Moderate ethanol drinking is sufficient to alter Ventral Tegmental Area dopamine neurons activity via functional and structural remodeling of GABAergic transmission.

Earlier studies have shown a major involvement of Ventral Tegmental Area (VTA) dopamine (DA) neurons in mediating the rewarding effects of ethanol (EtOH). Much less is known on the role of this system in mediating the transition from moderate to excessive drinking and abuse. Here we sought to explore the hypothesis that early stage drinking in rodents, resembling recreational EtOH use in humans, is sufficient to dysregulate VTA DA transmission thus increasing the propensity to use over time. To this purpose, midbrain slice recordings in mice previously exposed to an escalating (3, 6 and 12%) 18-day voluntary EtOH drinking paradigm was used. By recording from DA and γ-aminobutyric acid (GABA) VTA neurons in midbrain slices, we found that moderate EtOH drinking leads to a significant suppression of the spontaneous activity of VTA DA neurons, while increasing their response to acute EtOH application. We also found that chronic EtOH leads to the enhancement of GABA input frequency onto a subset of DA neurons. Structurally, chronic EtOH induced a significant increase in the number of GABA axonal boutons contacting DA neurons, suggesting deep rewiring of the GABA network. This scenario is consistent with a downmodulation of the reward DA system induced by moderate EtOH drinking, a neurochemical state defined as "hypodopaminergic" and previously associated with advanced stages of drug use in humans. In this context, increased sensitivity of DA neurons towards acute EtOH may represent the neurophysiological correlate of increased unitary rewarding value, possibly driving progression to addiction.

Longitudinal Association between Late-Life Depression (LLD) and Frailty: Findings from a Prospective Cohort Study (MiMiCS-FRAIL).

OBJECTIVES: The aim of the present study was to investigate whether late-life depression (LLD) is associated with incident frailty over time. DESIGN: Prospective cohort study, one-year follow-up. SETTING: Geriatric outpatient clinic, Southwestern of Brazil. PARTICIPANTS: 181 follow-up participants aged 60 years or over. MEASUREMENTS: Depressive disorders were classified as Major Depressive disorder (MDD) or Subthreshold Depression (STD) according to DSM-5 criteria. Depressive symptoms were assessed with validated versions of 15-item Geriatric Depression Scale (GDS-15) and 9-item Patient Health Questionnaire (PHQ-9). We performed binary logistic regressions to estimate the odds ratio (OR) for frailty in LLD adjusting for multiple confounders. Participants who were frail at baseline were excluded from the analyses according to measures of frailty (FRAIL questionnaire and 36-item Frailty Index, FI-36). We also estimated the risk ratio or relative risk (RR) and the risk difference (RD) for incident frailty. RESULTS: We observed a 2 to 4-fold increased risk for incident frailty among participants with LLD. The presence of a depressive disorder was significantly associated with the onset of frailty (adjusted OR for FRAIL and FI-36: 3.07 [95% CI = 1.03 - 9.17] and 3.76 [95% CI = 1.09 - 12.97], respectively. Notably, the risk for frailty due to LLD was significantly higher with the FI-36 compared to the FRAIL (RR: 3.03 versus 2.23). RD was of 17.3% and 12.7% with the FRAIL and the FI-36, respectively. CONCLUSION: Our data support the association between LLD and incident frailty over one year among geriatric outpatients, reinforcing longitudinal evidence from population-based studies.

Do cancer patients change their diet in the e-health information era? A review of the literature and a survey as a proposal for the Italian population.

In recent years, there has been an explosion in the amount of available information on cancer in parallel with an ever-increasing number of cancer survivors. Cancer patients and long-term survivors are known to be more sensitive to health-related information and dietary changes could represent a potential consequence of this huge availability of messages. In our review about dietary changes after cancer diagnosis, we found that this topic is particularly investigated among the breast cancer population. The literature examined show that breast cancer patients modify their eating habits after diagnosis in a percentage that varies between approximately 30% and 60%. The most reported changes were an increased consumption of fruit and vegetables, a decrease in the consumption of red meat, fats and sugary foods. Patients who reported changes were more likely to be younger, with higher educational levels and with a longer period of time since their diagnosis of cancer. It also emerged that cancer patients are often more likely to use supplements. This topic has not been investigated in cancer patients in Italy, therefore, we propose an approach to explore it with a structured questionnaire: The "ECHO SURVEY - Eating habits CHanges in Oncologic patients".

Measuring postural control during mini-squat posture in men with early knee osteoarthritis.

Studies have suggested a compromised postural control in individuals with knee osteoarthritis (OA) evidenced by larger and faster displacement of center of pressure (COP). However, quantification of postural control in the mini-squat posture performed by patients with early knee OA and its relation to muscle strength and self-reported symptoms have not been investigated. The main aim of this cross-sectional, observational, controlled study was to determine whether postural control in the mini-squat posture differs between individuals with early knee OA and a control group (CG) and verify the relation among knee extensor torque (KET) and self-reported physical function, stiffness and pain. Twenty four individuals with knee OA grades I and II (OAG) (mean age: 52.35±5.00) and twenty subjects without knee injuries (CG) (mean age: 51.40±8.07) participated in this study. Participants were assessed in postural control through a force plate (Bertec Mod. USA), which provided information about the anterior-posterior (AP) and medial-lateral (ML) COP displacement during the mini-squat, in isometric, concentric and eccentric knee extensor torque (KET) (90°/s) through an isokinetic dynamometer (BiodexMulti-Joint System3, Biodex Medical Incorporation, New York, NY, USA), and in self-reported symptoms through the WOMAC questionnaire. The main outcomes measured were the AP and ML COP amplitude and velocity of displacement; isometric, concentric, and eccentric KET and self-reported physical function, stiffness and pain. No significant differences were found between groups for postural control (p>0.05). Significant lower eccentric KET (p=0.01) and higher scores for the WOMAC subscales of pain (p=<0.001), stiffness (p=0.001) and physical function (p<0.001) were found for the OAG. Moderate and negative correlations were found between the AP COP amplitude of displacement and physical function (ρ=-0.40, p=0.02). Moderate and negative correlations were observed between the AP COP velocity of displacement and physical function (ρ=0.47, p=0.01) and stiffness (ρ=-0.45, p=0.02). The findings of the present study emphasize the importance of rehabilitation from the early degrees of knee OA to prevent postural instability and the need to include quadriceps muscle strengthening, especially by eccentric contractions. The relationship between the self-reported symptoms and a lower and slower COP displacement suggest that the postural control strategy during tasks with a semi-flexed knee should be further investigated.

Percutaneous ablative treatment of metastatic bone tumours: visual analogue scale scores in a short-term series.

INTRODUCTION: The aim of this study was to examine the role of palliative percutaneous secondary lesions bone treatment by comparing the visual analogue scale (VAS) scores of cryoablation plus vertebroplasty versus radiofrequency (RF) plus vertebroplasty so as to determine their feasibility, reliability and efficacy in a short-term series. METHODS: Combined RF thermal ablation plus osteoplasty or cryoablation plus osteoplasty was performed in osteolytic secondary bone localisations in 30 consecutive patients who were suffering from pain refractory to conservative therapies. We evaluated pain with the VAS during the preoperative period and at four hours, 24 hours, one week, one month, three months and six months post procedure. RESULTS: There were no statistically significant differences in the VAS score between patients treated with cryoablation plus osteoplasty and those treated with RF ablation plus osteoplasty at one week (p-value is 0.34), one month (p-value is 1), three months (p-value is 0.68) and six months (p-value is 0.65) post procedure. Patients treated with cryoablation plus vertebroplasty have less pain at four hours (p-value less than 0.001) and 24 hours (p-value less than 0.001) than patients treated with RF ablation plus vertebroplasty. CONCLUSION: Both RF ablation and cryoablation are optimal techniques in the treatment of painful bone metastatic cancer. Cryoablation achieves less treatment-related pain during the early period of follow-up and better volume control by real-time depiction of ablation margins.

"CADEAT": considerations on the use of CAD (computer-aided diagnosis) in mammography.

Computer-aided diagnosis (CAD) has been extensively reported to increase sensitivity by about 10% when added to a single reading while increasing recall rate by 12%, and its current use can be safely recommended in clinical practice. CAD has been suggested as a possible alternative to conventional double reading in screening. Uncontrolled comparison is consistent and suggests that CAD is comparable to double reading in incremental cancer detection rate (CAD +10.6%, double reading +9.1%) and possibly better in recall rate (CAD +12.5%, double reading +28.8%). However, controlled studies comparing single reading + CAD to conventional double reading are not consistent and on average suggest a lower cancer detection rate (-5.1%) and a lower recall rate (-9.8%) for CAD. Scientific evidence is not sufficient for a safe recommendation of single reading + CAD as a current alternative to conventional double reading.

[New drugs and targeted therapeutic agents in ovarian cancer]. / Nouvelles molécules et thérapeutiques moléculaires ciblées dans les adénocarcinomes ovariens de stades avancés.

Ovarian cancers are the leading cause of death from gynaecological malignancies in Western countries. Despite optimal treatment combining surgery and chemotherapy, relapse is observed in the majority of patients. This review aims to present the results of trials having evaluated new drugs in ovarian cancers. Advances in the understanding of cancer biology and more specifically of cell signalling pathways have led to the identification of several potential molecular targets and to the development of new agents directed against these targets. The assessment of targeted therapies is relatively recent in this field. So far, only the results of phase II trials have been published, but many phase III trials are underway. Some targets (HER-2, EGFR) initially regarded as promising have already been abandoned due to the lack of results. The most advanced molecular therapies target angiogenesis (VEGF, VEFGR). PARP and mTOR inhibitors may also represent a significant therapeutic improvement. It remains to confirm the interest of these new approaches by assessing the benefit on overall survival. The goal remains to individualize and to tailor the drugs to the tumour biology, in order to provide personalized treatment to each patient.

Effectiveness of service screening: a case-control study to assess breast cancer mortality reduction.

The aim of this study was the evaluation of the impact of service screening programmes on breast cancer mortality in five regions of Italy. We conducted a matched case-control study with four controls for each case. Cases were defined as breast cancer deaths occurred not later than 31 December 2002. Controls were sampled from the local municipality list and matched by date of birth. Screening histories were assessed by the local, computerised, screening database and subjects were classified as either invited or not-yet-invited and as either screened or unscreened. There were a total of 1750 breast cancer deaths within the 50 to 74-year-old breast cancer cases and a total of 7000 controls. The logistic conditional estimate of the cumulative odds ratios comparing invited with not-yet-invited women was 0.75 (95% CI: 0.62-0.92). Restricting the analyses to invited women, the odds ratio of screened to never-respondent women corrected for self-selection bias was 0.55 (95% CI: 0.36-0.85). The introduction of breast cancer screening programmes in Italy is associated with a reduction in breast cancer mortality attributable to the additional impact of service screening over and above the background access to mammography.

Atypical cutaneous manifestation of HSV-2 with Candida albicans co-infection in a patient with HIV-1.

Herpes simplex virus type 2 (HSV-2) infection was one of the first opportunistic infections identified among patients with AIDS. In the literature there are many data suggesting that the natural history of HSV-2 infection is altered in HIV-HSV-2 co-infected patients. Furthermore, a relationship between HIV seropositivity and HBV infection because of their analogous way of transmission is also described. We report the case of a 37-year-old patient who suffered from multiple painful ulcerative lesions of the perianal region. Laboratory examination showed positivity for HIV and HBV infections. In HIV-positive patients perianal HSV-2 can have atypical manifestations, especially if co-infection by Candida albicans occurs.

Rationale for maintenance of the M184v resistance mutation in human immunodeficiency virus type 1 reverse transcriptase in treatment experienced patients.

The M184V substitution in HIV-1 RT develops rapidly following initiation of therapy with 3TC and confers high-level phenotypic resistance to this drug both in vitro and in vivo. Interestingly, the presence of M184V is also associated with alteration of several mechanisms relating to RT function that include decreased RTprocessivity, reduced nucleotide-dependent primer unblocking, increased fidelity, hypersensitization to other NRTIs, impaired viral fitness, and delayed appearance of mutations in RT that are responsible for resistance to thymidine analogues (i.e. thymidine-associated mutations or TAMs). In addition, M184V may affect viral transmission and immunological response. Collectively, these factors might explain the residual antiviral effect and clinical benefit observed with continued use of 3TC in combination therapy regimens following the emergence of M184V.

HIV drug resistance and implications for the introduction of antiretroviral therapy in resource-poor countries.

The development and transmission of HIV drug-resistant viruses is of serious concern and has been shown to significantly diminish the effectiveness of antiretroviral therapy. In addition, cross-resistance between drugs of the same class can seriously limit therapeutic options and may potentially be most problematic in resource-poor settings where new drugs are not widely available. Strategies based on avoidance of virological failure are therefore essential for the long-term success of therapy. In this regard, regionally adapted programs to facilitate proper adherence with therapy need to be urgently implemented, concomitant with expanded access to new antiretroviral drugs. The value of genotypic resistance testing as a prognostic tool to help guide therapeutic decisions has been established. However, the relatively high cost of this novel technology does not warrant its routine utilization at this time in resource-poor countries. Lastly, the genetic barrier of the antiretroviral agents that are prescribed is also an important consideration that needs to be integrated with knowledge of HIV-1 subtypes, drug pharmacology, and medical management of concurrent illnesses. The selection of appropriate first-line antiretroviral combination regimens may be an even more important consideration in developing than developed countries, given that options in the aftermath of treatment failure may be more limited in such settings.

Modification of mitogen-induced proliferation of murine splenic lymphocytes by in vitro tocopherol.

The effect of alpha-tocopherol on in vitro proliferation of murine splenic lymphocyte cultures supplemented with various concentrations of the vitamin has been measured at sub-optimal, optimal and supra-optimal levels of the T-cell mitogen Concanavalin A (Con A). In the concentration range (1-25 micrograms/ml), tocopherol enhanced proliferation when administered up to 24 hours after exposure to sub-optimal and optimal concentrations of Con A; however, at supra-optimal levels of the mitogen, it appeared to inhibit proliferation. In the concentration range 50-100 micrograms/ml, tocopherol supplementation only enhanced proliferation in response to sub-optimal concentration of Con A. The spontaneous proliferation of lymphocytes in the absence of mitogens was increased by tocopherol supplementation at all concentrations tested. In contrast, there appeared to be only slight stimulation of B-cell proliferation in response to optimal concentration of bacterial lipopolysaccharide (LPS) by lower levels of vitamin E. Tocopherol supplementation of cultures over a broad range of concentrations (0.5-100 micrograms/ml) had no significant effect on cell viability before onset of proliferation at 18 hours after exposure to Con A, nor was there evidence of earlier onset of DNA synthesis in response to mitogen in the presence of 5 micrograms/ml of the vitamin. Although macrophage depletion of cultures impaired proliferation induced by Con A, tocopherol supplementation continued to stimulate proliferation at optimal and sub-optimal levels of mitogen.

[Changes in sleep organization in two patients with progressive supranuclear palsy]. / Modificazioni dell'organizzazione ipnica in due pazienti con paralisi sopranucleare progressiva.

Sleep-EEG of two subjects affected by Progressive Supranuclear Palsy was studied. Morphological, reduced and poorly organized sleep transients (spindles) in stage 2 and decreased REMs during desynchronized sleep were observed. The quantitative sleep analysis showed a poor and fragmented sleep with an increase of stage 1 and stage 3 and a decrease of stage 2 and REM sleep.

Comparison between the results of an automatic and a visual scoring of sleep EEG recordings.

In this paper, results from the visual scoring of nocturnal polygraphic recordings, carried out by nine different groups of readers from different Italian sleep laboratories, are analyzed; inter-and intragroup variability is shown and statistically discussed. Data are then compared with the results of an automatic scoring of the same recordings, carried out by the Medilog Sleep Stager. The validity of this automatic method of scoring is discussed. Finally, an epoch by epoch analysis is described, with the aim of achieving a more detailed evaluation of the intergroup variability.

Fragile-X syndrome: a particular epileptogenic EEG pattern.

A clinical and EEG study of 12 fragile-X syndrome subjects (six with epilepsy) is presented. All subjects had clinical-family history examinations, EEG evaluations, and karyotyping. Spikes were present in the sleep EEG of one nonepileptic and four epileptic subjects: these spikes were similar in location, occurrence, voltage, frequency, and morphology (and similar to those of the Rolandic spikes). These data, together with the clinical similarities (type of epilepsy, responses to drugs, ages of seizure onset, etc.), have resulted in the postulation of EEG characteristics of epileptic and nonepileptic fragile-X patients. However, further studies with fragile-X patients are needed to confirm this hypothesis.