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Aims Disturbances in personality and addictions are associated with an increased risk of committing crimes and therefore of being imprisoned. In this study, the relationship between these factors is analyzed through a sample of inmates in the Prison of Pereiro de Aguiar, Ourense. Material and method 204 inmates participated in this transversal simple blind design study. The following variables were analyzed: presence of personality disorders and psychopathy, history of addictive psychoactive substance use, criminal history and socio-demographic variables. Results 101 (49.5%) inmates received a diagnosis of personality disorder, the most frequent being: narcissistic, 43 (21.08%); antisocial, 38 (18.63%); and paranoid, 29 (14.22%). The presence of any personality disorder was associated with an increase in the risk of committing crimes, especially violence and crimes against property. The most frequent personality disorders were associated with higher scores in the psychopathy assessment tools. Higher scores in the Psychopathy Checklist Reviewed (PCL-R) correlated with an increased risk of committing the following crimes: violent, against public health, against property and disorderly conduct. The consumption of addictive psychoactive substances was associated with the commission of crimes against property. Methadone stood out for its protective role against the commission of violent crimes. Discussion This sample shows that inmates have a higher prevalence of personality disorders, psychopathy and consumption of addictive psychoactive substances. These three variables significantly increased the risk of committing crimes.

Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and slightly effective, so there is a need of developing more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA(1)) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA(1) agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA(1) receptor agonist described so far (E(max)=118%, EC(50)=0.24 μM, K(D)=19.6 nM; inactive at autotaxin and LPA(2–6) receptors). This compound induces characteristic LPA(1)-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.

To provide a description of the frequency and main features of the episodes of voluntary total fasting (VTF) taking place in Spanish prisons.Information on the episodes of VTF reported between 04/01/2013 and 03/31/2014 was gathered. Once the appropriate informed consent was given, other data on social, demographic, penitentiary and clinical aspects were collected. A descriptive study of such variables together with a bivariate analysis was then carried out by means of standard statistical techniques and binary logistic regression models. IBM SPSS Statistics v.20 software was used for this purpose. This study was approved by an accredited Clinical Research Ethics Committee.354 episodes of VTF took place among an average population of 29,762 prisoners. Therefore, the incidence rate was 11.9 VTF episodes per ‰ inmates-year. Informed consent (IC) was given in 180 cases (50.8%). 114 were of Spanish nationality and the average age was 38.7 years old (95% CI 37.2-40.1). The median duration of the episodes was 3 days (IQR 1-10), ranged between 1 and 71 days. The main reason was a disagreement on the decisions of treatment groups (57 cases, 31.7%). The average weight loss was 1.3 kg (70.8 vs. 69.5; p 0.0001) and 0.7 of the BMI (24.5 vs. 23.8; p 0.0001). 60 prisoners (33.3%) lost no weight at all and only 8 (4.4%) lost over 12% of the basal weight (8.5 kg). Ketone smell was identified in 61 cases (33.9%) and ketonuria in 63 (35%).Only one third of those who go on hunger strike in prison actually fast. Revindicative episodes of voluntary total fasting are somewhat common in Spanish prisons, but rarely are they carried out rigorously and entail a risk for those who fast.

Objective Recently, the DSM-5 has developed a new diagnostic category named "Substance-related and Addictive Disorders". This category includes gambling disorder (GD) as the sole behavioral addiction, but does not include sex addiction (SA). The aim of this study is to investigate whether SA should be classified more closely to other behavioral addictions, via a comparison of the personality characteristics and comorbid psychopathology of individuals with SA with those of individuals with GD, which comes under the category of addiction and related disorders. Method The sample included 59 patients diagnosed with SA, who were compared to 2190 individuals diagnosed with GD and to 93 healthy controls. Assessment measures included the Diagnostic Questionnaire for Pathological Gambling, the South Oaks Gambling Screen, the Symptom CheckList-90 Items-Revised and the Temperament and Character Inventory-Revised. Results No statistically significant differences were found between the two clinical groups, except for socio-economic status. Although statistically significant differences were found between both clinical groups and controls for all scales on the SCL-90, no differences were found between the two clinical groups. The results were different for personality characteristics: logistic regression models showed that sex addictive behavior was predicted by a higher education level and by lower scores for TCI-R novelty-seeking, harm avoidance, persistence and self-transcendence. Being employed and lower scores in cooperativeness also tended to predict the presence of sex addiction. Conclusions While SA and GD share some psychopathological and personality traits that are not present in healthy controls, there are also some diagnostic-specific characteristics that differentiate between the two clinical groups. These findings may help to increase our knowledge of phenotypes existing in behavioral addictions.

The biolipid sphingosine-1-phosphate (S1P) is an essential modulator of innate immunity, cell migration, and wound healing. It is released locally upon acute tissue injury from endothelial cells and activated thrombocytes and, therefore, may give rise to acute post-traumatic pain sensation via a yet elusive molecular mechanism. We have used an interdisciplinary approach to address this question, and we find that intradermal injection of S1P induced significant licking and flinching behavior in wild-type mice and a dose-dependent flare reaction in human skin as a sign of acute activation of nociceptive nerve terminals. Notably, S1P evoked a small excitatory ionic current that resulted in nociceptor depolarization and action potential firing. This ionic current was preserved in “cation-free” solution and blocked by the nonspecific Cl− channel inhibitor niflumic acid and by preincubation with the G-protein inhibitor GDP-β-S. Notably, S1P3 receptor was detected in virtually all neurons in human and mouse DRG. In line with this finding, S1P-induced neuronal responses and spontaneous pain behavior in vivo were substantially reduced in S1P3−/− mice, whereas in control S1P1 floxed (S1P1fl/fl) mice and mice with a nociceptor-specific deletion of S1P1−/− receptor (SNS-S1P1−/−), neither the S1P-induced responses in vitro nor the S1P-evoked pain-like behavior was altered. Therefore, these findings indicate that S1P evokes significant nociception via G-protein-dependent activation of an excitatory Cl− conductance that is largely mediated by S1P3 receptors present in nociceptors, and point to these receptors as valuable therapeutic targets for post-traumatic pain., The authors thank K. Braun, T. Martha, and M. Doblander for expert technical assistance. This work was supported by la Generalitat Valenciana and the Ministerio de Economia y Competitividad (A.V.F.M.), the Australian National Health and Medical Research Council Project Grant 535055 to R.V.H., the Intramural Research Programs of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases to R.L.P., and the Austrian Research Funding Agency FWF Project Grants P20562, P25345, and SPIN to M.K.

To assess the initial treatment persistence with inhaled corticosteroids and long-acting beta-2 adrenergic bronchodilators (ICS/LABA) depending on the inhaler device used (pMDI or DPI), for the treatment of asthma and COPD.An multicenter observational study. Subjects in initial treatment with ICS/LABA during 2007-2011 were included, and a follow-up period of 3 years. 2 groups of study (asthma, COPD) and 2 subgroups were prepared according to the device type inhaler (pMDI or DPI). The main measurements were: sociodemographic, comorbidity, adherence (rate possession medication -RPM-), persistence, drugs, exacerbation rates, resources use, and their costs (direct and indirect costs). Multivariate methods were used for the variables correction, with significance level of P.05.The study included 2,082 asthma patients (pMDI: N = 566, 27.2%; DPI = 1,516, 72.8%). Patients with MDI devices showed a higher degree of persistence (32.5 vs. 27.8%; P=.037), treatment adherence (RPM: 83.1 vs. 80.5%; P.001), fewer exacerbations (17.7 vs. 24.9%; P=.001) and lower health care costs (2,583 vs. 2,938 EUR; P = 0.042). 1,418 patients with COPD also were analyzed (pMDI: N = 524, 41.9%; DPI: N = 824, 58.1%) were analyzed. Patients with MDI devices also showed a higher degree of persistence (31.5 vs. 24.8%; P=.005), treatment adherence (RPM: 83.3 vs. 80.1%; P= .001), less exacerbations (40.1 vs. 48.2%; P=.002) and lower health care costs (3,922 vs. 4,588 EUR; P=.021).pMDI devices (as ICS/LABA initial treatment) are associated with higher treatment persistence either in asthma or COPD, with lower exacerbation rates, and use of health resources and cost.

Summary Background Imported cases of malaria constitute an important public health problem in many countries, even in those with autochthonous cases, where disease could be acquired in these areas and then seen in non-endemic regions. Non-immune populations are susceptible to complications due to malaria infection, particularly in malaria caused by Plasmodium falciparum . However, Plasmodium vivax the predominant Plasmodium spp. in Venezuela can also lead to severe malaria. Methods We reviewed retrospectively cases of malaria to identify the clinical features of those imported cases diagnosed at two institutions in Margarita Island (a non-endemic area), Venezuela, in an 8-year period. We conducted a retrospective observational study to identify the clinical and epidemiological features among hospitalized patients at Hospital Central and Hospital Agustin Hernandez with malaria acquired at malaria-endemic locations. Results We identified eighteen imported cases of malaria confirmed by thin and thick peripheral blood smears at these two institutions over an 8-year period. The mean age of diagnosis was 27 years. P. vivax was responsible for the majority of cases. All patients presented with fever, 89% with malaise, 78% with chills, and 67% with myalgia, among others symptoms. Mean haemoglobin levels on admission were 8.1 g/dL (100% 3 (89% had platelets below 150,000); and a mean total leukocyte count: 3.4 × 10 3 cells/mm 3 (78% had leukopenia). Thirty nine percent of patients required blood transfusions. Two fatalities were identified (CFR = 11%), one associated to severe malaria due to P. falciparum and the other due to a complicated case of P. vivax malaria. Discussion Imported cases of malaria due to P. vivax and P. falciparum in the studied population are associated with significant hematological complications. These findings illustrate the importance of educating non-immune populations about the malaria risk and prevention strategies; and from a pubic health perspective, the need to develop further malaria prevention strategies at a national level.

Background: Chronic obstructive pulmonary disease (COPD) is currently the fourth cause of mortality and morbility in the developed world. Patients with COPD experience a progressive deterioration of health-related quality of life (HRQOL). A new model of severity classification, the body mass index, bronchial obstruction, dyspnoea, exercise (BODE) index, has recently been proposed. Objective: To evaluate the relationship between HRQOL and the BODE index, and the predictive ability of BODE on HRQOL measurements. Methods: Two HRQOL questionnaires were administered, namely the Nottingham Health Profile (NHP) and St George's Respiratory Questionnaire (SGRQ), in a sample of 67 patients with severe COPD. Results: Pearsonś correlation coefficient analysis shows a positive correlation between the BODE index and the total scores of the specific ( P < 0.001), and general HRQOL ( P < 0.001); the analysis shows a significant correlation between the BODE index and the subscales of symptoms, activity and impact of SGRQ ( P < 0.001) and the subscales energy and physical mobility of the NHP ( P < 0.001). The regression analysis shows that the BODE index is a significant predictor of HRQOL, explaining 46,1% of the total score of the SGRQ ( P < 0.001) and 14.8% of the total score of the NHP ( P < 0.001). Conclusions: The BODE index is good at predicting the worsening of HRQOL in patients with severe COPD. Chronic Respiratory Disease 2008; 5: 7—11

This work compares several fiducial points to detect the arrival of a new pulse in a photoplethysmographic signal using the built-in camera of smartphones or a photoplethysmograph. Also, an optimization process for the signal preprocessing stage has been done. Finally we characterize the error produced when we use the best cutoff frequencies and fiducial point for smartphones and photopletysmograph and compare if the error of smartphones can be reasonably be explained by variations in pulse transit time. The results have revealed that the peak of the first derivative and the minimum of the second derivative of the pulse wave have the lowest error. Moreover, for these points, high pass filtering the signal between 0.1 to 0.8 Hz and low pass around 2.7 Hz or 3.5 Hz are the best cutoff frequencies. Finally, the error in smartphones is slightly higher than in a photoplethysmograph

Objective The objective of this study was to describe tissue procurement activity performed during 10 years (2004–2014) by trained medical students in a large university hospital. Methods In this study, third to sixth year medical students were trained as in-hospital Tissue Coordinators (Tc) to perform tissue procurement activity on a 24/7 schedule supervised by an on-call senior Transplant Coordinator (sTC) in a large university hospital. Tc duty consisted of detection, initial evaluation of all hospital deaths, donor's family approach for tissue donation, and retrieval logistics organization, including corneal tissue retrieval after training and certification. They also assist sTC in organ procurement activity. Results A total of 18,931 deaths were prospectively evaluated, 79% of whom (n = 14,879) presented medical contraindications for tissue donation. Of the remaining 4052 (21%) potential tissue donors (PTD), 2522 (62%) were not converted into real donors, mostly due to family refusal (66%; n = 1650) followed by detection system failure and other logistical issues (34%; n = 872). A total of 2814 corneal units, 225 skin donations, 327 muscleskeletal tissue donations, 91 blood vessels donations, and 177 heart valve donations were obtained from the remaining 1530 (38%) real donors. Tissue potentiality increased from 19% to 43% throughout the study period as a consequence of the fluctuating acceptance criteria used by tissue banks depending on tissue demand. Conclusions The tissue donation program performed by trained students was successful in achieving a high and sustainable tissue donation rate in a large university hospital.

Summary Background Surgical site infection (SSI) after colorectal procedures represents a measurable quality indicator of a healthcare system. There is an increasing interest in comparing SSI rates between different hospitals and countries: however, the variability of the data regarding the incidence of SSI makes this comparison difficult. For the purposes of evaluation, data collection must be standardized and must include reliable post-discharge surveillance (PDS). Aim To determine impact and risk factors for PDS SSI after elective colorectal surgery. Methods VINCat is a nosocomial infection surveillance programme in Catalonia, Spain. Between 2007 and 2011, 52 hospitals joined the programme. Hospitals performed active, prospective, standardized surveillance of elective colorectal resection. PDS was implemented by a multimodal approach and was mandatory within the first 30 days after surgery. Findings During the study period, 13,661 elective colorectal procedures were included. SSI was diagnosed in 2826 (20.7%) patients, of whom 22.5% during PDS; of these, 52% required readmission. Patients with PDS SSI were younger (odds ratio: 1.57; 95% confidence interval: 1.29–1.91), predominantly female (1.40; 1.16–1.69), had more frequently undergone endoscopic procedures (1.56; 1.30–1.88) and had more incisional SSI (1.88; 1.54–2.28) than patients with in-hospital SSI. Conclusion SSI rates in elective colorectal procedures at VINCat hospitals were inside the higher range of those reported by other national programmes. PDS SSI increased the overall rate of SSI, had a significant clinical impact, and accounted for almost a quarter of SSI. Younger age and laparoscopic procedures were the most relevant risk factors. Standardized multimodal PDS should be implemented for hospitals performing surveillance of colorectal surgery.

To evaluate the effectiveness of NEPs in prison to reduce the prevalence of infections associated with intravenous drug use and to know more about acceptance of the program by inmates and staff.cross-sectional observational study at baseline, 6 and 12 months and 10 years of program development. Interviews were conducted with program users, as well as random sample surveys of officials at the various cuts, and a random sample of inmates from the centre after10 years. Activity indicators of the program were recorded continuously, and the prevalence of HIV, HBV and HCV at baseline and after 10 years was evaluated. For the statistical analysis, the chi-square test was used with the Yates correction when necessary.In ten years we have supplied a total of 15,962 syringes to 429 users, (average 20.2 users/month), and 11,327 (70.9%) were returned. The prevalence of HIV infection decreased from 21% in 1999 to 8.5% in 2009, HCV prevalence from 40% to 26.1% (p0.01), finding no significant differences in the prevalence of HBsAg +. Most of the inmates and civil servants believe that the program did not increase intravenous drug use and improves hygienic living conditions in prison.After ten years of development of the NEP, there was a significant decrease in the prevalence of HIV and HCV in the prison population at the centre, and the program is accepted as beneficial by most of the inmates and staff participating in the survey.

The scrapie prion protein (PrPsc) requires the cellular prion protein (PrPc) for its propagation and replication. In this work we studied the expression and localization of the PrPc in the central nervous system (SNC) of the rat, mouse, cat, cow and human, using immunohistochemistry and Western blot techniques to understand more about prionopathies and Alzheimer's disease (EA).For the immunohistochemistry study we used human, cat, rat and cow samples to analyse frontal, temporal and occipital cortex, as well as the hippocampus and the thalamus. For the Western blot analysis we used mouse, cat, cow and human brain samples.We observed a decrease in the amount of PrPc in the SNC in a rostrocaudal shift in the species mentioned above. We observed inhibitory cells in the cat cortex. The Western blot analysis showed a similar pattern of expression in the different species studied with a preponderance of the diglycosylated band, in relation to the other bands observed in the analysis.These data suggest that in prionopathies PrPsc could be transmitted and could be replicated in and from the areas with most expression of PrPc. Similarly, a higher amount of this protein (PrPc) in some brain areas could explain some histopathological aspects of EA.Our findings support the hypothesis of a retrograde transport of PrPsc in the SNC. PrPc could be related to the pathophysiology of EA.

The structural basis of phosphorylation and its putative role in internalization were investigated in the human dopamine transporter (hDAT). Activation of protein kinase C (PKC) was achieved either directly by treatment with 4-alpha-phorbol 12-myristate 13-acetate (PMA) or by activating the Galpha(q)-coupled human substance P receptor (hNK-1) co-expressed with hDAT in HEK293 cells and in N2A neuroblastoma cells. In both cell lines, activation of the hNK-1 receptor by substance P reduced the V(max) for [(3)H]dopamine uptake to the same degree as did PMA ( approximately 50 and approximately 20% in HEK293 and N2A cells, respectively). In HEK293 cells, the reduction in transport capacity could be accounted for by internalization of the transporter, as assessed by cell surface biotinylation experiments, and by fluorescence microscopy using enhanced green fluorescent protein-tagged hDAT. In HEK293 cells, hNK-1 receptor activation, as well as direct PKC activation by PMA, was accompanied by a marked increase in transporter phosphorylation. However, truncation of the first 22 N-terminal residues almost abolished detectable phosphorylation without affecting the SP- or PMA-induced reduction in transport capacity and internalization. In this background truncation construct, systematic mutation of all the phosphorylation consensus serines and threonines in hDAT, alone and in various combinations, did also not alter the effect of hNK-1 receptor activation or PMA treatment in either HEK293 or N2A cells. Mutation of a dileucine and of two tyrosine-based motifs in hDAT was similarly without effect. We conclude that the major phosphorylation sites in hDAT are within the distal N terminus, which contains several serines. Moreover, the present data strongly suggest that neither this phosphorylation, nor the phosphorylation of any other sites within hDAT, is required for either receptor-mediated or direct PKC-mediated internalization of the hDAT.

The magnitude and duration of dopamine (DA) signaling is defined by the amount of vesicular release, DA receptor sensitivity, and the efficiency of DA clearance, which is largely determined by the DA transporter (DAT). DAT uptake capacity is determined by the number of functional transporters on the cell surface as well as by their turnover rate. Here we show that inhibition of phosphatidylinositol (PI) 3-kinase with LY294002 induces internalization of the human DAT (hDAT), thereby reducing transport capacity. Acute treatment with LY294002 reduced the maximal rate of [(3) H]DA uptake in rat striatal synaptosomes and in human embryonic kidney (HEK) 293 cells stably expressing the hDAT (hDAT cells). In addition, LY294002 caused a significant redistribution of the hDAT from the plasma membrane to the cytosol. Conversely, insulin, which activates PI 3-kinase, increased [(3)H]DA uptake and blocked the amphetamine-induced hDAT intracellular accumulation, as did transient expression of constitutively active PI 3-kinase. The LY294002-induced reduction in [(3)H]DA uptake and hDAT cell surface expression was inhibited by expression of a dominant negative mutant of dynamin I, indicating that dynamin-dependent trafficking can modulate transport capacity. These data implicate DAT trafficking in the hormonal regulation of dopaminergic signaling, and suggest that a state of chronic hypoinsulinemia, such as in diabetes, may alter synaptic DA signaling by reducing the available cell surface DATs.

Peroxynitrite (ONOO − ) has been implicated as a causative factor in dopamine neuronal damage resulting from exposure to methamphetamine and1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and it may be involved in the etiology of Parkinson9s Disease. ONOO − causes a concentration-dependent and irreversible reduction in dopamine uptake by EM4 cells stably expressing the human dopamine transporter (hDAT). The effect of ONOO − is manifested as a reduction in V max . Cysteine, dithiothreitol, glutathione, and N -acetyl-cysteine, reagents that interact directly with ONOO − , prevent this inhibition, whereas a scavenger of hydroxyl radical (dimethylsulfoxide), hydrogen peroxide (catalase), and superoxide (superoxide dismutase) did not. Dopamine in the extracellular medium protects the hDAT from ONOO − , whereas intracellular dopamine does not. Parachloromercuribenzoic acid and 2-aminoethyl methanethiosulfonate (MTSEA), which share with ONOO − the ability to modify cysteine sulfhydryls, also inhibit hDAT function. ONOO − treatment lowers cysteine-specific labeling of the hDAT by MTSEA-biotin, suggesting that ONOO − reacts with one or more cysteines in hDAT. A mutant of hDAT (X7C) in which all intracellular and extracellular loop cysteines were mutated was resistant to inhibition by ONOO − . Sensitivity to ONOO − was restored in mutants of hDAT in which reduced cysteines were present only in the first (C135) and third (C342) intracellular loops (CD-DAT), or in which C342 alone had been reintroduced into X7C (X7C-M342C). These results indicate that the hDAT is inhibited by ONOO − through oxidation of cysteine 342. Our studies also substantiate the possibility that drugs known to decrease DAT function in vivo (e.g., methamphetamine and MPTP) may exert their effects through ONOO − -mediated oxidative stress.

In an effort to develop a tritiated dopamine transporter radioligand with higher affinity than the widely used [ 3 H]WIN 35,428, we have synthesized [ 3 H]2β-carbomethoxy-3β-(3′,4′-dichlorophenyl)tropane ([ 3 H]MFZ 2-12). Unlabeled MFZ 2-12 and the N -demethylated intermediate (MFZ 2-13) inhibited dopamine uptake by the human dopamine transporter with IC 50 's of 1.1 and 1.4 nM, respectively. The N-nor-intermediate (MFZ 2-13) was treated with CT 3 I resulting in [ 3 H]MFZ 2-12; S.A.=80 Ci/mmol). [ 3 H]MFZ 2-12 reversibly bound with a K D of 2.8 nM to human dopamine transporter expressed heterologously in EM4 cells.

Increasingly growing evidence exists of the involvement of oxidative stress mechanisms in Parkinson's disease. Lower levels of GSH in the sustantia nigra, an increase in iron buildup, an increase in the byproducts of lipid peroxidation and alterations in the mitochondrial complex I have been described. However, few studies have been made of levels of antioxidants in the peripheral bloodstream and of the influence of the intake of nutrients on the development of this disease.In a group of 79 patients afflicted with idiopathic Parkinson's disease and a control group comprised of 107 subjects, compared by age, sex and place of residence, the lowered levels in the plasma of glutathione (GSH), malon dialdehyde (MDA), uric acid, tocophenol, beta-carotene, lycopene and different iron metabolism parameters were studied. Likewise, the intake of certain antioxidants was estimated based on a dietary survey.Significant differences (por = 0.001) were found in the plasma levels of GSH between cases (0.10 mumol/ml +/- 0.06) and controls (0.29 mumol/ml +/- 0.12). Likewise, the plasma levels of uric acid were lower (por = 0.05) in the cases (4.96 mg/ml +/- 1.96) than in the control groups (5.39 mg/ml +/- 1.13). No significant difference was found in the plasma levels of MDA, tocopherol, beta-carotene and lycopene. With regard to iron metabolism, significantly higher ferritine and transferrin values were found in the patients with EP than in the control group, showing a lower transferrin saturation percentage (por = 0.05). The iron showed no significant changes between cases and control groups.The results of this study support the possible involvement of oxidative stress in the pathogenesis of Parkinson's disease and reveal, in turn, alterations in some peripheral blood parameters in keeping with known findings in the sustantia nigra.

The binding affinity of the cocaine analog [(3)H]2 beta-carbomethoxy-3beta-(4-fluorophenyl) tropane (WIN) for the dopamine transporter (DAT) is increased by the reaction of Cys-90, at the extracellular end of the first transmembrane segment, with methanethiosulfonate (MTS) reagents. Cocaine enhances the reaction of Cys-90 with the sulfhydryl reagents, thereby augmenting the increase in binding. In contrast, cocaine decreases the reaction of Cys-135 and Cys-342, endogenous cysteines in cytoplasmic loops, with MTS reagents. Because this reaction inhibits [(3)H]WIN binding, cocaine protects against the loss of binding caused by reaction of these cysteines. In the present work, we compare the abilities of DAT inhibitors and substrates to affect the reaction of Cys-90, Cys-135, and Cys-342 with MTS ethyltrimethylammonium (MTSET). The results indicate that the different abilities of compounds to protect against the MTSET-induced inhibition of binding are attributable to differences in their abilities to attenuate the inhibitory effects of modification of Cys-135 and Cys-342 as well as to enhance the reaction with Cys-90 and the resulting potentiation of binding. The inhibitor benztropine was unique in its inability to protect Cys-135. Moreover, whereas cocaine, WIN, mazindol, and dopamine enhanced the reaction of Cys-90 with MTSET, benztropine had no effect on this reaction. These two features combine to give benztropine its weak potency in protecting ligand binding to wild-type DAT from MTSET. These results indicate that different inhibitors of DAT, such as cocaine and benztropine, produce different conformational changes in the transporter. There are differences in the psychomotor stimulant-like effects of these compounds, and it is possible that the different behavioral effects of these DAT inhibitors stem from their different molecular actions on DAT.

This study focuses on the comorbidity between medical and psychiatric illnesses in a sample taken from the general population.We design a two-stage epidemiological community study in the island of Formentera (Spain), using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). In the first stage, the sample (N=697) was screened using the General Health Questionnaire (GHQ-28). In the second stage, the SCAN, subjects' clinical histories and General Practitioners' diagnosis were used to evaluate psychiatric disorders and medical illnesses. The final sample comprised 242 subjects.Subjects with diagnosed ICD-10 mental disorders presented higher comorbidity with medical pathologies than the group of respondents without psychiatric diagnosis, although the differences were not statistically significant. Of the psychiatric conditions, mood disorders (in which differences were significant) and neurotic disorders were the ones that most frequently presented comorbidity, followed by sleep disorders. Mean scores on the GHQ-28 used at the screening stage, and mean scores on neurotic, depressive and somatic symptoms on the SCAN, were significantly higher in the comorbid group. Comorbidity was more frequent in females.More studies on comorbidity in general population are required, with diagnostic instruments that cover the whole of the psychiatric spectrum and correct assessment systems for medical diagnosis.

There is evidence to suggest that dopamine (DA) oxidizes to form dopamine ortho-quinone (DAQ), which binds covalently to nucleophilic sulfhydryl groups on protein cysteinyl residues. This reaction has been shown to inhibit dopamine uptake, as well as other biological processes. We have identified specific cysteine residues in the human dopamine transporter (hDAT) that are modified by this electron-deficient substrate analog. DAQ reactivity was inferred from its effects on the binding of [(3)H]2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (beta-CFT) to hDAT cysteine mutant constructs. One construct, X5C, had four cysteines mutated to alanine and one to phenylalanine (Cys(90)A, Cys(135)A, C306A, C319F and Cys(342)A). In membrane preparations 1 mM DAQ did not affect [(3)H]beta-CFT binding to X5C hDAT, in contrast to its effect in wild-type hDAT in which it reduced the B:(max) value by more than half. Wild-type cysteines were substituted back into X5C, one at a time, and the ability of DAQ to inhibit [(3)H]beta-CFT binding was assessed. Reactivity of DAQ with Cys(90) increased the affinity of [(3)H]beta-CFT for the transporter, whereas reactivity with Cys(135) decreased the affinity of [(3)H]beta-CFT. DAQ did not change the K:(D) for [(3)H]beta-CFT binding to wild-type. The reactivity of DAQ at Cys(342) decreased B:(max) to the same degree as wild-type. The latter result suggests that Cys(342) is the wild-type residue most responsible for DAQ-induced inhibition of [(3)H]beta-CFT binding.

Smoking is the main single avoidable cause of death in our country. Little research in the treatment of such disorder has been made.To report the results of a prospective follow up for one year of outpatients from our "Smoker's Clinic" at the Department of Psychiatry of the Catholic University.One hundred twenty-seven patients (84 male, aged 21 to 70 years old), with DSM-IV criteria for nicotine dependence, were included in a total of 18 groups. Each group received an intensive treatment program of 10 sessions with cognitive-behavioral relapse prevention techniques and nicotine replacement. Patients with active psychiatric diseases were not included in the program.Eighty-seven percent of subjects were abstinent at the first month and 50% were still abstinent after twelve months of follow up. We did not find differences in gender, age, previous psychiatric disease, number of cigarettes and breath carbon monoxide level between abstinent and non abstinent patients after 12 months of follow up.This intensive nicotine dependence treatment in seriously dependent patients, proved to be successful, regardless of the previous psychiatric history.

The dopamine transporter (DAT) is a target of amphetamine (AMPH) and cocaine. These psychostimulants attenuate DAT clearance efficiency, thereby increasing synaptic dopamine (DA) levels. Re-uptake rate is determined by the number of functional transporters at the cell surface as well as by their turnover rate. Here, we present evidence that DAT substrates, including AMPH and DA, cause internalization of human DAT, thereby reducing transport capacity. Acute treatment with AMPH reduced the maximal rate of [ 3 H]DA uptake, decreased AMPH-induced currents, and significantly redistributed the immunofluorescence of an epitope-tagged DAT from the plasma membrane to the cytosol in human embryonic kidney 293 cells. Conversely, DAT inhibitors, such as cocaine, mazindol, and nomifensine, when administered with AMPH, blocked the reduction in [ 3 H]DA uptake and the redistribution of DAT immunofluorescence to the cytosol. The reductions of [ 3 H]DA uptake and AMPH-induced DAT internalization also were inhibited by coexpression of a dominant negative mutant of dynamin I (K44A), indicating that endocytosis modulates transport capacity, likely through a clathrin-mediated pathway. With this mechanism of regulation, acute application of AMPH would reduce DA uptake not only by direct competition for uptake, but also by reducing the available cell-surface DAT. Moreover, AMPH-induced internalization might diminish the amount of DAT available for DA efflux, thereby modulating the cytotoxic effects of elevated extracellular DA.

The effect of covalent sulfhydryl modification on dopamine uptake by the human dopamine transporter was determined by rotating disc electrode voltammetry. A transporter construct, X5C, with five mutated cysteines (C90A, C135A, C306A, C319F, and C342A) and the constructs into which the wild-type cysteines were substituted back into X5C, one at a time, all showed nearly normal binding affinity for [(3)H]CFT and for cocaine, but they displayed significant reductions in K(m) and V(max) for DA uptake. Reaction of Cys-90 or Cys-306 with impermeant methanethiosulfonate derivatives enhanced dopamine uptake to a similar extent as the previously observed enhancement of [(3)H]CFT binding caused by the same reaction, suggesting that cocaine may bind preferentially to a conformation in the transport cycle. m-Tyramine increased the rate of reaction of (2-aminoethyl)methanethiosulfonate (MTSEA) with X-A342C, the construct with a cytoplasmic loop residue Cys-342 restored. This m-tyramine-induced increase in reactivity appeared to require the inward transport rather than the outward transport or external binding of m-tyramine, and it was prevented by cocaine. Thus, inward translocation of substrates may involve structural rearrangement of hDAT, which likely exposes Cys-342 to reaction with MTSEA, and Cys-342 may be located on a part of the transporter associated with cytoplasmic gating.

The purpose of the study was to register antibody prevalences of HHV-7 in various locations of the world in comparison to the closely related HHV-6.Sera of healthy blood donors from nine countries in five continents were titered by indirect immunofluorescent assays using HHV-6 infected HSB2 and HHV-7 infected SupT1 cells.Antibody prevalence for HHV-7 is high (75-98%) in practically all countries except for Northern Japan (44%), with no simple correlation to elevated HHV-6 antibody titers. There were regions of low, intermediate and high mean antibody titers against HHV-7 such as 78.5-91.3 for Belgium, Israel, Japan, USA and Australia, 175.4-182.6 for Mexico and Cologne/Germany, and 389.2 for South Africa for which geographic characteristics may be responsible.HHV-7, similar to HHV-6, is a widespread human herpesvirus with elevated antibody titers in the healthy human population essentially everywhere. The data warrant further studies to evaluate its possible pathologic potential, preferentially in persons with defective immune responses.

Cocaine and other psychostimulants act by blocking the dopamine transporter. Binding of the cocaine analog, [ 3 H]2-β-carbomethoxy-3-β-(4-fluorophenyl) tropane (CFT) to the dopamine transporter is sensitive to polar sulfhydryl-specific derivatives of methanethiosulfonate (MTS). These reagents preferentially react with water-accessible, reduced cysteines. The human dopamine transporter has 13 cysteines. Their topology is not completely determined. We sought to identify those cysteine residues the modification of which affects CFT binding and to determine the topology of these reactive cysteines. We mutated each of the cysteines, one at a time and in various combinations, to residues that preserved binding and transport, and we tested the sensitivity of each of the mutant transporters to the reagents. One construct, X5C, had five mutated cysteines (C90A, C135A, C306A, C319F, and C342A). Using a membrane preparation in which both extracellular and intracellular cysteines could be accessible, we found that CFT binding in X5C, as compared with wild-type transporter, was two orders of magnitude less sensitive to MTS ethylammonium (MTSEA). The wild-type cysteines were substituted back into X5C, one at a time, and these constructs were tested in cells and in membranes. Cys-90 and Cys-306 appear to be extracellular, and Cys-135 and Cys-342 appear to be intracellular. Each of these residues is predicted to be in extramembranous loops. The binding of cocaine increases the rate of reaction of MTSEA and MTS ethyltrimethylammonium with the extracellular Cys-90 and therefore acts by inducing a conformational change. Cocaine decreases the rate of reaction of MTSEA with Cys-135 and Cys-342, acting either directly or indirectly on these intracellular residues.

Spanish prisons have a high number of inmates whose behaviour puts them at risk of being infected by hepatitis C virus (HCV). The object of this study was to establish the prevalence of this infection and its associated factors in the prison population of the north-east of Spain.Inmates in seven prisons in the north-east of Spain were studied. Socio-demographic and prison variables were gathered, as well as risk factors for infection by HCV. Antibodies against HCV were determined (EIA and INNO-LIA HCV III), Hepatitis B virus (VHB) (EIA), and human immunodeficiency virus (HIV) (EIA and Western-Blott). The analysis of associated factors was based on logistic regression.Of the total number of inmates studied, 47.9% presented HCV antibodies. There was greater prevalence in the case of the following: UDVP (89.6%); those who shared needles (94%); those infected by HIV (92.7%); carriers of Australia antigen (65.1%) and antibodies to the HBV core antigen (79.8%); those who had been in prison before (60.9%); unmarried men (54.8%); gypsies (52%); unqualified workers (50.4%); those who had no basic school qualifications (50.9%); those with tattoos (66.7%); and those with a background of self-inflicted injuries (79.3%). In the logistic regression analysis the variables associated to infection by HCV were: UDVP (OR = 33.3; I.C. 95% = 25-50), HBcAc (+) (OR = 4.1; I.C. 95% = 1.1-5.3), age (OR = 0.98; I.C. 95% = 0.96-1.00), months in prison (OR = 1.011; I.C. 95% = 1.004-1.019) and a background of previous prison sentences (OR = 2.3; I.C. 95% = 1.5-3.6).The prevalence of infection by HCV in prison inmates is very high. It is therefore recommended that preventive measures be increased (harm reduction programmes) and that clinical and analysis protocols be drawn up for those infected and for treatment in cases of chronic active hepatitis in order to control this serious public health problem.

A patient with a remitting non-microcytic pulmonary carcinoma was subjected to Doppler-echocardiography. The detection of a pericardial effusion with compression of the pulmonary artery due to an extrinsic mass indicated that the disease was progressing. The Doppler technique was used to evaluate the degree of arterial stenosis by determining the pressure gradient caused by it (49 mmHg) and to calculate the right ventricle pressure (75 mmHg). Tumor infiltration of mediastinal structures was posteriorly confirmed by computed tomography.

The human immunodeficiency virus type 1 (HIV-1) Vpu protein is an integral membrane phosphoprotein that induces CD4 degradation in the endoplasmic reticulum and enhances virus release from the cell surface. CD4 degradation is specific, requires phosphorylation of Vpu, and involves the interaction between Vpu and the CD4 cytoplasmic domain. In contrast, regulation of virus release is less specific and not restricted to HIV-1 and may be mechanistically-distinct from CD4 degradation. We show here that a mutant of Vpu, Vpu35, lacking most of its cytoplasmic domain has residual biological activity for virus release but is unable to induce CD4 degradation. This finding suggests that the N terminus of Vpu encoding the transmembrane (TM) anchor represents an active domain important for the regulation of virus release but not CD4 degradation. To better define the functions of Vpu's TM anchor and cytoplasmic domain, we designed a mutant, VpuRD, containing a scrambled TM sequence with a conserved amino acid composition and alpha-helical structure. The resulting protein was integrated normally into membranes, was able to form homo-oligomers, and exhibited expression levels, protein stability, and subcellular localization similar to those of wild-type Vpu. Moreover, VpuRD was capable of binding to CD4 and to induce CD4 degradation with wild-type efficiency, confirming proper membrane topology and indicating that the alteration of the Vpu TM domain did not interfere with this function of Vpu. However, VpuRD was unable to enhance the release of virus particles from infected or transfected cells, and virus encoding VpuRD had replication characteristics in T cells indistinguishable from those of a Vpu-deficient HIV-1 isolate. Mutation of the phosphorylation sites in VpuRD resulted in a protein which was unable to perform either function of Vpu. The results of our experiments suggest that the two biological activities of Vpu operate via two distinct molecular mechanisms and involve two different structural domains of the Vpu protein.

We have presented a working hypothesis showing the possible interrelations between proliferative, aproliferative and autoimmune disorders that may follow infection with lymphotropic herpesviruses. Aproliferative disorders in this context may also indicate immune or hematopoietic deficiency. Although this hypothesis can currently be best documented with the lymphotropic viruses (herpesviruses as well as similarly HTLV and HIV), the model may apply as well--with certain variations--to other viral infections such as with hepatitis virus B or C with acute or chronic infectious diseases, post-infectious arthritis, aplastic anemia, and other autoimmune liver diseases, as well as neoplastic diseases (hepatocellular carcinoma, chronic lymphocytic leukemia). The working hypothesis as depicted in Figure 2 permits a preview of which combinations of symptoms may occur in an individual disease independent of its initial classification and what clinical testing should be done respectively, and it also permits certain prognostic considerations. The above-mentioned transitions or combinations of various disease patterns have been repeatedly described in the medical literature (to refer to only a few examples: APL and MPD, HD and MDS, SLE and aplastic anemia, SLE and Kikuchi's disease; 23, 80-83). Finally the hypothesis can ideally serve as the basis for future planning of clinical research.

The dopamine transporter (DAT) regulates the clearance of dopamine (DA) released into the extracellular space and is an important site on which psychostimulants act to produce their effects. Here, we show that mitogen-activated protein kinase (MAPK) regulates the transport capacity and intracellular trafficking of DAT. Incubation of striatal synaptosomes or epitope-tagged human DAT (hDAT) human embryonic kidney (HEK) 293 cells with the MAPK kinase (MEK) inhibitors 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one decreased DA uptake in a concentration- and time-dependent manner. Kinetic studies revealed a decrease in the capacity of transport (Vmax) but no change inKm. Immunoblotting confirmed labeling of p42 and p44 MAPK in untreated striatal synaptosomes and HEK 293 cells, consistent with constitutive MAPK activation, and the inhibitors used decreased MAPK phosphorylation. Biotinylation and confocal imaging studies showed that MAPK inhibition promoted the clathrin-associated redistribution of hDAT from the plasma membrane to the cytosol. In contrast, transient transfection of hDAT-expressing cells with constitutively active MEK increased theVmaxof DA transport without alteringKm. However, only a small increase in hDAT cell surface expression was seen. These data demonstrate an involvement of the MAPK cascade in regulating DAT transport capacity in striatum and that inhibition of this cascade decreases DAT cell surface expression in HEK 293 cells. Furthermore, they highlight the potential role of MAPK as a presynaptic mechanism that regulates DA signaling.

The aim of this paper is to present a smartphone based system for real-time pulse-to-pulse (PP) interval time series acquisition by frame-to-frame camera image processing. The developed smartphone application acquires image frames from built-in rear-camera at the maximum available rate (30 Hz) and the smartphone GPU has been used by Renderscript API for high performance frame-by-frame image acquisition and computing in order to obtain PPG signal and PP interval time series. The relative error of mean heart rate is negligible. In addition, measurement posture and the employed smartphone model influences on the beat-to-beat error measurement of heart rate and HRV indices have been analyzed. Then, the standard deviation of the beat-to-beat error (SDE) was 7.81 ± 3.81 ms in the worst case. Furthermore, in supine measurement posture, significant device influence on the SDE has been found and the SDE is lower with Samsung S5 than Motorola X. This study can be applied to analyze the reliability of different smartphone models for HRV assessment from real-time Android camera frames processing.

The cellular prion protein (PrP(C)) is a membrane-bound glycoprotein especially abundant in the central nervous system (CNS). The scrapie prion protein (PrP(Sc,) also termed prions) is responsible of transmissible spongiform encephalopathies (TSE), a group of neurodegenerative diseases which affect humans and other mammal species, although the presence of PrP(C) is needed for the establishment and further evolution of prions. The present work compares the expression and localization of PrP(C) between healthy human brains and those suffering from Alzheimer disease (AD). In both situations we have observed a rostrocaudal decrease in the amount of PrP(C) within the CNS, both by immunoblotting and immunohistochemistry techniques. PrP(C) is higher expressed in our control brains than in AD cases. There was a neuronal loss and astogliosis in our AD cases. There was a tendency of a lesser expression of PrP(C) in AD cases than in healthy ones. And in AD cases, the intensity of the expression of the unglycosylated band is higher than the di- and monoglycosylated bands. With regards to amyloid plaques, those present in AD cases were positively labeled for PrP(C), a result which is further supported by the presence of PrP(C) in the amyloid plaques of a transgenic line of mice mimicking AD. The work was done according to Helsinki Declaration of 1975, and approved by the Ethics Committee of the Faculty of Medicine of the University of Navarre.

changes cannot follow from changes in fluidity. More recently, we have shown that nonylphenol, which strongly inhibits ATPase activity, reduces the equilibrium level of phosphorylation of the ATPase by phosphate, again a result which cannot be explained in terms of effects of fluidity (F. Michelangeli, S. Orlowski, P. Champed, J. M. East & A. G. Lee, unpublished work). The idea that the activity of membrane-bound enzymes should be sensitive to membrane fluidity is intrinsically attractive for, after all, we know that enzymes undergo conformational changes and it seems reasonable that the more fluid the environment the easier will be these'changes. Nevertheless, for the (Ca"-Mg'+)-ATPase there is no evidence that the fluidity of the surrounding lipid has any significant effect on activity, while there is evidence that other effects must be important. There seems to be no reason to suppose that the ATPase is in any way unusual in this respect.