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We discuss the production of a class of heavy sterile neutrinos νh in proto-neutron stars. The neutrinos, of mass around 50 MeV, have a negligible mixing with the active species but relatively large dimension-5 electromagnetic couplings. In particular, a magnetic dipole moment μ≈10−6 GeV−1 implies that they are thermally produced through e+e−→ν¯hνh in the early phase of the core collapse, whereas a heavy–light transition moment μtr≈10−8 GeV−1 allows their decay νh→νiγ with a lifetime around 10−3 s. This type of electromagnetic couplings has been recently proposed to explain the excess of electron-like events in baseline experiments. We show that the production and decay of these heavy neutrinos would transport energy from the central regions of the star to distances d≈400 km, providing a very efficient mechanism to enhance the supernova shock front and heat the material behind it.

We discuss the spectrum of the different components in the astrophysical neutrino flux reaching the Earth, and the possible contribution of each component to the high-energy IceCube data. We show that the diffuse flux from cosmic ray (CR) interactions with gas in our galaxy implies just two events among the 54-event sample. We argue that the neutrino flux from CR interactions in the intergalactic (intracluster) space depends critically on the transport parameter δ describing the energy dependence in the diffusion coefficient of galactic CRs. Our analysis motivates a neutrino spectrum with a drop at PeV energies that fits the data well, including the non-observation of the Glashow resonance at 6.3 PeV. We also show that a CR flux described by an unbroken power law may produce a neutrino flux with interesting spectral features (bumps and breaks) related to changes in the CR composition. [ABSTRACT FROM AUTHOR]

Objective: To evaluate, in patients with chronic migraine (CM) in real-world conditions, the persistence, effectiveness, and tolerability of erenumab, fremanezumab, and galcanezumab anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies (mAbs) and the persistence and effects of switching., Background: Anti-CGRP mAbs represent a novel therapeutic approach to the management of CM; however, real-world data on persistence, effectiveness, and tolerability, especially after switching, are scarce., Methods: This was a retrospective observational cohort study including all patients with CM treated with erenumab, fremanezumab, and/or galcanezumab in a tertiary hospital between January 2019 and December 2022. Treatment persistence was measured as the number of days between treatment start and end dates or the end of follow-up and also as a percentage of persistent patients at 3, 6, and 12 months; effectiveness as a ≥50% reduction in monthly migraine days (MMD); and tolerability as the number and type of adverse events., Results: Included were 281 patients (383 treatments) with CM (91.5% [257/281] female) receiving anti-CGRP mAbs. Median (interquartile range [IQR]) treatment persistence was 267 (103-550) days. At 12 months, persistence was greater for the first (66.7%) compared to the second (49.8%) and third (37.2%) anti-CGRP mAb treatments (hazard ratio [HR] = 1.93, 95% confidence interval [CI]: 1.35-2.74; HR = 2.75, 95% CI: 1.69-4.47, respectively). Persistence minimum observed median (IQR) was also greater for the first (291 [112-594] days) compared to both the second (188 [90-403] days; p < 0.001) and third (167 [89-352] days; p < 0.001) anti-CGRP mAb treatments. For the first anti-CGRP mAb treatment, there were no differences in persistence among the different drugs. In terms of effectiveness of the first, second, and third anti-CGRP mAb treatments, a ≥50% reduction in MMD was achieved by 57.6% (117/203), 25.0% (11/44), and 11.8% (2/17) of patients, respectively, at 3 months, and by 55.8% (87/156), 29.6% (8/27), and 12.5% (1/8) of patients, respectively, at 6 months. At 12 months, no significant effectiveness differences were observed among anti-CGRP mAb treatments. As for tolerability, 55 adverse events were reported by 43 (15.3%) patients, mostly mild and leading to treatment discontinuation in only 14 (5.0%) patients. The most common adverse events were constipation, injection site reaction, and pruritus. Erenumab patients (3%, 3/99) experienced a higher rate of discontinuation for constipation., Conclusions: Our findings showed a 12-month higher treatment persistence with the use of a first anti-CGRP mAb treatment when the switch to a second treatment was due to ineffectiveness or severe side events. This persistence was lower after a second or third anti-CGRP. Additionally, in terms of effectiveness, the first anti-CGRP treatment achieved a higher response in terms of ≥50% reduction in MMD; however, some patients may benefit from a switching strategy. Finally, the tolerability profile for anti-CGRP mAbs was favorable. Further studies are needed to identify predictors of response after switching from the first anti-CGRP mAb treatment., (© 2024 American Headache Society.)

Introduction: Integrated care pathways (ICPs) are crucial for delivering individualised care. However, the development of ICPs is challenging and must be well designed to provide the expected benefits. Regarding this, healthcare organisations are increasingly adopting management systems based on Lean Thinking to improve their organisational processes by eliminating non-value-added steps. This study elucidates the process and evaluates the impact of applying Lean Thinking to redesign an ICP for patients with spondyloarthritis, a chronic inflammatory disease affecting young adults., Methods: A multidisciplinary team was assembled and trained in Lean Thinking. Patient's perspective was gathered through a focus group. Guided by an expert methodologist, the team constructed a value stream map of the entire care pathway and analysed each step. Five work streams were defined to increase value at each step, leading to targeted process improvements. Key process and outcome metrics were collected and compared in 2-month baseline and post-implementation audits., Results: A total of 118 patients were included in the baseline audit (September-October 2022), and 116 in the post-implementation audit (January-February 2023). Process redesign resulted in statistically significant improvements (p < 0.05), including a reduction in the mean number of hospital visits per patient over a 2-month period from 2.54 (SD = 0.93) to 1.84 (SD = 0.79), an increase in complementary exams scheduled on the same day (81.4% to 94.8%) and an increase in baseline disease and treatment education (from 22.2% to 84.2% and from 18.2% to 84.6%, respectively). Regarding standardisation of clinical practice, there were significant increases in collecting data for medical records on composite activity indices (76.3% to 95.7%), reporting of pharmacological treatment adherence (68.6% to 94%) and providing nonpharmacological recommendations (31.3% to 95.7%)., Conclusions: The application of Lean Thinking to redesign the spondyloarthritis ICP led to significant improvements in outpatient appointment scheduling, reduced patient hospital visits, improved interdepartmental coordination and standardised clinical practice., (© 2024 John Wiley & Sons Ltd.)

Objectives: People living with HIV (PLWH) are common users of complementary and alternative medicine (CAM). The main objective of this study was to study the frequency and patterns of CAM natural products use in a large cohort of PLWH and to identify potential drug-drug interactions (DDIs) and the impact on their antiretroviral treatment (ART) adherence and efficacy., Methods: This was a cross-sectional multicenter survey including 420 PLWH from different Spanish hospitals. Participants completed a face-to-face questionnaire on CAM consumption and different sociodemographic and clinical data were collected. DDIs between CAM and ART were identified and classified according to the Liverpool University Database and patient factors related to CAM consumption were assessed., Results: 420 participants were included (82.6% male, mean age 47 years); 209 patients (49.8%) were taking at least one CAM. The most consumed CAM were green, black and red tea (n=146, 25.4%), ginger (n=26, 4.5%), fish oil (n=25, 4.4%) and cannabis (n=24, 4.2%). An ART based on integrase inhibitors was the only factor independently associated with CAM consumption (OR 1.54, 95% CI 1.04 to 2.26). 50 potential CAM-ART interactions in 43 (20.6%) patients taking CAM were identified, being clinically significant in 80% of the cases. CAM products most frequently involved with a potential significant DDI were supplements containing divalent cations (n=11) and garlic (n=7). No differences in ART efficacy and adherence were observed between patients with and without CAM consumption., Conclusions: Almost 50% of patients were taking at least one CAM product and its use was associated with an integrase inhibitor based ART. One out of every six patients was at risk of presenting with an interaction between a CAM and their ART, confirming the need to review continuously the use of CAM as part of the medication review process., Competing Interests: Competing interests: EC-G has received fees from Gilead, Abbvie y Amgen as a speaker. MDA has received fees from VIIV and MDS as a speaker. MM has received compensation for presentations from Janssen-Cilag and Merck Sharp & Dohme, research funding from Gilead Sciences as well as support for attending meetings and/or travel from Janssen-Cilag, ViiV Healthcare and Gilead Sciences. GC has served as a speaker or has received advisory fees from AbbVie, Biogen, Jansen-Cilag, MSD, Pfizer and UCB. SL has received fees from Pfizer, Shionogi, Angelini and Advanz Pharma as a speaker and participant in advisory board meetings. Other authors declare no conflicts of interest, (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: People living with human immunodeficiency virus could particularly benefit from mobile health (mHealth). The objective of the study was to  contribute to the design and development of a new standard of care for people  living with human immunodeficiency virus and the mHealth app needed to  support it by 1) exploring the view of people living with human  immunodeficiency virus and healthcare professionals on the possibilities of  mHealth tools on HIV care, and 2) implementing their feedback into the new  app and into the new journey of people living with human immunodeficiency  virus., Method: The study was conducted in two different phases: phase one was to  apprise patients' and healthcare professionals' perspectives on mHealth using  the qualitative methodology of the focus groups, whereas phase two aimed to  implement their feedback into the application., Results: A total of five people living with human immunodeficiency virus and  nine healthcare professionals (three clinical pharmacists, three nurses, two  physicians, and one pharmacy technician) participated in the focus groups. The  patients identified the following main aspects to be improved in the  current patients' journey: insufficient information (n = 5), lack of general  population disease awareness (n = 5), and medication dispensation model (n =  3). Moreover, healthcare professionals identified the next health outcomes  to be enhanced with mHealth tools: patients' quality of life (n = 7), control of  the disease (n = 5) and comorbidities (n = 3), and adherence to medication (n = 5). According to these needs, the new healthcare model was designed. The  mHealth was provided with different features, such as information about the  disease, health promotion and prevention, the possibility of two-way patient- healthcare professionals communication, or synchronization with other devices. The new human immunodeficiency virus care journey and the app are currently being tested in a group of people living with human immunodeficiency virus in real-world conditions in our hospital., Conclusions: Improving patients' quality of life, therapeutic adherence, or  disease control are key objectives for optimizing people living with human  immunodeficiency virus care. Our digital health tool and the new healthcare  model have been implemented based on end-users' feedback to achieve better  patients-healthcare professionals communication and patient engagement with their care., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Background Guselkumab is indicated for moderate-to-severe plaque psoriasis. Data from real-life clinical practice regarding its use are scarce, especially concerning patients who relapse after previous biologic therapies. Aim This study aimed to evaluate the effectiveness, safety, and adherence to guselkumab in psoriasis refractory to biologic therapies. Method This real-life, retrospective study included patients who initiated guselkumab between February 2019 and October 2020. The main objective was to assess effectiveness, expressed as the psoriasis area and severity index (PASI) ≤5, ≤2 and 0, at the first follow-up medical visit. As secondary effectiveness outcomes, we assessed the body surface area (BSA) and dermatology life quality index (DLQI). We also evaluated adverse events and adherence (using the medication possession ratio [MPR]). Results The study included 35 patients who had previously received a median of two biologic drugs. The median basal PASI score (IQR) was 11 (7.3-15.9), decreasing to 0 (0-1.4) at first follow-up medical visit. At this point, 32 patients (94.1%) reached PASI ≤5, 28 (82.4%) PASI ≤2 and 19 (55.9%) PASI 0. We also found statistically significant improvements in PASI, BSA and DLQI at first follow-up (p<0.001). Three patients developed adverse events. Most patients (N=29, 85.3%) had an MPR ≥90%. The MPR was not associated with PASI score at first follow-up. Conclusion Our study supports evidence that guselkumab is an effective and safe drug in psoriasis refractory to biologic therapies. Adherence to treatment is not related to effectiveness, suggesting that, in some cases, the interval between doses could be increased., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Chimpanzees used as pets and in the entertainment industry endure detrimental living conditions from early infancy onwards. The preferred option for ending their existence as pet or circus chimpanzees is their rescue and transfer to a primate sanctuary that will provide them with optimal living and social conditions, so that they can thrive. In this case study, we had the rare opportunity to compare the activity budgets of three chimpanzees from their time as pets in 2004 to their time living at the MONA sanctuary in 2020, after almost a decade in the centre. We found their behaviour patterns changed in accordance with the sanctuaries' rehabilitation objectives. Resting periods increased considerably while vigilance simultaneously declined sharply. Moreover, the chimpanzees' social competence increased as allogrooming became the predominant social behaviour, and agonistic interactions diminished even though they were living within a larger social group at the sanctuary. All three chimpanzees expanded their allogrooming and proximity networks at the sanctuary, which included new group members, but they maintained the closest relationships to those conspecifics who they were rescued with. In conclusion, these findings suggest that the sanctuary environment and social group setting made it possible for these three chimpanzees to improve their social competence and increase their well-being over time.

Background: Medication adherence is a complex area of behaviour. Little is known about what influences chronic patients to take their medicines. This study has aimed to compare and contrast the health-related beliefs, experiences and types of behaviour typical among patients who have at least one chronic condition and are following a pharmacological treatment in accordance with their level of medication adherence., Methods: A questionnaire-based cross-sectional study, consisting of socio-demographic data, the 4-item Morisky-Green scale and 37 statements about health beliefs, perceptions and experiences, was conducted at different levels of healthcare (primary and tertiary settings)., Results: A total of 577 questionnaires were analyzed. Respondents had a mean age of 64 and took an average of 4.6 drugs. Optimal adherence was reported by 58.6% of respondents. Bivariate analysis showed adherent subjects were older, took more medications, were in better spirits and had greater confidence and information regarding their treatment. Multivariate analysis found older age and the statements 'My doctor periodically reviews my treatment' and 'I am motivated to continue with the treatment' to be significantly related to medication adherence, while 'I make variations when taking medication depending on how I feel' was significant for medication non-adherence., Conclusion: Medication non-adherence is common among chronic patients. Patient-centred approaches should be implemented in daily clinical practice as patient health beliefs, experiences and conduct influence medication-taking. Motivational interviewing might improve medication adherence in permitting emotional state managing and increasing educational skills, patient motivation and confidence between patients and healthcare providers., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Objectives: Drug interactions, poor adherence to medication and high-risk sexual behaviour may occur in individuals with HIV using recreational drugs. Thus, we aimed to assess the prevalence of recreational drugs use and to explore its clinical impact in HIV patients on treatment., Methods: Observational, cross sectional, study conducted in a 700 bed university hospital, Barcelona, Spain. A total of 208 adults living with HIV on treatment were included. A questionnaire was administered by clinical pharmacists, including evaluation of sociodemographic variables, past 12-month drug consumption, adherence to antiretrovirals (Simplified Medication Adherence Questionnaire) and high-risk sexual behaviour (condomless sex/multiple partners). Additional data were obtained from clinical records. Recreational drug-antiretroviral interactions were checked in reference databases. Prevalence was calculated for 5% precision and 95% CI. Crude and adjusted binary logistic regressions were performed to identify associations between recreational drug use and adherence problems, and between recreational drug use and high-risk sexual behaviour., Results: From the overall sample, 92 participants (44.2%) consumed recreational drugs over the past 1 year. Of these, 44 (48.8%) had used different types of recreational drugs in this period. We detected 11 recreational substances, including sildenafil and nitrites. The most consumed drugs were: cannabis (68.5%), cocaine (45.5%), nitrites (31.5%), sildenafil (28.3) and ecstasy (19.6%). Relevant interactions occurred in 46 (50%) of the individuals consuming drugs. Recreational drug consumption was found to be related to adherence problems with antiretrovirals (OR: 2.51 (95% CI 1.32 to 4.77) p=0.005) and high-risk sexual behaviour (OR: 2.81 (95% CI 1.47 to 5.39) p=0.002)., Conclusions: Recreational drugs are frequently used by HIV patients on treatment. Classical drugs and new substances consumed in sexual context are usual. Recreational drug consumption interferes with several clinical outcomes, including potentially relevant interactions between drugs and antiretrovirals, adherence problems and high-risk sexual behaviour. Thus, there is the urgent need of implementing patient-centred care involving recreational drug consumption., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Introduction: About 50% of patients do not take their long-term therapy for chronic conditions as prescribed. Many studies have centered on patients' adherence to a specific treatment or single conditions, but few have taken all chronic conditions into consideration from a patient's perspective. This study aims to explore factors that impact on drug compliance and to identify strategies to improve this from the perspective of patients with at least one chronic condition., Methods: Patients were recruited by healthcare professionals from a hospital pharmacy, four community pharmacies, patient associations, and a primary care center in Barcelona. Five focus groups were conducted (N = 36). Conversations were audiotaped and transcribed verbatim to allow qualitative analysis., Results: Study subjects were aged 39-90 years (mean 65 years) and the mean number of comorbidities per patient was 2.3 (range 1-7). The main modifiers of therapeutic conduct were: patients' health beliefs, patient-prescriber relationships, and patients' motivation and perception of illness control. Study participants wanted greater participation in decision-making concerning their health and increased education about their illness and medication. They also wanted individualized healthcare that took their preferences and personal and emotional issues into account., Conclusion: Our results highlight how the patient-prescriber's relationship and factors such as health beliefs, motivation and perception of illness control impact on medication adherence in chronic patients. Future interventions to optimize adherence to treatment should focus on shared decision-making and more extensive health education., Funding: Celgene Corporation.

Background: Current treatment combinations for chronic hepatitis C virus infection still include pegylated interferon and ribavirin despite the new therapeutic options available. Interferon-based treatments are associated with a high incidence of adverse effects. Central nervous system events are among the most frequent adverse drug reactions and their influence on treatment adherence and effectiveness is controversial., Objective: The aim of the study was to evaluate neuropsychiatric adverse effects of interferon-based treatment for chronic hepatitis C in standard multidisciplinary clinical practice. Risk factors for these adverse effects and their impact on adherence and sustained viral response were also evaluated. Setting Ambulatory care pharmacy in coordination with the liver unit and the infectious diseases unit at a 650-bed tertiary university hospital., Methods: We included all consecutive patients with chronic hepatitis C who completed treatment with pegylated interferon and ribavirin between 2005 and 2013. All patients underwent a multidisciplinary follow-up during treatment., Main Outcome Measures: Neuropsychiatric adverse effects were evaluated in relation to severity, management and outcome. The presence of anxiety and depression was evaluated by means of specific tests., Results: A total of 717 treatments in 679 patients were included. During treatment, we detected 1679 neuropsychiatric adverse effects in 618 patients (86.2 %), generating 1737 clinical interventions. Fifty-seven (3.3 %) neuropsychiatric adverse effects were severe and 2 (0.1 %) were life-threatening (suicidal attempts). Most neuropsychiatric adverse effects (1555 events, 92.6 %) resolved without sequelae. Psychiatric medication was required in 289 patients (40.3 %). Sustained viral response was achieved in 400 cases (55.8 %) and was associated with adherence (OR = 1.942, 95 % CI = 1.235-3.052, p = 0.004). A multivariate analysis did not show any relationship between neuropsychiatric adverse effects and treatment adherence or sustained viral response. A psychiatric history was a strong risk factor for depression, anxiety and other psychiatric disorders during treatment., Conclusion: Neuropsychiatric adverse effects during interferon-based treatments in patients with chronic hepatitis C were common but mostly mild or moderate. Early detection and accurate multidisciplinary management avoided treatment discontinuation, ensuring adherence and attaining sustained viral response. The identified risk factors could be used to determine patients eligible for interferon-free combinations, thus optimizing health system economics.

Ever since work on pluripotency induction was originally published, reporting the reprogramming of somatic cells to induced pluripotent stem cells (iPS cells) by the ectopic expression of the four transcription factors Oct4, Sox2, Klf4 and c-Myc, high expectations regarding their potential use for regenerative medicine have emerged. Very recently, the direct conversion of fibroblasts into functional neurons with no prior pluripotent stage has been described. Interconversion between adult cells from ontogenically different lineages by an induced transdifferentiation process based on the overexpression of a cocktail of transcription factors, while avoiding transition through an embryonic stem cell-like state, provides a new impetus in the field of regenerative medicine. Here, we review the induced reprogramming of somatic cells with defined factors and analyze their potential clinical use. Beginning with induced pluripotency, we summarize the initial objections including their extremely low efficiency and the risk of tumor generation. We also review recent reports describing iPS cells' capacity to generate viable offspring through tetraploid complementation, the most restrictive pluripotency criterion. Finally, we explore the available evidence for 'induced transdifferentiated cells' as a novel tool for adult cell fate modification.

Posttranscriptional events such as RNA stabilization are important for cell differentiation, but little is known about the impact of AU-rich binding proteins (AUBPs) on the fate of neural cells. Expression of destabilizing AUBPs such as AUF1 and neuronal-specific stabilizing proteins such as HuB, HuC and HuD was therefore analyzed in the developing central nervous system. Real-time RT-PCR indicated a specific developmental pattern in the postnatal cerebellum, with a progressive down-regulation of AUF1 from P1, whereas HuB was strongly up-regulated at about P7. These changes were accompanied by a progressive increase in AUF1p45 and the disappearance of one HuB isoform from P15, suggesting particular roles for these AUBPs in the developing cerebellum. AUF1 was detected in the three main cerebellar layers, whereas Hu proteins were found only in postmitotic neurons. A role for Hu proteins in the early stages of neuronal differentiation is further supported by arrest of cell proliferation following induction of HuB or HuD expression in a neural stem cell line. The decrease in nestin expression suggest that HuD, but not HuB, favors the transition of neural progenitors into early neuroblasts, but other factors are most probably required for their full differentiation into neurons, insofar as GAP-43 was not detected in HuD-transfected cells. These data suggest critical roles for HuB at the very earliest stages of neuronal differentiation, such as cell cycle exit, and HuD might also be involved in the transition of neural progenitors into early neuroblasts. Taken together, the present results strengthen the importance of AUBPs in brain ontogenesis.

There is growing evidence about the role of mesenchymal stem cells (MSCs) as cancer stem cells in many sarcomas. Nevertheless, little is still known about the cellular and molecular mechanisms underlying MSCs transformation. We aimed at investigating the role of p53 and p21, two important regulators of the cell cycle progression and apoptosis normally involved in protection against tumorigenesis. Mesenchymal stem cells from wild-type, p21(-/-)p53(+/+), and p21(-/-)p53(+/-) mice were cultured in vitro and analyzed for the appearance of tumoral transformation properties after low, medium, and high number of passages both in vitro and in vivo. Wild-type or p21(-/-)p53(+/+) MSCs did not show any sign of tumoral transformation. Indeed, after short-term in vitro culture, wild-type MSCs became senescent, and p21(-/-)p53(+/+) MSCs showed an elevated spontaneous apoptosis rate. Conversely, MSCs carrying a mutation in one allele of the p53 gene (p21(-/-)p53(+/-) MSCs) completely lost p53 expression after in vitro long-term culture. Loss of p53 was accompanied by a significant increase in the growth rate, gain of karyotypic instability, loss of p16 expression, and lack of senescence response. Finally, these cells were able to form fibrosarcomas partially differentiated into different mesenchymal lineages when injected in immunodeficient mice both after subcutaneous and intrafemoral injection. These findings show that MSCs are very sensitive to mutations in genes involved in cell cycle control and that these deficiencies can be at the origin of some mesodermic tumors.

Objective: To investigate the prevalence of sexual dysfunction in female patients with fibromyalgia (FM), the impact of FM on sexual activity and the factors associated with sexual dysfunction in these patients., Methods: Thirty-one consecutive women with FM were enrolled; two groups of 20 aged-matched healthy women and 26 patients with rheumatoid arthritis (RA) were used as controls. Demographic features were recorded in all patients. A cross-sectional analysis of pain (100-mm VAS scale), anxiety and depression (as determined by the STAI and Beck Depression Inventory scales, respectively) was performed. Sexual function was assessed by the Changes in Sexual Functioning Questionnaire (CSFQ)., Results: FM and RA patients showed a significantly higher rate of sexual dysfunction compared to healthy controls. Sexual dysfunction was more frequent among FM patients (97%) than in RA patients (84%) but without statistical differences. A univariate analysis showed that age (p=0.0002), marital (p=0.036) and work status (p=0.048), pain intensity (p=0.007), level of anxiety (p=0.002), level of depression (p=0.0005), were significantly associated with sexual dysfunction in FM. However, only the intensity of depression was associated with the sexual dysfunction in patients with FM in the multivariate analysis (p=0.012)., Conclusions: Sexual function was very frequently and severely affected in patients with FM and this impairment appeared to be particularly associated with the degree of depression. The recognition of this dysfunction and its inclusion for the multidisciplinary management of FM may contribute to improve quality of life of these patients.

Introduction: Numerous clinical trials have demonstrated the efficacy of treatment with pegylated interferon and ribavirin but little is known about the results obtained in clinical practice., Objective: To evaluate treatment response and factors influencing the treatment of chronic hepatitis C in clinical practice., Material and Methods: Between August 2001 and December 2005, we treated 219 patients with pegylated interferon (alpha 2a -fixed dose, or alpha 2b, according to weight) and ribavirin. Patients with genotype 1 or 4 received treatment with pegylated interferon alpha 2a (180 microg/week) and ribavirin (1000 mg/day if body weight was <75 kg or 1200 mg/day if body weight was >75 kg) or interferon alpha 2b (1.5 microg/kg/week) and ribavirin (10.6 mg/kg/day) for 48 weeks. Patients with genotype 2 or 3 were treated for 24 weeks with the same regimen of pegylated interferon alpha-2a or alpha-2b, but with 800 mg of ribavirin divided in two daily doses. Sustained viral response was defined as absence of HCV-RNA 6 months after the end of treatment., Results: A total of 219 patients were included (69% men; mean age 44+/-10). As epidemiological antecedents, 22.4% of the treated patients had previously consumed drugs parenterally and 22.4% had received blood transfusions before 1992. Forty-seven percent of the patients with liver biopsy had fibrosis bridges or established liver cirrhosis. The genotype was distributed as follows: 69.8% genotype 1, 4.1% genotype 2, 17.8% genotype 3, and 8.2% genotype 4. Of the 219 patients, 76 (35%) were treated with pegylated interferon alpha 2a and 143 (65%) with interferon alpha 2b. Analysis of response by genotype revealed that sustained viral response was obtained in 46% genotype 1, 88.9% genotype 2, 78.9% genotype 3, and 33.3% genotype 4. Univariate analysis showed that the only variable influencing sustained viral response was genotype., Conclusion: Treatment with pegylated interferon and ribavirin in clinical practice shows a similar pattern of sustained viral response to that obtained in clinical research. The main variable correlated with sustained viral response continues to be viral genotype.

Auricle therapy is the method which diagnoses and treats the human body via the external ear. The author describes its simple application as its principal characteristics and contrasts these with the efficiency of its results. Furthermore, the author provides a wide range of therapeutic possibilities.

Asparagine 54 of alpha-sarcin is a conserved residue within the proteins of the ribotoxin family of microbial ribonucleases. It is located in loop 2 of the protein, which lacks repetitive secondary structure elements but exhibits a well-defined conformation. Five mutant variants at this residue have been produced and characterized. The spectroscopic characterization of these proteins indicates that the overall conformation is not changed upon mutation. Activity and denaturation assays show that Asn-54 largely contributes to protein stability, and its presence is a requirement for the highly specific inhibitory activity of these ribotoxins on ribosomes.

The existence of extra dimensions allows the possibility that the fundamental scale of gravity is at the TeV. If that is the case, gravity could dominate the interactions of ultrahigh energy cosmic rays. In particular, the production of microscopic black holes by cosmogenic neutrinos has been estimated in a number of papers. We consider here gravity-mediated interactions at larger distances, where they can be calculated in the eikonal approximation. We show that for the expected flux of cosmogenic neutrinos these elastic processes give a stronger signal than black hole production in neutrino telescopes. Taking the bounds on the higher-dimensional Planck mass M(D) (D=4 + n) from current air shower experiments, for n=2(6) elastic collisions could produce up to 118 (34) events per year at IceCube. On the other hand, the absence of any signal would imply a bound of M(D) > or approximately 5 TeV.

Secreted fungal RNases, represented by RNase T1, constitute a family of structurally related proteins that includes ribotoxins such as alpha-sarcin. The active site residues of RNase T1 are conserved in all fungal RNases, except for Phe 100 that is not present in the ribotoxins, in which Leu 145 occupies the equivalent position. The mutant Leu145Phe of alpha-sarcin has been recombinantly produced and characterized by spectroscopic methods (circular dichroism, fluorescence spectroscopy, and NMR). These analyses have revealed that the mutant protein retained the overall conformation of the wild-type alpha-sarcin. According to the analyses performed, Leu 145 was shown to be essential to preserve the electrostatic environment of the active site that is required to maintain the anomalous low pKa value reported for the catalytic His 137 of alpha-sarcin. Enzymatic characterization of the mutant protein has revealed that Leu 145 is crucial for the specific activity of alpha-sarcin on ribosomes.

Ribotoxins are a family of highly specific fungal ribonucleases that inactivate the ribosomes by hydrolysis of a single phosphodiester bond of the 28 S rRNA. alpha-Sarcin, the best characterized member of this family, is a potent cytotoxin that promotes apoptosis of human tumor cells after internalization via endocytosis. This latter ability is related to its interaction with phospholipid bilayers. These proteins share a common structural core with nontoxic ribonucleases of the RNase T1 family. However, significant structural differences between these two groups of proteins are related to the presence of a long amino-terminal beta-hairpin in ribotoxins and to the different length of their unstructured loops. The amino-terminal deletion mutant Delta(7-22) of alpha-sarcin has been produced in Escherichia coli and purified to homogeneity. It retains the same conformation as the wild-type protein as ascertained by complete spectroscopic characterization based on circular dichroism, fluorescence, and NMR techniques. This mutant exhibits ribonuclease activity against naked rRNA and synthetic substrates but lacks the specific ability of the wild-type protein to degrade rRNA in intact ribosomes. The results indicate that alpha-sarcin interacts with the ribosome at two regions, i.e. the well known sarcin-ricin loop of the rRNA and a different region recognized by the beta-hairpin of the protein. In addition, this latter protein portion is involved in interaction with cell membranes. The mutant displays decreased interaction with lipid vesicles and shows behavior compatible with the absence of one vesicle-interacting region. In agreement with this conclusion, the deletion mutant exhibits a very low cytotoxicity on human rhabdomyosarcoma cells.

Alpha-sarcin, a cyclizing ribonuclease secreted by the mould Aspergillus giganteus, is one of the best characterized members of a family of fungal ribotoxins. This protein induces apoptosis in tumour cells due to its highly specific activity on ribosomes. Fungal ribotoxins display a three-dimensional protein fold similar to those of a larger group of microbial noncytotoxic RNases, represented by RNases T1 and U2. This similarity involves the three catalytic residues and also the Arg121 residue, whose counterpart in RNase T1, Arg77, is located in the vicinity of the substrate phosphate moiety although its potential functional role is not known. In this work, Arg121 of alpha-sarcin has been replaced by Gln or Lys. These two mutations do not modify the conformation of the protein but abolish the ribosome-inactivating activity of alpha-sarcin. In addition, the loss of the positive charge at that position produces dramatic changes on the interaction of alpha-sarcin with phospholipid membranes. It is concluded that Arg121 is a crucial residue for the characteristic cytotoxicity of alpha-sarcin and presumably of the other fungal ribotoxins.

In scenarios with the fundamental unification scale at the TeV one expects string excitations of the standard model fields at accessible energies. We study the neutrino-nucleon cross section in these models. We show that duality of the scattering amplitude forces the existence of a tower of massive leptoquarks that mediate the process in the s channel. Using the narrow-width approximation we find a sum rule for the production rate of resonances with different spin at each mass level. We show that these contributions can increase substantially the standard model neutrino-nucleon cross section, although they seem insufficient to explain the cosmic ray events above the Greisen-Zatsepin-Kuz'min cutoff energy.

The yield of purified recombinant alpha-sarcin increases approximately three- to fourfold when this toxin is co-expressed in Escherichia coli with thioredoxin. This increased production is attributed to the existence, in the presence of thioredoxin, of a reducing environment which allows rearrangement of incorrect disulphide bonds to produce the soluble native conformation. The protein thus produced retains the structural, spectroscopic and enzymatic features of the natural fungal alpha-sarcin.

Objective: Description and quantification of self medication in a general paediatric office., Design: Descriptive and prospective study. SITE. Cervantes Health Centre (Guadalajara)., Patients: 387 cases of both sexes until 8 that attended to on demand consultation during the period of two months., Measurements and Main Results: 36% of the patients were given drugs before attending to consultation and in 18.7% of these cases, the actuation was incorrect. Parents were, mainly the responsible of incorrect treatment. The most often registered pathology was common cold. We did not found relation between self medication and the next variables: child's age or sex, parents' age or studies, number of children in the family, number of consultation for the same pathologic event and mother working outside home., Conclusions: Self medication is a common practice. Parents should be instructed about management of the commonest pathologies and when they should ask the doctor.