. This factor accounted for a percentage of roughly 10% (Pisa and Ca-Na) of total variance, while the sampling period was marginally effective (about 1-4% of total variability). Because laboratories were equipped and supplied with the same materials and consumables and technicians were rotated constantly, the only variable ascertained was represented by the three different models of CO2 incubators used for lymphocyte culturing. When "month" and "incubator" variables were considered jointly, experimental variability accounted for 15-20% of total variance, both for PIs and mean values SCEs and MN. The variability due to slide scoring was reduced by assigning each slide to five different scorers and matching low with high scorers in each group. Present data show that when the study is performed under these controlled conditions, about 20% of total interdonor variability can be explained by experimental or seasonal factors.

Progressive multifocal leukoencephalopathy (PML), a viral-induced demyelinating disease, is becoming relatively common, while many diagnostic and pathogenetic aspects remain to be clarified. A study was therefore undertaken in 64 AIDS patients suffering from various neurological disorders, including PML (12 subjects), with the specific objective of searching for JC virus (JCV) DNA by nested PCR (n-PCR) in cerebrospinal fluid (CSF), peripheral blood mononuclear cells (PBMCs), and urine collected from all patients. CSF examination, CD4 and CD8 counts, neurological examinations, and neuroradiological investigations were undertaken. JCV DNA was detected in 92% of CSF specimens in 75% of the PBMCs and urine samples from the PML patients, whereas among the non-PML patients JCV DNA was not detected in any CSF samples, but was found in 10% of PBMCs and in 39% of the urine specimens. BKV and JCV DNA viruria was observed simultaneously in 6% of the AIDS patients without PML. The routine CSF tests including IgG oligoclonal bands, the Link, and Tourtellotte IgG indexes, did not show a typical pattern in PML cases. The data obtained clearly indicate that the detection of JCV DNA in CSF constitutes an efficient marker for PML diagnosis. The simultaneous presence of JCV DNA in the CSF, PBMCs, and urine samples from the PML patients, who did not differ from controls with regard to their immunosuppressive status, suggests that JCV could be carried into the central nervous system (CNS) by infected PBMCs.

Diplopia is one of the neuro-ophthalmic manifestations that can be observed during HIV-infection. The etiologic agents of diplopia in HIV-positive patients can be identified with HIV itself or opportunistic pathogens or other related conditions. We reviewed the clinical records of 13 HIV-positive patients with mono or bilateral diplopia, focusing on etiologic agents, clinical evaluation and prognosis. This review encompassed all cases observed from January 1992 to June 1995 at the Infectious Diseases Department, Policlinico S. Matteo, University of Pavia. All patients underwent a complete ophthalmologic examination, including visual acuity, anterior segment evaluation with biomicroscopy, dilated indirect ophthalmoscopy and ocular motility evaluation (with Cover test and Hess-Lancaster test). If requested by clinical findings, radiologic (TC and/or MRI) and cerebrospinal fluid examination were performed in some patients. The most common causes of diplopia-CNS lesions or ocular diseases-, resulted in agreement with those reported in the literature (T. gondii, C. neoformans, non-Hodgkin lymphomas, HIV, JC virus, CMV). We were able to confirm, according to our experience, that diplopia occurrence is often a negative prognostic factor, since it is commonly associated with CNS conditions. In most cases diplopia can herald a near demise (8 patients on 13 died with 60 days from diplopia onset). In those cases where a treatment was available (2 cases of cryptococcosis, 1 case of neurotoxoplasmosis and 1 case of CMV retinitis) a complete resolution of neuro-ophthalmic symptoms was achieved.

The number of subjects with HIV infection or full-blown Acquired Immunodeficiency Syndrome (AIDS) is increasing throughout the world and the range of related opportunistic conditions (infections, neoplasms or degenerative disorders) is also increasing. Consequently, AIDS patients are likely to be prescribed a great number of different drugs. HIV infection is a progressive phenomenon, characterized by inevitable and often irreversible changes which may influence drug disposition, enhancing the risk of toxic adverse effects and drug interactions. One of the stages for the development of new agents and the establishment of an effective therapy is to conduct pharmacokinetic studies. Even though such studies are difficult to realize in AIDS subjects, the knowledge of altered pharmacokinetics of a drug in disease states offers an unique approach for improving and perhaps optimizing the therapeutic management. The purpose of this article is to review our current understanding of how HIV infection influences the various processes of drug disposition (i.e. absorption, distribution, metabolism and excretion).

The human lymphocyte micronucleus (MN) test combined with fluorescence in situ hybridization (FISH) of a centromeric probe is considered a useful screening assay to distinguish between clastogenic and aneugenic agents. Four suspected aneuploidy-inducing chemicals, acetaldehyde (AA), diethylstilbestrol (DES), diethylstilbestrol dipropionate (DESdp) and griseofulvin (GF), have been evaluated with the assay. All compounds induced a significant increase of MN at all doses tested. After the application of the FISH technique with a pancentromeric DNA sequence, DES, DESdp and GF showed a statistically significant increase in the percentage of positive signals compared with the control culture. GF induced the highest percentage of centromere-positive MN observed to date (>90% on average). AA did not show a significant difference in the percentage of centromere-positive MN. The results indicate that in human lymphocytes DES, DESdp and GF act primarily as aneugens, while AA seems capable of causing both chromosome breakage and aneuploidy.