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1.  Are Periventricular Lesions Specific for Multiple Sclerosis? 
The presence of periventricular lesions (PVL) on MRI scans is part of the revised McDonald multiple sclerosis (MS) diagnostic criteria. However, PVL can be found in other neurological diseases including stroke and migraine. Migraine is highly prevalent in patients with MS.
To determine if PVL are specific for patients with MS compared to stroke and migraine.
We studied patients diagnosed with clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), migraine, and ischemic stroke. The number, location and the volume of PVL were identified on brain MRI scans and analyzed.
The number and volume of PVL adjacent to the body and the posterior horn of the lateral ventricles were significantly increased on fluid-attenuated inversion recovery MRI in RRMS compared to migraine. There were no significant differences in the total number and volume of PVL in ischemic stroke patients compared to the age-matched RRMS patients nor in the number and volume of PVL adjacent to the anterior and temporal horns of the lateral ventricles on FLAIR images in migraine compared to CIS or RRMS.
In contrast to PVL adjacent to the body and the posterior horn of the lateral ventricles, PVL adjacent to the anterior and temporal horns of the lateral ventricles may not be specific for CIS/RRMS when compared to migraine, the disease highly prevalent among patients with MS. PVL are not specific for MS when compared to ischemic stroke.
PMCID: PMC4283830  PMID: 25568815
Multiple sclerosis; Migraine; Stroke; MRI
2.  Knowledge about tuberculosis among undergraduate health care students in 15 Italian universities: a cross-sectional study 
BMC Public Health  2014;14(1):970.
The Italian Study Group on Hospital Hygiene of the Italian Society of Hygiene, Preventive Medicine and Public Health conducted a multicentre survey aiming to evaluate undergraduate health care students’ knowledge of tuberculosis and tuberculosis control measures in Italy.
In October 2012–June 2013, a sample of medical and nursing students from 15 Italian universities were enrolled on a voluntary basis and asked to complete an anonymous questionnaire investigating both general knowledge of tuberculosis (aetiology, clinical presentation, outcome, screening methods) and personal experiences and practices related to tuberculosis prevention. Data were analysed through multivariable regression using Stata software.
The sample consisted of 2,220 students in nursing (72.6%) and medicine (27.4%) courses. Our findings clearly showed that medical students had a better knowledge of tuberculosis than did nursing students.
Although the vast majority of the sample (up to 95%) answered questions about tuberculosis aetiology correctly, only 60% of the students gave the correct responses regarding clinical aspects and vaccine details. Overall, 66.9% of the students had been screened for tuberculosis, but less than 20% of those with a negative result on the tuberculin skin test were vaccinated. Multivariable regression analysis showed that age and type of study programme (nursing vs. medical course) were determinants of answering the questions correctly.
Although our data showed sufficient knowledge on tuberculosis, this survey underlines the considerable need for improvement in knowledge about the disease, especially among nursing students. In light of the scientific recommendations concerning tuberculosis knowledge among students, progress of current health care curricula aimed to develop students’ skills in this field is needed.
PMCID: PMC4192330  PMID: 25236852
Knowledge; Tuberculosis; Undergraduate health care students
3.  Monitoring air pollution effects on children for supporting public health policy: the protocol of the prospective cohort MAPEC study 
BMJ Open  2014;4(9):e006096.
Genotoxic biomarkers have been studied largely in adult population, but few studies so far have investigated them in children exposed to air pollution. Children are a high-risk group as regards the health effects of air pollution and some studies suggest that early exposure during childhood can play an important role in the development of chronic diseases in adulthood. The objective of the project is to evaluate the associations between the concentration of urban air pollutants and biomarkers of early biological effect in children, and to propose a model for estimating the global risk of early biological effects due to air pollutants and other factors in children.
Methods and analysis
Two biomarkers of early biological effects, DNA damage by the comet assay and the micronuclei (MN) test, will be investigated in oral mucosa cells of 6–8-year-old children. Concurrently, some toxic airborne pollutants (polycyclic aromatic hydrocarbon (PAH) and nitro-PAH) and in vitro air mutagenicity and toxicity in ultra-fine air particulates (PM0.5) will be evaluated. Furthermore, demographic and socioeconomic variables, other sources of exposures to air pollutants and lifestyle variables will be assessed by a structured questionnaire. The associations between sociodemographic, environmental and other exposure variables and biomarkers of early biological effect using univariate and multivariate models will be analysed. A tentative model for calculating the global absolute risk of having early biological effects caused by air pollution and other variables will be proposed.
Ethics and dissemination
The project has been approved by the Ethics Committees of the local Health Authorities. The results will be communicated to local Public Health Agencies, for supporting educational programmes and health policy strategies. LIFE+2012 Environment Policy and Governance. LIFE12 ENV/IT/000614.
PMCID: PMC4166251  PMID: 25227631
PUBLIC HEALTH; air pollution; early biological effect; children; DNA damage; mucosa buccal cells
4.  A Remote Lab for Experiments with a Team of Mobile Robots 
Sensors (Basel, Switzerland)  2014;14(9):16486-16507.
In this paper, a remote lab for experimenting with a team of mobile robots is presented. Robots are built with the LEGO Mindstorms technology and user-defined control laws can be directly coded in the Matlab programming language and validated on the real system. The lab is versatile enough to be used for both teaching and research purposes. Students can easily go through a number of predefined mobile robotics experiences without having to worry about robot hardware or low-level programming languages. More advanced experiments can also be carried out by uploading custom controllers. The capability to have full control of the vehicles, together with the possibility to define arbitrarily complex environments through the definition of virtual obstacles, makes the proposed facility well suited to quickly test and compare different control laws in a real-world scenario. Moreover, the user can simulate the presence of different types of exteroceptive sensors on board of the robots or a specific communication architecture among the agents, so that decentralized control strategies and motion coordination algorithms can be easily implemented and tested. A number of possible applications and real experiments are presented in order to illustrate the main features of the proposed mobile robotics remote lab.
PMCID: PMC4208184  PMID: 25192316
remote labs; control education; multi-robot systems; mobile robotics
5.  Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept study 
European Journal of Heart Failure  2014;16(9):977-983.
Heart failure (HF) pathophysiology is believed to be mediated by autonomic dysfunction, including chronic sympathoexcitation and diminished baroreflex sensitivity, which correlate with mortality risk. Baroreflex activation therapy (BAT) is a device-based treatment providing chronic baroreflex activation through electrical stimulation of the carotid sinus. BAT chronically reduces sympathetic activity in resistant hypertension. The purpose of this investigation is to determine BAT effects in clinical HF.
Methods and results
In a single-centre, open-label evaluation, patients with NYHA class III HF, EF <40%, optimized medical therapy, and ineligible for cardiac resynchronization received BAT for 6 months. Efficacy was assessed with serial measurement of muscle sympathetic nerve activity (MSNA) and clinical measures of quality of life and functional capacity. Eleven patients participated in the trial. MSNA was reduced over 6 months from 45.1 ± 7.7 to 31.3 ± 8.3 bursts/min and from 67.6 ± 12.7 to 45.1 ± 11.6 bursts/100 heartbeats, decreases of 31% and 33%, respectively (P < 0.01). Concomitant improvements occurred in baroreflex sensitivity, EF, NYHA class, quality of life and 6 min hall walk (6MHW) distance (P ≤ 0.05 each). On an observational basis, hospitalization and emergency department visits for worsening HF were markedly reduced. One complication, perioperative anaemia requiring transfusion, occurred during the study.
BAT was safe and provided chronic improvement in MSNA and clinical variables. Based on present understanding of HF pathophysiology, these results suggest that BAT may improve outcome in HF by modulating autonomic balance. Prospective, randomized trials to test the hypothesis are warranted.
PMCID: PMC4237551  PMID: 25067799
Heart failure; Sympathetic nervous system; Non-pharmacological therapy; Baroreflex
6.  Potential Anticancer Heterometallic Fe-Au and Fe-Pd Agents: Initial Mechanistic Insights 
Journal of medicinal chemistry  2013;56(14):10.1021/jm4007615.
A series of gold(III) and palladium(II) heterometallic complexes with new iminophosphorane ligands derived from ferrocenyl-phosphanes [{Cp-P(Ph2)=N-Ph}2Fe] (1), [{Cp-P(Ph2)=N-CH2-2-NC5H4}2Fe] (2) and [{Cp-P(Ph2)=N-CH2-2-NC5H4}Fe(Cp)] (3) have been synthesized and structurally characterized. Ligands 2 and 3 afford stable coordination complexes [AuCl2(3)]ClO4, [{AuCl2}2(2)](ClO4)2, [PdCl2(3)] and [{PdCl2}2(2)]. The complexes have been evaluated for their antripoliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), in human breast cancer cells (MCF7) and in a non-tumorigenic human embryonic kidney cell line (HEK-293T). The highly cytotoxic trimetallic derivatives M2Fe (M = Au, Pd) are more cytotoxic to cancer cells than their corresponding monometallic fragments. Moreover, these complexes were significantly more cytotoxic than cisplatin in the resistant A2780R and the MCF7 cell lines. Studies of the interactions of the trimetallic compounds with DNA and the zinc-finger protein PARP-1 indicate that they exert anticancer effects in vitro based on different mechanisms of actions with respect to cisplatin.
PMCID: PMC3880617  PMID: 23786413
Gold and palladium complexes; ferrocenyl phosphane-iminophosphorane ligands; cytotoxicity; DNA; zinc-finger proteins
7.  Mediterranean diet and non-alcoholic fatty liver disease: New therapeutic option around the corner? 
Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in Western countries, being considered as the hepatic manifestation of metabolic syndrome. NAFLD has a common pathogenic background to that of metabolic syndrome, and shares many risk factors such as obesity, hypertension, insulin resistance and dyslipidemia. Although there is no currently available evidence-based established treatment for NAFLD, all the recommendations from the medical associations indicate that the most effective treatment is to reduce weight through lifestyle modifications. Diet, indeed, plays a key role in the management of NAFLD patients, as both the quantity and quality of the diet have been reported to have a beneficial role in the onset and severity of the liver disease. Among all the diets that have been proposed, a Mediterranean diet was the most effective dietary option for inducing weight loss together with beneficial effects on all the risk factors associated with metabolic syndrome and NAFLD. Over the last few years, research has demonstrated a beneficial effect of a Mediterranean diet in NAFLD. In this review, we will examine all the available data on the association between diet, nutrients and the Mediterranean diet in association with onset and severity of NAFLD.
PMCID: PMC4064079  PMID: 24966604
Mediterranean diet; Diet; Prevention; Metabolic syndrome; Non-alcoholic fatty liver disease
8.  Density-Dependence in Space and Time: Opposite Synchronous Variations in Population Distribution and Body Condition in the Baltic Sea Sprat (Sprattus sprattus) over Three Decades 
PLoS ONE  2014;9(4):e92278.
Spatio-temporal density-dependent processes are crucial regulatory factors for natural populations. However, there is a lack of studies addressing spatial density-dependence in fish growth. A previous investigation has suggested spatio-temporal density-dependence in body condition of Baltic sprat. Here, we used different techniques, such as centre of gravity, distance, and homogeneity indices, to better characterize the spatial and temporal variations in sprat density and body condition in the Baltic Proper. Our results evidenced a negative spatio-temporal co-variation between the centres of gravity of density and maximum condition. In the 1980s-early 1990s both centres were located in the middle of the Baltic Proper. From the mid 1990s the centres progressively separated in space, as the sprat population moved towards the north-eastern Baltic Proper, and the centre of maximum condition towards the south-western areas. Moreover, at low abundances, sprat density and condition were homogeneously distributed in space, whereas at high abundances both density and condition showed pronounced geographical gradients. The ecological processes potentially explaining the observed patterns were discussed in the light of the Ideal Free Distribution theory. We provide evidence that the shift in the spatial distribution of cod, the main predator of sprat, has been the main factor triggering the overall spatial changes in sprat density, and thus condition, during the past thirty years. The spatial indices shown here, synthesizing the spatio-temporal patterns of fish distribution, can support the implementation of the EU Marine Strategy Framework Directive.
PMCID: PMC3974706  PMID: 24699501
9.  Proteins as Possible Targets for Cytotoxic trans-Platinum(II) Complexes with Aliphatic Amine Ligands: Further Exceptions to the DNA Paradigm 
ChemMedChem  2010;5(8):1335-1343.
The reactivity of three cytotoxic trans-PtII complexes bearing aliphatic amine ligands, with transferrin and single-stranded oligonucleotides as DNA models, was investigated by ESI-MS and the results obtained are discussed in comparison with cisplatin. Tandem MS studies provided additional information on the preferential Pt binding sites. To determine whether trans-PtII complexes can migrate from a peptide to an oligonucleotide, transfer experiments were also performed using ESI-MS, and competitive binding of the trans-PtII complexes toward a model peptide and different oligonucleotides was also investigated. Significant differences in the reactivity of the trans complexes with respect to cisplatin were observed. In general, adduct formation with the selected peptide is favored for the trans compounds, whereas cisplatin shows a preference for oligonucleotides, especially if adjacent G–G residues are present. The results are discussed in relation to the possible mechanism of action of the trans-PtII complexes.
PMCID: PMC3920175  PMID: 20564276
cancer; mass spectrometry; oligonucleotides; peptides; platinum
10.  Synergistic Activity of Colistin plus Rifampin against Colistin-Resistant KPC-Producing Klebsiella pneumoniae 
Infections caused by carbapenem-resistant KPC-producing Klebsiella pneumoniae are responsible for high rates of mortality and represent a major therapeutic challenge, especially when the isolates are also resistant to colistin. We used the checkerboard method to evaluate the synergistic activity of 10 antibiotic combinations against 13 colistin-resistant KPC-producing K. pneumoniae isolates (colistin MIC range of 8 to 128 mg/liter). Colistin plus rifampin was the only combination that demonstrated consistent synergistic bacteriostatic activity against 13/13 strains tested, reducing the colistin MIC below the susceptibility breakpoint (MIC ≤ 2 mg/liter) in 7/13 strains at rifampin concentrations ranging from 4 to 16 mg/liter. Bactericidal synergistic activity was also documented for 8/13 tested strains. Other antimicrobial combinations with carbapenems, gentamicin, and tigecycline showed variously synergistic results. Colistin plus rifampin also exhibited bacteriostatic synergistic activity against 4/4 colistin-susceptible KPC-producing K. pneumoniae isolates (colistin MIC range of 0.5 to 2 mg/liter) and 4/4 ertapenem-resistant extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae isolates (ertapenem MIC range of 16 to 32 mg/liter). Collectively, our data suggest that colistin plus rifampin is the most consistently synergistic combination against KPC-producing K. pneumoniae isolates, including colistin-resistant strains. Colistin-rifampin combinations may have a role in the treatment of multidrug-resistant K. pneumoniae and may possibly slow the selection of heteroresistant subpopulations during colistin therapy.
PMCID: PMC3719736  PMID: 23752510
12.  Early-onset colorectal cancer patients without family history are “at very low risk” for lynch syndrome 
Several studies evaluated the prevalence of Lynch Syndrome (LS) in young onset colorectal cancer (CRC) patients and the results were extremely variable (5%-20%). Immunohistochemistry (IHC) for MMR proteins and/or MSI analysis are screening tests that are done, either by themselves or in conjunction, on colon cancer tissue to identify individuals at risk for LS. The primary aim of our study was to evaluate the prevalence of LS in a large series of early-onset CRC without family history compared with those with family history. The secondary aim was to assess the diagnostic accuracy of IHC and MSI analysis as pre-screening tools for LS.
Early-onset CRC patients (≤ 50 years) were prospectively recruited in the study. IHC and MSI analysis were performed in all the patients. Germ-line mutation analysis (GMA) was carried out in all MMR deficient tumors. A logistic regression model was performed to identify clinical features predictive of MSI-H.
117 early onset CRC cases were categorized in three groups (A, B, C) according with family history of CRC. IHC and MSI analysis showed MMR deficiency in 6/70 patients (8.6%) of group A, 24/40 patients (60%) of group B and none of group C. GMA showed a deleterious mutation in 19 (47.5%) patients of group B. MSI analysis had a diagnostic accuracy of 95.7% (CI 92.1-99.4) and IHC of 83.8% (CI 77.1-90.4). The logistic regression model revealed that by using a combination of the two features “No Amsterdam Criteria” and ”left sided CRC” to exclude MSI-H, accuracy was 89.7% (84.2-95.2).
Early-onset CRC patients, with left sided CRC and without family history are “at very low risk” for Lynch syndrome. The two simple criteria of family history and CRC site could be used as a pre-screening tool to evaluate whether or not patients should undergo tissue molecular screening. In the few cases of suspected LS (right sided CRC and/or Amsterdam Criteria), a reasonable approach could be to perform MSI analysis first and IHC afterwards only in MSI-H patients.
PMCID: PMC3892010  PMID: 24383517
Early-onset colorectal cancer; Lynch syndrome; Immunohistochemistry; Microsatellite instability
13.  Detecting and correcting partial errors: Evidence for efficient control without conscious access 
Appropriate reactions to erroneous actions are essential to keeping behavior adaptive. Erring, however, is not an all-or-none process: electromyographic (EMG) recordings of the responding muscles have revealed that covert incorrect response activations (termed “partial errors”) occur on a proportion of overtly correct trials. The occurrence of such “partial errors” shows that incorrect response activations could be corrected online, before turning into overt errors. In the present study, we showed that, unlike overt errors, such “partial errors” are poorly consciously detected by participants, who could report only one third of their partial errors. Two parameters of the partial errors were found to predict detection: the surface of the incorrect EMG burst (larger for detected) and the correction time (between the incorrect and correct EMG onsets; longer for detected). These two parameters provided independent information. The correct(ive) responses associated with detected partial errors were larger than the “pure-correct” ones, and this increase was likely a consequence, rather than a cause, of the detection. The respective impacts of the two parameters predicting detection (incorrect surface and correction time), along with the underlying physiological processes subtending partial-error detection, are discussed.
PMCID: PMC4125819  PMID: 24347086
Cognitive control; Error detection; Action awareness
14.  PGC-1α and Reactive Oxygen Species Regulate Human Embryonic Stem Cell-Derived Cardiomyocyte Function 
Stem Cell Reports  2013;1(6):560-574.
Diminished mitochondrial function is causally related to some heart diseases. Here, we developed a human disease model based on cardiomyocytes from human embryonic stem cells (hESCs), in which an important pathway of mitochondrial gene expression was inactivated. Repression of PGC-1α, which is normally induced during development of cardiomyocytes, decreased mitochondrial content and activity and decreased the capacity for coping with energetic stress. Yet, concurrently, reactive oxygen species (ROS) levels were lowered, and the amplitude of the action potential and the maximum amplitude of the calcium transient were in fact increased. Importantly, in control cardiomyocytes, lowering ROS levels emulated this beneficial effect of PGC-1α knockdown and similarly increased the calcium transient amplitude. Our results suggest that controlling ROS levels may be of key physiological importance for recapitulating mature cardiomyocyte phenotypes, and the combination of bioassays used in this study may have broad application in the analysis of cardiac physiology pertaining to disease.
Graphical Abstract
•PGC-1α regulates a mitochondrial biogenesis program in hESC-derived cardiomyocytes•The PGC-1α program can result in potentially detrimental increased ROS levels•Controlling ROS is essential for maximizing the calcium transient•PGC-1α deficiency is exposed by hypertrophic or beta-adrenergic stress/stimulation
Mitochondrial function is critically important for the heart. In this study, Mummery and colleagues identify the gene PGC-1α as a key regulator of mitochondrial function in hESC-derived cardiomyocytes, controlling respiration and ROS production. Investigation of this phenotype exposed a trade-off between energetic capacity and oxidative stress. Controlling this balance may help improve PSC-derived cardiomyocyte function.
PMCID: PMC3871390  PMID: 24371810
15.  Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome 
The EMBO Journal  2013;32(24):3161-3175.
Patient-specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long-QT syndromes (LQTS). To study the LQT2-associated c.A2987T (N996I) KCNH2 mutation under genetically defined conditions, we derived iPSCs from a patient carrying this mutation and corrected it. Furthermore, we introduced the same point mutation in human embryonic stem cells (hESCs), generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the current (IKr) conducted by the HERG channel and the action potential (AP) duration in iPSC-derived cardiomyocytes (CMs). Introduction of the same mutation reduced IKr and prolonged the AP duration in hESC-derived CMs. Further characterization of N996I-HERG pathogenesis revealed a trafficking defect. Our results demonstrated that the c.A2987T KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype.
Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome
Isogenic pairs of patient-derived iPS- and ES-cell lines reveal the molecular problems contributing to cardiac arrest in long-QT syndrome.
PMCID: PMC3981141  PMID: 24213244
gene targeting; HERG; human embryonic stem cells; induced pluripotent stem cells; long-QT syndrome
16.  One-pot DNA construction for synthetic biology: the Modular Overlap-Directed Assembly with Linkers (MODAL) strategy 
Nucleic Acids Research  2013;42(1):e7.
Overlap-directed DNA assembly methods allow multiple DNA parts to be assembled together in one reaction. These methods, which rely on sequence homology between the ends of DNA parts, have become widely adopted in synthetic biology, despite being incompatible with a key principle of engineering: modularity. To answer this, we present MODAL: a Modular Overlap-Directed Assembly with Linkers strategy that brings modularity to overlap-directed methods, allowing assembly of an initial set of DNA parts into a variety of arrangements in one-pot reactions. MODAL is accompanied by a custom software tool that designs overlap linkers to guide assembly, allowing parts to be assembled in any specified order and orientation. The in silico design of synthetic orthogonal overlapping junctions allows for much greater efficiency in DNA assembly for a variety of different methods compared with using non-designed sequence. In tests with three different assembly technologies, the MODAL strategy gives assembly of both yeast and bacterial plasmids, composed of up to five DNA parts in the kilobase range with efficiencies of between 75 and 100%. It also seamlessly allows mutagenesis to be performed on any specified DNA parts during the process, allowing the one-step creation of construct libraries valuable for synthetic biology applications.
PMCID: PMC3874208  PMID: 24153110
18.  Rapidly produced SAM® vaccine against H7N9 influenza is immunogenic in mice 
The timing of vaccine availability is essential for an effective response to pandemic influenza. In 2009, vaccine became available after the disease peak, and this has motivated the development of next generation vaccine technologies for more rapid responses. The SAM® vaccine platform, now in pre-clinical development, is based on a synthetic, self-amplifying mRNA, delivered by a synthetic lipid nanoparticle (LNP). When used to express seasonal influenza hemagglutinin (HA), a SAM vaccine elicited potent immune responses, comparable to those elicited by a licensed influenza subunit vaccine preparation. When the sequences coding for the HA and neuraminidase (NA) genes from the H7N9 influenza outbreak in China were posted on a web-based data sharing system, the combination of rapid and accurate cell-free gene synthesis and SAM vaccine technology allowed the generation of a vaccine candidate in 8 days. Two weeks after the first immunization, mice had measurable hemagglutinin inhibition (HI) and neutralizing antibody titers against the new virus. Two weeks after the second immunization, all mice had HI titers considered protective. If the SAM vaccine platform proves safe, potent, well tolerated and effective in humans, fully synthetic vaccine technologies could provide unparalleled speed of response to stem the initial wave of influenza outbreaks, allowing first availability of a vaccine candidate days after the discovery of a new virus.
PMCID: PMC3821287
influenza; RNA vaccine; SAM vaccine; vaccine platform
19.  The Neuropeptide Systems and their Potential Role in the Treatment of Mammalian Retinal Ischemia: A Developing Story 
Current Neuropharmacology  2013;11(1):95-101.
The multiplicity of peptidergic receptors and of the transduction pathways they activate offers the possibility of important advances in the development of specific drugs for clinical treatment of central nervous system disorders. Among them, retinal ischemia is a common clinical entity and, due to relatively ineffective treatment, remains a common cause of visual impairment and blindness. Ischemia is a primary cause of neuronal death, and it can be considered as a sort of final common pathway in retinal diseases leading to irreversible morphological damage and vision loss. Neuropeptides and their receptors are widely expressed in mammalian retinas, where they exert multifaceted functions both during development and in the mature animal. In particular, in recent years somatostatin and pituitary adenylate cyclase activating peptide have been reported to be highly protective against retinal cell death caused by ischemia, while data on opioid peptides, angiotensin II, and other peptides have also been published. This review provides a rationale for harnessing the peptidergic receptors as a potential target against retinal neuronal damages which occur during ischemic retinopathies.
PMCID: PMC3580795  PMID: 23814541
Angiotensin; glutamate release; neuronal death; PACAP; peptide receptors; opioid peptides; somatostatin.
20.  Expression of the γ-Aminobutyric Acid (GABA) Plasma Membrane Transporter-1 in Monkey and Human Retina 
To determine the expression pattern of the predominant γ-aminobutyric acid (GABA) plasma membrane transporter GAT-1 in Old World monkey (Macaca mulatta) and human retina.
GAT-1 was localized in retinal sections by using immunohistochemical techniques with fluorescence and confocal microscopy. Double-labeling studies were performed with the GAT-1 antibody using antibodies to GABA, vasoactive intestinal polypeptide (VIP), tyrosine hydroxylase (TH), and the bipolar cell marker Mab115A10.
The pattern of GAT-1 immunostaining was similar in human and monkey retinas. Numerous small immunoreactive somata were in the inner nuclear layer (INL) and were present rarely in the inner plexiform layer (IPL) of all retinal regions. Medium GAT-1 somata were in the ganglion cell layer in the parafoveal and peripheral retinal regions. GAT-1 fibers were densely distributed throughout the IPL. Varicose processes, originating from both the IPL and somata in the INL, arborized in the outer plexiform layer (OPL), forming a sparse network in all retinal regions, except the fovea. Sparsely occurring GAT-1 processes were in the nerve fiber layer in parafoveal regions and near the optic nerve head but not in the optic nerve. In the INL, 99% of the GAT-1 somata contained GABA, and 66% of the GABA immunoreactive somata expressed GAT-1. GAT-1 immunoreactivity was in all VIP-containing cells, but it was absent in TH-immunoreactive amacrine cells and in Mab115A10 immunoreactive bipolar cells.
GAT-1 in primate retinas is expressed by amacrine and displaced amacrine cells. The predominant expression of GAT-1 in the inner retina is consistent with the idea that GABA transporters influence neurotransmission and thus participate in visual information processing in the retina.
PMCID: PMC3696021  PMID: 16565409
21.  Neurokinin 1 Receptor Expression in the Rat Retina 
Tachykinin (TK) peptides influence neuronal activity in the inner retina of mammals. The aim of this investigation was to determine the cellular localization of the neurokinin 1 receptor (NK1), whose preferred ligand is the TK peptide substance P (SP), in the rat retina. These studies used a polyclonal antiserum directed to the C-terminus of rat NK1. The majority of NK1-immunoreactive (IR) cells were located in the proximal inner nuclear layer (INL), and very rarely they were found in the distal INL. Some small and large NK1-IR somata were present in the ganglion cell layer. NK1-IR processes were densely distributed across the inner plexiform layer (IPL) with a maximum density over lamina 2 of the IPL. Immunoreactive processes also crossed the INL and ramified in the outer plexiform layer where they formed a sparse meshwork. NK1-IR processes were rarely observed in the optic nerve fiber layer. Double-label immunofluorescence studies with different histochemical markers for bipolar cells indicated that NK1 immunoreactivity was not present in bipolar cells. Together, these observations indicate that NK1 immunoreactivity is predominantly expressed by amacrine, displaced amacrine, interplexiform, and some ganglion cells. Double-label immunofluorescence experiments were also performed to characterize NK1-containing amacrine cells. Sixty-one percent of the γ-aminobutyric acid (GABA)-IR cells, 71% of the large tyrosine hydroxylase (TH)-IR cells, and 100% of the small TH-IR cells contained NK1 immunoreactivity. In addition, most (91%) of the NK1-IR cells had GABA immunoreactivity. In contrast, vasoactive intestinal polypeptide-, TK-, choline acetyltransferase-, and parvalbumin-IR amacrine cells did not express NK1 immunoreactivity. Overall, the present findings suggest that SP acts directly upon several cell populations, including GABA-containing amacrine cells and ganglion cells, to influence visual information processing in the inner retina. J. Comp. Neurol. 389:496–507, 1997.
PMCID: PMC3696024  PMID: 9414009
substance P; amacrine cells; bipolar cells; GABA; dopamine
23.  Job Strain and Cardiovascular Disease Risk Factors: Meta-Analysis of Individual-Participant Data from 47,000 Men and Women 
PLoS ONE  2013;8(6):e67323.
Job strain is associated with an increased coronary heart disease risk, but few large-scale studies have examined the relationship of this psychosocial characteristic with the biological risk factors that potentially mediate the job strain – heart disease association.
Methodology and Principal Findings
We pooled cross-sectional, individual-level data from eight studies comprising 47,045 participants to investigate the association between job strain and the following cardiovascular disease risk factors: diabetes, blood pressure, pulse pressure, lipid fractions, smoking, alcohol consumption, physical inactivity, obesity, and overall cardiovascular disease risk as indexed by the Framingham Risk Score. In age-, sex-, and socioeconomic status-adjusted analyses, compared to those without job strain, people with job strain were more likely to have diabetes (odds ratio 1.29; 95% CI: 1.11–1.51), to smoke (1.14; 1.08–1.20), to be physically inactive (1.34; 1.26–1.41), and to be obese (1.12; 1.04–1.20). The association between job strain and elevated Framingham risk score (1.13; 1.03–1.25) was attributable to the higher prevalence of diabetes, smoking and physical inactivity among those reporting job strain.
In this meta-analysis of work-related stress and cardiovascular disease risk factors, job strain was linked to adverse lifestyle and diabetes. No association was observed between job strain, clinic blood pressure or blood lipids.
PMCID: PMC3688665  PMID: 23840664
24.  Associations of job strain and lifestyle risk factors with risk of coronary artery disease: a meta-analysis of individual participant data 
It is unclear whether a healthy lifestyle mitigates the adverse effects of job strain on coronary artery disease. We examined the associations of job strain and lifestyle risk factors with the risk of coronary artery disease.
We pooled individual-level data from 7 cohort studies comprising 102 128 men and women who were free of existing coronary artery disease at baseline (1985–2000). Questionnaires were used to measure job strain (yes v. no) and 4 lifestyle risk factors: current smoking, physical inactivity, heavy drinking and obesity. We grouped participants into 3 lifestyle categories: healthy (no lifestyle risk factors), moderately unhealthy (1 risk factor) and unhealthy (2–4 risk factors). The primary outcome was incident coronary artery disease (defined as first nonfatal myocardial infarction or cardiac-related death).
There were 1086 incident events in 743 948 person-years at risk during a mean follow-up of 7.3 years. The risk of coronary artery disease among people who had an unhealthy lifestyle compared with those who had a healthy lifestyle (hazard ratio [HR] 2.55, 95% confidence interval [CI] 2.18–2.98; population attributable risk 26.4%) was higher than the risk among participants who had job strain compared with those who had no job strain (HR 1.25, 95% CI 1.06–1.47; population attributable risk 3.8%). The 10-year incidence of coronary artery disease among participants with job strain and a healthy lifestyle (14.7 per 1000) was 53% lower than the incidence among those with job strain and an unhealthy lifestyle (31.2 per 1000).
The risk of coronary artery disease was highest among participants who reported job strain and an unhealthy lifestyle; those with job strain and a healthy lifestyle had half the rate of disease. A healthy lifestyle may substantially reduce disease risk among people with job strain.
PMCID: PMC3680555  PMID: 23670152
25.  Primary care Physicians’ perspective on the management of anxiety and depressive disorders: a cross-sectional survey in Emilia Romagna Region 
BMC Family Practice  2013;14:75.
Evidences from literature suggest that Primary Care Physicians’ (PCPs) knowledge and attitude about psychological and pharmacological treatments of anxiety and depressive disorders could influence their clinical practice. The aim of the study is double: 1) to assess PCPs’ opinions about antidepressants (ADs) and psychotherapy for the management of anxiety and depressive disorders; 2) to evaluate the influence of PCPs’ gender, age, duration of clinical practice, and office location on their opinions and attitudes.
This cross-sectional multicentre survey involved 816 PCPs working in four Local Health Units of the Emilia Romagna Region. Participating PCPs were asked to complete a questionnaire during educational meetings between October 2006 and December 2008.
The response rate was 65.1%. Eighty-five percent of PCPs agreed on the effectiveness of ADs for depressive disorder whereas lower agreement emerged for anxiety disorder and on psychotherapy for both anxiety and depression. Forty percent of PCPs reported to feel “very/extremely confident” in recognizing depression and 20.0% felt equally confident in treating it with pharmacotherapy. Considering anxiety disorder, these proportions increased. Female PCPs and those located in the rural/mountain areas reported to adopt more psycho-educational support compared to male and suburban colleagues.
Our results suggest that an effort should be made to better disseminate recent evidences about the management of anxiety and depressive disorders in Primary Care. In particular, the importance of psychological interventions and the role of drugs for anxiety disorder should be addressed.
PMCID: PMC3688370  PMID: 23758941
Anxiety; Depression; Primary care; Antidepressants; Psychotherapy

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