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Background: The goal of this study was to describe the clinical and epidemiologic manifestations of a syphilis outbreak in downtown Madrid, Spain. Because human immunodeficiency virus (HIV)-positive patients may be at increased risk of serologic failure during syphilis treatment, analysis of factors determining the response to treatment was performed in a cohort of HIV-positive and HIV-negative patients with syphilis., Methods: We performed a longitudinal, retrospective study of patients with syphilis who received the diagnosis at a university-affiliated hospital in Madrid from 2003 through 2007., Results: Three hundred forty-seven cases of syphilis were identified and treated (30 primary, 164 secondary, 77 early latent, and 76 late cases of syphilis). Forty-one percent of patients were immigrants, mostly from South America and the Caribbean, and 49.3% were known to be HIV positive. Syphilis incidence increased from 15.6 to 35 cases per 100,000 person-years from 2003 to 2007. Most patients were men, and 50.4% were men who had sex with other men. Meningitis (4.9%) and uveitis (2.9%) were the complications most frequently observed, and their frequency did not differ between HIV-positive and HIV-negative patients. Serologic failure was observed in 44 (23.5%) patients: 37 (29.6%) of 125 HIV-positive patients and 7 (11.2%) of 62 HIV-negative patients (odds ratio, 3.3; 95% confidence interval, 1.38-7.93; P < .05). Men (hazard ratio [HR], 0.38), patients in the late stage of syphilis (HR, 0.46), and HIV-positive persons (HR, 0.61) demonstrated slower serological responses to treatment. HIV-negative patients responded more frequently to treatment, but after 2 years of follow-up, both groups shared similar response rates. Antiretroviral treatment reduced the time to serologic response (HR, 2.08; 95% confidence interval, 1.35- 3.20; P < .001)., Conclusion: Syphilis incidence rose 223% from 2003 to 2007, affecting mostly HIV-positive men, men who have sex with men, and immigrants. Men, patients in the late stages of syphilis, and HIV-positive persons may be at increased risk of serologic failure. Antiretroviral therapy significantly reduced the time to achieve response to syphilis treatment in HIV-positive patients.

The study of the linear stage of the incompressible Rayleigh-Taylor instability in elastic-plastic solids is performed by considering thick plates under a constant acceleration that is also uniform except for a small sinusoidal ripple in the horizontal plane. The analysis is carried out by using an analytical model based on the Newton second law and it is complemented with extensive two-dimensional numerical simulations. The conditions for marginal stability that determine the instability threshold are derived. Besides, the boundary for the transition from the elastic to the plastic regime is obtained and it is demonstrated that such a transition is not a sufficient condition for instability. The model yields complete analytical solutions for the perturbation amplitude evolution and reveals the main physical process that governs the instability. The theory is in general agreement with the numerical simulations and provides useful quantitative results. Implications for high-energy-density-physics experiments are also discussed.

Store-operated Ca(2+) entry (SOCE) is a major mechanism for Ca(2+) influx in platelets and other cells activated by a reduction in Ca(2+) concentration in the intracellular stores. SOCE has been reported to be regulated by extracellular Ca(2+), although the underlying mechanism remains unclear. Here we have examined the involvement of plasma membrane-located STIM1 (PM-STIM1) in the regulation of SOCE by extracellular Ca(2+). Treatment of platelets with the SERCA inhibitor thapsigargin (TG) induced Mn(2+) entry, which was inhibited by extracellular Ca(2+) in a concentration-dependent manner. Incubation of platelets with a specific antibody, which recognizes the extracellular amino acid sequence 25-139 of PM-STIM1 that contains the Ca(2+)-binding domain, prevented the inactivation of Ca(2+) entry induced by extracellular Ca(2+). TG induced translocation of STIM1 to the plasma membrane (PM), an event that was found to be Ca(2+)-dependent. In addition, TG stimulated association of PM-STIM1 with Orai1, an event that was not prevented by stabilization of the membrane cytoskeleton using jasplakinolide. These findings suggest that PM-STIM1 is important for the inactivation of SOCE by extracellular Ca(2+), an event that is likely to be mediated by interaction with Orai1.

Opposition to utopianism on ontological and political grounds has seemingly relegated it to a potentially dangerous form of antiquated idealism. This conclusion is based on a restrictive view of utopia as excessively ordered panoptic discursive constructions. This overlooks the fact that, from its inception, movement has been central to the utopian tradition. The power of utopianism indeed resides in its ability to instantiate the tension between movement and place that has marked social transformations in the modern era. This tension continues in contemporary discussions of movement-based social processes, particularly international migration and related identity formations, such as open borders transnationalism and cosmopolitanism. Understood as such, utopia remains an ongoing and powerful, albeit problematic instrument of social and political imagination.

Selective pituitary resistance to thyroid hormones is a syndrome that involves inadequate response of thyroid-stimulating hormone to changes in thyroid hormones. Unlike generalized resistance syndromes, this entity produces central hyperthyroidism and clinical thyrotoxicosis. Sometimes the disease may not be properly diagnosed and is treated with drugs with harmful effects on the thyroid, such as amiodarone, hampering diagnosis and possibly exacerbating the disorder. The treatment of this condition can be symptomatic, based on control of tachycardia and anxiety, or etiological, acting on the pituitary to regulate thyrotropin secretion or on the thyroid gland to control thyroid hormone production. We report the case of a patient with pituitary resistance to thyroid hormone, who was treated with amiodarone to control paroxysmal atrial fibrillation.

Type 2 diabetes mellitus (DM2) is a metabolic syndrome that contributes to both macrovascular and microvascular disorders, where platelet hyperaggregability, associated to abnormal intracellular Ca(2+) homeostasis, plays an important role. We have now investigated the expression of different proteins associated to Ca(2+) entry, a major Ca(2+) signalling event. DM2 donors were randomly selected from normotensive patients with glycosylated Hb levels (HbA1c) over 6%. Control subjects were normal age- and gender-matched healthy people with HbA1c levels in the normal range (3.5-5%). Expression of TRPC1, 3 and 6, STIM1 and Orai1 was analyzed by Western blotting in DM2 patients and controls. Expression of TRPC1 in platelets from DM2 donors and controls was similar; however, expression of TRPC6 is reduced in platelets from DM2 patients as compared to healthy controls. We have found that expression of TRPC3, Orai1 and STIM1 is enhanced in DM2 subjects as compared to controls. Our findings provide an explanation to the enhanced Ca(2+) entry induced by physiological agonists in platelets from DM2 patients.

Purpose: To describe the incidence and characterize the clinical manifestations, diagnosis and outcome of spontaneous epidural abscess (SEA) not associated with neurosurgical procedures or instrumentation of the spine., Methods: Review of cases of SEA over 10 years. Diagnosis was made by imaging-techniques and surgical examination., Results: Fifteen patients were studied. The incidence of SEA was 0.4 cases per 100,000 person-years. Infection gained access to the epidural space haematogenously in 9 patients (60%). SEA was located at the lumbar (7 cases), cervical (4), cranial (2) and thoracic (1) areas. Local pain was the most common manifestation (93.3%); fever was absent in 40%. One third did not show neurologic abnormalities. Staphylococcus aureus was the most commonly isolated agent (87% of cases). All the patients received antimicrobial therapy for a mean period of 6.1+/-3.9 weeks. In addition, open surgical drainage or CT-guided needle aspiration was successfully performed in 10 and 3 patients respectively. Two patients were managed with antibiotics alone. Poor outcome occurred more frequently in patients with abscess at higher levels (67% in cranial or cervical abscesses versus 0% in thoracic or lumbosacral abscesses). An association was found between delayed diagnosis and poor outcome (p<0.05). Overall, 54% of our patients recovered without sequelae., Conclusions: SEA resulted from the extension of nearby or distant infections into the epidural space. Diagnosis was frequently delayed and the patient's neurologic status at presentation was the most important predictor of the outcome. The onset of spinal pain in patients with focal infections should prompt MRI of the spine, even in the absence of neurologic abnormalities or fever., (2009 European Federation of Internal Medicine.)

Three Klebsiella oxytoca isolates and one Klebsiella pneumoniae isolate from three children admitted to the Hematology Unit of Hospital Vall d'Hebron (Barcelona, Spain) exhibited a susceptibility pattern suggesting OXY beta-lactamase hyperproduction. All the isolates contained a 95-kb plasmid that harbored bla(OXY-1), which was transferred by electrotransformation but could not be self-transferred by conjugation. A qnrS1 gene was also harbored in the bla(OXY-1)-carrying plasmid. This is the first report of a plasmid-encoded OXY beta-lactamase.

Background: Apoptosis or programmed cell death involves a number of biochemical events, including the activation of caspases, which lead to specific cell morphology changes and ultimately cell death. Traditionally, two apoptotic pathways have been described: the cell-surface death receptor-dependent extrinsic pathway and the mitochondria-dependent intrinsic pathway. Alternatively, apoptosis has been reported to be induced by endoplasmic reticulum (ER) stress, which is mainly induced by a reduction in intraluminal free Ca(2+) concentration ([Ca(2+)](ER))., Objectives: The present study aimed to investigate the development of apoptotic events after ER stress induced by N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), an ER Ca(2+) chelator, in human platelets., Methods: Changes in cytosolic free Ca(2+) concentration, caspase activity and phosphatidylserine externalization were determined by fluorimetric techniques., Results: Our results indicate that TPEN reduces the amount of free Ca(2+) releasable by the Ca(2+)-mobilizing agonist thrombin. TPEN induced activation of caspase-3, -8 and -9 and subsequent phosphatidylserine externalization. The ability of TPEN to induce phosphatidylserine externalization was smaller than that of thrombin. In addition, TPEN was able to induce phosphorylation of the eukaryotic initiation factor 2 alpha (eIF2 alpha). TPEN-mediated caspase-3 activation requires functional caspase-8, but is independent of H(2)O(2) generation. Activation of caspase-3 and -8 by TPEN was prevented by salubrinal, an agent that prevents ER stress-induced apoptosis., Conclusion: These findings provide experimental evidence for the existence of ER stress-mediated apoptosis in human platelets, a process that might limit platelet life span upon prolonged stimulation with agonists.

Objective: Establishing the prevalence of people living in the Suba district of Bogotá using medication at their own risk and determining the factors related to it., Methods: A guided survey was applied to a random sample. Demographic variables were measured and inquires were made about health problems related to self- medication, the reasons for not seeing a doctor and the medications consumed during the last two weeks., Results: Self-medication reached 27,3 % (19,2-35,3 % 95 % CI) and self-prescription was 7,7 % (2,8-12,5 % 95 % CI). Being affiliated to the Social Health Security's beneficiaries system (OR=2,61: 1,4-4,8 95 % CI) was related to such behaviour. No relationship with other variables was found. The medications most consumed by people indulging in self-medication were analgesics (59,3 %), anti-flu medicine (13,5 %) and vitamins (6,8 %). The main problems for which people resorted to self-medication were pain, fever and flu. The main reasons mentioned for not seeing a doctor were lack of time (40 %) and lack of economic resources (43 %), in addition to other arguments, such as the people s perception that the problem was mild and emergency rooms are always congested., Conclusions: Although still worrying from the public health point of view, self-medication figures were lower than those encountered in similar studies; self-medicated drugs were the over-the-counter medication type. The rate of consuming self-medicated antibiotics dropped, probably due to the spreading of the restriction on the sale of antibiotics without a medical prescription which came into force a few months before the survey took place.

This study reports on the level of knowledge about correct blood pressure (BP) measurement procedures among 175 third-year and 176 sixth-year students at a medical faculty and 58 third-year students at a nursing college. Only 51.8% of all students thought that they knew how to measure BP correctly (28.6% in the third year and 61.9% in the sixth year at the medical faculty and 91.4% at the nursing college). Among sixth-year medical students, 12.5% knew the appropriate cuff size, 35% that the stethoscope diaphragm should not be placed under the cuff, and 43% that the cuff deflation rate affects BP measurement. Among nursing students, 33% knew the appropriate cuff size, 22% that an outpatient's BP should be measured more than once during each visit, and 55% that a diagnosis of hypertension can only be made if the BP is elevated on more than one visit.

Background: Chemotherapy is widely used in colorectal cancer that has relapsed or failed to respond to first-line treatment., Objectives: To determine the efficacy of second-line chemotherapy for the treatment of advanced colorectal cancer., Search Strategy: We performed electronic searches in the following databases: MEDLINE (via PubMed; 1964-September 2007), EMBASE (via OVID; 1980-September 2007) and The Cochrane Library 2007, Issue 2., Selection Criteria: Studies assessing the efficacy of second-line chemotherapy (single or combined treatment with any chemotherapeutic agent, at any dose and number of cycles) in patients with advanced colorectal cancer that progressed, recurred or did not respond to first-line chemotherapy., Data Collection and Analysis: A descriptive analysis of the included trials was performed, due to the huge clinical heterogeneity between them., Main Results: Seven randomized controlled trials (RCTs) were included; one of high quality, five of moderate quality, and one conference abstract. Second-line chemotherapy (irinotecan) showed moderate benefits in overall survival and progression-free survival over Best Supportive Care (BSC) and fluorouracil (5-FU). Fractionated administration has not proven to be more beneficial and is more toxic. Definitive results concerning the benefits and risks of oxaliplatin are pending publication., Authors' Conclusions: Second-line chemotherapy is effective in prolonging time to progression and survival in patients with advanced colorectal cancer. Further RCTs are needed to assess the optimal chemotherapy regimen.

S-(-)-Limonene oxide (4-isopropenyl-1-methyl-7-oxabicyclo[4.1.0]heptane) is a secondary metabolite and an atmospheric pollutant product of oxidation of other terpenes, such as limonene and alpha-pinene, among others. For the first time, a theoretical study of the molecular structure and a theoretical and experimental analysis of the infrared and Raman spectra of this chemical species are presented. Theoretical calculations reveal the existence of two conformers depending on the position of the isopropenyl group (axial and equatorial) and twelve rotamers (six equatorials and six axials), with the six equatorial ones as the most stable (around 97%) on the basis of Boltzmann's distribution law. In the current work, from a reliable assignment of the IR and Raman spectra and with the help from the study of the VCD spectrum of the title compound, five rotamers have been detected experimentally in the liquid phase. The present work reveals that IR, Raman and VCD are helpful complementary techniques to characterize flexible systems, as terpenes, which present several conformers.

Melatonin exerts immunomodulatory actions that enhance the magnitude and quality of immune responses specific for certain antigens; this has raised the possibility of using melatonin to design novel vaccine adjuvant systems. The present study investigated the effect of subcutaneous slow-release melatonin implants and subcutaneous melatonin injections on the responsiveness of circulating platelets in sheep after vaccination against Dichelobacter nodosus (A1 and C serotypes), the bacterium that causes ovine footrot, a major cause of lameness in sheep. The experiments were carried out in sheep from a farm located in an area of Mediterranean-type ecosystem. Plasma melatonin levels were determined by radioimmunoassay, sheep platelet aggregation was monitored using an aggregometer and Ca2+ mobilization was determined by spectrofluorimetry using fura-2. Administration of melatonin either by implants or subcutaneous injections increased plasma melatonin concentrations, an effect that was found to be greater and more sustained when melatonin was administered via implants. Vaccination per se, as well as melatonin, increased the percentage and rate of platelet aggregation and reduced the lag-time in response to the physiological agonist thrombin, an effect that was found to be significantly greater when melatonin was administered to vaccinated animals. Melatonin enhanced thrombin-evoked Ca2+ release and entry and further increased Ca2+ mobilization observed in platelets from vaccinated sheep. These observations suggest that the use of melatonin, as a novel adjuvant, induces beneficial effects on platelet function and haemostasis, and opens new perspectives for therapeutic manipulation of immune responses to vaccination.

This phase II clinical trial evaluated the antitumour response of Kahalalide F (KF) 650 microg/m(2) given as a 1-h weekly infusion in advanced malignant melanoma patients, both untreated and those who relapsed or progressed after one line of systemic therapy. Of 24 enrolled patients (median age, 55 years; range, 28-89), 14 patients had been previously treated with chemotherapy or biological therapy. No RECIST responses occurred; five chemotherapy-naïve patients with cutaneous melanoma had disease stabilisation for > or = 3 months; median progression-free survival was 1.7 months (95% CI, 1.2-1.9 months); and median overall survival was 10.8 months (95% CI, 5.0-upper limit not reached). The most common laboratory toxicities were non-cumulative increase of transaminases (ALT/AST) and gamma-glutamyltransferase (GGT). No patients experienced leukopenia and thrombocytopenia during the study. KF was a well-tolerated and safe chemotherapy regimen. Despite a favourable safety profile, this trial was closed after the first stage because of the lack of objective response in patients with malignant melanoma.

Aims: Vibrio populations in the seawater supply and the water of seven exhibition aquaria that simulate various Mediterranean and tropical ecosystems were compared. The similarity of Vibrio populations in the intestine of various fish species, feed and water was examined. Resistance to the antibiotics used in fish health management was analysed for the dominant Vibrio isolates., Methods and Results: Samples were collected for 1 year from seven exhibition tanks reproducing different ecosystems. The diversity and population similarity among vibrios were determined using a miniaturized biochemical phenotyping method. Similar Vibrio populations were found in the water supply and in the water of the Mediterranean ecosystems. However, different Vibrio populations were found in the water of tanks with tropical ecosystems. Vibrio populations in the water seemed to have a greater effect on the composition of intestinal Vibrio populations than those in feed. No resistance to antibiotics was observed, indicating their appropriate use for health management., Conclusions: Water characteristics have a greater impact on the composition of Vibrio populations in aquaria and fish intestinal microbiota than bacteria in feed., Significance and Impact of the Study: The microbiological monitoring water could provide valuable information for managing the health of exhibition aquaria.

Ca(2+) mobilization regulates a wide variety of cellular functions. Platelets possess agonist-releasable Ca(2+) stores in acidic organelles where sarcoendoplasmic reticulum Ca(2+)-ATPase-3 (SERCA) pump is involved in store refilling. Stromal interaction molecule 1 (STIM1), which has been presented as a central regulator of platelet function, is a Ca(2+) sensor of the intracellular Ca(2+) stores. Here we present that STIM1 is required for acidic store refilling. Electrotransjection of cells with anti-STIM1 (Y(231)-K(243)) antibody, directed towards a cytoplasmic sequence of STIM1, significantly reduced acidic store refilling, which was tested by remobilizing Ca(2+) from the acidic stores using 2,5-di-(t-butyl)-1,4-hydroquinone (TBHQ) after a brief refilling period that followed thrombin stimulation. Platelet treatment with thrombin or thapsigargin in combination with ionomycin, to induce extensive Ca(2+) store depletion, resulted in a transient increase in the interaction between STIM1 and SERCA3, reaching a maximum 30 s after stimulation. The coupling between STIM1 and SERCA3 was abolished by electrotransjection with anti-STIM1 antibody. The interaction between STIM1 and SERCA3 induced by thrombin or by treatment with thapsigargin plus ionomycin is reduced in platelets from type 2 diabetic patients, as well as Ca(2+) reuptake into the acidic Ca(2+) stores. These findings provide evidence for a role of STIM1 in acidic store refilling in platelets probably acting as a Ca(2+) sensor and regulating the activity of SERCA3. This action is impaired in platelets from type 2 diabetics, which might lead to the enhanced cytosolic Ca(2+) concentration observed and, therefore, in platelet hyperactivity.

Objectives: Commensal and opportunistic bacteria producing extended-spectrum beta-lactamases (ESBL-PB) have undergone a broad and rapid spread within the general population; however, the routes of dissemination have not been totally elucidated. The aim of this study was to determine whether individuals involved in an outbreak of acute gastroenteritis, in addition to the enteropathogenic microorganism, share an ESBL-PB as indirect demonstration of its transmission from a common food source., Methods: From 2003 to 2004 in Barcelona, Spain, stool samples from 905 people involved in 132 acute gastroenteritis outbreaks and 226 food handlers related to the outbreaks were investigated., Results: In 31 outbreaks, 58 diners carrying one or more ESBL-PB were detected. In 10 outbreaks, two or more diners shared the same ESBL-PB, and in four of them, the strain was shared with the food handlers., Conclusions: This study provides circumstantial evidence that foods can be a transmission vector for ESBL-PB, probably from two reservoirs, food animals and food handlers.

Cinnamtannin B-1 is a naturally occurring trimeric A-type proanthocyanidin, present in a limited number of plants, which exhibits a large number of cellular actions mostly derived from its antioxidant properties. Cinnamtannin B-1 modulates several biological processes such as changes in cytosolic free Ca(2+) concentration, endogenous reactive oxygen species generation, protein tyrosine phosphorylation and platelet aggregation. Proanthocyanidins, such as cinnamtannin B-1, have been reported to exert antitumoral activity mediated by a selective proapoptotic action in a number of tumoral cell lines associated with antiapoptotic activity in normal cells. The opposite effects of proanthocyanidins in normal and tumoral cells suggest that these compounds might be the base for therapeutic strategies directed selectively against tumoral cells. In addition, cinnamtannin B-1 shows antithrombotic actions through inhibition, in platelets, of endogenous ROS generation, Ca(2+) mobilization and, subsequently, aggregation. This has been reported to be especially relevant in platelets from diabetic patients, where cinnamtannin B-1 reverses both platelet hypersensitivity and hyperactivity. Considering the large number of cellular effects of cinnamtannin B-1 the development of therapeutic strategies for thrombotic disorders or certain types of cancer deserves further studies. This review summarizes the current knowledge on the actions and relevance of the signalling pathways modulated by cinnamtannin B-1.

Objectives: To identify protective factors and risk factors for the initiation and length of breastfeeding and full breastfeeding, in the Region of Murcia (Spain)., Patients and Methods: The Malama study (Medio Ambiente y Lactancia Materna) is a follow up study from birth up to years of 1,000 mother-child pairs. A description of breastfeeding practices are presented here, the survival curve of breastfeeding and a Cox regression model of the pilot study that includes 101 mother-child pairs and 6 months of follow-up., Results: After six months the prevalence of breastfeeding was 35 %. The mean duration of full breastfeeding was 63 days (median 45 days) with six months prevalence of 8 %. Hazard ratios (HR) for full breastfeeding were, to be a smoker (1.89; 95 % CI: 1.18-3.02), older than 35 years of age (2.04; 95 % CI: 1.22-3.42), caesarean birth (1.63; 95 % CI: 1.00-2.66). As well as those previously mentioned risks for breastfeeding, there were also hazard ratios for primary school education or less (1.63; 95 % CI: 0.98-2.82); to have breastfed an earlier child for at least 16 weeks (0.33; 95 % CI: 0.13-0.79), and to be the first birth (0.50; 95 % CI: 0.27-0.95). The length of both breastfeeding and full breastfeeding increased with the length of the maternal leave (0.96; 95 % CI: 0.94-0.99). Pregestational occupational exposure to endocrine disruptors did not seem to interfere with the duration of breastfeeding., Conclusions: In order to improve quality and duration of breastfeeding programmes, paediatric research and training on breastfeeding practice should be encouraged, to reduce unnecessary caesarean sections, promote tobacco cessation, focus human and economic resources to women with less education, and include legal mechanisms to ensure longer maternal leave.

Store-operated Ca2+ entry (SOCE), a major mechanism for Ca2+ entry in non-excitable cells, is regulated by the filling state of the intracellular Ca2+ stores. We have previously reported that a de novo conformational coupling between the type II IP3 receptor (IP3RII) and hTRPC1 channel occurs after depletion of the intracellular Ca2+ stores in human platelets, which might be involved in the activation of SOCE in these cells. Here we present for the first time direct evidence for the functional relevance of the coupling between hTRPC1 and IP3RII in SOCE in human platelets. Our data suggest that at least two pathways may contribute to SOCE in these cells. An early component, insensitive to cytochalasin D (Cyt D), is followed by a late component which is sensitive to Cyt D. Introduction of a peptide corresponding to IP3RII(317-334) (IP3BD-peptide(317-334)) in the cells by electrotransjection impairs the coupling between hTRPC1 and IP3RII but not the interaction between hTRPC1 and STIM1 induced by store depletion. Coimmunoprecipitation experiments indicated that endogenously expressed hTRPC1 interacts with the IP3BD-peptide(317-334). Electrotransjection of cells with IP3BD-peptide(317-334), significantly attenuated the late stage of Ca2+ and Mn2+ entry induced by 10 nM thapsigargin (TG) or 20 microM 2,5-di-(tert-butyl)-1,4-hydroquinone (TBHQ), providing evidence for a functional role of the de novo coupling between hTRPC1 and IP3RII in the activation of SOCE in human platelets.

In this work, a DMPA Langmuir monolayer at the air/water interface was studied by molecular dynamics simulations. Thus, an atomistic picture of a Langmuir monolayer was drawn from its expanded gas phase to its final solid condensed one. In this sense, some properties of monolayers that were traditionally poorly or even not reproduced in computer simulations, such as lipid domain formation or pressure-area per lipid isotherm, were properly reproduced in this work. Thus, the physical laws that control the lipid domain formation in the gas phase and the structure of lipid monolayers from the gas to solid condensed phase were studied. Thanks to the atomistic information provided by the molecular dynamics simulations, we were able to add valuable information to the experimental description of these processes and to access experimental data related to the lipid monolayers in their expanded phase, which is difficult or inaccessible to study by experimental techniques. In this sense, properties such as lipids head hydration and lipid structure were studied.

Two separate Ca2+ stores have been reported in human platelets: the dense tubular system (DTS) and lysosome-like acidic organelles. Recent work has reported that Ca2+ release from the DTS is mediated by the generation of inositol 1,4,5-trisphosphate, whereas Ca2+ efflux from the acidic stores is mostly linked to nicotinic acid adenine dinucleotide phosphate. Platelet agonists release Ca2+ selectively from one or both stores, which provides additional insight into the complexity of Ca2+ signaling and the cellular functions activated. Here, we review the role of multiple Ca2+ mobilizing messengers and Ca2+ stores in the activation of specific functions in platelets in response to different physiologic agonists.

Objectives: To evaluate the presence of qnr genes among enterobacterial isolates carrying extended-spectrum beta-lactamases (ESBLs) in Barcelona, Spain., Methods: Screening for the qnrA, qnrB and qnrS genes was carried out by PCR amplification with specific primers in 305 non-duplicate, clinically relevant ESBL-producing enterobacterial isolates obtained from February 2003 to August 2004. ESBLs from all qnr-positive isolates were characterized by isoelectric focusing, PCR amplification and DNA sequencing. Plasmid analysis was performed by S1 digestion and hybridization with specific probes for the qnr and bla genes. Plasmids containing qnr genes were transferred by conjugation or transformation. The genetic environment of qnrA1 in selected isolates was characterized by cloning experiments., Results: Fifteen isolates, each from a different individual, carried qnr. Among them, 14 had qnrA1 (6 Klebsiella pneumoniae, 6 Enterobacter cloacae and 2 Escherichia coli isolates) and 1 had qnrS1 (K. pneumoniae). None of the isolates carried qnrB. Among the qnrA1-carrying isolates, 10 possessed both bla(CTX-M-9) and bla(SHV-12), 2 had both bla(CTX-M-9) and bla(SHV-92) and 2 had bla(CTX-M-9) alone. The isolate with qnrS1 possessed bla(SHV-12). The qnrA1 and ESBL genes were located together on plasmids ranging in size from 40 to 320 kb. qnrS1 and bla(SHV-12) were not located on the same plasmid. Transfer of quinolone resistance was successfully achieved from all but three isolates. The cloned region surrounding qnrA in two K. pneumoniae isolates revealed a novel genetic organization., Conclusions: The prevalence of qnr among enterobacterial clinical isolates carrying ESBLs between 2003 and 2004 in Barcelona was 4.9%. qnrA1 was the most prevalent, whereas only one qnrS and no qnrB were detected.

Understanding the structure and dynamics of phospholipid bilayers is of fundamental relevance in biophysics, biochemistry, and chemical physics. Lipid Langmuir monolayers are used as a model of lipid bilayers, because they are much more easily studied experimentally, although some authors question the validity of this model. With the aim of throwing light on this debate, we used molecular dynamics simulations to obtain an atomistic description of a membrane of dimyristoylphosphatidic acid under different surface pressures. Our results show that at low surface pressure the interdigitation between opposite lipids (that is, back-to-back interactions) controls the system structure. In this setting and due to the absence of this effect in the Langmuir monolayers, the behavior between these two systems differs considerably. However, when the surface pressure increases the lipid interdigitation diminishes and so monolayer and bilayer behavior converges. In this work, four computer simulations were carried out, subjecting the phospholipids to lateral pressures ranging from 0.17 to 40 mN/m. The phospholipids were studied in their charged state because this approach is closer to the experimental situation. Special attention was paid to validating our simulation results by comparison with available experimental data, therebeing in general excellent agreement between experimental and simulation data. In addition, the properties of the lipid/solution interface associated with the lipid barometric phase transition were studied.

The aim of this study was to determine if low-dose dobutamine infusion can enhance Tc-99m methoxy isobutyl isonitrile (MIBI) uptake of hyperfunctioning parathyroid glands of patients with secondary hyperparathyroidism (SHP). We studied 24 patients with chronic renal failure and SHP. Median age of the sample was 47.5 years. A single-tracer, double-phase technique was performed, acquiring planar images of the neck and thorax after the injection of 740 to 1110 MBq (20-30 mCi) of Tc-99m MIBI. After 2 to 7 days, the study was repeated after the infusion of low-dose dobutamine of 2.0 microg . kg . min for 60 minutes. The scan was considered positive for hyperfunctioning parathyroid tissue when an area of increased uptake that persisted on late imaging was found. Parathyroid-to-thyroid count rates (PT/T) were calculated for each abnormal focus. Hyperplasic parathyroid tissue was confirmed in 12 of 24 patients who underwent neck surgery whereas the remaining group had persistent or worsening disease, verified by clinical follow-up between 6 and 25 months after the nuclear studies (median: 12 months). An MIBI baseline study was positive in 21 of 24 patients (87%), whereas the dobutamine study was positive in all patients. Thirty-five abnormal foci were seen on baseline MIBI studies and 43 on dobutamine scans (1.46 +/- 1.02 vs. 1.79 +/- 0.88, mean +/- SD, respectively, P = 0.043). Dobutamine PT/T ratios were significantly higher than those from the baseline study (1.49 +/- 0.30 vs. 1.38 +/- 0.28, mean +/- SD, respectively, P = 0.0002, n = 43). We concluded that low-dose dobutamine Tc-99m MIBI scintigraphy has the potential of enhancing tracer uptake and retention in patients with SHP.

Platelet hyperaggregability plays a pivotal role in the pathogenesis of cardiovascular diseases. Thrombin evokes aggregation through Ca(2+) mobilization, tyrosine phosphorylation and generation of reactive oxygen species (ROS). We have investigated the antiaggregant properties of Arbutus unedo extracts in human platelets. Changes in cytosolic Ca(2+) concentration and intracellular oxidants production were registered by espectrofluorimetry using fura-2 and dichlorodihydrofluorescein, respectively, platelet aggregation was assessed by aggregometry and protein tyrosine phosphorylation was detected by Western blotting. Platelet treatment with increasing concentrations (0.015-1.5mg/mL) of crude aqueous, ethyl acetate or diethyl ether extracts reduced platelet aggregation evoked by thrombin (0.5 U/mL) and show a potent ROS scavenger activity, preventing thrombin-evoked endogenous generation of ROS. Treatment with Arbutus unedo extracts did not alter thrombin-evoked Ca(2+) release from the intracellular stores but reduced store-operated Ca(2+) entry induced by thrombin or by selective depletion of the two Ca(2+) stores in platelets, the dense tubular system and the acidic stores. In addition, platelet treatment with extracts reduced both basal and thrombin-stimulated protein tyrosine phosphorylation. We conclude that Arbutus unedo extracts show antiaggregant actions due to attenuation of Ca(2+) mobilization, ROS production and protein tyrosine phosphorylation and might be used for the treatment and/or prevention of cardiovascular diseases.

Equilibrium structures of H(4-n)Ti(OH)n (n = 2-4) molecules and the Ti(OH)4 dimer and trimers were optimized at the B3LYP level of theory. Theoretical vibrational frequencies of TiO stretching modes obtained with several basis sets were compared with the existing experimental frequencies of these vibrations, and the 6-31+G(d) set was chosen for cluster calculations. Only one energy minimum was found for the [Ti(OH)4](2) dimer, but two isomers without symmetry elements stabilized by internal hydrogen bonds and two isomers, belonging to C(s) and C(i) point groups, with free OH groups were found as minima at the [Ti(OH)4](3) potential energy surface. The structure with the linear arrangement of hexacoordinated titanium atoms in the Ti3O12 skeleton may be proposed for trimeric species observed in liquid titanium alkoxides as the only structure satisfying experimental spectroscopic evidence about the presence of center of inversion in these species. Frequency changes of TiO4 modes which accompany the oligomer formation are predicted and discussed.

We have investigated the intracellular mechanisms involved in microtubular remodelling by thrombin and its possible involvement in platelet aggregation and secretion. Platelet stimulation with thrombin induces a time- and concentration-dependent regulation of the microtubular content, which was found to be maximally effective at the concentration 0.1 U/ml. Thrombin (0.1 U/ml) evoked an initial decrease in the microtubule content detectable at 5 seconds (sec) and reached a minimum 10 sec after stimulation. The microtubular content then increased, exceeding basal levels again approximately 30 sec after stimulation. Inhibition of tyrosine phosphatases using vanadate abolished thrombin-induced microtubular depolymerisation while inhibition of tyrosine kinases by methyl-2,5-dihydroxycinnamate prevented microtubule polymerisation. Thrombin activates the cytosolic Bruton's tyrosine kinase (Btk) and Src proteins. Inhibition of Btk or Src by LFM-A13 or PP1, respectively, abolished thrombin-induced microtubular polymerisation, while maintaining intact its ability to induce initial depolymerisation. Microtubular disruption by colchicine significantly reduced thrombin-induced platelet aggregation and ATP secretion. Similar results were observed after inhibition of microtubular disassembly by paclitaxel. These findings indicate that thrombin induces microtubular remodelling by modifying the balance between protein tyrosine phosphorylation and dephosphorylation. The former seems to be required for microtubular polymerisation, while tyrosine dephosphorylation is required for microtubular depolymerisation. Both, initial microtubular disassembly and subsequent polymerisation are required for thrombin-induced platelet aggregation and secretion in human platelets.

Discrete-time domain methods provide a simple and flexible way to solve initial boundary value problems. With regard to the sources in such methods, only monopoles or dipoles can be considered. However, in many problems such as room acoustics, the radiation of realistic sources is directional-dependent and their directivity patterns have a clear influence on the total sound field. In this letter, a method to synthesize the directivity of sources is proposed, especially in cases where the knowledge is only based on discrete values of the directivity diagram. Some examples have been carried out in order to show the behavior and accuracy of the proposed method.

We have investigated, theoretically, the structural properties of potassium trimethylsilanolate in the gas phase at a B3LYP/6-31+G* level. For this purpose, a simplified ionic cluster model based on potassium trimethylsilanolate tetramers, proposed in the literature as the structural units of this compound in the solid state, was developed. Furthermore, we compared the validity of the model with two simpler ones: a monomer of potassium trimethylsilanolate and a trimethylsilanolate anion in the gas phase. The developed ionic cluster model was found to be best in reproducing the experimental structure of potassium trimethylsilanolate, supporting, at the same time, the existence of such tetrameric species (previously identified experimentally from mass spectrometry data by Weiss et al.) in the gas phase. Finally, NBO calculations highlighted the important role of the potassium counterion as a charge localizer in the structure of these chemical species.

People with athetoid cerebral palsy (CP) have difficulty using computers due to unintentional involuntary movements in the upper extremities. A neural network-based system has been developed to cancel the undesired motion, and speed up the movements and accuracy in target acquisition and path tracking tasks while using an isometric joystick (IJ). Nonlinear filtering algorithms were created with neural networks using nonlinear models to help people with athetoid CP to access the computer. This paper presents unfiltered test data that have been collected from patients, and describes the planned filtering approach.

We present a single-molecule study unraveling the effect of static disorder on the vibrational-assisted ultrafast exciton dynamics in multichromophoric systems. For every single complex, we probe the initial exciton relaxation process by an ultrafast pump-probe approach and the coupling to vibrational modes by emission spectra, while fluorescence lifetime analysis measures the amount of static disorder. Exploiting the wide range of disorder found from complex to complex, we demonstrate that static disorder accelerates the dephasing and energy relaxation rate of the exciton.

99mTc-MIBI is a radiopharmaceutical that has been successfully used for the detection of hyperfunctioning parathyroid glands and for radioguided surgery techniques. We report on the case of a 55 year old woman in hemodialysis, with secondary persistent hyperparathyroidism after total parathyroidectomy. The conventional double-phase 99mTc-MIBI parathyroid scintigraphy was negative. The study was repeated after sensibilization with intravenous low-dose dobutamine showing an area of increased focal uptake in the lower cervical region. With this finding, radioguided 99mTc-MIBI surgery was performed after dobutamine administration, using a hand held gamma probe. The technique was considered successful with the resection of parathyroid cervical tissue which was further confirmed as nodular hyperplasia. We conclude that this methodology has the potential of being a an useful tool for the intraoperative localization of remanent tissue in patients with secondary persistent/recurrent hyperparathyroidism.

STIM1 (stromal interaction molecule 1) has recently been proposed to communicate the intracellular Ca(2+) stores with the plasma membrane to mediate store-operated Ca(2+) entry. Here we describe for the first time that Ca(2+) store depletion stimulates rapid STIM1 surface expression and association with endogenously expressed human canonical TRP1 (hTRPC1) independently of rises in cytosolic free Ca(2+) concentration. These events require the support of the actin cytoskeleton in human platelets, as reported for the coupling between type II inositol 1,4,5-trisphosphate receptor in the Ca(2+) stores and hTRPC1 in the plasma membrane, which has been suggested to underlie the activation of store-operated Ca(2+) entry in these cells. Electrotransjection of cells with anti-STIM1 antibody, directed toward the N-terminal sequence that includes the Ca(2+)-binding region, prevented the migration of STIM1 toward the plasma membrane, the interaction between STIM1 and hTRPC1, the coupling between hTRPC1 and type II inositol 1,4,5-trisphosphate receptor, and reduced store-operated Ca(2+) entry. These findings provide evidence for a role of STIM1 in the activation of store-operated Ca(2+) entry probably acting as a Ca(2+) sensor.

Resistance to beta-lactams and quinolones in two isogenic Enterobacter cloacae isolates was studied. One was susceptible to cefoxitin and amoxicillin-clavulanate. The other one showed its natural beta-lactam resistance pattern. Both isolates had a nonfunctional AmpR regulator. However, within the second one, the presence of a plasmid carrying ampR and qnrA1 allowed reversion to the wild-type beta-lactam resistance phenotype and decreased susceptibility to fluoroquinolones.

This work is a comparative analysis of three general approaches for rater agreement measurement which produce three different statistical coefficients: descriptive (sigma, pi y kappa coefficients), based on log-linear models and on mixture models. Although loglinear and mixture approaches assume a different concept of chance correction, their flexibility allow using its parameters to analyze agreement and disagreement patterns. We show that all descriptive measures can also be obtained by introducing constraints to a basic loglinear (or mixture) quasi-independence model. Due to the different measurement scale used, both loglinear and mixture approaches have a similar interpretation when diagonal parameters are positive but a different interpretation otherwise.

Objective: Temozolomide is a novel oral alkylating agent, active against metastatic melanoma. Combinations of chemotherapy and biological response modifiers have been associated with increased antitumour activity. A multicentre phase II study was performed to assess the activity and toxicity of temozolomide in combination with interferon alpha-2b., Patients and Methods: Eligible patients had histologically confirmed metastatic melanoma. Previously untreated patients received temozolomide administered orally at a dose of 150 mg/m/day for 5 days every 4 weeks, in combination with interferon given continuously subcutaneously twice a week at a dose of 10 MU/m. Treatment continued until disease progression or for a maximum of 12 months., Results: From June 1999 to August 2002, 27 eligible patients were included in the study at six centres. Median age was 59 (28-77) years; 17 male and 10 female patients were recruited; the median Karnofsky performance score was 90 (70-100); three patients had received prior adjuvant interferon; the majority of patients had fewer than three involved sites. A total of 96 cycles were administered; there were one complete response, four partial response and five stable disease (overall response rate: 18.5%, 95% confidence interval: 6.3-38.1). All responses were seen in patients with exclusively lymph node and pulmonary disease [M1a (one patient); M1b (four patients)]. The median response duration was 6.9 months. One patient remains in complete remission at 4 years. The median time to progression and the median survival were 1.87 and 9.5 months, respectively. Haematological toxicity was neutropenia G-IV: 1, G-III: 4, thrombocytopenia G-III: 2, and anaemia G-III: 2. Predominant non-haematological toxicity was hepatotoxicity G-III: 4. Other toxicities were mild or moderate. Dose reduction was required for nine cycles of interferon, one of temozolomide and two of both drugs., Conclusions: Temozolomide in combination with interferon is a well-tolerated palliative regimen that has moderate activity against metastatic melanoma. Further evaluation of this regimen in comparative studies or in combination with other drugs is warranted.

In aged rodents, neuronal plasticity decreases while spatial learning and working memory (WM) deficits increase. As it is well known, rats reared in enriched environments (EE) show better cognitive performances and an increased neuronal plasticity than rats reared in standard environments (SE). We hypothesized that EE could preserve the aged animals from cognitive impairment through NO dependent mechanisms of neuronal plasticity. WM performance and plasticity were measured in 27-month-old rats from EE and SE. EE animals showed a better spatial WM performance (66% increase) than SE ones. Cytosolic NOS activity was 128 and 155% higher in EE male and female rats, respectively. Mitochondrial NOS activity and expression were also significantly higher in EE male and female rats. Mitochondrial NOS protein expression was higher in brain submitochondrial membranes from EE reared rats. Complex I activity was 70-80% increased in EE as compared to SE rats. A significant increase in the area of NADPH-d reactive neurons was observed in the parietotemporal cortex and CA1 hippocampal region of EE animals.

Jaundice in Hodgkin's disease occurs in 3-13% of the cases reported in the medical literature and can be due to several causes. Cholestatic jaundice associated with ductopenia may be a consequence of an associated paraneoplastic process and can occur several months before the development of Hodgkin's disease. When there is a finding of jaundice of unknown etiology associated with ductopenia, the possible existence of Hodgkin's disease should be investigated. We describe a case of cholestatic jaundice associated with Hodgkin's disease. The first clinical and laboratory manifestations were symptoms of bloody diarrhea months before the development of Hodgkin's disease. We discuss the differential diagnoses considered, given the complexity of the case.

Recent studies propose the existence of two distinct Ca2+ compartments in human platelets based on the expression of different SERCA isoforms with distinct sensitivity to thapsigargin and 2,5-di-(tert-butyl)-1,4-hydroquinone (TBHQ). Using fura-2-loaded human platelets we have found that depletion of the TBHQ sensitive store reduces thrombin--but not ADP--or vasopressin (AVP)-induced Ca2+ release. Redistribution of cytosolic Ca2+ after thrombin stimulation resulted in overloading of the TBHQ-sensitive store. This phenomenon was not observed with ADP or AVP. We found that NAADP decreases the Ca2+ concentration into the stores in permeabilized platelets, which is prevented by depletion of the TBHQ-sensitive store. Nimodipine, an inhibitor of the NAADP receptor, reduced thrombin-induced Ca2+ release from the TBHQ-sensitive stores, without having any effect on the responses elicited by ADP or AVP. Finally, the phospholipase C inhibitor, U-73122, abolished ADP- and AVP-induced Ca2+ release, suggesting that their responses are entirely dependent on IP3 generation. In contrast, treatment with both U-73122 and nimodipine was required to abolish thrombin-induced Ca2+ release. We suggest that thrombin evokes Ca2+ release from TBHQ-sensitive and insensitive stores, which requires both NAADP and IP3, respectively, while ADP and AVP exert an IP3-dependent release of Ca2+ from the TBHQ-insensitive compartment in human platelets.

The joint experimental and theoretical study of the vibrational spectra of the molecular series (CH3)3SiX (with X=H, F and Br) is carried out. Data from newly recorded IR and Raman spectra for the bromo derivative, experimental data obtained previously for the remaining species, DFT theoretical calculations and the use of the SQMFF procedure have allowed us to propose common patterns and to unify criteria in their assignment. In addition, two sets of averaged scale factors for the B3LYP force field obtained with two different basis sets (6-31G* and DZP+diff) have been proposed for the common bulky moiety of that molecular series. These parameters were used successfully in order to reproduce the frequency of the bands assigned to the (CH3)3Si- group in the vibrational spectra of the corresponding silanolic and methoxy derivatives, i.e., trimethylsilanol and methoxytrimethylsilane, proving their transferability.